Silicon-Mediated Transformations of Functional Groups

H. Vorbrüggen

Silicon-mediated Transformationsof Functional Groups

Silicon-mediated Transformations of Functional Groups. H. VorbrüggenCopyright © 2004 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30668-4

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Silicon-mediated Transformationsof Functional Groups

Prof. Dr. Helmut Vorbrüggen

Free UniversityDepartment of Organic ChemistryTakustr. 314195 BerlinGermany

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Preface XI

1 Introduction 1

1.1 Experimental Example 5

2 Techniques for Preparative Silylations–Desilylations 7

2.1 Silylations with Monofunctional Silylating Reagents 7

2.2 Silylations with Di- and Tetrafunctional Silylating Reagents 17

2.3 Transsilylation and Deprotection of Silylethers 18

2.4 Mobility of Silyl Groups and the Importanceof Hypervalent Silicon Species 20

2.5 Activation of Silicon Bonds by Transition Metal Saltsand Complexes 22

2.6 Concluding General Remarks on Preparative Silylations 23

2.7 Experimental Examples 25

3 Preparation and Properties of Silyloxy Leaving Groups 27

3.1 Preparation and Properties of Trimethylsilanol and other Trialkyl-or Arylsilanols 27

3.2 Reactions of Trimethylsilanol and other Trialkyl-, Alkylaryl-,or Triarylsilanols 29

3.3 Preparation, Properties and Reactions of Dialkyl- or Diaryldisilanols,and Alkyl- or Aryltrisilanols 31

3.4 Preparation, Properties and Reactions of Tetra(alkoxy)-, Tetra(acetoxy)-,Tetra(dialkylamino)-, and Tetrachlorosilanes 32


4 Reactions of Free and Derivatized Carboxylic Acids and Carbon Dioxide 39

4.1 Introduction 39

4.2 Aminations 40

4.2.1 Amination of Free Carboxylic Acids to Amides and Imides 40

4.2.2 Amination of Amides, Lactams, and Imides, to Amidines 45

V

Contents


4.2.3 Amination of Aromatic Heterocyclic Lactam Systems(Synthesis of Cytidines) 50

4.2.4 Amination of Aromatic Heterocyclic Lactam Systems(Synthesis of Adenosines) 55

4.2.5 Amination of Aromatic Heterocyclic Lactam Systems 59

4.3 Dehydration of Amides, Oximes, and Ketene Imines into Nitriles 66

4.4 Hydration of Nitriles into Amides 67

4.5 Conversion of Carbamates into Urethanes, Isocyanates, Ureas,and Carbodiimides 68

4.6 Conversion of Free or Silylated Carboxylic Acids into Esters,Thioesters, Lactones, or Ketenes. Transesterification of Esterswith Alcohols 70

4.7 Saponification of Esters or Lactones and Reaction of PersilylatedAmides and Lactams with Alkali Trimethylsilanolates.Conversion of Aromatic Esters into Nitriles by Useof Sodium-HMDS 71

4.8 C-Substitutions of Lactones, Amides, Lactams and Imides 73


5 Reactions of Aldehydes and Ketones 83

5.1 Conversion of Carbonyl Groups into Acetalsand Analogous Reactions 83

5.1.1 Conversion of Carbonyl Groups into O,O-Acetalsand Analogous Reactions 83

5.1.2 Conversion of Carbonyl Groups into O,N-, N,N-, N,S-,and O,S-Acetals 88

5.1.3 Conversion of Carbonyl Groups into Schiff Bases, Iminium Salts,and Enamines 95

5.1.4 Conversion of Formaldehyde into N-Chloromethyl Lactams, Amides,and Ureas 105

5.1.5 Conversion of Carbonyl Compounds into S,S-Acetals 105

5.1.6 Conversion of Carbonyl Compounds into Thio- and Selenoaldehydesand Ketones 108

5.2 Conversion of Carbonyl Groups, their O,O- and O,N-Acetals,O-Silylenoethers, and Iminium Salts into C-SubstitutionProducts 111

5.3 Conversion of Carbonyl Groups and their O,O- or O,N-Acetalsinto �-Halo, �-Azido, �-Alkinyl, and �-Phosphono Ethers 120

5.4 Reduction of Carbonyl Groups and their Acetals into Ethers 122

5.5 Reactions of �-Dicarbonyl or Tricarbonyl Compounds 123

5.5.1 Reaction of �-Dicarbonyl or Tricarbonyl Compounds with HMDSto Give Amino Compounds or Pyridines 123

5.5.2 Reactions of Alkyl 4-Chloro-3-trimethylsilyloxycrotonateswith Amidines to Give Alkyl Imidazole(4,5)-acetates 126

ContentsVI

5.5.3 Reactions of Alkyl 4-Chloro-3-trimethylsilyloxycrotonateswith Amines and Enamines 127

5.5.4 1,4-Additions of Amines to �,�-Unsaturated Ketones 129

5.6 Aminations of Silylated �-Hydroxyaldehydes or �-Hydroxyketones 129


6 Reactions of Alcohols, Esters, Silyl Ethers, Epoxides, and Haloalkanes 135

6.1 Conversion of Alcohols, Esters, and Silyl Ethersinto their Corresponding Halides, Azides, and Ethers 135

6.2 Conversion of Allyl alcohols into their Corresponding Thiolsor Diallyl Sulfides 138

6.3 C-Substitution Reactions of Silylated Allyl or Benzyl Alcohols 138

6.4 Conversion of Ethers and Ketals into Iodides, Bromides, Chlorides,and �-Iodo Ethers 141

6.5 C–C Bond-formation from Haloalkanes with Allyltrimethylsilane 144


7 Reactions of N–O Systems 147

7.1 Reactions of Heterocyclic N-Oxides with Trimethylsilyl Cyanide,Trimethylsilyl Azide, Trimethylsilyl Isothiocyanate,and Trimethylsilyl Halides 147

7.2 Additions of Allyl- and Benzyltrimethylsilanesto Aromatic Heterocyclic N-Oxides 159

7.3 Reactions of Nitrones and Aliphatic N-Oxides with TrimethylsilylCyanide, Allyltrimethylsilane, Enolsilyl Ethers,and other Nucleophiles 161

7.4 Reductions of Heterocyclic N-Oxides and Aromatic Nitro Groups 165

7.5 Additions of Active Methylene Groups to Aromaticand Unsaturated Aliphatic Nitro Compounds 167

7.6 Reactions of Silylated Aliphatic Nitro Compounds 170

7.7 Reactions of N,O-Bis(trimethylsilylated) Hydroxylamines 179


8 Reactions of S–O and Se–O Systems 189

8.1 Sila–Pummerer Rearrangements of Sulfoxides 189

8.1.1 Introduction 189

8.1.2 Sila–Pummerer Reactions to Vinylsulfides 191

8.1.3 Nucleophilic Substitutions and Cyclizations via Silyl–PummererReactions 194

8.1.4 Sila–Morin-Rearrangement of Penicillin Sulfoxidesto Cephalosporins 200

8.2 Reactions with DMSO 201

8.2.1 Reaction of DMSO-Me3SiCl Reagents with Nucleophiles 201

8.2.2 Oxidations with DMSO/Me3SiCl 204

8.3 Reactions with SO2 and SO3 and their Derivatives 205

Contents VII

8.4 Reactions of Selenoxide and SeO2 and their Derivatives 208

8.5 Preparation of Aldehydes and Ketones from Thio-and Selenoethers 210

8.6 Conversion of Carbonyl Groups into Thiocarbonyl Groups 212

8.7 Reduction of Sulfoxides 213


9 Cyclizations and Ring Enlargements 217

9.1 Introduction 217

9.2 Cyclizations of Aliphatic Systems 217

9.3 Cyclizations to Aromatic Systems 226

9.4 Cyclizations to 5-Membered Aromatic Heterocycles 227



10 Base-catalyzed, Acid-catalyzed and Thermal Eliminations of Trimethylsilanol.Peterson Reactions 241

10.1 Base Catalyzed Eliminations of Trimethylsilanol 241

10.2 Peterson Reactions 243

10.3 Lewis Acid-catalyzed Elimination of Trimethylsilanol 246

10.4 Thermal Elimination of Trimethylsilanol 249


11 Formation of Carbon–Phosphorus Double Bonds 253

11.1 Formation of Carbon–Phosphorus Double Bonds 253

11.2 Preparation of Carbon–Phosphorus Triple Bonds 257


12 Reductions and Oxidations 261

12.1 Reductions with Trimethylsilyl Iodide, Trimethylsilyl Azide,and Trimethylsilyl Cyanide 261

12.2 Reduction with Silanes 267

12.3 Reductions with Hexamethyldisilane, Hexamethyldisilthianeand Phenylthiotrimethylsilane 277

12.4 Reductions of Esters with Metals in the Presenceof Trimethylchlorosilane 281

12.5 Oxidations with Bis(trimethylsilyl)peroxide 284

12.6 Oxidations with Phenyliodoso Compounds 293

12.7 Miscellaneous Oxidations 296


13 Dehydration–Halogenation–Activation and Silylation of Inorganicand Organic Salts and Metallorganic Compounds 305

13.1 Dehydration–Activation of Inorganic and Organic Salts 305

ContentsVIII

13.2 Conversion of Inorganic Oxides into the Corresponding Halidesand Triflates 308

13.3 Supplement 319


14 Formation of Organic and Inorganic Polymers 327

14.1 Introduction 327

14.2 Formation of Organic Polymers 327

14.3 Formation of Inorganic Polymers 331


Appendix 335

Subject Index 337

Author Index 345

Contents IX

About 30 years ago we had at Schering AG the need of synthesizing a series ofN4-substituted cytidines and N6-substituted adenosines as potential antiviral andbiologically active compounds. Because the hitherto used conventional methods ofsynthesizing such compounds implied at least four reaction steps, we looked fornew methods and discovered that just heating of uridine or thymidine with excesshexamethyldisilazane, Me3SiNHSiMe3, (HMDS) in the presence of ammonia, pri-mary and secondary amines not only O-silylates and thus protects the hydroxylgroups in the ribose moieties but also silylates-activates the O4-oxygen function inuridines, which is aminated to give in one reaction step the corresponding persily-lated cytidines as well as persilylated water= hexamethyldisiloxane, Me3SiOSiMe3,(HMDSO). The O-SiMe3 protecting groups in the ribose moieties are subse-quently removed by in situ transsilylation with added excess boiling methanol,whereupon the free cytidines crystallize out in high yields. Analogously, the O6-oxygen functions in inosine, guanosine or xanthosine are silylated-aminated inthe presence of catalytic amounts of Lewis acids to the corresponding N6-substi-tuted persilylated adenosines, which give on transsilylation with boiling methanolthe corresponding biologically active free crystalline adenosines in high yields.

Thus encouraged, we applied this principle of silylation-activation of oxygenfunctions to a number of aliphatic as well as heteroaromatic systems followed bysubsequent or concomitant nucleophilic substitution e.g. with amines, cyanides,halides or hydrides while removing water as HMDSO. Although we could investi-gate only a rather limited range of such reactions, we were pleased to note thatthis principle of silylating-activating oxygen functions followed by nucleophilicsubstitution has subsequently been more and more frequently applied by othergroups as discussed in detail in this review.

Thus we hope that these O-silylations-activations with the readily availableHMDS (Me3SiNHSiMe3), TCS (Me3SiCl), dimethyldichlorosilane (Me2SiCl2), hexa-methylcyclotrisilazane (HNSiMe2)3, OMCTS (HNSiMe2)4, tetra(alkoxy)silane(Si(OR)4) or silicon tetrachloride (SiCl4), most of which can also effect the transi-ent protection of any present hydroxyl group, and the subsequent or concomitantreaction with nucleophiles accompanied by formation of silylated water asHMDSO (Me3SiOSiMe3), (OSiMe2)n or SiO2 will be applied more often in the fu-

XI

Preface


ture to those numerous reactions in preparative organic and inorganic chemistry,in which water is being eliminated.

AcknowledgementsI want to thank in particular my former excellent collaborators Mr. K. Krolikie-wicz and Mrs. B. Bennua-Skalmowski at Schering AG as well as my former grad-uate students Drs. D. Bohn, W. Bühler and M. Marschner for all of their work. Iam furthermore obliged to my colleagues Drs. H. Künzer and S. Hecht for read-ing and commenting on part of the manuscript!

The writing of this review during the last years after my retirement from Sche-ring AG in 1995 as well as some connected experimental work would not havebeen possible without the generous hospitality extended to me by my colleaguesProfessors H.H. Limbach, J. Mulzer, H.-U. Reissig and A. D. Schlüter at the De-partment of Organic Chemistry of the Free University of Berlin, where a laborato-ry and an office was made available to me in 1995. My work on silylation-amina-tion was furthermore supported by a generous gift of hexamethyldisilazane(HMDS) from Bayer AG, of hexamethylcyclotrisilazane from K. Bucher GmbHand of other chemicals from Schering AG.

Last but not least, I want to thank my wife for her understanding and patiencewith me spending many hours with the manuscript of this review either at homeor at our seaside retreat in summer.

Berlin H. VorbrüggenJune 2004

PrefaceXII

Many common synthetic reactions in preparative organic chemistry, for exampleamide (peptide or polyamide synthesis), aliphatic, or heteroaromatic amidine, orguanidine syntheses and ester and ketal (glycoside) formation or Stobbe and Clai-sen–Schmidt condensations involve the generation of water, which usually has tobe removed to achieve clean and quantitative conversions. Because of its highheat of evaporation removal of water, e.g. during esterification by azeotropic distil-lation with solvents such as benzene [1], toluene, or xylene, usually implies ex-tended heating in the presence of Lewis acids, bases, or molecular sieves, whichoften causes side reactions or partial decomposition of the desired end products.Because of these inherent problems associated with removal of water duringchemical reactions, any new technique for activating reaction partners and ofeliminating water in the form of new simple derivatives is of general interest.

Whereas almost all organic chemists are familiar with the different aspects ofsilylation for protection of functional groups [2–6], the concept of protecting any alco-holic or phenolic hydroxyl groups present by silylation while simultaneously silylat-ing–activating [2, 7] suitable amide, lactam, imide, urea, carboxyl, nitro, or sulfoxidegroups or hydroxy-N-heterocycles such as uracils, imidazolones [7], or 1,2,4-triazo-lones [7] as well as benzylic or allylic hydroxyl groups [8, 9] (cf. Scheme 1.1) shouldalways be kept in mind. The activated silylated intermediates that can react with nu-cleophiles, such as amines, or electrophiles, such as acid chlorides, under rathermild reaction conditions with elimination of the very non-polar and volatile persily-lated water (= hexamethyldisiloxane, Me3SiOSiMe3, HMDSO, 7, b.p. 100 �C) insteadof the polar water or of Me3SiCl 14 instead of HCl, are only gradually entering com-mon chemical knowledge. The included table of sources of surprisingly cheap

1

1

Introduction


[1] N.S. Barta, K. Paulvannan, J. P. Schwarz, J. R. Stille, Synth. Commun. 1994, 24, 583[2] L. Birkofer, A. Ritter, Angew. Chem. 1965, 77, 414[3] J. F. Klebe, Adv. Org. Chem. 1972, 8, 97[4] B. E. Cooper, Chem. Ind. 1978, 794[5] G. van Look, Fluka Chemika, Silylating Agents, 1988, 9–105[6] J. Cossy, P. Pale, Tetrahedron Lett. 1987, 28, 6039[7] L. Birkofer, P. Richter, A. Ritter, Chem. Ber. 1960, 93, 2804[8] J. M. Midgley, J. S. Millership, W. B. Whalley, J. Chem. Soc. Perkin I 1976, 1384[9] M. Akita, H. Yasuda, A. Nakamura, Bull. Chem. Soc. Jpn. 1984, 57, 480

silicon chemicals should convince chemists in development and production that thischemistry is also suited to any large scale synthesis.

We became involved in silylation–activation–amination ca. 30 years ago whiletrying to simplify the amination of uridine 1 to modified cytidines 6 [10, 11](Scheme 1.1), which using conventional procedures requires at least three or fourreaction steps (cf. Section 4.2.3). In the first cytidine synthesis 2�,3�,5�-tri-O-acetyl-4-O-ethyluridine (cf. compound 211 in Section 4.2.3) was converted on heating withammonia into cytidine 6 a and ethanol as the leaving group [12]. Because the UVspectrum of 2�,3�,5�-tri-O-acetyl-4-O-ethyluridine 211 is very similar to that of per-silylated uridine 3, which is readily obtained from uridine 1 by heating with hexam-ethyldisilazane (HMDS) 2, we heated uridine 1 with excess hexamethyldisilazane(HMDS) 2, whereupon NH3 is evolved, and excess primary or secondary amines,without solvent, to give, in a one-step/one-pot reaction, persilylated uridine 3, fol-lowed by addition of the amines to the activated 4-position of 3 (cf. structure 214in Scheme 4.15 in Section 4.2.3) and, after elimination of trimethylsilanol 4 as theleaving group, the persilylated cytidines 5 [10, 11]. The leaving group trimethylsila-nol 4, which is more acidic [13] (cf. Section 3.1) and thus much more reactive thantert-butanol, is silylated in situ by excess hexamethyldisilazane (HMDS) 2 to therather non-polar hexamethyldisiloxane (HMDSO) 7 and ammonia, which escapesat normal pressure. Thus elimination of the polar water in these aminations is re-placed by elimination of persilylated water (= Me3SiOSiMe3, HMDSO, 7). Becausetrimethylsilanol 4 and the water, which is formed by the acid- or base catalyzed di-merization of two equivalents of trimethylsilanol 4 to hexamethyldisiloxane 7 [14],can deactivate the activated 4-trimethylsilyloxy group in 3 to give deactivated 2,3,5-O-silylated uridine and HMDSO 7, silylation of trimethylsilanol 4 by excess hexam-

1 Introduction2

Scheme 1.1

[10] H. Vorbrüggen, K. Krolikiewicz, U. Nieballa, Angew. Chem. Int. Ed. 1971, 10, 657[11] H. Vorbrüggen, K. Krolikiewicz, U. Nieballa, Liebigs Ann. Chem. 1975, 988[12] G. A. Howard, B. Lythgoe, A.R. Todd, J. Chem. Soc. 1947, 1052[13] R. West, R. H. Baney, J. Am. Chem. Soc. 1959, 81, 6145[14] W. T. Grubb, J. Am. Chem. Soc. 1954, 76, 3408

ethyldisilazane (HMDS) 2 to hexamethyldisiloxane (HMDSO) 7 is mandatory toachieve high yields. To shift all these equilibria to the right it is, furthermore, opti-mum for preparative scale silylation–aminations employing higher boiling amines(b.p. > 120–130 �C), to remove hexamethyldisiloxane (HMDSO) (b.p. 100 �C) [15]or its azeotrope (b.p. 89–91 �C) [13] with trimethylsilanol 4 (b.p. 99 �C) (cf. Sec-tion 2.1) by distillation over a short Vigreux column during the reaction.

After silylation–amination in situ transsilylation (cf. Section 2.3) of the intermedi-ate persilylated cytidines 5 with excess boiling methanol for 3–5 h gives the de-sired free cytidines 6 and methoxytrimethylsilane 13 a (b.p. 57 �C) [13]. Thus protec-tion of the alcoholic hydroxyl groups of the ribose moiety and silylation–activationof the 4-position in the pyrimidine moiety in persilylated uridine 3, and the con-comitant amination of 3, all in one reaction step, to 5 is followed finally by in situtranssilylation (cf. Section 2.3) with excess boiling methanol in one reaction vessel.All these steps proceed to afford free or N4-substituted crystalline cytidines 6 inhigh yields [11] (cf. the preparation of N4(tetramethylene)cytidine 6b in 95.4%yield in Section 1.1.). This simple one-pot reaction is also very easy to perform ona technical scale, as are the subsequently discussed analogous silylation–amina-tions of purine nucleosides and other hydroxy-N-heterocycles (cf. Sections 4.2.4and 4.2.5). The concept of silylation–activation while simultaneously protecting hy-droxyl groups in alcohols, phenols, or phosphoric acids by silylation was subse-quently “rediscovered” and appropriately termed “transient protection” [16–18].

Most of the other silylation–activation–substitution reactions reported in this re-view are mechanistically related. Several new reactions (such as those discussed inSections 7.1, 7.2, and 7.4) have been discovered by following these lines of think-ing about activation of functional groups by O-silylation and subsequent or con-comitant reaction with nucleophiles giving the expected products and hexamethyl-disiloxane 7. It can thus be expected that current and new silylation–activation reac-tions will be more commonly used in preparative chemistry in the future.

In retrospect, the first review [19] on the subsequently discussed mobility of tri-methyl- or other trialkylsilyl groups (cf. Section 2.4), which discusses the equilib-rium between the N-silylated form 8 and the O-silylated form 9 of the 6,7-benzo-caprolactam as determined by 1H NMR, (Scheme 1.2) should have drawn generalattention to this field, because 9 is a reactive O-trimethylsilyl iminoether, whichcan be expected to undergo addition–elimination reactions of nucleophiles Nu–Hor Nu–SiMe3, in particular in the presence of Lewis acids to give 10 and trimethyl-silanol 4 as the leaving groups and, eventually, HMDSO 7. Likewise, the N- or O-trimethylsilyl groups in the subsequently discussed N,O-bis(trimethylsilyl)aceta-mides or formamides 22 can be assumed to be in equilibrium [19].

1 Introduction 3

[15] R. O. Sauer, J. Am. Chem. Soc. 1944, 44, 1707[16] G. S. Ti, B. L. Gaffney, R. A. Jones, J. Am. Chem. Soc. 1982, 104, 1316[17] N.D. Sinha, P. Davis, L.M. Schultze, K. Upadhya, Tetrahedron Lett. 1995, 36, 9277[18] Z. Cui, L. Zhang, B. Zhang, Tetrahedron Lett. 2001, 42, 561[19] J.F. Klebe, Acc. Chem. Res. 1970, 3, 299

After three previous short reviews [20–22] covering mainly our own work, thisreview discusses initially, in Chapters 1–3, the techniques of preparative silylation,the properties of the different silyloxy leaving groups, and the techniques of de-silylation. The major part of this review, beginning with Chapter 4, however, sur-veys the different applications of silylation–activation and silicon-induced reac-tions of a whole range of functional groups in which hydroxy groups are elimi-nated as silyloxy-leaving groups ranging from trimethylsilanol 4 to hydrated formsof SiO2 or Cl3SiOH while these functional groups are transformed into amino-,oxygen-, halogen, or C-substituents; in these chapters we describe our own workas well as that by other groups. Because of the large number of publications, e.g.on reductions with silanes in Section 12.2, this review is not, and cannot be, com-prehensive but tries to indicate the most important trends and to quote reviews ineach particular field.

1.1Experimental Example

1 Introduction4

Scheme 1.2

Scheme 1.3

[20] H. Vorbrüggen, K. Krolikiewicz, U. Niedballa, Ann. N.Y. Acad. Sci. 1975, 255, 82[21] H. Vorbrüggen in “Current Trends in Organic Chemistry”, Ed. H. Nozaki, Pergamon

Press, Oxford, 1983, pp. 323–330[22] H. Vorbrüggen, Acc. Chem. Res. 1995, 28, 509

In a 100 mL round-bottomed flask connected to a reflux condenser, 4.88 g(20 mmol) uridine 1 is suspended and stirred in 12.44 mL (60 mmol) HMDS 2,4.15 mL (50 mmol) pyrrolidine, 0.1 mL Me3SiCl 14, and 15 mL abs. pyridine.After 4.5 h heating in an oil bath at 140–145 �C the reaction mixture turns yellow-ish and is complete according to TLC (acetone–methanol, 3:1). After evaporationof the solvents in vacuo, the yellowish, partly crystalline residue of crude 5 b isboiled for 3 h in 100 mL methanol and then kept at room temperature for 16 h.After evaporation of the solvent, 6.09 g crude 4-pyrrolidino-1-(�-d-ribofuranosyl)-1,2-dihydropyrimidine-2-one 6b is obtained. This is recrystallized from 90 mL boil-ing methanol and subsequently from 30 mL methanol to give, in two crops,5.677 g (95.4%) pure 6 b, m.p. 211–213 �C [11].

1.1 Experimental Example 5

2.1Silylations with Monofunctional Silylating Reagents

Polar functional groups such as alcohols or phenols 11 or trimethylsilanol 4 aretransformed by monofunctional silylating reagents Me3SiX 12 into their lipophilicand often volatile trimethylsilyl ethers 13 whereas water is converted into persilyl-ated water (= Me3SiOSiMe3, hexamethyldisiloxane, HMDSO, 7, b.p. 100 �C). Thepersilylation of phenols and, in particular, catechol (or hydroquinone) systems(Scheme 2.1) protects them efficiently against air oxidation even at temperaturesof up to 180 �C. (cf., e.g., the silylation–amination of purine nucleosides with do-pamine hydrochloride in Section 4.2.4)

For preparative purposes the most important and cheapest monofunctional re-agents Me3SiX 12 are trimethylchlorosilane (TCS) 14 (b.p. 57 �C) (12, X= Cl) andhexamethyldisilazane (HMDS) 2= Me3SiNHSiMe3 (b.p. 126 �C) (12, X= NHSiMe3),which are both produced on a large technical scale. Because HCl is formed onsilylation of functional groups with TCS 14, bases such as triethylamine must beadded, e.g., on silylation of amino acids or peptides [1, 1 a, 1 b, 2], preferably inboiling CH2Cl2, to give the desired N,O-bis(trimethylsilylated) amino acids or di-peptides and the insoluble Et3N · HCl [2]. The silylation of a-amino acids [1] with

7

2

Techniques for Preparative Silylations–Desilylations


[1] L. Birkofer, A. Ritter, Chem. Ber. 1960, 93, 424[1a] K. Rühlmann, Chem. Ber. 1961, 94, 1876[1b] K. Rühlmann, J. Hills, H.-J. Graubaum, J. Prakt. Chem. 1966, 32, 37[2] H.R. Kricheldorf, Liebigs Ann. Chem. 1972, 763, 17

Scheme 2.1

boiling HMDS 2 at 130 �C affords the desired N,O-bis(trimethylsilylated)aminoacids whereas on silylation of 3- or 4-aminocarboxylic acids and dipeptides withboiling HMDS 2 the corresponding pyrrolidones, piperidones, or diketopipera-zines [2, 2a] are obtained, as discussed in Section 9.2.

On silylation with HMDS 2 only ammonia is formed, and is normally evolvedwithout participating in the reactions. Exceptions are silylation–aminations of car-boxylic acids with HMDS 2 at room temperature to give 80–85% of the desired O-trimethylsilyl esters and up to 15% of ammonium carboxylates RCO2

–NH4+ [2b].

But, as subsequently shown in Scheme 4.1, the corresponding amides can also beformed. Furthermore, silylation–aminations of heterocyclic lactam systems withHMDS 2 afford, at higher temperatures under pressure, amino-N-heterocycles (cf.Sections 4.2.1–4.2.5). HMDS 2 can also add to pyrones in the presence of DBU togive pyridine-2-ones [3] or to 2-(trifluoromethyl)acrylic acid in CH2Cl2 to give 2-tri-fluoro-3-aminopropionic acid [4]. HMDS 2 converts �-diketones into pyridines (cf.Section 5.5.1) and 1,4-diones into pyrroles [4a,b] (cf. Section 9.4).

Silylations of alcohols or phenols 11 with HMDS 2 are accelerated by acidic cat-alysts [5–7] such as small amounts of trimethylchlorosilane (TCS) 14, whereuponammonium chloride is generated during silylation. On silylation of alcohols orphenols 9 with equivalent amounts of HMDS 2 and TCS 14 [8] at ambient tem-perature in absolute acetonitrile the silylated alcohols or phenols 13 are obtained,and an equivalent amount of ammonium chloride, which rapidly precipitatesfrom acetonitrile during the reaction, indicating the progress of silylation [9]. Ob-viously, the ammonium chloride can be removed by filtration during work-upwith exclusion of humidity. Alternatively, on boiling such a reaction mixture inacetonitrile the ammonium chloride sublimes into the reflux condenser and canthus be removed by changing the reflux condenser. Several publications reportuse of other ratios of HMDS 2 and TCS 14, from a ratio of two equivalents ofHMDS 2 to one equivalent TCS 14 to a ratio of one equivalent of HMDS 2 to twoequivalents of TCS 14 [10]. In the latter reaction the generated HCl is only par-tially neutralized by the liberated ammonia. In the rapid reaction of TCS 14 withsmall amounts of water in the presence of bases such as triethylamine trimethyl-silanol 4 is formed as an intermediate which dimerizes on heating, especially in

2 Techniques for Preparative Silylations–Desilylations8

[2 a] L. Birkofer, A. Ritter, P. Neuhausen, Liebigs Ann. Chem. 1962, 659, 190[2b] K. A. Adrianov, V. V. Astakhin, B. P. Nikiforov, Zh. Org. Khim. 1964, 34, 914; Chem.

Abstr. 1964, 60, 90966[3] V. Kvita, Synthesis 1991, 883[4] I. Ojima, K. Kato, K. Nakahashi, T. Fuchikami, M. Fujita, J. Org. Chem. 1989, 54, 4511[4a] B. Rigo, D. Valligny, S. Taisne, Synth. Commun. 1988, 18, 167[4b] B. Rousseau, F. Nydegger, A. Gossauer, B. Bennua-Skalmowski, H. Vorbrüggen,

Synthesis 1996, 1336[5] B. E. Cooper, Chem. Ind. 1978, 794[6] J. Cossy, P. Pale, Tetrahedron Lett. 1987, 28, 6039[7] C.A. Bruynes, T.K. Jurriens, J. Org. Chem. 1982, 47, 3966[8] S.L. Langer, S. Connell, I. Wender, J. Org. Chem. 1958, 23, 50[9] H. Vorbrüggen, Acc. Chem. Res. 1995, 28, 509

[10] R. Hässig, H. Siegel, D. Seebach, Chem. Ber. 1982, 115, 1990

the presence of acidic catalysts, to HMDSO 7 and water (cf. Chapter 3). Thiswater must be removed by additional amounts of TCS 14/triethylamine, TCS 14/HMDS 2 or HMDS 2 alone, as depicted in Scheme 2.2. The reaction of twoequivalents of trimethylsilanol 4 with HMDS 2 to HMDSO 7 and ammonia hasalready been mentioned in the Introduction (Chapter 1). Even HMDSO 7, whichis cleaved by alkali hydroxides to the crystalline alkali trimethylsilanolates (cf. Sec-tion 3.1), has been used as a mild silylation reagent [11–13] to give, in equilibriumwith alcohols ROH 11, the silylated alcohols 13. Addition of HMDSO 7 to a radi-cal reaction of lauroyl peroxide with an olefin containing a tertiary alcohol appar-ently protects the alcohol against dehydration [13]. The slow reaction of HMDS 2with water affords trimethylsilanol 4 and trimethylsilylamine 15, which is prob-ably an intermediate in silylations with HMDS 2 but can, however, only be iso-lated under special reaction conditions [14]. Trimethylsilanol 4 and trimethyl-silylamine 15 combine normally on heating to HMDSO 7 and ammonia, whichevolves. On preparative silylations, silylation-aminations (cf. Sections 4.2.1–4.2.5)or silylation–C-substitutions (cf. Section 4.8) employing HMDS 2, the initially gen-erated trimethylsilanol 4 (b.p. 99 �C) and the subsequently formed HMDSO 7(b.p. 100 �C) give rise to an azeotropic mixture (b.p. 89–91 �C) [15] which, likepure 7, can be readily removed by distillation over a small distillation column andthus separated from as yet unreacted HMDS 2 (b.p. 126 �C). In the closely relatedreaction of methoxytrimethylsilane 13a with trimethylsilanol 4 to give HMDSO 7and MeOH, HCl as catalyst is 500 times more active than KOH [16].

Further important silylating reagents Me3SiX 12 are Me3SiBr 16 [17], Me3SiI 17[18, 19] (Scheme 2.3), Me3SiCN 18 [19, 20 a], and Me3SiN3 19 [19, 20], most of


Scheme 2.2

[11] M.G. Voronkov, Z. I. Shabarova, Zh. Obshch. Khim. 1959, 29, 1528[12] H.W. Pinnick, B. S. Bal, N.H. Lajis, Tetrahedron Lett. 1978, 44, 4261[13] J. Boivan, J. Pothier, L. Ramos, S.Z. Zard, Tetrahedron Lett. 1999, 40, 2939[14] N. Wiberg, W. Uhlenbrock, Chem. Ber. 1971, 104, 2643[15] R. O. Sauer, J. Am. Chem. Soc. 1944, 66, 1707[16] M. Grubb, J. Am. Chem. Soc. 1954, 76, 3408[17] E.C. Friederich, G. de Luca, J. Org. Chem. 1983, 48, 1678[18] G. A. Olah, S.C. Narang, Tetrahedron 1982, 38, 2225[19] W. C. Groutas, D. Felker, Synthesis 1980, 861[20] H. Vorbrüggen, K. Krolikiewcz, Synthesis 1979, 35[20] G. Schirawski, U. Wannagat, Monatsh. Chem. 1969, 100, 1901

which can be readily prepared in situ from TCS 14 in combination with NaI[22, 23] (cf. Section 12.1), NaCN, KCN [19, 24] (cf. Section 7.1), or NaN3 [19, 20] inacetonitrile or DMF. A very reactive silylating agent is trimethylsilyl triflateCF3SO2OSiMe3 (TMSOTf) 20 [25, 25a, 25b, 26], which is prepared on boiling trif-lic acid with TCS 14, with evolution of HCl [27], in situ from triflic acid and amixture of TCS 14 and HMDS 2 [28, 29], or, much less economically, on reactionof triflic acid with allyltrimethylsilane 82 [30], tetramethylsilane [31], or 3-tri-methylsilyl-2-oxazolidinone [32]. The even more reactive trimethylsilyl nonaflate,n-C4F9SO2OSiMe3 (TMSONf) 21, is synthesized analogously from free nonaflicacid with TCS 14, with evolution of HCl, or prepared in situ from potassium non-aflate and TCS 14 in acetonitrile with formation of KCl [28, 29]. TMSOTf 20 andTMSONf 21 are used in combination with tertiary bases such as triethylamine[33], diisopropylethylamine (DIPEA; Hünig’s base) [33, 34], or DBU [35, 36].Although trimethylsilyl iodide 17 [18, 19] is very reactive in some silylations in thepresence of triethylamine, e.g. in the conversion of ketones into their trimethyl-


Scheme 2.3

[20a] K. Mai, G. Patil, J. Org. Chem. 1986, 51, 3545[21] E. J. Corey, J.-J. Wu, J. Am. Chem. Soc. 1993, 115, 8871[22] G. A. Olah, S.C. Narang, B. G. B. Gupta, R. Malhotra, J. Org. Chem. 1979, 44, 1247[23] M. Arend, J. Prakt. Chem. 1998, 340, 760[24] J. Rasmmussen, S. M. Heilmann, Synthesis 1978, 219[25] H.W. Roesky, H.H. Giere, Z. Naturforsch. 1970, 25b, 773[25a] M. Schmeisser, P. Sartori, B. Lippsmeyer, Chem. Ber. 1970, 103, 868[25b] H. Emde, D. Domsch, H. Feger, U. Frick, A. Götz, H.H. Hergott, K. Hofmann,

W. Kober, K. Krägeloh, T. Oesterle, W. Steppan, W. West, G. Simchen, Synthesis1982, 1

[26] R. Noyori, S. Murata, M. Suzuki, Tetrahedron 1981, 37, 3910[27] H.C. Marsmann, H.-G. Horn, Z. Naturforsch. 1972, 27b, 1448[28] H. Vorbrüggen, B. Bennua, Tetrahedron Lett. 1978, 1339[29] H. Vorbrüggen, B. Bennua, Chem. Ber. 1981, 114, 1279[30] G. A. Olah, A. Husain, B. G.B. Gupta, G. F. Salem, S.C. Narang, J. Org. Chem. 1981,

46, 5212[31] M. Demuth, G. Mikhail, Tetrahedron 1983, 39, 991[32] M. Ballister, A.L. Palomo, Synthesis 1983, 571[33] H. Emde, A. Götz, K. Hofmann, G. Simchen, Liebigs Ann. Chem. 1981, 1657[34] T. Bach, H. Brummerhop, J. Prakt. Chem. 1999, 341, 410

silyl enol ethers [37, 38], 17 can cause a number of side-reactions such as readilycleaving esters and ethers. Trimethylsilyl cyanide 18, which has the least bulkycyanide as leaving group, has been used successfully for silylation of stericallyhindered 2,6-dimethylphenol [20] or tertiary alcohols [20a, 21].

It is obvious that the silylating power of all these silylating agents Me3SiXdepends on the leaving group capability of X. Consequently one can expect thefollowing sequence of the silylating power of Me3SiX: X= NHSiMe3 < Cl < I <OSO2CF3 < OSO2C4F9, although Me3SiI 17 occasionally seems to be superior toTMSOTf 20 [37, 38]. In particular, the very strong silylating agents TMSOTf 20 orTMSONf 21 can be expected to interact with tertiary bases such as triethylamineor diisopropylethylamine (DIPEA) and with aromatic heterocyclic bases such aspyridine or substituted (O-trimethylsilylated) pyridines or pyrimidines to form �-complexes [38, 38 a], whose amounts in the equilibria can be measured by NMR[38, 38 a] and which are the active silylating species (c.f. the last reaction inScheme 2.3).

Alternative silylating reagents such as N,O-bis(trimethylsilyl)acetamide 22a(BSA) [39–43], N,O-bis(trimethylsilyl)trifluoracetamide 22 b (BSTFA) [44], or N,N-bis(trimethylsilyl)formamide 22 c (BSF) [41, 46], in which the N- and O-trimethyl-silyl groups are in equilibrium [45] (Scheme 2.4), are much more powerful silylat-ing reagents [40, 45] but are more expensive than HMDS 2, because they areusually prepared by heating formamides or acetamides with TCS 14/triethylamine


Scheme 2.4

[35] S. Murata, M. Suzuki, R. Noyori, J. Am. Chem. Soc. 1979, 101, 2738[36] S. Murata, M. Suzuki, R. Noyori, Bull. Chem. Soc. Jpn. 1982, 55, 247[37] H.H. Hergott, G. Simchen, Liebigs Ann. Chem. 1980, 1718[38] A. R. Bassindale, T. Stout, Tetrahedron Lett. 1985, 26, 3403[38a] H. Vorbrüggen, G. Höfle, Chem. Ber. 1981, 114, 1256[39] L. Birkofer, A. Ritter, W. Giessler, Angew. Chem. 1963, 75, 93[40] J. F. Klebe, H. Finkbeiner, D.M. White, J. Am. Chem. Soc. 1966, 88, 3390[41] C.H. Yoder, W.C. Copenhafer, B. DuBeshter, J. Am. Chem. Soc. 1974, 96, 4283[42] A. M. El-Khawaga, H.M.R. Hoffmann, J. Prakt. Chem. 1995, 337, 332[43] M.T. El Gihan, H. Heaney, Synthesis 1998, 357[44] G. Van Look, G. Simchen, Fluka Chemika, Silylating Agents 1988, 9–105[45] J. F. Klebe, Acc. Chem. Res. 1970, 3, 299[46] G. Schirawski, U. Wannagat, Monatsh. Chem. 1969, 100, 1901

or with HMDS 2. They are, furthermore, less practical for preparative silylations,because the liberated free formamides or acetamides usually remain in the reac-tion mixture and can thus complicate work-up of the reaction mixture and the iso-lation of the final products. On working, however, with equivalent amounts ofBSA 22 a, N-trimethylsilylacetamide, which boils at 45–47 �C/0.2 mm [40], isformed and can thus be removed by distillation after silylation of non-volatile endproducts. These activated N,O-bis(trimethylsilylated)amides 22 (cf. also N,O-bis(trimethylsilyl)benzamide 296) or generally 37 (R�= Si(Me3) can, however, be ex-pected to react with primary or secondary amines in the presence of, e.g., NH4Clor NH4I, giving the corresponding amidinium salts (Section 4.2.2).

The mono-silylated or free acetamides, which are liberated during silylationwith 22 a, can, furthermore, interfere with any subsequent reaction, e.g. with elec-trophiles. Thus in the one-pot/one-step silylation, Friedel–Crafts catalyzed, nucleo-side synthesis starting from protected sugar derivatives and pyrimidine or purinebases, the mono- or bis-silylated amides such as 22 a can compete with less reac-tive silylated heterocyclic bases for the intermediate electrophilic sugar cation toform protected 1-acetylamino sugars in up to 49% yield [42, 47]. On silylationwith trimethylsilylated urea 23a the liberated free urea is nearly insoluble in mostsolvents, for example CH2Cl2, and thus rapidly precipitated [43].

As already mentioned, the N,O-bis(trimethylsilyl)amides 22 (see Scheme 2.4)and N,N-bis(trimethylsilyl)ureas such as 23 a and 23 b [48] are much faster silylat-ing reagents than HMDS 2, because silylation with 22a is energetically favored by9 kcal mol–1 over silylation with HMDS 2 [49]. Thus the highly hindered 2,6-di(tert-butyl)phenol is converted to its trimethylsilyl ether on heating to 90 �C withBSA 22a in acetonitrile for 15 h whereas Me3SiCl 14/NEt3 gives, after boiling for5 days, only 10% of the trimethylsilyl ether [40]. The N,O-bis-(trimethylsilyl)amides 22 and ureas such as 23 a and 23b probably also react with alcohols orphenols 11 and with trimethylsilanol 4 via a six-membered cyclic transition state24. An alternative silylating reagent for preparative applications, which is alsocommercially available, N,O-bis(trimethylsilyl)urethane or N,O-bis(trimethylsilyl)carbamate 25 [50] probably silylates similarly via a six-membered transition statesuch as 24 giving, however, only carbon dioxide and ammonia as side products.Yet 25 reacts with primary or secondary amines to give ammonia and trimethyl-silyloxyurethanes 26 [51], which afford, e.g., with excess aniline at 185 �C, N,N�-di-phenylurea and the replaced secondary amine such as diethylamine and HMDSO7 [51a].


[47] C. Ochoa, R. Provencio, M.L. Jimeno, J. Balzarini, E. De Clercq, Nucleos. Nucleot.1998, 17, 901

[48] J. F. Klebe, J. Am. Chem. Soc. 1964, 86, 3399[49] W. Hehre, “WaveFunction Inc”, Personal Communication, 2000[50] L. Birkofer, P. Sommer, J. Organomet. Chem. 1975, 99, C1[51] V. P. Kozyukov, N.V. Mironova, Zh. Obshch. Khim. 1980, 50, 2022; Chem. Abstr. 1981,

94, 47403[51a] V. D. Sheludyakov, A.D. Kirilin, V. F. Mironov, Zh. Obshch. Khim. 1977, 47, 1515;

Chem. Abstr. 1977, 87, 201638

Silylation of alcohols or phenols 11 with HMDS 2 (compared, e.g., with 22) totheir silyl ethers 13 and of trimethylsilanol 4 with HMDS 2 to HMDSO 7 pro-ceeds more slowly, because 2 silylates the alcohols or phenols 11 and 4 apparentlyvia an kinetically less favored four-membered cyclic transition state 27(Scheme 2.4).

Although the rate of silylation of carboxylic acids 28 is generally considered to belower than the rate of silylation of alcohols and phenols (cf. the subsequently dis-cussed sequence of silylation rates of different functional groups), reactions of car-boxylic acids 28 (see Scheme 2.5) with HMDS 2 proceed probably likewise via a fa-vorable six-membered transition state such 29 to afford the trimethylsilyl esters 30,ammonia, and trimethylsilylamine 15, which converts another equivalent of car-boxylic acid 28 into 30. Carboxylic acids 28, for example trichloroacetic acid, can alsobe readily converted into trimethylsilyl ester 30 by heating with TCS 14 in 1,2-di-chloroethane at 65 �C with evolution of HCl [52]. Because HMDS 2 is a base, proto-nation of the nitrogen in the transition state 29 probably proceeds and eases thetransfer of the trimethylsilyl group to the carbonyl group. Thus, the two carboxylgroups in l-aspartic acid 32 are readily and selectively silylated on reflux with excesshexamethyldisilazane 2 to afford the bis(trimethylsilyl) ester 33 in quantitative yield,whereas the less reactive amino group will only be silylated on extensive heatingwith HMDS 2, as demonstrated in the subsequently described silylation of allyla-mine 41 to mono(trimethylsilyl)allylamine 42 and bis(trimethylsilyl) allylamine 43(cf. also the reactivity scale in Scheme 2.7) [53]. N,O-Bis(trimethylsilyl)aminoacids, which are obtained from amino acids with TCS 14/triethylamine in ben-zene, can be readily reduced to aminoalcohols, in high yields, by LiAlH4 in Et2O [54].

But, as already mentioned, on working at ambient or lower temperatures andnormal pressure, and at higher temperatures under pressure, the trimethylsilyl es-ters 30 react slowly with the liberated ammonia (or trimethylsilylamine 15) toform the primary amides 31 (Scheme 2.5) or their N-monosilylated analogs (cf.Section 4.2.1).


Scheme 2.5

[52] H.H. Hergott, G. Simchen, Synthesis 1980, 626[53] A. M. Castano, A. M. Echivarren, Tetrahedron 1992, 48, 3377[54] P.S. Venkatesvaran, T. J. Bardos, J. Org. Chem. 1967, 32, 1256

One can also assume that amides, peptides, lactams 34 (Scheme 2.6) and ami-dines 38 are silylated analogously on heating with HMDS 2, via cyclic six-mem-bered transition states such as 35 and 39, to their mono(trimethylsilyl)derivatives36 or 40 (cf. Section 4.2.2). The mono(trimethylsilyl) amides 36, which rearrangeto 37, and the mono(trimethylsilyl)amidines 40 are converted on longer heatingwith HMDS 2, when R�= H, via transition states analogous to 35 (R�= SiMe3) tobis(trimethylsilyl)amides such as 37 (with R�= SiMe3 = 22) or via transition state 39(R = SiMe3) to the bis(trimethylsilyl) amidines 40 (R�= Si(Me3; see also Sec-tion 5.1.3).

In view of the above discussed rapid silylation of hydroxy compounds withsilylated amides 22 or ureas 23 compared with silylations with HMDS 2, smallamounts of primary amides such as acetamide, formamide or urea and N-phenyl-urea might act as catalysts to accelerate silylations of alcohols, phenols, or hydroxyN-heterocycles with HMDS 2 via formation of 22 a, 22 c, or 23. It is, furthermore,obvious, and has been known for quite a number of years, that addition of pro-tons or Lewis acids to the nitrogen of HMDS 2 [5–8, 55, 56] in four-memberedtransition states 27 and six-membered transition states 24 will weaken the nitro-gen–silicon bond in HMDS 2, and in other silylating reagents such as 22, andthus facilitate and accelerate transfer of trimethylsilyl groups in silylations. By sev-eral different methods the basicity of nitrogen-containing silylating agents such ashexamethyldisilazane 2 has been estimated to be lower than that of the corre-sponding substituted amines [55, 56]. Nevertheless, the nitrogen in HMDS 2 isstill basic enough to enable activation of the nitrogen by protonation or additionof a Lewis acid [8]. Because alcoholic hydroxyl groups apparently form alcoholateswith the strong base DBU, these alcoholates will also attack HMDS 2 to give thecorresponding silylated alcohols. It should, furthermore, be noted that differentfunctional groups are silylated with quite different reaction rates by HMDS 2 (orother silylating agents) [5]. Whereas alcohols, phenols, and carboxylic acids areusually silylated most rapidly, amines and, in particular, mercaptans react muchmore slowly. Mercaptans are usually only silylated under special conditions, be-cause compounds R–S–SiMe3 are less favored combinations between the “hard”


Scheme 2.6

[55] A. W. Jarwie, D. Lewis, J. Chem. Soc. 1963, 1073[56] G. Huber, H. Schmidbaur, Z. Naturforsch. 1998, 53b, 1103

potential Me3Si cation and the “soft” mercaptide anion [57, 58] (Scheme 2.7) (cf.also Chapter 8).

Because steric factors strongly influence the rate of silylations, primary alcoholsare normally silylated much more rapidly than secondary alcohols whereas tertiaryalcohols are silylated much more slowly. The same is true for phenols – ortho-sub-stituted phenols such as o-cresol are silylated much more slowly than unsubsti-tuted phenols. Obviously, the same applies to cleavage of silylated alcohols or phe-nols on transsilylation, e.g. with excess boiling methanol (Section 2.3).

The relatively slow rate of silylation of amines ensures the presence of freeamines in silylation–aminations (Sections 4.2.1–4.2.5) and enables selective silyla-tion of alcoholic or phenolic hydroxyl groups or carboxyl groups in mono- or poly-hydroxy amines or amino acids (cf. also the ready formation of 33). This order ofreactivity reflects the thermodynamic stability of O-trimethylsilyl derivatives, be-cause the O-trimethylsilyl bond in trimethylsilylated alcohols and phenols 11 ismuch stronger than, e.g., a nitrogen-silicon bond as in silylated amines, whichare silylating agents. Typically, primary amines such as allylamine 41(Scheme 2.8) are only silylated to mono-silylated allylamine 42 on heating for 18 hwith HMDS 2/(NH4)2SO4 [59, 59 a] or with HMDS 2/TCS 14 [59 b]. Allylamine 41(and other primary amines) can, however, be silylated with TCS 14 in the pres-ence of triethylamine and TiCl4 in 83% yield to the persilylated allylamine 43 (orto other N,N-bis(trimethylsilyl)-amines) [60]. Additional methods for preparationof N,N-bis(trimethylsilyl) primary amines such as benzylamine, aniline, or alanineemploying trimethylsilyl triflate 20 or Me3SiI 17 in combination with triethyla-mine without solvent or in boiling 1,2-dimethoxyethane have recently been sum-marized [60]. Persilylated amines such as 43 or the more stable stabase derivatives46, which are obtained from primary amines 44 on treatment with the bifunc-tional silylating agent 1,2-bis(chlorodimethylsilyl)ethane 45 [44, 61], are not af-fected by quite a range of organometallic reagents [61, 62]. On treatment withaqueous acids the amine 44 is recovered and the bis(sila)hydrofuran 47 is ob-tained; this compound is also commercially available.

For silylation of mercapto groups or hindered amide systems, the combinationof HMDS 2 with TCS 14 [8] (cf. also Section 5.1.5), or the combination of tri-


[57] T.-L. Ho, Chem. Rev. 1975, 75, 1[58] T.-L. Ho, “Hard and Soft Acids And Bases Principle in Organic Chemistry”, Academic

Press, New York, 1977[59] J. L. Speier, R. Zimmerman, J. Webster, J. Am. Chem. Soc. 1956, 78, 2278[59a] J. Hils, V. Hagen, H. Ludwig, K. Rühlmann, Chem. Ber. 1966, 99, 776[59b] L. Birkofer, D. Brokmeier, Tetrahedron Lett. 1968, 1325[60] M. Schorr, W. Schmitt, Phosphorus, Sulfur, Silicon 1992, 68, 25[61] S. Djuric, J. Venit, P. Magnus, Tetrahedron Lett. 1981, 22, 1787[62] F. Z. Basha, J. F. DeBernardis, Tetrahedron Lett. 1984, 25, 5271

Scheme 2.7

methylsilyl triflate 20, trimethylsilyl nonaflate 21, or trimethylsilyl cyanide 17 withtriethylamine or a strong base such as DBU (cf. cyclizations in Chapter 9) or reac-tion of the lithium salts of mercaptans with TCS 14 or trimethylsilyl triflate 20should always be regarded as a last resort.

Whereas silylations with trimethylchlorosilane (TCS) 14 (b.p. 57 �C) demand thepresence of a base to neutralize the HCl evolved, giving rise to the hydrochlorideof the base, the use of hexamethyldisilazane (HMDS) 2 (b.p. 126 �C), in particularin the presence of 0.01–0.05 equivalents of acidic catalysts such as TCS 14 or am-monium sulfate, should normally be preferred as the preparative silylating re-agent, because HMDS 2:

� gives, on silylation, only volatile ammonia as a side product and traces of am-monium chloride if small amounts of TCS 14 are used as a catalyst, and

� enables silylations at normal pressure at temperatures of up to ca. 130 �C.

Last but not least HMDS 2 is, in the laboratory and in pilot plants, quite stablewhen stored in a normal closed vessel whereas trimethylchlorosilane (TCS) 14should be stored in a hood, because it reacts with humidity to hexamethyldisilox-ane 7 and HCl. Because HMDS 2 is a very non-polar compound, the silylation ofvery polar compounds, e.g. purines or pteridines, with HMDS 2 will often pro-ceed only on addition of a polar solvent such as pyridine which is, however, read-ily removed after silylation, with excess HMDS 2, on codistillation with abs. xy-lene. Interestingly, it was recently reported that addition of catalytic amounts of io-dine dramatically accelerates the silylation of alcohols, in particular tertiary alco-hols, with HMDS 2 in CH2Cl2 at room temperature [63].

It should be noted here that the lithium salt of hexamethyldisilazane Li-HMDS492 (and Na-HMDS-(486) and K-HMDS in Sections 5.1.2 and 5.1.3), which isreadily obtained on treatment of a solution of HMDS 2 in hexane or THF withbutyllithium at –78 �C, is not only a very useful and selective strong base, e.g. forWittig reactions, but can also add to carbonyl groups to yield the silylated Schiffbases or nitriles (cf. Sections 4.7 and 5.1.3) or to nitriles to afford N-silylated ami-dines. Alkylation of the Li-HMDS 492, e.g. with allyl bromide, affords, further-more, N,N-bis(trimethylsilylated) primary amines such as 43 [64]. The combina-


Scheme 2.8

[63] B. Karimi, B. Golshani, J. Org. Chem. 2000, 65, 7228[64] K. Paulini, H.-U. Reissig, Liebigs Ann. Chem. 1991, 455

tion of HMDS 2 with DBU leads, as already mentioned, to condensation reac-tions, e.g. with �- or �-diketones to afford pyridines (cf. Section 5.5.1) or pyrroles(cf. Section 9.4) whereas N,O-bis(trimethylsilyl)acetamide 22 a (BSA) or N,N-bis(trimethyl-silyl)formamide 22c (BSF) condense with active methylene groups,such as in ethyl cyanoacetate (cf. Section 4.8).

2.2Silylations with Di- and Tetrafunctional Silylating Reagents

Difunctional reagents, for example the very cheap dimethyldichlorosilane 48,which is produced on a large technical scale, and the much more reactive and ex-pensive dimethylsilyl bis(O-triflate) 49 [65–67] (Scheme 2.8) convert alcohols orphenols 11 in the presence of bases, for example triethylamine or DBU, into thesilylated compounds 50. Thus 48 and 49 and other bifunctional reagents such asdi-tert-butyldichlorosilane [68] or di(tert-butylsilyl)-bis(O-triflate) [69] and the subse-quently described 51 and 52 combine two alcohols to silicon-tethered molecules50, which can undergo interesting intramolecular reactions [70–74].

By analogy with hexamethyldisilazane 2, the liquid difunctional commercial re-agents hexamethylcyclotrisilazane 51 (b.p. 188 �C) and the crystalline and high-boiling octamethylcyclotetrasilazane (OMCTS; m.p. 97�C, b.p. 225 �C) 52 generateonly ammonia during silylation. The mixture of, mainly, 51 and 52 and other oli-gomers, from which 52 crystallizes, is readily prepared by treating dimethyldi-chlorosilane 48 with dry ammonia [75–77].

The high boiling 52 enables silylation–aminations at temperatures up to 230 �C(cf. Section 4.2.5). For large scale silylation–aminations one should also consideremploying a crude mixture of 51, 52, and other oligomers or polymers resultingfrom reaction of dimethyldichlorosilane 48 with ammonia. On combining eitherhexamethylcyclotrisilazane 51 or octamethylcyclotetrasilazane (OMCTS) 52 withappropriate amounts of dimethyldichlorosilane 48 ammonium chloride will beprecipitated on working in abs. acetonitrile at room temperature. Reactions of di-methyldichlorosilane 48, hexamethylcyclotrisilazane 51, or OMCTS 52 with H2O

2.2 Silylations with Di- and Tetrafunctional Silylating Reagents 17

[65] M. Schmeisser, P. Sartori, B. Lippsmeier, Chem. Ber. 1970, 103, 868[66] K. Krägeloh, G. Simchen, K. Schweiker, Liebigs Ann. Chem. 1985, 2352[67] W. Uhlig, Chem. Ber. 1996, 129, 733[68] B. M. Trost, C.G. Caldwell, Tetrahedron Lett. 1981, 22, 4999[69] E. J. Corey, P.B. Hopkins, Tetrahedron Lett. 1982, 23, 4871[70] K. Furusawa, K. Ueno, T. Katsura, Chem. Lett. 1990, 97[71] M. Bols, T. Skrydstrup, Chem. Rev. 1995, 95, 1253[72] L. Fensterbank, M. Malacria, S.M. Sieburth, Synthesis 1997, 813[73] D.R. Gauthier, K.S. Zandi, K.L. Shea, Tetrahedron 1998, 54, 2289[74] T.R. Hoye, M.A. Promo, Tetrahedron Lett. 1999, 40, 1429[75] S.T. Brewer, C.P. Haber, J. Am. Chem. Soc. 1948, 70, 3888[76] R. C. Osthoff, S. W. Kantor, Inorg. Synth. 1957, 5, 55[77] S. Pawlenko in Houben–Weyl, “Methoden der Organischen Chemie” Vol. XIII-5, 1980,

252

lead, via the crystalline dimethyldisilanol 53 [78, 79], to cyclic oligomers of 53 forexample the volatile 54 and 55 and silicone oil 56, all of which will be readilyremoved from crude reaction mixtures on extraction with hexane or methyl-tert-butyl ether (Scheme 2.9).

The tetravalent reagents silicon tetrachloride, SiCl4, 57, tetramethoxysilane,Si(OMe)4, 58, or tetraethoxysilane, Si(OEt)4, 59, are also produced in largeamounts on a technical scale and are thus readily available. (The reactions ofSiCl4 57, Si(OMe)4 58, and Si(OEt)4 59 are discussed in Section 3.4).

2.3Transsilylation and Deprotection of Silylethers

As emphasized in the Introduction (Chapter 1), all alcoholic (or phenolic) hydrox-yl groups present in the nucleoside uridine 1 or other starting compounds areprotected by silylation during silylation–activation of any suitable amide, lactam,imide, urea, sulfoxide, or nitro groups and subsequent reaction with suitable nu-cleophiles. This “transient protection” by silylation of hydroxyl groups can then bereadily reversed in situ by preparative transsilylation either on boiling for 3–4 hwith a large excess of methanol or on keeping the methanol solution overnight orover the weekend at room temperature [80, 81] (cf. Sections 4.2.2–4.2.5). The highmobility [45] of trimethylsilyloxy groups leads to equilibrium between methanol,the silylated alcohols or phenols 13, the free alcohols or phenols 11 (seeScheme 2.10), and methoxytrimethylsilane 13 a, in which the latter predominates.In larger-scale experiments the transsilylation in boiling methanol can be acceler-ated and the equilibrium between 13 and methoxytrimethylsilane 13a shifted to-


Scheme 2.9

[78] S.W. Kantor, J. Am. Chem. Soc. 1953, 75, 2712[79] J. A. Cella, J.C. Carpenter, J. Organomet. Chem. 1994, 480, 23[80] H. Steimann, G. Tschernko, H. Hamann, Z. Chem. 1977, 17, 89[81] T.D. Nelson, R.D. Crouch, Synthesis 1996, 1031

wards exclusive formation of methoxytrimethylsilane 13 a (b.p. 55 �C) [16] by distil-ling the azeotropic mixture of methoxytrimethylsilane 13 a and methanol (b.p.49.6–50 �C) [15] from excess methanol (b.p. 64 �C), by use of a short distillationcolumn. In the silylation–amination of nucleosides (cf. Section 4.2.3), the result-ing aminated free nucleosides, for example cytidines 6 or the subsequently dis-cussed N6-substituted adenosines (cf. Section 4.2.4), usually crystallize on coolingfrom the hot methanol solution.

It is obvious that bifunctional dimethylsilyl derivatives such as 50 behave analo-gously in boiling methanol to form the free alcohols or phenols 11 and dimethox-ydimethylsilane 60 and that all of these transsilylations can be accelerated by cata-lytic amounts of Lewis acids and by fluorides such as KF, CsF, or the commer-cially available solution of Bu4NF · 2–3H2O in THF [81, 82]. The transsilylation oftrimethylsilylated tertiary alcohols such as 61 to 62 and methoxytrimethylsilane13 a is very slow in boiling methanol and can, in practice, be effected by fluorideions only [82, 83]. Fluorides such as TBAF · 2–3H2O [82] or more recentlyZn(BF4)2 [84] are used to cleave the more stable O-tert-butyldimethylsilyl ethers.The cleavage of different O-silyl protecting groups was recently reviewed [81].Likewise, HMDSO 7 can be transsilylated by triethylsilyl chloride 63 in the pres-ence of FeCl3 to give 1,1,1-trimethyl-3,3,3-triethyldisiloxane 64 and probably somehexaethyldisiloxane 65 [85]. In this connection it should be noted that in reactionsof triethylsilylchloride 63 hexaethyldisiloxane 65 is usually formed (Scheme 2.10).

The relative ease of these transsilylations is because of the mobility of silylgroups, which is a consequence of the coordination number of silicon of 6, as dis-cussed in the subsequent section.

2.3 Transsilylation and Deprotection of Silylethers 19

Scheme 2.10

[82] E. J. Corey, A. Venkatesvarlu, J. Am. Chem. Soc. 1972, 94, 6190[83] H. Vorbrüggen, K. Krolikiewicz, Liebigs Ann. Chem. 1976, 745[84] B. C. Ranu, U. Jana, A. Majee, Tetrahedron Lett. 1999, 40, 1985[85] M.G. Voronkov, L.M. Chudeova, J. Obshch. Khim. 1959, 29, Chem. Abstr. 1960, 54,

44067

2.4Mobility of Silyl Groups and the Importance of Hypervalent Silicon Species

Because silicon has empty d-orbitals it can easily assume coordination numbers of5 or 6, which explains the very high mobility [45] of the trimethylsilyl group, inparticular, as exemplified by the equilibrium between 8 and 9, which was dis-cussed in the Introduction (Chapter 1). This mobility, e.g., of the trimethylsilylgroup (and also of the dimethylsilyl group) is why the thermodynamically moststable silylated structure is nearly always formed. Nevertheless, thermodynami-cally less favored structures are often also present in the equilibrium. Thus, themore favored N-trimethylsilylsuccinimide 201, as detected by 1H NMR, seems,nevertheless, to be in equilibrium with the activated O-trimethylsilylated form202, which reacts with primary and secondary amines on heating (cf. Sec-tion 4.2.2) to give products such as the cyclic acylamidine 203 or, with ethyl cya-noacetate, to give products such as 380. Likewise, 2-trimethylsilyloxybenzoxazole290 seems to be in equilibrium with 2-trimethylsilyloxyphenylisocyanate 291,which reacts with primary or secondary amines to give ureas such as 292 (cf. Sec-tion 4.2.5). Furthermore, N,N�-bis(trimethylsilyl)carbodiimide 328 condenses,apparently as N,N-bis(trimethylsilyl)cyanamide 553, with carbonyl groups to giveN-cyanoimides (cf. Section 5.1.3). The potential equilibria between trimethylsilylisothiocyanate Me3SiNCS 937 and its isomer Me3SiSCN 940 (cf. Section 7.1) or be-tween trimethylsilylcyanide Me3SiCN 18 and trimethylsilyl isocyanide Me3SiNC[86, 86a, 86b] and between the trimethylsilyl nitronates 1036 and 1037 should beremembered (cf. Section 7.6). In a recent synthesis of a cis-enamide, the C-triethyl-silyl compound 66 rearranges, on heating, to the unsaturated O-triethylsilylimi-noether 67 to give, on hydrolysis, the desired cis-enamide 68 [87] (Scheme 2.11).

Numerous examples of silicon rearrangements [88], for example the Brook rear-rangement [89], are covered in pertinent reviews [88, 89].

This ability of silicon to assume coordination numbers of five and six is alsovery important in the already mentioned catalytic affects of fluoride ions, because


[86] T.A. Bither, W. H. Knoth, R. V. Lindsey Jr, W. H. Sharkey, J. Am. Chem. Soc. 1958,80, 4151

[86a] D. Seyferth, N. Kahlen, J. Am. Chem. Soc. 1960, 82, 1080[86b] J. A. Seckar, J. S. Thayer, Inorg. Chem. 1976, 15, 501[87] S. Lin, S. Danishefsky, Angew. Chem. Int. Ed. 2002, 41, 512[88] E. Colvin, “Silicon in Organic Synthesis”, Butterworths, London, 1981, 30–39[89] A. G. Brook, Acc. Chem. Res. 1974, 7, 77

Scheme 2.11

the fluoride anion attacks the silicon atom, e.g. in trimethylsilyl compounds 69, toform reactive pentacoordinate intermediates 70 (Scheme 2.12), which decomposeto the volatile trimethylsilylfluoride 71 (b.p. 17 �C) and the more or less reactivesalts R– · cat+ 72. Depending on the stability of the anions R– in the salt 72 this re-action, however, will only proceed to give less stable and therefore more reactivebenzyl, allyl, or Me3Si anions 72 with the corresponding counter cation, if thefluoride anion is nearly or completely anhydrous and thus very reactive (cf. thediscussion of fluoride-catalyzed CN-substitutions of heterocyclic N-oxides in Sec-tion 7.1; or the fluoride-catalyzed addition of allyl- and benzyltrimethylsilanes 82and 83 to aromatic heterocyclic N-oxides in Section 7.2 and in Section 13.1).

Thus removal of water from classical rather inactive fluoride reagents such astetrabutylammonium fluoride di- or trihydrate by silylation, e.g. in THF, is a pre-requisite to the generation of such reactive benzyl, allyl, or trimethylsilyl anions.The complete or partial dehydration of tetrabutylammonium fluoride di- or trihy-drate is especially simple in silylation–amination, silylation–cyanation, or analo-gous reactions in the presence of HMDS 2 or trimethylsilyl cyanide 18, which ef-fect the simultaneous dehydration and activation of the employed hydrated fluo-ride reagent (cf., also, discussion of the dehydration of such fluoride salts in Sec-tion 13.1). For discussion and preparative applications of these and other anhy-drous fluoride reagents, for example tetrabutylammonium triphenyldifluorosilicateor Zn(BF4)2, see Section 12.4. Finally, the volatile trimethylsilyl fluoride 71 (b.p.17 �C) will react with nucleophiles such as aqueous alkali to give trimethylsilanol4, HMDSO 7, and alkali fluoride or with alkaline methanol to afford methoxytri-methylsilane 13 a and alkali fluoride.

Attack of excess methanol, in the presence of bases or acids, on trimethylsilyl-oxy ethers such as 13 or on dimethylsilyloxy compounds such as 50 during trans-silylations (cf. the preceding section) probably also proceeds via transition statessuch as 73 or 74 to afford the free alcohols or phenols 11 and methoxytrimethylsi-lane 13a.

2.4 Mobility of Silyl Groups and the Importance of Hypervalent Silicon Species 21

Scheme 2.12

Phenyltrimethoxysilane 75 is activated by fluoride anion to 76, which undergoespalladium-catalyzed coupling with 4-methyliodobenzene 77 to give a nearly quanti-tative yield of 4-methyldiphenyl 78 [90]. Such Heck-, Stille-, or Suzuki-type C–Ccoupling of arylsilanes such as 75 were recently reviewed [91] (Scheme 2.12).

The hypervalent properties of silicon are of importance in reactions of SiO2

with alcohols or phenols 11, in particular with glycols and catechols. Thus heatingof catechol 79 with SiO2 and NaOH readily affords the hypervalent crystalline so-dium salt 80 in high yield [92–96] (Scheme 2.13). These reactions of SiO2 explainthe gradual washing out of silica columns (leaking) on chromatography of alco-hols or phenols and, especially, of glycol and catechol systems. In this connectionit should be noted that such organosilicon complexes with sugars such as glucu-ronic acid [97, 98] apparently transport silicon in plants and microorganisms [99].

The hypervalence of silicon compounds has recently been reviewed [100, 101].

2.5Activation of Silicon Bonds by Transition Metal Salts and Complexes

In addition to activation of silicon bonds by fluoride ions as discussed in Section 2.4,silicon–silicon, silicon–carbon, silicon–hydrogen, and silicon–nitrogen bonds are ac-tivated by transition metal salts and transition metal complexes. Thus, hydrolysis ofsilicon–carbon bonds such as in phenyltrimethylsilane 81 can be induced by


Scheme 2.13

[90] M.E. Mowery, P. DeShong, J. Org. Chem. 1999, 64, 1684[91] P. DeShong, C. J. Handy, M.E. Mowery, Pure Appl. Chem. 2000, 72, 1655[92] A. Rosenheim, B. Raibmann, Z. Anorg. Allg. Chem. 1931, 196, 160[93] A. Boudin, G. Cerveau, C. Chuit, R. J.P. Coriu, C. Reye, Organometallics 1988, 7,

1165[94] R. M. Laine, K. Y. Blohowiak, T.R. Robinson, M.L. Hoppe, P. Nardi, J. Kampf, J.

Uhm, Nature, 1991, 353, 642[95] J. V. Kingston, M.N.S. Rao, Tetrahedron Lett. 1997, 27, 4841[96] V. Chandrasekhar, S. Nagendran, S. Andavan, G.T.S. Andavan, Tetrahedron Lett.

1998, 39, 8505[97] S.D. Kinrade, J.W. Del Nin, A.S. Schach, T.A. Sloan, K.L. Wilson, C.T. G. Knight,

Science 1999, 285, 1542[98] S.T. Kinrade, A.S. Schach, R. J. Hamilton, C.T. G. Knight, J. Chem. Soc. Chem.

Commun. 2001, 1564[99] M. Freemantle, Chem. Eng. News, February 2002, 27

[100] R. J.P. Corriu, J. Organomet. Chem. 1990, 400, 81[101] C. Chuit, R. J. P. Corriu, C. Reye, J. C. Young, Chem. Rev. 1993, 93, 1371

(C2H4)2Pt2Cl4 to give benzene and hexamethyldisiloxane 7 [102]. On heating withhexamethyldisilane 857 in the presence of Pd(PPh3)4 bromobenzene reacts to formphenyltrimethylsilane 81 [103]. Primary amides such as 2-picolinamide, in which theadjacent ring nitrogen is available for complex formation, reacts in DMF withPhSi(OMe)375/Bu4NF · 2–3H2O/Cu(OAc)2 to give the corresponding N-phenylatedamide [104]. Likewise, allyltrimethylsilane 82 is cleaved by methanol in the presenceof Pd(OAc)2 to give propylene and methoxytrimethylsilane 13 a [105] (Scheme 2.14).Benzyltrimethylsilane 83, which is very similar to allyltrimethylsilane 82 (cf. Sec-tion 7.2), can be expected to be cleaved analogously. For further examples of reac-tions catalyzed by transition metal complexes, see conversion of the fluoride-acti-vated compound 70 to 72 in the preceding section and other transformations in Sec-tions 3.2 and 4.4. For activation of trimethylsilane (Me3SiH) 84 a, e.g. for addition topyridine, see Chapter 13. Triethylsilane 84b normally behaves similarly. Comparealso the reaction of 100 to 101 in Section 3.2. Transition metal-catalyzed reactionsof silicon compounds have been reviewed [106–108].

2.6Concluding General Remarks on Preparative Silylations

It should be emphasized here that the aforementioned high mobilities of di-methylsilyl or trimethylsilyl groups in silylation at ambient or elevated tempera-tures almost always gives the thermodynamically controlled products. Because ofthe high affinity of silicon for oxygen, silylation of aromatic hydroxy-N-hetero-cycles results in exclusive formation of the corresponding aromatic O-silylatedproducts. By analogy, silylation of �-ketoesters or of �-diketones affords predomi-nantly the 3-trimethylsilyloxycrotonesters or �-trimethylsilyloxyenones. In contrast,however, silylation of amides, lactams (cf. the N-silylated lactam 8 in Chapter 1),cyclic imides (cf. the reactions of succinimides 201 and 202 in Sections 4.2.2 and4.8), and ureas 23 often give mainly the N-silylated derivatives such as 201, be-

2.6 Concluding General Remarks on Preparative Silylations 23

Scheme 2.14

[102] D. Mansui, J. Pusset, J. C. Chotard, J. Organomet. Chem. 1976, 105, 169[103] H. Matsumoto, S. Nagashima, K. Yoshihiro, Y. Nagai, J. Organomet. Chem. 1975,

85, C1[104] P.Y. S. Lam, S. Deudon, E. Hauptmann, C.G. Clark, Tetrahedron Lett. 2001, 42, 2427[105] J. M. Kliegman, J. Organomet. Chem. 1971, 29, 73[106] M.D. Curtis, P.S. Epstein, Adv. Organomet. Chem. 1981, 19, 213[107] K. H. Horn, Chem. Rev. 1995, 95, 1317[108] H.K. Sharma, K. H. Pannel, Chem. Rev. 1995, 95, 1351

cause O-silylation would mean activated states of higher energy with loss of reso-nance energy. But, because of the aforementioned mobility of the silyl groups be-tween the N-silylated lactam 8 and the O-silylated lactam 9, a small amount of theactivated O-silyl compounds, for example 9 or 202, can be assumed to be nearlyalways present in an equilibrium to enable addition–elimination reactions of theO-silylated amides, lactams, imides, and ureas (cf. also, e.g., the formation of ali-phatic and aromatic polyfunctional silylating reagents such as 22).

In all these reactions it is important that the different stoichiometries are adjustedsuch that trimethylsilanol 4 is transformed into hexamethyldisiloxane 7 and di-methyldisilanol 46 into the oligomers 54, 55, or 56 in stoichiometric amounts.The silylation of very polar and insoluble heterocyclic compounds, for example somepurines, with hexamethyldisilazane (HMDS) 2 and acidic catalysts to give the corre-sponding stable, lipophilic, and volatile persilylated derivatives can often be achievedonly on addition of polar solvents such as pyridine, acetonitrile, or N,N-dimethylfor-mamide (DMF). After silylation with HMDS 2 in pyridine the trimethylsilylated pur-ines, in particular, can be readily obtained in a pure state after codistillation withxylene, whereupon the more volatile HMDSO 7 (b.p. 100 �C) or unreacted HMDS2 (b.p. 126 �C) and the cosolvent pyridine are removed practically quantitatively, fol-lowed by short-path (Kugelrohr) vacuum distillation of the residual persilylated pur-ines with exclusion of moisture. Furthermore, a slight excess of the silylation agent,HMDS 2 in particular, will not only convert any invading humidity into HMDSO 7but will also remove water from hydrates such as TsOH· H2O, to give anhydrousTsOH, HMDSO 7, and ammonia or ammonium tosylate.

On considering technical large-scale reactions not only the prices of reagents tri-methylchlorosilane 14, hexamethyldisilazane (HMDS) 2, hexamethylcyclotrisila-zane 51, or octamethylcyclotetrasilazane (OMCTS) 52 but also the cost of dealingwith the side products hexamethyldisiloxane (HMDSO) 7, hexamethylcyclotrisilox-ane 54, octamethylcyclotetrasiloxane 55, and silicon oil 56 must also be taken intoaccount. Instead of burning these side products they can all be re-converted intotrimethylchlorosilane 14 or dimethyldichlorosilane 48, e.g. on treatment withphosgene (Scheme 2.15). This reconversion of larger amounts of HMDSO 7 toMe3SiCl 14 is also being performed by special companies.

Reaction of tert-butyldimethylsilanol 85a or tert-butyldiphenylsilanol 85 b, whichare obtained on cleavage of O-silyl compounds, with SOCl2 in CHCl3, affords thedesired re-usable chlorosilanes 86a and 86b in 39 and 81% yield, respectively[109] (Scheme 2.16).

Hexamethyldisiloxane 7 can, furthermore, be used to transform aromatic tri-chloro- or dichloromethyl compounds such as 87 and 89, in nearly quantitativeyield, into the corresponding acid chlorides, for example 88 [110], or aldehydes,for example 90, with formation of trimethylchlorosilane 14 [111] (Scheme 2.17).


[109] P.D. Lickiss, K.M. Stubbs, J. Organomet. Chem. 1991, 421, 171[110] T. Nakano, K. Ohkawa, H. Matsumoto, Y. Nakai, J. Chem. Soc. Chem. Commun.

1977, 808[111] J. Koetsch, J. Amort, H.J. Vahlensieck, Ger. Offen. 2,950,030; Chem. Abstr. 1981, 95,

132524v

Other disiloxanes, for example 65 and 94 a, 94 b, and 95, which are discussed inSection 3.1, can also be analogously reconverted into their reactive halides.

2.7Experimental Examples

Primary amine (0.5 mol) and triethylamine (111.2 g, 1.2 mol) are dissolved in CH2Cl2(500 mL) and slowly mixed with TiCl4 (1 mL). After stirring for 45 min at room tem-perature Me3SiCl 14 (119.45 g, 1.1 mol) is added dropwise, whereupon the tempera-ture rises to the boiling point of the solvent. Stirring under reflux is continued for 3–6 h, followed by evaporation of the solvent. To precipitate Et3N· HCl, the residue ismixed with diethyl ether or diisopropyl ether (500 mL), then filtered by suction, againevaporated, and the residue distilled with exclusion of humidity (Scheme 2.18) [60].


Scheme 2.15

Scheme 2.16

Scheme 2.17

Scheme 2.18

l-Aspartic acid 32 (506 mg, 3.80 mmol) is suspended in HMDS 2 (5 mL) andheated under reflux for 5 h to give a colorless solution. The solvent is evaporatedto yield, after Kugelrohr distillation at 130–140 �C/0.5 mm Hg, 1.070 g (100%) ofthe bis(trimethylsilyl)ester 33 as a colorless oil (Scheme 2.19) [53].

A solution of sodium methoxide (80 mmol) in methanol (40 mL) is added tosilica gel (2.7 g, 45 mmol) followed by a solution of catechol (13.2 g, 120 mmol) inmethanol (40 mL). The resulting mixture is stirred and heated under reflux for18 h. The methanol is then evaporated and the solid residue washed with ether.The black solid is dissolved in THF (400 mL) and the resulting solution is heatedfor 1 h in the presence of charcoal. After filtration and evaporation of the solventthe sodium tris(benzene-1,2-diolato)silicate 80 is isolated as a white powder(12.53 g, 70%; Scheme 2.20) [93].


Scheme 2.19

Scheme 2.20

3.1Preparation and Properties of Trimethylsilanol and other Trialkyl- or Arylsilanols

In connection with our studies on the transformation of uridine 1 via 3 and 5 tothe cytidines 6 (cf. Section 4.2.3) we became interested in the chemical and physi-cal properties of the leaving group trimethylsilanol 4 and in its dimerization prod-uct hexamethyldisiloxane 7. Pure trimethylsilanol 4 (monosilylated water), b.p.99 �C, is prepared in 70% yield from trimethylchlorosilane (TCS) 14 in diethylether on treatment with aqueous ammonia under careful pH control [1, 2], fromtrimethylfluorosilane 71 [1], from hexamethyldisiloxane 7 [1], from hexamethyldi-silazane (HMDS) 2 on reaction with aqueous AcOH [3], or by hydrolysis from N-trimethylsilylacetamide [4]. Trimethylsilanol 4 is much more acidic and onlyslightly less basic than tert-butanol, as was established by IR hydrogen-bondingstudies [5–7] and by 1H NMR measurements [8]. Furthermore, trimethylsilanol 4and tert-butanol are strongly associated, e.g. in cyclohexane [9]. Consequently, tri-methylsilanol 4 is a better leaving group than methanol, and methoxytrimethyl-silane 13 a is also less basic than the corresponding dialkyl ethers, for examplemethyl tert-butyl ether.

Under acidic conditions in a two-phase system the rate of hydrolysis is in theorder MeOSiMe3 13 a > (MeO)2SiMe2 > (MeO)3SiMe. Under the action of basic cata-lysis this order of reactivity is reversed [10].

Although apparently no 29Si NMR data have yet been published for Me3SiOH 4,several silicon–oxygen compounds, for example TMSOTf 20 [11], hexamethyldisil-

27

3

Preparation and Properties of Silyloxy Leaving Groups


[1] L.H. Sommer, E. W. Pietrusza, F. C. Whitmore, J. Am. Chem. Soc. 1946, 68, 2282[2] G. Greber, E. Reese, J. Tölle, Makromol. Chem. 1962, 53, 87[3] H. Kobayashi, K. Tsunoda, JP 63,227,591; Chem. Abstr. 1989, 110, 75795m[4] L. Birkofer, A. Ritter, H. Dickopp, Chem. Ber. 1963, 96, 1473[5] R. West, R.H. Baney, J. Am. Chem. Soc. 1959, 81, 6145[6] R. H. Baney, K. L. Lake, R. West, L.S. Whatley, Chem. Ind. 1959, 1129[7] J. Pola, V. Chvalovsky, Collect. Czech. Chem. Commun. 1978, 43, 746[8] H. Schmidbaur, Chem. Ber. 1964, 97, 830[9] W. T. Grubb, R.C. Osthoff, J. Am. Chem. Soc. 1953, 75, 2230

[10] K. A. Smith, J. Org. Chem. 1986, 51, 3827[11] H.C. Marsmann, H.G. Horn, Z. Naturforsch. 1972, 27b, 1448

oxane 7 [12], and trimethylsilyl ethers, for example MeOSiMe3 13 a, Me3COSiMe3,or Me3SiOSiMe3 7 [13, 14] have been studied by 29Si NMR to give an estimate ofmagnetic deshielding of the 29Si atom by the attached oxygen functions, whereasN-trimethylsilyl derivatives have been submitted to 29Si NMR [15], 13C NMR [15],or 15N NMR [16] measurements. The electron-induced cleavage or rearrange-ment–cleavage of silyloxy groups has been investigated [17–19] and reviewed [20].Flowing afterglow-selected ion flow (FA-SIFT) has been used to investigate thegas-phase acidity of silanols such as Me3SiOH 4 [21]. MM2 calculations have beendescribed for hexamethyldisiloxane 7 [22] and the nature of the Si–OH bond in tri-methylsilanol 4 has been discussed [23]. Because of the greater length of 1.89 Å ofthe C–Si bond in the trimethylsilyl group compared with 1.53 Å for the C–C bondin the tert-butyl group, a trimethylsilyloxy group is much less bulky than a tert-bu-tyloxy group [24]. Thus, the nitrogen in hexamethyldisilazane 2, which is less ba-sic than di-tert-butylamine, is much more accessible to protonation or Lewis acidsthan the nitrogen in di-tert-butylamine. In contrast with Me3SiOH 4, which di-merizes readily under the action of acidic and basic catalysis to HMDSO 7,triethylsilanol 93 [25], tert-butyldimethylsilanol 85a [26], tert-butyldiphenylsilanol85b [27], and triisopropylsilanol 92 [27a, b], which are also prepared from theirchloro compounds 63, 86 a, b and 91, dimerize because of their increasing stericbulk more and more slowly into the disiloxanes 65 [25, 26], 94a [26, 27], 94b [27],and 95 [27 a,b] (Scheme 3.1).

Because trimethylsilanol 4 is more acidic than methanol or tert-butanol, tri-methylsilanol 4 and hexamethyldisiloxane 7 react rapidly with 12 M NaOH, KOH,or LiOH to give colorless crystalline precipitates of sodium trimethylsilanolate 96

3 Preparation and Properties of Silyloxy Leaving Groups28

[12] H.C. Marsmann, Chem. Ztg. 1973, 97, 128[13] E. Kupce, E. Liepins, I. Zicmane, E. Lukevics, J. Chem. Soc. Chem. Commun. 1989,

818[14] J. Schraml, J. Pola, H. Jancke, G. Engelhardt, M. Cerny, V. Chvalovsky, Collect.

Czech. Chem. Commun. 1976, 41, 360[15] H. Jancke, G. Engelhardt, S. Wagner, W. Dirnens, G. Herzog, E. Thieme, K. Rühl-

mann, J. Organomet. Chem. 1977, 134, 21[16] P.R. Srinivasan, S. P. Gupta, S.-Y. Chen, J. Magn. Reson. 1982, 46, 163[17] H. Schwarz, M. Kliment, M.T. Reetz, G. Holzmann, Org. Mass Spectrom. 1976, 11,

989[18] H. Schwarz, C. Wesdemiotis, M.T. Reetz, J. Organomet. Chem. 1978, 161, 158[19] B. Clommer, H. Schwarz, J. Organomet. Chem. 1983, 244, 319[20] H. Schwarz, The Chemistry of Organic Silicon Compounds, S. Patai, Z. Rapoport

(Eds), Wiley, New York, 1989, p. 445[21] R. Damrauer, R. Simon, M. Kremp, J. Am. Chem. Soc. 1991, 113, 4431[22] M.T. Frierson, N.L. Allinger, J. Phys. Org. Chem. 1989, 2, 573[23] L. Allred, E.G. Rochow, F. G. A. Stone, J. Inorg. Nucl. Chem. 1956, 11, 416[24] J. R. Hwu, N. Wang, Chem. Rev. 1989, 89, 1599[25] W. T. Grubb, J. Am. Chem. Soc. 1954, 76, 3408[26] G. W. Ritter, M.E. Kenney, J. Organomet. Chem. 1978, 157, 75[27] J.-I. Tamura, J. Nishihara, Bioorg. Med. Chem. Lett. 1999, 14, 1911[27a] M.J. Park, E. S. Yim, S. J. Lee, M.K. Park, B. H. Han, Main Group Met. Chem. 1999,

22, 713; Chem. Abstr. 2000, 132, 194491y[27b] J. A. Soderquist, I. Rivera, A. Negron, J. Org. Chem. 1989, 54, 4051

[1, 28], potassium trimethylsilanolate 97 [28], or a solution of lithium trimethylsila-nolate 98 in THF [29]. (Scheme 3.2) The reaction of these alkali metal hydroxideswith HMDS 2 in an organic solvent ought to afford directly the anhydrous salts96–98 and NH3. The salts 96, 97, and 98 are commercially available and havefound preparative use, e.g. for the cleavage of esters and lactones. (cf. Section 4.7)For the postulated equilibrium between DBU and HMDSO 7 and the reaction ofDBU/trimethylsilanol 4 with activated nitriles, see Section 7.1.

Finally, thermochemical data on the heat of hydrolysis of Me3SiCl 14 and ofHMDS 2 in 1 M HCl to trimethylsilanol 6 or HMDSO 7 have been measured [30,31].

3.2Reactions of Trimethylsilanol and other Trialkyl-, Alkylaryl-, or Triarylsilanols

To mention a few synthetic applications of trialkylsilanols, trimethylsilanol 4 addsreadily to 2-chloroacrylonitrile in diethyl ether in the presence of triethylamine astriethylammonium trimethylsilanolate followed by elimination of triethylaminehydrochloride to give 99 [32] (cf. discussion of the strongly nucleophilic propertiesof ammonium trimethylsilanolate 155 in Section 4.2.1). The stable potassium tri-methylsilanolate 97 has also been used for the saponification of esters (Sec-tion 4.7). Dimethylphenylsilanol 100 adds readily to �,�-unsaturated carbonyl com-pounds such as methyl vinyl ketone 764 in the presence of Pd(OAc)2 in a Heck–Suzuki-type reaction to give the silicon-free �-phenylmethylvinylketone 101 [33].

3.2 Reactions of Trimethylsilanol and other Trialkyl-, Alkylaryl-, or Triarylsilanols 29

Scheme 3.1

Scheme 3.2

[28] J. F. Hyde, O.K. Johannson, W. H. Daudt, R. F. Fleming, H.B. Laudenslager, M.P.

Roche, J. Am. Chem. Soc. 1953, 75, 5615[29] D. Seyferth, D.A. Alleston, Inorg. Chem. 1963, 2, 418[30] A. E. Beezer, C.T. Mortimer, J. Chem. Soc. A 1966, 514[31] J. C. Baldwin, M.F. Lappert, J. P. Pedley, J.A. Treverton, J. Chem. Soc. A 1967, 1980[32] E.M. Movsum-zade, M.G. Mamedov, I.A. Shikiev, Zh. Obshch. Khim. 1978, 48, 610;

Chem. Abstr. 1978, 89, 43575b

tert-Butyldimethylsilanol 85a reacts readily with phenylphosphonic acid in hexaneto give the silyl ester [34] and adds to azlactone 102 in the presence of DBU togive 103 [35]. 1,4-Addition of triphenylsilanol 104 to the epoxyolefin 105 in thepresence of (dba)3Pd2 affords the 1,4-addition product 106 [36]. The potassiumsalt of triisopropylsilanol 92 [37, 38] has recently been used as a phase-transfer re-agent for dehydrohalogenations, e.g. of 1,2-dibromoalkanes to the correspondingacetylenes [38] (Scheme 3.3).

Because the trimethylsilyl enol ether of cyclohexanone 107a is considerablymore bulky than the corresponding dimethylsilyl enolate 107b, only the latter re-acts with the N-tosylimine 108 in the presence of catalytic amounts of diisopropyl-amine in DMF/H2O at 78 �C or at room temperature to give the Mannich typecompounds 109 in high yields [39] (Scheme 3.4).

In this connection a crude scale of the “bulkiness” of silyloxy leaving groupscan be conceived, with H3SiO assumed to be the least bulky leaving group.Although the Me3SiO leaving group is much less bulky than the Me3CO group,because the Si–O bond is longer than the C–O bond of 1.41 Å [24], replacementof one methyl group in 107a by a hydrogen in 107 b has a dramatic effect on theformation of 109.

With regard to the leaving group capability of silyloxy leaving groups, the hypo-thetical F3SiO group can be assumed to be the best leaving group (Scheme 3.5).


Scheme 3.3

[33] K. Hirabayashi, Y. Nishihara, A. Mori, T. Hiyama, Tetrahedron Lett. 1998, 39, 7893[34] I. Lukes, M. Borbaruah, L.D. Quin, J. Am. Chem. Soc. 1994, 116, 1737[35] S.A. Barbirad, F. Bacon, A. S. Kuczma, J. K. Rasmussen, S. M. Heilmann, L.R. Krepski,

Eur. Pat. EP 333,361; Chem. Abstr. 1990, 112, 120761b[36] B. M. Trost, N. Ito, P.D. Greenspan, Tetrahedron Lett. 1993, 34, 1421[37] C. Rücker, Chem. Rev. 1995, 95, 1009[38] J. A. Soderquist, J. Vaquier, M.J. Diaz, A. M. Rane, F.G. Bordwell, S. Zhang, Tetrahe-

dron Lett. 1996, 37, 1561

3.3Preparation, Properties and Reactions of Dialkyl- or Diaryldisilanols,and Alkyl- or Aryltrisilanols

As already discussed in Section 2.2, crystalline dimethylsilanediol 53 can be pre-pared by hydrolysis from hexamethylcyclotrisilazane 51, from dimethoxydimethyl-silane [40], and from octamethylcyclotetrasilazane (OMCTS) 52. The most simplepreparation of 53 is, however, controlled hydrolysis of dimethyldichlorosilane 48in the presence of (NH4)2CO3 or triethylamine [41]. Likewise, hydrolysis of hexam-ethylcyclotrisiloxane 54 and of octamethylcyclotetrasiloxane 55 eventually givesrise to dimethylsilanediol 53. In all these reactions the intermediacy of the veryreactive dimethylsilanone 110 has been assumed, which can be generated bypyrolytic [42, 43] and chemical methods [44–46] and which cyclizes or polymerizesmuch more rapidly, e.g. in contact with traces of alkali from ordinary laboratoryor even Pyrex glassware [40, 47] to 54, 55, and 56 than trimethylsilanol 4 poly-merizes to hexamethyldisiloxane 7. Compound 111 is readily converted into di-methylsilanone 110 and Me3SiI 17 [46] (Scheme 3.6).

The use of tethered alcohols 50 for cyclizations in ring-closing metatheses(RCM) or as protection agents has already been briefly mentioned in Section 2.2.

Silylation of 2-pyridone 245 with octamethyltetrasilazane (OMCTS) probablyleads to the activated dimer 246 (Section 4.2.3). Finally it should be mentioned

3.3 Preparation, Properties and Reactions of Dialkyl- or Diaryldisilanols, and Alkyl- or Aryltrisilanols 31

Scheme 3.4

Scheme 3.5

[39] K. Miuara, K. Tamaki, T. Nakagawa, A. Hosomi, Angew. Chem. Int. Ed. 2000, 39, 1958[40] S.W. Kantor, J. Am. Chem. Soc. 1953, 75, 2712[41] J. A. Cella, J.C. Carpenter, J. Organomet. Chem. 1994, 480, 23[42] T. J. Barton, G. P. Hussmann, J. Am. Chem. Soc. 1985, 107, 7581[43] G. Husmann, W. D. Wolff, T. J. Barton, J. Am. Chem. Soc. 1983, 105, 1263[44] Z.H. Aiube, J. Chojnowski, C. Eaborn, W.A. Staczyk, J. Chem. Soc. Chem. Commun.

1983, 493[45] C. Eaborn, W.A. Staczyk, J. Chem. Soc. Perkin II, 1984, 2099[46] M.G. Voronkov, S. Basenko, J. Organomet. Chem. 1995, 500, 325[47] W. T. Grubb, J. Am. Chem. Soc. 1954, 76, 3408

that silanediols such as 112 have recently been found to be potent inhibitors ofproteases [48] (Scheme 3.7).

Stable silanetriols such as Me3CSi(OH)3 or 2,4,6-tris(tert-butyl)phenylsilanetriolhave also been prepared and reviewed [49].

3.4Preparation, Properties and Reactions of Tetra(alkoxy)-, Tetra(acetoxy)-,Tetra(dialkylamino)-, and Tetrachlorosilanes

Tetra(alkoxy)silanes such as tetra(methoxy)silane 58 [50, 64], tetra(ethoxy)silane 59[50], tetra(acetoxy)silane Si(OAc)4 113 [51], tetra(dimethylamino)silane Si(NMe2)4

114 [52, 53], or tetrakis(1-pyrrolidino)silane 115 [53] are readily prepared fromSiCl4 57 and are available in any amounts.

Although SiCl4 57 has been employed, e.g., in the presence of sodium azide toconvert ketones into tetrazoles (Section 5.3), to condense cyclopentanone in highyields into 1.2.3.4.5.6-tris(trimethylene)benzene (Section 9.2), or used for the con-densation of amino acids to polyamides (Chapter 14) with formation of SiO2, enol-trimethylsilyl ethers 107a of ketones such as cyclohexanone are cleanly convertedby SiCl4 57 in the presence of Hg(OAc)2 into the trichlorosilylenol ether 116,which adds benzaldehyde in the presence of the asymmetric catalyst 117 to give


Scheme 3.6

Scheme 3.7

[48] M. wa Mutahi, T. Nittoli, L. Guo, S.M. Sieburth, J. Am. Chem. Soc. 2002, 124, 7363[49] R. Murugavel, V. Chandrasekhar, H.R. Roesky, Acc. Chem. Res. 1996, 29, 183[50] B. Helferich, J. Hausen, Ber. Deut. Chem. Ges. 1924, 57, 795[51] H.A. Schuyten, J. W. Weaver, J. D. Reid, J. Am. Chem. Soc. 1947, 69, 2110[52] H.N. Anderson, J. Am. Chem. Soc. 1952, 74, 1421[53] G. Huber, A. Schier, H. Schmidbaur, Chem. Ber. 1997, 130, 1167

the aldol 118 in 94% chemical yield and in high optical yield [54–59]. AsymmetricPasserini-type reactions with excellent enantioselectivity in the presence of SiCl4,and a new chiral BINAP-derived basic catalyst, have recently been reported [59 a].

In many of these reactions [55–59] SiCl4 or O-SiCl3 substitutents are possiblyfirst converted into the similarly very reactive hexachlorodisiloxane 119, which isreadily prepared in high yield by oxidation of SiCl4 with O2 at 960 �C [60] andwhich is also commercially available. Hexachlorodisiloxane 119 is decomposed bywater via 120 and via a whole series of linear and cyclic oligomeric hydrolysisproducts to SiO2 [61] (Scheme 3.8).

Tetra(methoxy)silane 58 or tetra(ethoxy)silane 59 convert aldehydes or ketonessuch as benzaldehyde into their ketals, for example benzaldehyde dimethyl acetal121 [62], with formation of oligomers 122 of SiO2. Likewise, the enol trimethoxy-silyl ether 123 reacts with benzaldehyde in the presence of BINAP·AgF to givethe aldols 124 in good chemical and optical yields [63]. Finally, esterification ofcarboxylic acids such as caprylic acid or benzoic acid with Si(OMe)4 58 proceedson heating to give the corresponding methyl esters in high yields [64](Scheme 3.9).

Heating of aromatic amines such as 2-iodoaniline 126 with sterically hinderedcarbonyl compounds such as 10-iodocamphor 125 in the presence of Si(OEt)4, 59and catalytic amounts of sulfuric acid, while distilling off the liberated ethanol,


Scheme 3.8

[54] S.E. Denmark, R. A. Stavenger, K.-T. Wong, J. Org. Chem. 1998, 63, 918[55] S.E. Denmark, S. Fujimori, SynLett 2001, 1024[56] S.E. Denmark, S.M. Phan, Org. Lett. 2001, 3, 2201[57] S.E. Denmark, S.K. Ghosh, Angew. Chem. Int. Ed. 2001, 40, 4759[58] S.E. Denmark, Y. Fan, J. Am. Chem. Soc. 2002, 124, 4233[59] S.E. Denmark, T. Wynn, G.L. Beutner, J. Am. Chem. Soc. 2002, 124, 13405[59a] S.E. Denmark, Y. Fen, J. Am. Chem. Soc. 2003, 125, 7825[60] D.W.S. Chambers, C. J. Wikins, J. Chem. Soc. 1960, 5088[61] H. Quellhorst, A. Wilkening, N. Söger, M. Binnewies, Z. Naturforsch. 1999, 54b,

577[62] H. Sakurai, K. Sasaki, J. Hayashi, A. Hosomi, J. Org. Chem. 1984, 49, 2808[63] A. Yanagisawa, Y. Nakatsuka, K. Asakawa, M. Wadamoto, H. Kageyama, H. Yamamo-

to, Bull. Chem. Soc. Jpn. 2001, 74, 1477[64] G. Sumrell, G.E. Ham, J. Am. Chem. Soc. 1956, 78, 5573

affords, after work-up, Schiff bases such as 127, in high yields, and SiO2 [65, 66],some (EtO)3SiOSi(OEt)3 129, and oligomers (EtO)3SiO[Si(OEt)2]nOSi(OEt)3 128(Scheme 3.10).

The combination of CsF with Si(OMe)4 58 is an efficient catalyst for Michael ad-ditions, e.g. of tetralone 130 to methacrylamide, followed by cyclization of the ad-dition product to the cyclic enamide 131 in 94% yield [67]. Likewise, addition ofthe lactone 132 to methyl cinnamate affords, after subsequent cyclization with tri-fluoroacetic acid, the lactam 133 in 58% yield [68] whereas �-valerolactam 134,with ethyl acrylate in the presence of Si(OEt)4 59/CsF, gives 135 in 98% yield [69].Whereas 10 mol% of CsF are often sufficient, equivalent amounts of Si(OEt)4 59seem to be necessary for preparation of 135 [69] (Scheme 3.11).

On heating with tetra(acetoxy)silane Si(OAc)4 113 in AcOH in the presence ofcatalytic amounts of ZnCl2 uridine 1 is converted via 136, in 54% yield, into O-peracetylated 2,2-anhydrouridine 137 [70] (Scheme 3.12).

Silicontetrabromide 138 dealkylates amines such as diethylaniline into ethyl bro-mide and the adduct 139 (Scheme 3.13), which is readily hydrolyzed into ethyl-aniline [71].


Scheme 3.9

[65] B. E. Love, J. Ren, J. Org. Chem. 1993, 58, 5556[66] J. E.H. Buston, I. Coldham, K. R. Mulholland, J. Chem. Soc. Perkin I 1999, 2327[67] R. J.P. Corriu, R. Perz, Tetrahedron Lett. 1985, 26, 1311[68] L.M. Harwood, G. Hamblett, A. I. Jimenez-Diaz, D. J. Watkin, SynLett 1997, 935[69] K. H. Ahn, S. J. Lee, Tetrahedron Lett. 1994, 35, 1875[70] K. Kondo, T. Adashi, I. Inoue, J. Org. Chem. 1976, 41, 2995[71] H. Breederveld, Rec. Chim. Pays Bas, 1959, 78, 589

Scheme 3.10

Finally, reaction of SiCl4 57 with HMDSO 2 affords 84% tetrakis(trimethyl-silyloxy)silane 140 and 16% hexakis(trimethylsilyloxy)disiloxane 141, both ofwhich might be very interesting silylating agents, e.g., for silicon surfaces [72].140 is also obtained in 38% yield on reaction of SiCl4 57 with excess sodium tri-methylsilanolate 96 [73] (Scheme 3.14).

Tetravalent silicon reagents are less suitable for transient protection of anyhydroxyl groups present, because the resulting activated oligomeric or polymericintermediates cannot be defined. It can, furthermore, be expected that any deriva-tives utilizing tetravalent silicon are much more polar and less lipophilic than


Scheme 3.11

Scheme 3.12

Scheme 3.13

[72] M.G. Voronkov, S. F. Pavlov, E. I. Dubinskaya, Dokl. Akad. Nauk SSSR. 1976, 227, 362;Chem. Abstr. 1976, 85, 21528

[73] L.O. Sommer, L.Q. Green, F. C. Whitmore, J. Am. Chem. Soc. 1949, 71, 3253

their trimethylsilyloxy analogs such as 3, 9, or dimethylsilyloxy derivatives such as50. Despite these drawbacks, tetrafunctional reagents such as the cheap tetra-chlorosilane SiCl4 57, MeSiCl3 (cf. Scheme 5.38) hexachlorodisiloxane Cl3SiOSiCl3119, tetramethoxysilane Si(OMe)4, tetraethoxysilane Si(OEt)4 59, tetra(acetoxy)si-lane Si(OAc)4 113, and tetra(dimethylamino)silane Si(NMe2)4 114, should alwaysbe considered as alternative activating and protecting reagents.


With stirring and cooling triethylamine (25.3 g) is added dropwise to a solution oftrimethylsilanol 4 (22.5 g) and 2-chloroacrylonitrile (22.0 g) in dry ether. The reac-tion mixture is then stirred for 7–8 h at 30–35 �C. The precipitated triethylammo-nium chloride is removed by filtration, the filtrate is concentrated, and the residueis distilled in vacuo (b.p. 85–86 �C/6 mm) to give 21.4 g (95%) 2-methoxyacryloni-trile 99 [32] (Scheme 3.15).

Iodotrimethylsilane 18 (1 mmol) is added with a syringe to a mixture of benz-aldehyde (1 mmol) and tetramethoxysilane 58 (1.1 mmol) in CH2Cl2 (2 mL) at–78 �C and then stirred for 4 h at room temperature. After addition of a few dropsof pyridine and, subsequently, of an aqueous solution of saturated NaHCO3, thereaction mixture is extracted with ether. Purification of the ether extracts by TLCgives benzaldehyde dimethylacetal 121 in 87% yield [62] (Scheme 3.16).

A mixture of methyl orthosilicate 58 (15.2 g, 0.1 mol) and caprylic acid (18.8 g)is heated under reflux for 4 h. The temperature of the boiling mixture drops grad-


Scheme 3.14

Scheme 3.15

Scheme 3.16

Scheme 3.17

3h/–78�;4h/24�/87%

ually during the first 2 h from 130 �C to 73 �C and remains unchanged thereafter.Fractionation yields 5.4 g (85%) methanol (b.p. 65 �C), 1.5 g of an intermediatefraction (b.p. 65–190 �C), and 28.6 g (90%) methyl caprylate (b.p. 190–192 �C), leav-ing 9 g white, powdery residue of crude silicic acid. (theory for anhydrousSiO2 = 6 g) [64] (Scheme 3.17).

Methyl acrylate (94.7 mg, 1.1 mmol) is added dropwise at room temperature toa suspension of morphinolone 132 (253 mg, 1 mmol), CsF (132 mg, 1 mmol),and Si(OMe)4 58 (150 �L) under argon. After stirring for 1 h the reaction mixtureis subjected to flash chromatography on silica gel (eluent petroleum ether–ethylacetate, 8 : 2) to afford a 1 : 1 mixture of isomers 133 (82% yield) as a colorless oil[68] (Scheme 3.18).


Scheme 3.18

4.1Introduction

During silylation–amination of free carboxylic acids, amides, lactams, imides,ureas, or heterocyclic lactam or imide moieties with excess silylating reagent suchas HMDS 2 or OMCTS 52, the onefold to threefold amount of primary or second-ary amine employed also serves as solvent. Part or most of the excess aminemight, on extended heating with excess HMDS 2 or OMCTS 52, eventually besilylated, with evolution of ammonia, giving the less basic and more bulky N-silylderivatives, which are apparently less reactive for aminations but will serve, never-theless, as silylating agents. Thus if a silylation–amination reaction seems to slowdown or to stop, because of silylation of the excess primary or secondary amineused, addition of 0.2–1.0 equivalents of isopropanol, n-butanol, tert-butanol, or gly-col should be considered, which will become silylated while liberating equivalentamounts of free amine. Likewise, addition of more acidic catalyst might also bebeneficial. If silylation–amination of an amide or lactam will lead to a rather basicamidine system, the catalytic amount of Lewis acid employed will be so stronglybound to the emerging new strong base that the reaction might slow down orstop altogether. In such reactions addition of slightly more than one equivalent ofLewis acid will guarantee a rapid reaction to give stable amidinium salts of the Le-wis acid used. Thus, if one desires a particular crystalline salt of the aminationproduct one should use excess ammonium chloride, ammonium bromide, ammo-nium iodide, ammonium sulfate, p-toluenesulfonic acid, or methanesulfonic acidto obtain amidinium or guanidinium salts in one reaction step. On heating thedifferent silylation–amination mixtures, however, one must realize that the hydro-chlorides, in particular, of the more volatile primary or secondary amines usedsublime much more readily into the reflux condenser, particularly in a stream ofargon or nitrogen, than the corresponding amine hydroiodides, bromides, sul-fates, mesylates, or tosylates.

Finally, it should be emphasized here that some silylated intermediates, for exam-ple the subsequently described O-trimethylsilylated succinimide 202a of silylatedsuccinimide 201, are apparently silylated at higher temperatures to the very air-sensitive O,O-bis(trimethylsilyl)succinimides (or 2,5-bis(trimethylsilyloxy)pyrroles)

39

4

Reactions of Free and Derivatized Carboxylic Acidsand Carbon Dioxide


202b, so silylation–aminations at elevated temperatures should always be conductedunder an atmosphere of nitrogen or argon. A stream of nitrogen or argon can, how-ever, carry away part of the volatile HMDS 2 (b.p. 126 �C) and HMDSO 7 (b.p. 100 �C)and low-boiling primary or secondary amines, even when an efficient condenser isused. Thus additional amounts of HMDS 2 must be added if the level of the colorlessupper liquid of the non-polar 2 and 7 in the reaction mixture diminishes during thereaction. On preparing larger amounts of amination products selective distillation ofthe lower-boiling HMDSO 7 (b.p. 100 �C) and of its azeotrope (b.p. 89–90 �C) [47a]with trimethylsilanol 4 (b.p. 99 �C) over a short distillation column is recommended.

4.2Aminations

4.2.1Amination of Free Carboxylic Acids to Amides and Imides

Because, as already discussed, trimethylsilanol 4 is more acidic than methanol, 4is a much better leaving group than methanol. Although the trimethylsilyloxygroup is much less bulky than a tert-butoxy group, as already emphasized (Sec-tion 3.1) there is still some steric hindrance to nucleophilic attack on the carbonylgroup of the trimethylsilyl ester. Thus, trimethylsilyl esters of carboxylic acids willreact most readily with the least hindered ammonia or primary amines and fasterwith pyrrolidine, piperidine, or pyrazine than with diethylamine, forming the cor-responding amides.

On reacting trimethylsilyl acetate 142 with n-butylamine in diethyl ether for 2 hat 24–40 �C only 40–45% of the desired N-butylacetamide 143, 95% of hexamethyl-disiloxane 7, and 53% of N-butylammonium acetate 144 are isolated [1]. Ob-viously, trimethylsilanol 4 generated on conversion of 142 with n-butylamine to143 or to the butylammonium salt of 4 (cf. also the subsequently discussed am-monium trimethylsilanolate 155) react with trimethylsilyl acetate 142 to give hex-amethyldisiloxane 7 and free acetic acid, which reacts with n-butylamine to formthe n-butylammonium acetate 144 [1]. Thus, trimethylsilyl acetate 142 should bereacted with n-butylamine in the presence of at least half an equivalent of HMDS2 to convert the leaving group trimethylsilanol 4 to hexamethyldisiloxane 7 andammonia, which should be removed by application of slightly reduced pressure ora stream of dry nitrogen. Alternatively, the more hindered N-trimethylsilylated n-butylamine 145 ought to give the desired amide 143 and HMDSO 7. Steric hin-drance of amination with 145 is, however, not important, because on using excess145 traces of humidity will lead to the formation of small amounts of hexamethyl-disiloxane 7 and free, and thus much less hindered, n-butylamine for aminationof 142 to the desired amide 143 (Scheme 4.1).

4 Reactions of Free and Derivatized Carboxylic Acids and Carbon Dioxide40

[1] K. Rühlmann, J. Prakt. Chem. 1962, 16, 172

Steric hindrance is of general importance, because even slightly hindered pri-mary amines, for example cyclohexylamine, or secondary amines, for examplediethylamine, react, as already mentioned, much more slowly with silyl esters.Likewise, trimethylsilyl benzoate reacts very slowly with cyclohexylamine to give,after 2 h at 150 �C, only 15% N-cyclohexylbenzamide yet 42% cyclohexylammo-nium benzoate [1]. Triethylsilyl acetate is converted by cyclohexylamine, after 2 hat 150 �C, to 85% N-cyclohexylacetamide and 85% hexaethyldisiloxane 65, whereastri-n-propylsilyl acetate does not react [1]. In these amide-forming reactions, tetra-acetoxysilane 113, methyltriacetoxysilane MeSi(OAc)3, and dimethyldiacetoxysilaneMe2Si(OAc)2 react more quickly with n-butylamine to give N-butylacetamide 143,rather than trimethylsilyl acetate 142, because HOSi(OAc)3 is a far better leavinggroup than trimethylsilanol 4 [1].

Trimethylsilyl acetate 142 reacts on boiling with N-trimethylsilyldiethylamine146 for 8 h at 100–120 �C, in the presence of trimethylchlorosilane (TCS) 14, togive an undefined yield of N,N-diethylacetamide 147 and 75% HMDSO 7 [2]. Incontrast, trimethylsilyl formate 148 affords with N-trimethylsilyldiethylamine 146without added TCS 14, on heating to 50–70 �C for 0.5 h, 63% yield of N,N-diethyl-formamide 149 and 75% of HMDSO 7 [2]. Trimethylsilyl formate 148 also gives87% N-methyl-N-phenylformamide 151 and HMDSO 7 on heating with N-tri-methylsilyl-N-methylaniline 150 for 0.5 h at 70–80 �C [2] (Scheme 4.2). Whereasthe more hindered trimethylsilyl benzoate does not react with N-trimethylsilyl-diethylamine 146 in the presence of TCS 14, even on heating for 8 h at 155 �C, tri-methylsilyl trifluoroacetate, on heating with 146 or at room temperature in thepresence of TCS 14, gives N,N-diethyltrifluoroacetamide in 33% yield [2].

4.2 Aminations 41

Scheme 4.1

[2] R. M. Pike, Recueil 1961, 80, 819

Scheme 4.2

4-Bromobutyric acid 152 reacts with HMDS 2 in 1 h at 20 �C in a closed vessel inthe presence of methanol in DMSO, in which the polar intermediate ammonium 4-bromobutyrate 154 is soluble and can thus be reconverted by HMDS 2 into the in-termediate trimethylsilylester 153, to give the N,O-bis(trimethylsilyl)butyramide 156(Scheme 4.3). The methanol reacts with excess HMDS 2 generating additionalamounts of ammonia while forming methoxytrimethylsilane 13 a to afford, via153, 99% N,O-bis(trimethylsilyl)butyramide 156, in which the 4-bromo substituenthas been replaced by a trimethylsilyloxy group by reaction with the rather nucleo-philic ammonium trimethylsilanolate 155 formed in situ (cf. also the reaction of2-chloroacrylonitrile with the nucleophilic triethylammonium trimethylsilanolateto 2-trimethyl-silyloxyacrylonitrile 99 in Section 3.2, the previously discussed reac-tion of n-butylammonium trimethylsilanolate 144, and the reaction of the DBU saltof Me3CSi(Me)2OH 85 a with the oxazolidone 102 to give 103, in Section 3.2) Tetra-methylammonium trimethylsilanolate has recently been used as a catalyst in poly-merizations [3 a–c]. Transsilylation of 156 with excess methanol provides the freeamide 157 and methoxytrimethylsilane 13 a [3]. Reaction of 4-bromobutyric acid152 with HMDS 2 in THF as solvent leads to the trimethylsilyl ester 153 as the ma-jor product and partly, via 153, to the polar ammonium salt 154, which is precipi-tated, whereas 152 is converted by HMDS 2 in abs. methanol into 78% butyrolac-tone and the O,N-silylated amide 156 [4].

Analogous reaction of 4-bromobutyric acid 152 with excess N-benzylhexamethyl-disilazane 158 in butyrolactone as polar solvent and added methanol affords, after1 h at 10 �C, 96% 4-trimethylsilyloxy-N-benzylbutyramide 159, which, on transsilyl-ation with methanol, gives the free crystalline N-benzyl-4-hydroxybutyramide 160and methoxytrimethylsilane 13a [3]. Likewise, reaction of 152 with excess N-2-(tri-methylsilyloxyethyl)hexamethyldisilazane 161 in butyrolactone–methanol affords


Scheme 4.3

[3] M.G. Voronkov, V. Yu. Vvedenskii, Zh. Obshch. Khim. 1985, 55, 1047; Chem. Abstr.1986, 104, 88651

[3a] M. Cypric, Polymery, 2001, 46, 468; Chem. Abstr. 2001, 136, 200556[3b] L.M. Kenrick, H. Yu, Eur. Pat. EP 881,249, 1998, Chem. Abstr. 1998, 130, 67188[3c] W. Gardiner, B. Elliott, Germ. Offen. 1,770,140, 1969; Chem. Abstr. 1969, 71, 102459[4] M.G. Voronkov, V. Yu. Vvedenskii, Zh. Obshch. Khim. 1984, 54, 1674; Chem. Abstr.

1985, 102, 6666

4-trimethylsilyloxy-N-trimethylsilyloxybutyramide 162 in nearly quantitative yield.N-Trimethylsilylaniline and N-trimethylsilyl-1-adamantylamine do not react with152 under these conditions, for electronic and steric reasons [3].

The ready exchange of silyl groups is apparent from the reaction of equimolecu-lar amounts of trimethylsilyl formate 148 with N-triethylsilylmethylamine 163 for1 h at room temperature (Scheme 4.4) whereupon two layers separate; the upperlayer consists of HMDSO 7 and 1,1,1-trimethyl-3,3,3-triethyldisiloxane 64 and thelower layer contains N-methylformamide 164 in almost quantitative yield [5].

Heating of aliphatic and aromatic carboxylic acids with one or two equivalentsof primary or secondary amines and one or two equivalents of HMDS 2 for 5–24 h at 110 �C affords amides in up to 93% yield (Scheme 4.5). Thus 3-hydroxybu-tyric acid 165 gives, on heating with piperazine and two equivalents of HMDS 2,the corresponding silylated amide 166 [6]. Tetrahydrofuran-2-carboxylic acid 167reacts with 3-methylaminopropylamine 168 to give the amide 169 in 83% yield,whereas thiophene-2-carboxylic acid 170 affords in 72% yield the piperazide 171[6]. N-BOC-alanine 172, however, racemizes on heating for 12 h at 110 �C withHMDS 2 and piperazine to afford the piperazide 173, whereas only very slight rac-emization is observed on heating to 75 �C [6]. Similar yields of the piperazides166, 169, or 171 are obtained on heating the methyl or ethyl esters of acids 165,167, or 170 with piperazine or 168 for 3–5 h at 110 �C [6a].

4.2 Aminations 43

Scheme 4.4

Scheme 4.5

[5] A. A. Zhdanov, B. A. Astapov, N.A. Dmitricheva, Zh. Obshch. Khim. 1985, 55, 1793Chem. Abstr. 1986, 105, 42906

[6] W.-C. Chou, M.C. Chou, Y.-Y. Lu, S.-F. Chen, Tetrahedron Lett. 1999, 40, 3419[6a] W.-C. Chou, C.-W. Tan, S.-F. Chen, H. Ku, J. Org. Chem. 1998, 63, 10015

Reaction of acetic acid 28 a or benzoic acid 28b with aniline at 24 �C in the pres-ence of SiCl4 57 in anhydrous pyridine affords the anilides 174a and 174b in 60and 70% yields, respectively, whereas boiling of 28 b with cyclohexylamine andSiCl4 57 gives rise to 90% N-cyclohexylbenzamide 175 [7] (Scheme 4.6). Reactionof protected amino acids such as Cbo-l-phenylalanine 176 (or N-BOC-�-alanine)with BSA 22 a in DMFA at 24 �C and subsequent addition of anhydrous hydrazineaffords the hydrazides 177 in 95% yield [8]. Heating of cyclic anhydrides such assuccinic or glutaric anhydride 178 a, b (or maleic and phthalic anhydride) in ben-zene with primary amines such as benzylamine in the presence of HMDS 2 andcatalytic amounts of ZnCl2 affords the N-benzylimides 179 in 80–89% yields [9].For further examples of HMDS- 2 or SiCl4-induced lactam formation, see the cy-clization of �-aminobutyric acid to butyrolactam in Chapter 9.

Silylation of amino acids such as l-leucine 180 with TCS 14 gives rise to the O-silylated ammonium salt 181, which reacts selectively with triphosgene andtriethylamine to afford the isocyanate 182. Subsequent reaction of 182 with pri-mary amines such as free l-leucine 180 or secondary amines such as N-BOC-pi-perazine 184 affords the ureas 183 and 185 in 49% or 77% overall yield, respec-tively [10] (Scheme 4.7).

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine toN-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment ofcarboxylic acids with oxalyl chloride, react with HMDS 2 at 24 �C in CH2Cl2 togive Me3SiCl 14 and primary amides in 50–92% yield [12]. Free amino acids suchas l-phenylalanine or �-alanine are silylated by Me2SiCl2 48 in pyridine to O,N-protected and activated cyclic intermediates, which are not isolated but reacted insitu with three equivalents of benzylamine to give, after 16 h and subsequent chro-


Scheme 4.6

[7] T.H. Chan, L.T.L. Wong, J. Org. Chem. 1969, 34, 2766[8] E.P. Krysin, V. N. Karel’skii, A.A. Antonov, G. E. Rostovskaya, Khim. Prirodn. Soed.

1979, 684; Chem. Abstr. 1981, 94, 175509[9] P.Y. Reddy, S. Kondo, T. Toru, Y. Ueno, J. Org. Chem. 1997, 62, 2652

[10] F. J. Weiberth, Tetrahedron Lett. 1999, 40, 2895[11] J. S. Davies, C.H. Hassall, K.H. Hopkins, J. Chem. Soc. Chem. Commun. 1971, 1118[12] R. Pellagata, A. Itala, M. Villa, Synthesis 1985, 517

matography, 98% of the N-benzylamide of l-phenylalanine. Sarcosine or �-alanineafford analogously 80 or 60% of the corresponding N-benzylamides [13]. This silyl-ation–amidation reaction is especially suited to highly functionalized carboxylicacids such as for free or N-protected amino acids, peptides, or hydroxy acids suchas 165 and might also work very well for solid-phase reactions in combinatorialchemistry.

4.2.2Amination of Amides, Lactams, and Imides, to Amidines

The conversion of substituted amides or lactams, e.g. into amidines, normally im-plies the protection of any free alcohol or phenol free hydroxy group present inthe amide or lactam-moiety followed by subsequent activation of the amide or lac-tam carbonyl groups, e.g. by O-methylation either with Meerwein reagentMe3OBF4 [14] or dimethyl sulfate [15] or by reaction with TiCl4 [16, 17], and, bythiation with P4S10 or Lawesson’s reagent [18], to give finally, on reaction of theprotected and activated intermediates with ammonia or primary or secondaryamines, the corresponding amidines [19, 20]. Free or N-substituted guanidines areusually prepared by the Rathke reaction [20a] of primary or secondary amines

4.2 Aminations 45

Scheme 4.7

[13] S.H. van Leeuwen, P. J. L.M. Quaedflieg, Q.B. Broxterman, R. J. J. Liskamp, Tetrahe-dron Lett. 2002, 43, 9203

[14] Neth. Appl. 6,413,085; Chem. Abstr. 1966, 65, 10571[15] H. Lüss, Chimia 1963, 27, 65[16] R. I. Fryer, J. V. Early, G. F. Field, W. Zally, L.H. Sternbach, J. Org. Chem. 1969, 34,

1143[17] W. Metlesics, T. Anton, M. Chaykovsky, V. Toome, L.H. Sternbach, J. Org. Chem.

1968, 33, 2874[18] M.P. Cava, M.I. Levinson, Tetrahedron 1985, 41, 5061[19] S.R. Sandler, W. Karo, “Organic Functional Group Preparations”, 1972, Chapter 6, Aca-

demic Press, New York[20] J.-A. Gautier, M. Miocque, C.C. Farnoux, 1975, Chapter 7 in “The Chemistry of Ami-

dines and Imidates”, Editor S. Patai, J. Wiley and Sons, New York

with S-alkylthioureas [21, 21a, 22] or with N,N�-bis(tert-butoxycarbonyl)thiourea inthe presence of HgCl2 and triethylamine [23–25].

Much simpler than these conventional methods is the silylation–amination offree or substituted amides, lactams or imides, whereupon any reactive free hydro-xy group present in the amide-urea moieties is protected by O-silylation, oftenleading, in high yields, to amidines [26] and to cyclic amidine structures [27] inaromatic N-heterocycles (see Sections 4.2.3–4.2.5). Thus, on heating with a three-fold excess of morpholine, HMDS 2, and catalytic amounts of TCS 14 benzamidereacts without solvent to give the substituted benzamidine 186, in 75% yield, andHMDSO 7 [26] (Scheme 4.8) whereas 2-indolinone 187, on heating with excesspyrrolidine, HMDS 2, and catalytic amounts of TsOH·H2O gives the crystallinecyclic amidine 188 in 76% yield [27]. Analogously, caprolactam, on heating withexcess p-anisidine-HMDS 2/TCS 14 and catalytic amounts of SnCl4, affords theamidine 189 in 76% yield [26].

On heating for 5 h to 160 �C with the trisilazane 190 N,N-dimethylformamide(DMF) is converted in 47% yield into the amidine 191 with the oligomers 54 and55 as leaving groups [28] (Scheme 4.9). 2-, 3- or 4-Substituted anilines such as 192condense with DMF in the presence of more than two equivalents of Me3SiCl 14or Me3SiBr 16 to give the N,N�-diarylformamidine hydrochlorides (or hydro-


Scheme 4.8

[21] B. Rathke, Ber. Deutsch. Chem. Ges. 1881, 14, 1774[21a] A. Mitrowski in Houben–Weyl, “Methoden der Organischen Chemie”, Vol. 8, Sauer-

stoffverbindungen III, 1952, 172–195, Georg Thieme, Stuttgart, New York[22] Y. Yamamoto, S. Kojima, Chapter 10 in Vol. 2, 1991 of “The Chemistry of Amidines and

Imidates”, Editor S. Patai, J. Wiley and Sons, New York[23] K.S. Kim, L. Quian, Tetrahedron Lett. 1993, 34, 7677[24] K. Nagasawa, A. Geogieva, H. Koshino, T. Nakata, T. Kita, Y. Hashimoto, Org. Lett.

2002, 4, 177[25] S. Kunha, B R. de Lima, A.R. de Souza, Tetrahedron Lett. 2002, 43, 49[26] H. Vorbrüggen, Ger. Offen 2,256,755; Chem. Abstr. 1974, 81, 63641c[27] H. Vorbrüggen, K. Krolikiewicz, Chem. Ber. 1984, 117, 1523[28] K. A. Andrianov, V. N. Talanov, M.M. Il’in, A. I. Chernyshev, V. V. Kazakova, E.E. Ste-

panova, Zh. Obshch. Khim. 1977, 47, 2071; Chem. Abstr. 1977, 88, 23030

bromides) 193, in up to 89% yield, and HMDSO 7 and Me2NH·HCl (orMe2NH·HBr) [29]. Analogously, aminopyrazines such as 902 with DMF/TCS 14give amidines such as 903 (cf. Section 7.1). Formamidines such as 193 are alsoreadily obtained within a few minutes at room temperature in yields of up to 94%on reaction of anilines 192 in DMF with a slight excess of tosyl chloride [29a]. Ali-phatic or heteroaromatic amino groups also condense readily at room tempera-ture, e.g. with N,N-dimethylformamide dimethylacetal, to give N,N-dimethylami-dines and methanol [29b, c].

Benzoic acids 194 react at 160 �C with 2 equivalents of anilines 192 in the pres-ence of polyphosphoric acid trimethylsilyl ester (PPSE) 195 (which is prepared byreaction of P2O5 with HMDSO 7) to give the amidines 196 in 69–88% yield [30,31] (Scheme 4.10)

It is obvious that N,O-bis(trimethylsilylated)acetamides or N,O-bis(trimethyl-silylated)formamides 22 or N,O-bis(trimethylsilyl)benzamide 296 should react like-wise with the hydrochlorides or hydriodides of primary or secondary amines orwith the free amines in the presence of equivalent amounts of, e.g., NH4Cl orNH4I to give the corresponding amidinium salts.

4.2 Aminations 47

Scheme 4.9

[29] H. Oehme, R. Wustrack, Z. Chem. 1983, 374[29a] Y. Han, L. Cai, Tetrahedron Lett. 1997, 38, 5423[29b] H. Meerwein, W. Florian, N. Schön, G. Stopp, Liebigs Ann. Chem. 1961, 641, 1[29c] R. F. Abdulla, R. S. Brinkmeyer, Tetrahedron 1979, 35, 1675[30] T. Imamoto, H. Yokoyama, M. Yokoyama, Tetrahedron Lett. 1981, 22, 1803[31] S.-I. Ogata, A. Mochizuki, M. Kakimoto, Y. Imai, Bull. Chem. Soc Jpn. 1986, 59, 2171

Scheme 4.10

The O-protected lactam 197a is aminated by ammonia and HMDS 2 on heatingto 130 �C in a pressure bottle with catalytic amounts of TsOH·H2O, via 198a and199a, to give, in 50–55% yield, HMDSO 7 and the O-protected 5-azasemicorrin200a, which is obtained in much lower overall yield by a conventional multi-stepsequence [32] (Scheme 4.11). Obviously, the free lactam 197b can also be used togive the directly silylated 5-azasemicorrin 200c via the silylated intermediates198 c and 199c.

Secondary amines such as dibenzylamine or 4-substituted piperidines are read-ily formylated in yields of up to 94% at room temperature by excess N,N-di-methylformamide (DMF)/Me3SiCl 14/imidazole with formation of HCl andHMDSO 7 [32 a].

Succinimide is readily silylated by HMDS 2 to the N-silylated product 201,which seems, however, to be in equilibrium with the O-silylated derivative 202a(cf. the closely related reactive center in persilylated uridine 3) and reacts after 6–10 days at 24 �C with one equivalent of primary or secondary amines such as mor-pholine to give the crystalline colorless cyclic acylamidine 203 and HMDSO 7,even in the absence of any protective gas [33] (Scheme 4.12). The reaction ismuch faster on heating to 120 �C under argon. At these temperatures 201 and202a, and possibly also the acylamidine 203, are apparently partially O-silylated byHMDS 2 to the very sensitive 2,5-bis(trimethylsilyloxy)pyrrole 202b or to 2-tri-


Scheme 4.11

Scheme 4.12

[32] U. Leutenegger, G. Umbricht, C. Fahrni, P. von Matt, A. Pfaltz, Helv. Chim. Acta,1992, 48, 2143

[32a] M.B. Berry, J. Blagg, D. Craig, M.C. Willis, SynLett. 1992, 659[33] D. Song, H. Vorbrüggen, unpublished

methylsilyloxy-5-morpholinopyrrole and to any of the other possible tautomericforms, which all seem to be readily oxidized even by traces of oxygen, to dark sideproducts therefore diminishing the yield of 203. Thus, on heating of succinimidewith HMDS 2 a protecting gas such as nitrogen or argon is absolutely essential tominimize the formation of these dark polymeric oxidation products during amina-tion reactions of succinimide (cf. also the formation of the C-substituted succini-mides 380 in Section 4.8). The cyclic acyl-amidine 203 is also obtained on heatingof morpholine with the O-ethylsuccinimide [34] which is synthesized via the silversalt of succinimide and subsequent O-alkylation with ethyl iodide [34 a]. The cyclicacylamidine 203 readily adds water, particularly in the presence of acidic catalysts,during chromatography, or even on recrystallization, to give mixtures of 203 andthe known crystalline bisamide 204, which is formed in high yield on heating ofsuccinimide with morpholine [34 b] and which can probably be converted to 203on heating with HMDS 2 and a trace of an acidic catalyst.

As yet, a number of experiments have failed to convert ureas 205 such as N-phenylurea or imidazolin-2-one by silylation amination with excess aminesR3NHR4 such as benzylamine or morpholine and excess HMDS 2 as well asequivalent amounts of NH4X (for X= Cl, I) via the silylated intermediates 206 and207 in one reaction step at 110–150 �C into their corresponding guanidines 208with formation of NH3 and HMDSO 7 [35] (Scheme 4.13). This failure is possiblydue to the steric repulsion of the two neighbouring bulky trimethylsilyl groups inthe assumed activated intermediate 207, which prevents the formation of 207 inthe equilibrium with 206. Thus the two step Rathke-method, which demands theprior S-alkylation of 2-thioureas followed by amination with liberation of alkyl-mercaptans, will remain one of the standard syntheses of guanidines [21,35 a,b, c].

For further related silylation–amination-cyclizations, see also Chapter 10.

4.2 Aminations 49

[34] N. Nagasaka, F. Hamaguchi, N. Ozawa, S. D. Ohki, Heterocycles 1978, 9, 1375[34a] K. Matoba, T. Yamazaki, Chem. Pharm. Bull. 1974, 22, 2999[34b] J. Sambeth, F. Grundschober, Angew. Chem. 1965, 77, 718[35] H. Vorbrüggen, unpublished[35a] S.A. Aspinall, E. J. Bianco, J. Amer. Chem. Soc. 1951, 73, 602[35b] P. Tronce, A. Amelot, J. Bayard, C. Laroussine, Ann. Pharm. Fr. 1963, 18, 726;

Chem. Abstr. 1959, 55, 11395f[35c] C.R. Rasmussen, F. J. Villani Jr, B. E. Reynolds, J. N. Plampin, A.R. Hood, L.R. Heck-

er, S. O. Nortey, A. Hanslin, M.J. Constanzo, R. M. Howse Jr, A. J. Molinari, Synthe-sis 1988, 460

Scheme 4.13

4.2.3Amination of Aromatic Heterocyclic Lactam Systems (Synthesis of Cytidines)

Although several methods are used to aminate heterocyclic aromatic hydroxy-N-heterocycles [36], some additional, special, amination procedures are used for nu-cleoside modification. When we planned to synthesize a series of N4-substitutedcytidines 5 starting from uridine 1 we considered known classical methods, whichimply (Scheme 4.14):

1. the O-acylation of the aliphatic hydroxyl groups of the ribose-moiety of uridine 1preferably with acetic anhydride/pyridine to give 2�,3�,5�-uridine tri-O-acetate 209,

2. activation of the heterocyclic 4-carbonyl group in 209 by heating with P4S10 inpyridine or dioxane, to give the 4-thio compound [37], followed by further acti-vation by S-methylation to 210a [38, 39], or by 4-chlorination of 209, e.g. withSOCl2 [40–42], to the 4-chloro compound 210b, and by reaction of 209 withtriazole [43–45] (or nitrotriazole [46]) in combination with OPCl3/triethyla-mine, (PhO)2POCl, or p-chlorophenylphosphodichloridate/pyridine to give the4-triazolyl-derivatives 210c, and

3. amination of 210 with ammonia, or primary or secondary amines to give2,3,5-tri-O-acylated cytidines, the O-acyl groups of which must finally

4. be saponified by methanolic ammonia to the free cytidines 6 and methyl ace-tate or acetamide

implying at least four reaction steps.As briefly mentioned in the Introduction (Chapter 1), 2�,3�,5�-tri-O-acetyl-4-O-

ethyl-uridine 211, obtained by means of a classical Hilbert–Johnson-reaction be-tween 2,4-diethoxypyrimidine and 2,3,5-tri-O-acetyl-1-bromoribofuranose and iso-lated as its picrate [47], on heating with methanolic ammonia, via 212 and subse-quent or concomitant saponification of the O-acetyl groups, generates free cyti-dine 213= 6 a (R1 = R2 = H), which is isolated as its hydrosulfate, ethanol being theleaving group [47].


[36] H. Vorbrüggen, Adv. Heterocycl. Chem. 1990, 49, 117[37] J. J. Fox, D. van Praag, I. Wempen, I.L. Doerr, L. Cheong, J. E. Knoll, M.L. Edinoff,

A. Bendich, G. B. Brown, J. Am. Chem. Soc. 1959, 81, 178[38] J. J. Fox, N. Miller, I. Wempen, J. Med. Chem. 1966, 9, 101[39] I. Wempen, N. Miller, E. A. Falco, J .J. Fox, J. Med. Chem. 1968, 11, 144[40] J. Zemlicka, F. Sorm, Collect. Czech. Chem. Commun. 1965, 30, 2052[41] J. Zemlicka, J. Smrt, F. Sorm, Collect. Czech. Chem. Commun. 1964, 29, 635[42] M. Kaneko, B. Shimizu, Chem. Pharm. Bull. 1972, 20, 1050[43] W. L. Sung, J. Chem. Soc. Chem. Commun. 1981, 1089[44] Y.-Z. Xu, P.F. Swann, Nucleic Acids Res. 1990, 18, 4061[45] M. Perbost, Y. S. Sanghvi, J. Chem. Soc. Perkin I, 1994, 2051[46] B. F. L. Li, C.B. Reese, P.E. Swann, Biochemistry 1987, 26, 1086[47] G. A. Howard, B. Lythgoe, A.R. Todd, J. Chem. Soc. 1947, 1052[47a] R. O. Sauer, J. Am. Chem. Soc. 1944, 66, 1707

Because we expected that O-persilylation of uridine 1 would not only protect thealcoholic hydroxyl groups of the ribose moiety in 1 but would also silylate andthus activate the 4-carbonyl group, we heated uridine 1 with hexamethyldisilazane(HMDS) 2 in the presence of catalytic traces of trimethylchlorosilane (TCS) 14and obtained the reactive 4-O-trimethylsilyl intermediate 3 (m/e= 532, M+) the UVspectrum of which, with a maximum at 280 nm, is practically identical with thatof the 4-O-ethyl-analogue 211, with evolution of ammonia (Scheme 4.15). Gratify-ingly, on heating with excess ammonia or primary or secondary amines the reac-tive persilylated uridine 3 is readily converted, in high yields, into persilylated cyti-dines 5, via the assumed intermediate 214, whereupon the leaving group tri-methylsilanol 4 is transformed in situ by additional amounts of HMDS 2 into hex-amethyldisiloxane 7 and NH3, to drive the reaction to completion [48, 49]. Be-cause the persilylation of uridine 1 to 3 and concomitant amination with excessamines, which serve also as solvents and which are only slowly silylated byHMDS 2 with evolution of ammonia to trimethylsilylated amines (which arethemselves silylating agents), do not interfere with each other, merely heating ofuridine 1 with a threefold excess of primary or secondary amines and 2.5–3equivalents of HMDS 2 results, via the persilylated uridine 3 and the assumed ad-dition–elimination intermediate 214, in high yields of persilylated cytidines 5 and,initially, of trimethylsilanol 4 (b.p. 99 �C) as leaving group. Because most of tri-methylsilanol 4 is quickly silylated to hexamethyldisiloxane 7 and NH3, on heat-ing with HMDS 2, hexamethyldisiloxane 7 (HMDSO; b.p. 100 �C) or the azeotrope

4.2 Aminations 51

Scheme 4.14

[48] H. Vorbrüggen, U. Niedballa, Angew. Chem. Int. Ed. 1971, 10, 657[49] H. Vorbrüggen, K. Krolikiewicz, U. Niedballa, Liebigs Ann. Chem. 1975, 988

of 7 with trimethylsilanol 4 (b.p. 89–90.2 �C) [47 a] can be readily removed by dis-tillation during the reaction, when the applied amine boils higher than ca 120 �C.The amount of distilled trimethylsilanol 4 and HMDSO 7 also indicates the pro-gress of the amination. Weaker basic amines such as aniline react only with 3 inthe presence of acidic catalysts such as ammonium sulfate, which apparently acti-vates the 2-carbonyl group in 2. Aminations of uridine 1 or thymidine 215 with“polar” ammonia or low-boiling amines, for example methylamine, must be per-formed in an autoclave at 140–160 �C under pressure. In amines containing hy-droxyl groups, for example ethanolamine or dopamine (cf. Section 4.2.4), these ali-phatic or aromatic hydroxyl groups are protected, as are the hydroxyl groups inthe ribose moieties during silylation–amination. Finally, on completion of thesilylation–amination the protecting O-trimethylsilyl groups in the ribose andamine moieties are removed by in situ transsilylation (cf. Section 2.3) by boilingfor 3–5 h with excess added methanol, to generate methoxytrimethylsilane 13 c, orby keeping the methanol solution at room temperature over the weekend, to ob-tain the free cytidines 6, which normally crystallize directly in 85–90% yield fromthe methanol solution on cooling [48, 49] (see also Section 1.1).

On heating with ammonia and HMDS in formamide, for 80 h at 140 �C in anautoclave, thymidine 215a is converted, via 216a, in 79% yield, to the biologicallyvery interesting 5-methyl-2�-deoxy-cytidine hydrochloride 217a [48–51] (Scheme4.16). Higher temperatures induce the decomposition of thymidine and its deriva-tives to thymine. This procedure is being used on a larger scale to produce bulk-amounts of 5-methyl-2�-deoxycytidine 217a [52]. Reaction of 5-trifluoromethyl-2�-deoxyuridine 215b with NH3, HMDS 2, and TCS 14 affords ca 20% of free 217b[53]. Silylation–amination of 2�-deoxyuridine 218 with 15N-benzylamine, HMDS 2,


Scheme 4.15

[50] H. Vorbrüggen, K. Krolikiewicz, in “Nucleic Acid Chemistry”, 1978, Part I, 227 Editors:L.B. Townsend, R. S. Tipson, Wiley, New York

[51] B. Bhat, N. J. Leonard, J. Am. Chem. Soc. 1992, 114, 7407[52] U. Sampath, J. A. Toce, J. Smoot, Abstract 260, Proc. XIV Roundtable: Nucleosides and

Their Biological Applications, Sept. 10–14, 2000, San Francisco[53] S.B. Greer, E. C. Stump, T. Psarras, Ger. Offen. 2,838,644; Chem. Abstr. 1980, 92,

129265

and TCS 14 to 219, followed by oxidative N-debenzylation with aqueous (NH4)2S2O4,provides 15N-labelled 2�-deoxycytidine 220 [54] (Scheme 4.16).

Analogous reaction of ara-uridine 221a with NH3 and HMDS 2, for 45 h at135 �C under 15 atm pressure, and subsequent transsilylation with boiling metha-nol, gives 77% ara-cytidine 222a and 13 a [55] whereas reaction of 2�,3�-dideoxyuri-dine 221b with NH3 and HMDS 2, at 160 �C for 76 h under 10 atm pressure, andsubsequent transsilylation with boiling methanol, gives 90% 2�,3�-dideoxycytidine222b and 13a [56] (Scheme 4.17).

Reaction of uridine 1 with equivalent amounts of 1,3-diaminopropane, HMDS2, and TCS 14 for 24 h at 150 �C has been reported to afford, after subsequenttranssilylation in boiling methanol, 94% of the dimer 223 and 13 a [57]. This re-

4.2 Aminations 53

Scheme 4.16

[54] M. Sako, T. Kihara, H. Kawada, K. Hirota, J. Org. Chem. 1989, 64, 9722[55] G. De Meglio, G. Ordanini, T. Bruzzzese, Eur. Pat. EP. 757,056; Chem. Abstr. 1997,

126, 199799r[56] H. Shiragami, Y. Irie, S. Nishi, N. Yasuda, Jpn Kokai JP 196,192, Chem. Abstr. 1989,

111, 134699d[57] T.L. Kalman, J. A. Sweatlock, in “Nucleic Acid Chemistry”, 1991, Part IV, 76 Eds: L.B.

Townsend, R.S. Tipson, Wiley, New York

Scheme 4.17

sult is surprising because reaction of 1 with equivalent amounts of 223 mighthave been expected to give, preferentially, N4(3-amino-propyl)cytidine (cf. also for-mation of 241d in Scheme 4.23). N4-�-Aminoalkyl-cytidines such as N4(5-amino-3-oxapentyl)cytidine have also been prepared by sodium bisulfite-catalyzed addi-tion (transamination) of 1,5-diamino-3-oxapentane to cytidine and used to attachbiotin to the �-5-amino-group [58] (Scheme 4.18).

Sodium uridine-5�-phosphate 224 is converted by HMDS 2/TCS 14 and pyrroli-dine at 145 �C, via the assumed persilylated intermediate 225, and after transsilyla-tion with boiling methanol and addition of NaOH, crystalline sodium-cytidine-5�-phosphate 226 in 69% yield [49] (Scheme 4.19).

Because activated 4-O-trimethylsilylated-2�,3�,5�-O-acyluridines such as 3 are alsoobtained as reactive intermediates in the Friedel–Crafts-catalyzed silyl–Hilbert–Johnson reaction [59, 59a] of persilylated uracils or 6-azauracils such as 227 withsugars such as 1-O-acetyl-2,3,5-tri-O-benzoyl-�-d-ribofuranose 228 in the presenceof SnCl4, treatment of the reactive intermediate 229 with a large excess of pyrroli-dine neutralizes the SnCl4 used and aminates 229 to afford the protected 6-aza-cytidine 230, although in 57% yield only [49, 59] (Scheme 4.20).


Scheme 4.18

[58] N.C. Mishra, H.S. Khorshidi, Y. Gan, P. Szweda, J. George, WO 9,641,006; Chem.Abstr. 1997, 126, 144508

[59] H. Vorbrüggen, C. Ruh-Pohlenz, Organic Reactions, Vol 55, 2000, Wiley, New York[59a] H. Vorbrüggen, C. Ruh-Pohlenz, Handbook of Nucleoside Synthesis, J. Wiley &

Sons, N.Y. 2001

Scheme 4.19

Finally, silylation–amination of 5,6-dihydro-6-oxauracil 231 with excess diphenyl-methylamine 232/HMDS 2 and (NH4)2SO4 for 17 h in boiling dioxane affords, viaprotonation of N1 or N3 of the persilylated intermediate 233 and subsequent addi-tion of the amine to the 4-position, the cytosine analogue 234 in 74% yield [60](Scheme 4.21).

4.2.4Amination of Aromatic Heterocyclic Lactam Systems (Synthesis of Adenosines)

By analogy with the conversion of uridine 1 into cytidines 6, the conventionalamination of inosine 235a, guanosine 235b, or xanthosine 235c and their 2�-deoxy analogues to the adenosines 237 requires:

1. O-acetylation of the aliphatic hydroxyl groups of the ribose moiety (or other su-gar moieties) to the 2�,3�,5�-tri-O-acetates;

2. activation of the heterocyclic 6-carbonyl group by 6-chlorination with POCl3[61], SOCl2, or (Me2N=CHCl)+Cl– [62] to the 6-chloro compounds;

3. amination with ammonia or primary or secondary amines to the correspond-ing 2�,3�,5�-tri-O-acetylated 6-amino purine nucleosides; and, finally

4.2 Aminations 55

Scheme 4.20

Scheme 4.21

[60] P.T. Berkowitz, R.A. Long, P. Dea, R.K. Robins, T.R. Mathews, J. Med. Chem. 1977,20, 134

[61] J. F. Gerster, J. W. Jones, R. K. Robins, J. Org. Chem. 1963, 28, 945[62] J. Zemlicka, J. Owens, in “Nucleic Acid Chemistry”, 1991, Part IV, 76 Editors: LB. Town-

send, R.S. Tipson, J. Wiley and Sons, New York

4. saponification of the O-acyl groups of the ribose moieties with methanolic am-monia.

Because we were interested in preparing a whole series of N6-substituted adenosines237 as potential new drugs, we tried our silylation–amination procedure. In contrastwith the silylation–amination of persilylated pyrimidine nucleosides, however, inwhich the 4-trimethylsilyloxy group is conjugated to the 2-carbonyl group as in per-silylated uridine 3, facilitating the addition–elimination reaction of amines in the 4-position, the silylation of the purine nucleosides inosine 235a, guanosine 235b, andxanthosine 235c results in the formation of aromatic persilylated inosine, guano-sine, and xanthosine, the silylation–amination of which with excess primary and sec-ondary aliphatic amines as reactants and solvents proceeds, however, only in thepresence of catalytic amounts of Lewis acids such as ammonium sulfate, camphorsulfonic acid (CSA), TsOH.H2O, HgCl2, trimethylsilyl triflate 20, or the hydrochlor-ides or hydrosulfates of the amine moieties [63, 64]. These Lewis acids facilitate theaddition of the amines to the 6-position of purine nucleosides 235 by activating themost basic N1 (or N3) nitrogen, as depicted for H+ in persilylated purine nucleosides236, to give, after elimination of trimethylsilanol 4 and subsequent in situ transsily-lation of the O-trimethylsilyl groups of the ribose moieties with boiling methanol,the free N6-substituted adenosines 237a, guanosines 237b, or xanthosines 237c inup to 95% yield [63, 64] (Scheme 4.22), It should be pointed out here, however, thatapplication of mercuric salts as catalysts is unsuitable for the preparation of com-pounds destined for any subsequent biological testing. The amounts of the aminesused, and of HMDS 2, OMCTS 52, and Lewis acids, are discussed in the Introduc-tion (Section 4.1). Silylation–aminations of aromatic N-heterocycles can, however,succeed even in the absence of Lewis acids, when an electron-accepting group suchas a 2- or 4 nitro group is present, as in 279, which readily gives 280 in boiling pyr-idine [85] (cf. Scheme 4.34 in Section 4.2.5).

Silylation–amination of inosine 235a with dopamine hydrochloride functioning asamine and Lewis acid proceeds in the presence of an appropriate excess of HMDS 2without use of any protecting gas, because the sensitive catechol-hydroxyl groups aretransiently protected against oxidation during silylation–amination, to afford, aftertranssilylation with excess boiling methanol, the substituted crystalline N-substi-tuted adenosine 237a (R1 = 3,4-dihydroxyphenethyl, R2 = H) in 84% yield [64, 65].Likewise, N-2-hydroxyethylpiperazine 251 gives, on heating for 46 h at 145 �C withinosine 235a and HMDS 2 in the presence of (NH4)2SO4, and subsequent in situtranssilylation with methanol, 237a (R1 = R2 = (CH2CH2)2N(CH2)2OH in 72% yield[63, 64]. Guanosine 235b, reacts with the weakly basic p-anisidine, HMDS 2, andHgCl2 as catalyst, after 72 h at 145 �C, to give 237b (R = NH2, R1 = 4-C6H4OMe,R2 = H) in only 32% yield, whereas xanthosine 235c affords with 2-phenethyl-


[63] H. Vorbrüggen, Angew. Chem. Int. Ed. 1972, 11, 304[64] H. Vorbrüggen, K. Krolikiewicz, Liebigs Ann. Chem. 1976, 745[65] H. Vorbrüggen, in “Nucleic Acid Chemistry”, 1978, Part II, 533 Editors: L. B. Townsend,

R. S. Tipson, J. Wiley and Sons, New York

amine, HMDS 2, and catalytic amounts of (NH4)2SO4, after 23 h at 145 �C, 80% of237c (R = OH, R1 = (CH2)2Ph, R2 = H) [64] (Scheme 4.22).

On silylation–amination of the disodium salts of inosine-5�-phosphate 238 a orof guanosine-5�-phosphate 238 b with benzylamine, the phosphate moieties arealso transiently protected during amination by silylation (cf. also the silylation ofuridine-5�-phosphate 224) to give, after transsilylation with methanol and additionof NaOH, the desired sodium salt of N6-benzyladenosine-5�-phosphate 239a in80% yield and the sodium salt of the 2-amino derivative 239b in 78% yield [64](Scheme 4.23).

As already mentioned, silylation–aminations with volatile amines such asmono- or dimethyl-amine and, in particular, with ammonia must be performed inan autoclave and take much longer with the “polar” ammonia. Nevertheless, theacid-catalyzed silylation–amination of guanosine 240a, with ammonia in the pres-ence of Lewis acids, to 2-aminoadenosine 241a (R1 = R2 = H) [64, 66] is currentlybeing performed at Schering AG in 85–95% yield in 100–200-kg batches in a bigautoclave under pressure [67]. The analogous silylation–amination of 2-deoxygua-nosine 240b with NH3, HMDS 2, and TMSOTf 20 proceeds likewise in ca 70%yield to 241 b [68, 69] whereas the silylation–amination of xanthosine 240c withNH3, HMDS 2, and (NH4)2SO4 affords 73% 241c [64, 70]. 2-Deoxyinosine 240d issilylated–aminated by ethylenediamine, HMDS 2, and TsOH·H2O to give N6-ami-noethyladenosine 241d in 50% yield [71] (Scheme 4.23; cf. also the formation ofthe claimed cytidine dimer 223). 1�-�-Inosine is silylated–aminated with benzyla-mine/HMDS 2 in the presence of HgCl2 and subsequently transsilylated withboiling ethanol to give N6-benzyl-1�-�-adenosine in 17% yield [72].

4.2 Aminations 57

Scheme 4.22

[66] M.J. Robins, F. Hasske, S. E. Bernier, Can. J. Chem. 1981, 59, 3360[67] K. Krolikiewicz, H. Vorbrüggen, Nucleos. Nucleot. 1994, 13, 673[68] F. Seela, B. Gabler, Z. Kazimierczuk, Coll. Czech. Chem. Commun. 1993, 58, 170[69] F. Seela, B. Gabler, Helv. Chim. Acta, 1994, 77, 622[70] D.S. Bhakuni, P.K. Gupta, Indian J. Chem. 1983, 22B, 48[71] S. Czernecki, G. Viswanadham, J.M. Valery, Nucleos. Nucleot. 1998, 17, 2087[72] B. Rayner, C. Tapiero, J.-L. Imbach, J. Heterocycl. Chem. 1982, 19, 593

In contrast with the ready addition–elimination reactions of ammonia and pri-mary and secondary amines with all those activated 6-trimethylsilyloxypurine nu-cleosides to afford, via intermediates such as 236, the 6-aminopurine nucleosides237a,b or 241 with Me3SiOH 4 as the leaving group, the related transamination ofpersilylated adenosine 237a (R1 = H, R2 = SiMe3) with primary or secondaryamines, in which ammonia or silylated ammonia Me3SiNH2 15 are formed asleaving groups instead of Me3SiOH 4, is very slow. Thus, heating of adenosine237a (R1 = R2 = H) at 160–170 �C with 2-phenethylamine, for days, in the presenceof HMDS 2 and HgCl2 gives only ca 20% of N6-(2-phenethyl)adenosine [64].

As might be expected, the acid-catalyzed silylation–amination of the free purine-bases such as hypoxanthine 242 (R = H) and guanine 242 (R = NH2) proceeds, via243, to the corresponding substituted adenines 244 in high yields [64] (Scheme 4.24).

Unfortunately, the two full papers on the silylation–amination of pyrimidine[49] and purine nucleosides [64] as discussed in Sections 4.2.3 and 4.2.4, werepublished in German and are thus not readily accessible, although a few detailedprocedures from Sections 4.2.3 and 4.2.4 were subsequently published in English[65]. The third paper on the silylation–amination of aromatic hydroxy-N-hetero-cycles, however, as discussed in Section 4.2.5 was, fortunately, published in Eng-lish [27].


Scheme 4.23

4.2.5Amination of Aromatic Heterocyclic Lactam Systems

The amination of aromatic hydroxy-N-heterocycles is a standard reaction in medic-inal and agricultural chemistry and has been reviewed [36]. The hitherto com-monly used two-step procedure for amination of hydroxy-N-heterocycles, startswith conversion into the chloro-N-heterocycles, e.g. by treatment of the hydroxy-N-heterocycle with POCl3, PCl5, or SOCl2, followed by reaction with the amine moi-ety. This methodology has several drawbacks however, for example:

1. chlorination of any alkyl or aralkyl groups in the hydroxy-N-heterocycle or ofelectron-rich aromatic rings (cf. Scheme 4.35) are major side-reactions duringtreatment of aromatic hydroxy-N-heterocycles with POCl3 or PCl5, (cf. the for-mation of compound 264 described in Scheme 4.29);

2. the difficulty of isolating the pure aromatic chloroheterocycles during work upfrom the viscous phosphoric acid–polyphosphoric acid on employing POCl3 orPCl5; and

3. the need to protect any additional reactive group, for example a hydroxyalkylside chain, in the N-heterocycle, for example the already discussed hydroxylgroups of the ribose moiety in, e.g., purine nucleosides, before reaction withchlorinating agents such as POCl3, PCl5, or SOCl2 (cf. Sections 4.2.3 and4.2.4).

Because aromatic purines and purine nucleosides and free purines such as hypo-xanthine and guanine 242 are readily silylated–aminated [64] (cf. Scheme 4.24), itis obvious that 6-membered hydroxy-N-heterocycles are analogously silylated–ami-nated, with reactivity in the order given in Scheme 4.25 [73]; X= OTf is the bestleaving group and X= NHSiMe3 (cf. the transamination as discussed in Sec-tion 4.2.4) is the weakest.

In the reactivity scale of Scheme 4.25 the reactivity of any of these heterocyclesis substantially increased by annellation with a conjugated aromatic ring. Thus 2-quinolone is much more reactive than pyridine-2-one 245, which is the least reac-tive hydroxyheterocycle and requires reaction temperatures higher than 190–200 �C for silylation–amination [27]. To achieve these temperatures at normal pres-

4.2 Aminations 59

Scheme 4.24

[73] R. G. Shepherd, J.L. Fedrick, Adv. Heterocycl. Chem. 1965, 4, 145

sure 245 is reacted with the high-boiling octamethylcyclotetrasilazane (OMCTS)52 (b.p. 230 �C), three equivalents of benzylamine, and perfluorobutanesulfonicacid as catalyst, to give, after 48 h at 200 �C, via the presumed intermediate dimer246, although in only 47% yield, 2-benzylaminopyridine 247a and oligomers 56 ofMe2SiO (Scheme 4.26). This low yield is because much of the benzylamine is, un-der these drastic reaction conditions, converted into di- and tribenzylamine andammonia. Heating of neat benzylamine with 0.1 equivalents of TsOH hydrate for48 h at 200 �C results in almost quantitative yield of tribenzylamine and NH3 [27](Scheme 4.26). The amounts of amines, HMDS 2, OMCTS 52, and Lewis acidsused are discussed in the Introduction (Section 4.1). Analogous reaction of 2-pyri-done 245 with �-phenethylamine and OMCTS 52 affords, after 25 h at 200 �C inthe presence of perfluorobutanesulfonic acid, 2(2-phenethylamino)pyridine 247bin 71% yield [27].

The much more reactive 2,3-dihydro-1,4-phthalazine 248, on reaction with fiveequivalents of benzylamine, HMDS 2, and (NH4)2SO4 for 24 h at 160 �C, fur-nishes the bis-aminated product 249 in 87% yield [27] (Scheme 4.26).

Reaction of 2,4-(1H,3H)-quinazolinedione 250 for 8 h at 130 �C with two equiva-lents of N-2-hydroxyethylpiperazine 251 (the alcohol group of which is in-situ pro-tected by silylation), HMDS 2, and catalytic amounts of TsOH·H2O, and subse-quent transsilylation with boiling methanol, affords 68% of the monoaminatedproduct 252 and methoxytrimethylsilane 13 a. Reaction of 250 with fivefold excessof N-2-hydroxyethylpiperazine 251 in the presence of octamethylcyclotetrasilazane


Scheme 4.25

Scheme 4.26

(OMCTS) 52 gives, after 24 h at 180 �C, the bis-aminated product 253 in 56%yield and 24% of the 2-amino product 254, which might be formed by transami-nation of 252 or 253 with 52 [27] (Scheme 4.27).

Silylation–amination of 4(1H)-quinolinone 255 with a twofold excess of dopa-mine hydrochloride 256 as amine and an acidic catalyst affords, on heating withexcess HMDS 2 for 21 h at 145 �C and subsequent transsilylation in excess boilingmethanol, 75% of the crystalline hydrate of 257 (Scheme 4.28). The silylation–ami-nation of 2-thio-6-azauracil 258 with homoveratrylamine 259, HMDS 2, and SnCl4as catalyst for 48 h at 145 �C furnishes 63% of the diamine 260, and Me3SiOSiMe3

7 and Me3SiSH or Me3SiSSiMe3 601 as leaving groups.Silylation–aminations of a variety of other hydroxy-N-heterocycles, for example

4(1H)-pyridinone, 2(1H)-pyrimidone, uracil, 2(1H)-quinoline, and 9(10H)-acridoneare described in the full paper, which was published in English [27].

The advantages of the one-step silylation–amination of hydroxy-N-heterocyclesare demonstrated by the amination of 2-methylpyrido[3,4-d]pyrimidin-4-one 261.Whereas silylation–amination of 261 with three equivalents of benzylamine–

4.2 Aminations 61

Scheme 4.27

Scheme 4.28

HMDS 2/(NH4)2SO4 gives the desired 4-benzylamino product 262 in one step in97% yield, chlorination of 261 with POCl3 affords the purified intermediate 4-chloro compound 263 in only 45% yield [74]. Although subsequent reaction of263 with benzylamine affords 262 in 96% yield, the overall yield of the aminationof 261 via 263 is only ca. 40%. Besides 263, larger amounts of chlorinated side-products such as 264 are apparently formed on treatment of 261 with POCl3 lead-ing, on amination, to undesired side products and thus drastically reducing theyield of the desired amination product 262 [74] (Scheme 4.29). Such chlorinationsof methyl groups, e.g. of 3-methylquinoline or 2-methylquinoxaline with POCl3/PCl5, have been reported [75].

Silylation–amination of 6-acetoxymethyl-5-deazapterine 265 with NH3, HMDS 2,and TsOH for 120 h at 155–160 �C in an autoclave affords, after subsequent trans-silylation with boiling methanol, the diamino compound 266 in 74% yield [76].Silylation–amination–cyclization of the substituted 4-quinolone 267 gives the alka-loid isoaptamine hydrochloride 268 in 51% yield [77, 78] (Scheme 4.30).

Whereas silylation–amination of 2-amino-5,8-dihydroxypyrimido[4,5-d]pyridazine269 with 3-amino-1-propanol, HMDS 2, and TsOH affords, after 24 h at 120–140 �C, the mono-8-hydroxypropylamino derivative 270 in 50% yield [79], reactionof 269 with a slight excess of ethanolamine and HMDS 2 provides, after 30 h at120–150 �C, only 20% of the bis(amino) product 271 [79]. (Scheme 4.31) A largerexcess of ethanolamine and longer reaction times will certainly increase the yieldof 271.

The silylation–amination of 1-benzyl-4,7-dihydroxy-1,2,3-triazolo[4,5-d]pyridazine272 with N-methylpiperazine, HMDS 2, and (NH4)2SO4 gives, after 24 h at


Scheme 4.29

[74] S. Nishikawa, Z. Kumazawa, N. Kashimura, S. Maki, Y. Nishikimi, Agric. Biol. Chem.1986, 50, 495

[75] D. Cartwright, J.R. Ferguson, T. Giannopoulos, G. Varvounis, B. J. Wakefield, J.Chem. Soc. Perkin I 1995, 2595

[76] T.-L. Su, J.-T. Huang, J.H. Burchenal, K. A. Watanabe, J. J. Fox, J. Med. Chem. 1986, 29,709

[77] R. G. Andrew, R. A. Raphael, Tetrahedron 1987, 43, 4803[78] A. J. Walz, R. J. Sundberg, J. Org. Chem. 2000, 65, 8001[79] K. J. Szab, J. Csábár, A. Tor, Tetrahedron 1989, 45, 4485

155 �C, the monoamino product 273 in 82% yield [80]. With (+)-phenethylamine,HMDS 2, and (NH4)2SO4 for 24 h at 140 �C the monoamino compound 274 is ob-tained in 84% yield [80–82] (Scheme 4.32).

Likewise, 1-[4-methylbenzyl]-4,7-dihydroxy-1,2,3-triazolo[4,5-d]pyridazine 275 re-acts with phenylhydrazine, HMDS 2, and (NH4)2SO4 to give the monoaminoproduct 276 in 60% yield [83]. Reaction of 1-benzyl-3-n-butyl-4-hydroxy-1,2,3-triazo-lo[4,5-d]-pyrimidine 277 for 8 h at 120 �C with cyclopentylamine, HMDS 2, and(NH4)2SO4 affords the aminated product 278 in 49% yield [84] (Scheme 4.33).

4.2 Aminations 63

Scheme 4.30

Scheme 4.31

[80] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, A. Lucacchini, G. Senatore, P.L. Barili, IlFarmaco 1994, 49, 357

[81] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, S. Velo, C. Martini, G. Senatore, P.L. Barili, IlFarmaco 1995, 50, 99

[82] G. Biagi, I. Giorgi, O. Livi, C. Manera, V. Scartoni, A. Lucacchini, G. Senatore, IlFarmaco 1996, 51, 601

[83] G. Biagi, I. Giorgi, O. Livi, C. Manera, V. Scartoni, J. Heterocycl. Chem. 1997, 34, 65[84] G. Biagi, I. Giorgi, O. Livi, C. Manera, V. Scartoni, A. Lucacchini, C. Martini, P.

Tacchi, Il Farmaco 1994, 49, 183

50%

1,7-Dimethyl-4-nitro-3(2H)benzo[b]furo[2,3-c]pyridone 279, which is activated bythe �-nitro group, is readily silylated–aminated by benzylamine and HMDS 2 inboiling pyridine, without any Lewis acid, to give 75% of 280 [85] (Scheme 4.34).

The silylation–amination of 5,10-dihydroxy-1,4-dioxo-1,2,3,4-tetrahydroben-zo[g]phthalazine 281 for 27 h at 170 �C with excess N(2-aminoethyl)piperidine 282and HMDS 2 proceeds with catalytic amounts of TsOH·H2O to afford, via the ac-tivated persilylated intermediate in which the sensitive phenolic hydroxy groupsare protected, the 1,4-bis-amine 283 in 67% yield. All conventional efforts withPOCl3, PCl5, or SOCl2 to convert 281 into the corresponding 1,4-dichloro com-pound, to be followed by amination, resulted in failure [86] (Scheme 4.35).

1-Methylimidazo[1,2-a]quinoxalin-4(5H)-one 284 is converted by excess cyclopen-tylamine, HMDS 2 and (NH4)2SO4 into 4-cyclopentylamino-1-methyl-imidazo[1,2-


Scheme 4.32

Scheme 4.33

[85] S.V. Tolkunov, M.N. Kal’nitskii, E.A. Zemskaya, Khim. Geterotsikl. Soed. 1991, 1552;Chem. Abstr. 1992, 117, 111490

[86] C.A. Gandolfi, G. Beggiolin, E. Menta, M. Palumbo, C. Sissi, S. Spinelli, F. John-

son, J. Med. Chem. 1995, 38, 528

�]-quinoxaline 285 in moderate yield [87]. During syntheses of ellipticines themethoxy group in the tetracycle 286 is cleaved with Me3SiCl 14/NaI (= Me3SiI 17)in acetonitrile into the intermediate trimethylsilyloxyisoquinoline moiety 287,which is not isolated but treated in situ with excess 3-diethylamino-n-propylamine,HMDS 2, and TsOH·H2O to give, after 20 h reflux, the ellipticine analogue 288 in36% overall yield [88] (Scheme 4.36).

In contrast with the hitherto described silylation–aminations of six-memberedheterocycles, silylation–amination of five-membered hydroxy-N-heterocycles suchas benzoxazol-2-one 289 with excess benzylamine and HMDS 2, to give 2-benzyla-minobenzoxazole, fails, because of the equilibrium between 2-trimethylsilyloxy-

4.2 Aminations 65

Scheme 4.34

Scheme 4.35

Scheme 4.36

[87] S. Cecarelli, S. Zanarella, M. Altobelli, A. D’Allessandro, PCT Int. Appl. WO 9719,079; Chem. Abstr. 1997, 127, 65790t

benzoxazole 290 [89] and the much more reactive 2-trimethylsilyloxyphenylisocya-nate 291 [89] this results (via 291) in 60% yield of N,N�-dibenzylurea 292 [27](Scheme 4.37).

The silylation–amination of the condensed tropone derivative 293 to 295 by useof N-trimethylsilylmorpholine 294 (cf. also Section 5.2) is somehow related [90].

4.3Dehydration of Amides, Oximes, and Ketene Imines into Nitriles

Continued heating of carboxamides such as benzamide with HMDS 2 at 200 �C leadsvia N,O-bis(trimethylsilyl)benzamide 296 to the formation of benzonitrile and hex-amethyldisiloxane 7. Heating of N,O-bis(trimethylsilyl)acetamide (BSA) 22 a in aclosed vessel for 12 h at 215 �C affords practically quantitative yield of acetonitrileand hexamethyldisiloxane 7 [91, 92] whereas N,O-bis(trimethylsilyl)pivalamide mustbe boiled for 8 days to provide pivalonitrile in high yield [93] (Scheme 4.38). Alterna-tively, benzamide or phenylacetamide are dehydrated on heating with either hexa-methylcyclotrisilazane 51 or OMCTS 52 [94] and benzamide or acetamide are alsodehydrated by Me2SiCl2 48 [95], Me3SiCl 14/FeCl3/ZnCl2 [96, 97], or by silanes[98]. Free carboxylic acids such as benzoic acid, phenylacetic acid, or 4-hydroxyben-zoic acid 297 are converted on heating with HMDS 2 or OMCTS 52, via their N,O-bis(silylated) amides such as 22 a, into nitriles such as 298 [99, 100] (Scheme 4.38).


Scheme 4.37

[88] J.-R. Dormoy, A. Heymes, Tetrahedron 1993, 49, 2915[89] H.R. Kricheldorf, Liebigs Ann. Chem. 1973, 772[90] G. Seitz, H.-S. The, Synthesis 1984, 119[91] J. Pump, U. Wannagat, Monatsh. Chem. 1962, 93, 352[92] C. Krüger, E.G. Rochow, U. Wannagat, Chem. Ber. 1963, 96, 2138[93] J. Pump, E.G. Rochow, Chem. Ber. 1964, 97, 627[94] W. E. Dennis, J. Org. Chem. 1970, 35, 3253[95] J. F. Klebe, J. Am. Chem. Soc. 1968, 90, 5246[96] B. Rigo, C. Lespagnol, M. Pauly, Tetrahedron Lett. 1986, 27, 347[97] B. Rigo, C. Lespagnol, M. Pauly, J. Heterocycl. Chem. 1986, 23, 183[98] R. Calas, E. Frainnet, A. Bazouin, C.R. Hebd. Seance Acad. Sci. 1962, 254, 2357[99] G. Bakassian, M. Lefort, Ger. Offen. 2,205,360; Chem. Abstr. 1972, 77, 151710

[100] G. Bakassian, M. Lefort, US Patent 3,884,957; Chem. Abstr. 1975, 83, 58487

The oxime 299 is silylated in the presence of catalytic amounts of TMSOTf 20to 300, which affords, via the Beckmann fragmentation intermediate 301 andalkylation with allyltrimethylsilane 82, 66% of the seco nitrile 302 [101, 102](Scheme 4.39). Tris(trimethylsilyl) ketenimine 303 reacts with aldehydes such asbenzaldehyde in the presence of BF3·OEt2, via the aldol adduct 304, to give theunsaturated nitriles 305, in 99% yield, and HMDSO 7 [103].

4.4Hydration of Nitriles into Amides

Neat nitriles 306 are converted by TCS 14 and H2O, in 75–94%, yield into theamide hydrochlorides 309 and hexamethyldisiloxane 7. On reacting nitriles con-

4.4 Hydration of Nitriles into Amides 67

Scheme 4.38

Scheme 4.39

[101] H. Fujioka, M. Miyazaki, T. Yamanaka, H. Yamamoto, Y. Kita, Tetrahedron Lett. 1990,31, 5951

[102] H. Nishiyama, K. Sakuta, N. Osaka, H. Arai, M. Matsumoto, K. Itoh, Tetrahedron1988, 44, 2413

[103] I. Matsuda, H. Okada, Y. Izumi, Bull. Chem. Soc. Jpn. 1983, 56, 528

taining a basic tertiary nitrogen atom, a further equivalent of TCS 14 and an addi-tional half equivalent of H2O must be employed. Mechanistically, TCS 14 can beexpected to react with water to form trimethylsilanol 4 and HCl, whereupon thenitrilium salt 307 adds trimethylsilanol 4 to give 308, which is converted by afurther equivalent of trimethylsilanol 4 to the amide hydrochloride 309 andHMDSO 7 [104] (Scheme 4.40). Application of trimethylsilyl triflate 20 instead ofTCS 14 should afford amide triflate salts.

4.5Conversion of Carbamates into Urethanes, Isocyanates, Ureas, and Carbodiimides

On treatment with two equivalents of TCS 14 (or with HMDS 2/H2SO4), twoequivalents of ammonium carbamate 310 give, via 311, the silylating agent N,O-bis(trimethylsilyl)carbamate 25 (m.p. 80 �C) in good yield and NH4Cl, CO2, andNH3 [105]. Reaction of N,O-bis-(trimethylsilyl)acetamide 312a (= 22a) with phos-gene affords acetylisocyanate 313 [106], which trimerizes to 314. Treatment of312b (= 296) with phosgene gives, via the intermediate benzoylisocyanate 315, thedimer 3-benzoyl-6-phenyl-2H-1,3,5-oxadiazine 316 in quantitative yield [106]. Heat-ing of BSA 312a = 22a with methyl chloroformate affords acetylisocyanate 313 in86% yield and Me3SiCl 14 and methoxytrimethylsilane 13 a. On heating to 150–200 �C the N,O,O-tris(trimethylsilylated) derivative 317 of hydroxycarbamic acid isdecomposed to hexamethyldisiloxane 7 (b.p. 100 �C) and the previously unknowntrimethylsilyloxy isocyanate 318 (b.p. 100–101 �C) in 94% yield. Because 7 and 318are difficult to separate, the authors recommend treatment of 317 with Et3SiCl 63to afford Me3SiCl 14 and Me3SiON(SiEt3)CO2SiMe3, which on pyrolysis gives 318and the higher boiling Me3SiOSiEt3 64 [107] (Scheme 4.41).

Heating of silylated N-substituted carbamates such as 319 results in the forma-tion of 96% of the urea 320, and CO2 and hexamethyldisiloxane 7 [108]. Heating


Scheme 4.40

[104] M.K. Basu, F.-T. Luo, Tetrahedron Lett. 1998, 39, 3005[105] L. Birkofer, P. Sommer, J. Organomet. Chem. 1972, 35, C15[106] V. D. Sheludyakov, V. V. Shcherbinin, E.S. Rodionov, V. F. Mironov, Zh. Obshch.

Khim. 1972, 42, 1859; Chem. Abstr. 1973, 78, 29881[107] V. D. Sheludyakov, A. B. Dimitrieva, A.D. Kirilin, E. A. Chernyshev, Zh. Org. Khim.

1983, 53, 706; Chem. Abstr. 1983, 99, 70806[108] V. D. Sheludyakov, E. L. Kotrikadze, L.M. Khananshvili, M.G. Kuznetsova, A. V. Ki-

sin, A. D. Kirilin, Zh. Obshch. Khim. 1981, 51, 2481; Chem. Abstr. 1982, 96, 199764

of the N-trimethylsilylated compound 321, however, furnishes the N,N �-bis(trimethylsilyloxyethyl)carbodiimide 322 in 99% yield [108]. Heating of N-tri-methylsilyl-aniline 323 with CO2 in the presence of catalytic amounts ofRu3(CO)12 gives rise to quantitative yield of N,N �-diphenylurea 324 [109], whereasthe Sn(II)-HMDS compound 325 reacts with CO2 under pressure to afford tri-methylsilyl isocyanate 327 and N,N �-bis(trimethylsilyl)carbodiimide 328 in quanti-tative yield, and dimeric bis(trimethylsilyloxy)tin(II) 326 [110] (Scheme 4.42). N,N �-Bis-(trimethylsilyl)carbodiimide 328 is, however, readily accessible on silylation ofcyanamide with Me3SiCl 14/NEt3 [110a] (cf. Scheme 5.38 in Section 5.1.3).

4.5 Conversion of Carbamates into Urethanes, Isocyanates, Ureas, and Carbodiimides 69

Scheme 4.41

Scheme 4.42

[109] A. T. Zoeckler, R. M. Laine, J. Org. Chem. 1983, 48, 2539[110] L.R. Sita, J. R. Babcock, R. Xi, J. Am. Chem. Soc. 1996, 118, 10912[110a] L. Birkofer, A. Ritter, P. Richter, Tetrahedron Lett. 1962, 195

4.6Conversion of Free or Silylated Carboxylic Acids into Esters, Thioesters, Lactones,or Ketenes. Transesterification of Esters with Alcohols

Carboxylic acids such as acetic acid react with alcohols such as methanol or withmethoxytrimethylsilane 13 a in the presence of trimethylchlorosilane (TCS) 14 inTHF or 2-methyl-THF to give esters such as methyl acetate in 97% yield and hex-amethyldisiloxane 7. Even methyl pivalate can be readily prepared in 91% yield[111]. Reaction of a variety of carboxylic acids, for example N-benzoylglycine 329,with two equivalents of �-trimethylsilylethanol 330 and with 14 has been shown toafford esters such as 331 in 98% yield [112, 112a]. Likewise, silylated carboxylicacids react with silylated alcohols or thiophenols in the presence of 4-trifluoro-methylbenzoic anhydride and TiCl4/AgClO4 to furnish esters or thioesters in highyields [113, 114] (Scheme 4.43).�-Hydroxycarboxylic acids give, after silylation to bis(trimethylsilylated) intermedi-

ates and subsequent treatment with mild Lewis acids, small- and large-ring lactonesin high yields. Thus �-hydroxytridecanoic acid 332 (n= 12) affords, via 333 (n= 12), atroom temperature, the macrolide 334 in 89% yield [115]. The medium-sized 8- and 9-membered lactones are, however, not formed, only diolides. Likewise, trimethylsilyl6-trimethylsilyloxyhexanoate 333 is readily lactonized in the presence of 4-trifluoro-


Scheme 4.43

[111] R. Nakao, K. Oka, T. Fukumoto, Bull. Chem Soc. Jpn. 1981, 54, 1267[112] M.A. Brook, T.H. Chan, Synthesis 1983, 201[112a] H. Estermann, D. Seebach, Helv. Chim. Acta. 1988, 71, 1824[113] T. Mukaiyama, M. Miyashita, I. Shiina, Chem. Lett. 1992, 1747[114] M. Miyashita, I. Ishiina, S. Miyoshi, T. Mukaiyama, Bull. Chem. Soc. Jpn. 1993, 66,

1516[115] N. Tanigushi, H. Kinoshita, K. Inomata, H. Kotake, Chem. Lett. 1984, 1347

methylbenzoic anhydride/TiCl4/AgClO4, via 335, to give 71% caprolactone 336 [116].Treatment of 12-hydroxydodecanoic acid with bis(dimethylsilyl)ethane andRhCl(PPh3)3 (and perhaps also with 1,2-bis(chlorodimethylsilyl)ethane 45 andtriethylamine) in benzene gives the 13-membered lactone in 63% yield andbis(sila)hydrofuran 47 [116 a].

Finally, esters, for example methyl benzoate, are readily transesterified by excessalcohol, for example ethanol, in the presence of trimethylsilyl iodide 17, in boilingchloroform, to give, via trimethylsilyl benzoate, the desired ethyl benzoate in 98%yield [117].

On thermolysis of bis(trimethylsilyl) malonate 337 at 160 �C in the presence ofP4O10 carbon suboxide 339 is formed in 54% yield, via 338; two equivalents of tri-methylsilanol 4 are also formed and react in situ with P4O10 to give polyphosphoricacid trimethylsilylester (PPSE) 195 [118] (Scheme 4.44). Pyrolysis of trimethylsilyl2,2-dimethylmalonate at 700 �C gives dimethyl ketene and HMDSO 7 [118 a].

4.7Saponification of Esters or Lactones and Reaction of Persilylated Amidesand Lactams with Alkali Trimethylsilanolates. Conversion of Aromatic Estersinto Nitriles by Use of Sodium-HMDS

Treatment of methyl p-chlorobenzoate with an equivalent amount of commercialpotassium silanolate 97 in abs. diethyl ether affords, after 4 h, pure, anhydrouspotassium p-chlorobenzoate in 84% yield and methoxytrimethylsilane 13 a. Tri-methylsilyl trifluoroacetate reacts likewise with sodium trimethylsilanolate 96 inTHF to give sodium trifluoroacetate, in 98% yield, and hexamethyldisiloxane 7[119] (Scheme 4.45).

In the first total synthesis of thromboxane A2, lactone 340 is opened by potas-sium trimethylsilanolate 97 to give the potassium salt 341 [120]. The potassiumsalt of the methoxymethyl ether of salicylic acid is prepared likewise [121], as are

4.7 Saponification of Esters or Lactones and Reaction of Persilylated Amides and Lactams with Alkali 71

Scheme 4.44

[116] T. Mukaiyama, J. Izumi, M. Miyashita, I. Shiina, Chem. Lett. 1993, 907[116a] T. Mukaiyama, J. Izumi, I. Shiina, Chem. Lett. 1997, 187[117] G. A. Olah, S.C. Narang, G. F. Salem, B. G.B. Gupta, Synthesis 1981, 142[118] L. Birkofer, P. Sommer, Chem. Ber. 1976, 109, 1701[118a] R. Bloch, J.M. Denis, J. Organomet. Chem. 1975, 90, C9[119] E.D. Langanis, B. L. Chenard, Tetrahedron Lett. 1984, 25, 5831[120] S.S. Bhagwat, P.R. Hamann, W.C. Still, J. Am. Chem. Soc. 1985, 107, 6372[121] L.S. Liebeskind, M.S. Yu, R.W. Fengl, J. Org. Chem. 1993, 58, 3543

other potassium salts in some recent syntheses of natural products [122, 123]. Theallylic alcohol 342 can be readily converted with TsCl in the presence of the ratherlipophilic Me3SiOK 97 as base, in Et2O, to the O-tosylate 343 in 50% yield [124].

N-Trimethylsilylamides or lactams 344 react with sodium trimethylsilanolate 96to generate the anhydrous N-sodium salts 345 and hexamethyldisiloxane 7 in prac-tically quantitative yield [125]. Likewise, silylated succinimide 201 is converted bysodium trimethylsilanolate 96 into hexamethyldisiloxane 7 and the anhydrous so-dium salt 346, which reacts with aldehydes RCHO (R = C2H5, n-C3H7), in the pres-ence of catalytic amounts of 96 to give, via 346, the silylated adducts 347 in 43–62% yield [125]. The imide chloride 348 gives, analogously, sodium chloride and 7and the N-sodium salt 349, which condenses in situ with unreacted imide chloride348 to give 91% of the amidine 350 [126] (Scheme 4.46).


Scheme 4.45

Scheme 4.46

[122] I. Paterson, V.A. Doughty, M.D. McLeod, T. Trieselmann, Angew. Chem. Int. Ed.2000, 39, 1308

[123] K. R. Hornberger, C.L. Hamblett, J.L. Leighton, J. Am. Chem. Soc. 2000, 122, 12894[124] J. L. Musachio, J. R. Lever, Tetrahedron Lett. 1989, 28, 3613[125] L. Birkofer, H. Dickopp, Chem. Ber. 1968, 101, 3579[126] L. Birkofer, H. Dickopp, S. K. Majlis, Chem. Ber. 1969, 102, 3094

Condensation of aromatic methylesters such as methyl 4-methoxybenzoate 351aor methyl 4-hydroxybenzoate 351b with excess sodium-HMDS 486 in a mixture ofTHF-1,3-dimethyl-imidazolin-2-one (DMEU) at 185 �C in a closed vessel affords 59or 93% of 4-hydroxybenzonitrile 298 as well as 26% 352 with smooth cleavage ofthe aromatic methyl ether in 351a (Scheme 4.47). Methyl indole-3-carboxylategives likewise 3-cyanoindole in 81% yield [127] (cf. also ref [92] in section 4.3).

4.8C-Substitutions of Lactones, Amides, Lactams and Imides

In the presence of SbCl5, (CH3)3SiCl/SnI2, or (C6H5)3CSbCl6 lactones such as va-lerolactone 353 react with silylated ketene acetals such as 354, via 355, with elimi-nation of the O-anion of Me3CSi(Me)2OH, 85 a, to give intermediate cations suchas 356 which add allyltrimethylsilane 82 or trimethylsilyl cyanide 18 to give theproducts 357 and 358; 356 is also reduced by triethylsilane 84b to give the ester359 [128] (Scheme 4.48). Reactions of aldehydes are covered in Section 5.2.

Conventional conversion of amide, lactam, imide, and urea carbonyl groupsinto enaminones, enamino esters, or enamino nitriles requires prior activation ofthe carbonyl groups either by alkylation to imino ethers, followed by reaction withactivated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groupsfollowed by alkylation (and possibly also oxidation), and, again, subsequent reac-


Scheme 4.47

Scheme 4.48

[127] J. R. Hu, C.H. Hsu, F. F. Wong, C.-S. Chung, G. H. Hakimelahi, Synthesis 1998, 329[128] T. Mukaiyama, K. Homma, H. Takenoshita, Chem. Lett. 1988, 1725

tion with activated methylene groups. Alternatively, the thiocarbonyl groups ofthioamides or thiolactams can be S-alkylated by �-halo ketones or esters followedby “Eschenmoser sulfide contraction” [129] with trivalent phosphorus compoundsto give the desired enaminones or enamino esters. Before these carbonyl groupscan be activated by these methods, however, any additional functional groups pre-sent, for example free alcohol or phenol hydroxy groups, must be protected, e.g.by O-acetylation, to give, eventually, the desired (protected) end products. This re-sults in a multi-step reaction sequence.

Whereas silylation–amination of carbonyl groups in amide, lactam, imide, or ureamoieties to give amidines or guanidines with concomitant protection of, e.g., anyhydroxyl group present (c.f. Sections 4.2.2–4.2.5) has already found quite a numberof applications, few examples of the related silylation–C-substitutions with N,O-bis-(trimethylsilyl)acetamide (BSA) 22 a, N,N-bis(trimethylsilyl)formamide 22 c, or N,N-tert-butyl(trimethylsilyl)formamide 363 have yet been described. The basic com-pounds 22a, 22 c, and 363 occur, according to NMR-studies, exclusively in the (reac-tive) N,O-bis(trimethylsilyl) form (22 a), in the N,N-bis(trimethylsilyl)-form 22 c, or inthe N-alkyl-N-silyl-form 363, although 22 c and 363 are certainly in equilibrium withtheir reactive O-trimethylsilyl-forms 360 and 364 (cf. also Section 2.4). Because theyare powerful silylation agents (cf. Section 2.1), they tend to silylate any functionalgroup present but condense nevertheless with methyl cyanoacetate and malonitrileto afford the condensation products 361, 362 [130], 365, and 366 [131] in 56–65%yield, and HMDSO 7 (Scheme 4.49).

During silylation–C-substitution malonitrile and methyl or ethyl cyanoacetateare, however, partially N-silylated in situ, e.g. on treatment with N-trimethylsilyldi-phenylurea 23 in benzene [132] or on reaction with trimethylsilyl triflate 20/triethylamine [133] to give the reactive intermediate N-trimethylsilylated ketenei-mines 367a or 367b [134, 135], which trimerize to give 30% or 80% of silylated1,3,5-tricyano-2,4,6-tris(trimethylsilylamino)benzene 368 a and 1,3,5-tris-(ethoxy-carbonyl)-2,4,6-tris(trimethylsilylamino)benzene 368 b, thus reducing yields of thedesired C-substitution products 361, 362, 365, and 366. Consequently, excess mal-onitrile and methyl or ethyl cyanoacetate is usually employed (Scheme 4.50). A re-lated trimerization of the keteneimine analogue to 367b in the presence ofCu(OAc)2 in dioxane, at ambient temperature to 368 b, is discussed elsewhere[135 a].


[129] M. Roth, P. Dubs, E. Göschi, A. Eschenmoser, Helv. Chim. Acta 1971, 54, 710[130] W. Kantlehner, W. Kugel, H. Bredereck, Chem Ber. 1972, 105, 2264[131] W. Kantlehner, P. Fiascher, W. Kugel, E. Möhring, H. Bredereck, Liebigs Ann.

Chem. 1978, 512[132] J. F. Klebe, J. Am. Chem. Soc. 1964, 86, 3399[133] H. Emde, D. Domsch, H. Feger, U. Frick, A. Götz, H.H. Hergott, K. Hofmann, W.

Kober, K. Krägeloh, T. Oesterle, W. Steppan, W. West, G. Simchen, Synthesis 1982,1

[134] G. R. Krow, Angew. Chem. 1971, 83, 455[135] L.F. Clarke, A.F. Hegarty, J. Org. Chem. 1992, 57, 1940[135a] G. Desmoni, A.G. Invernezzi, A. Gamba, P. Quadrelli, P.P. Rhigetti, Gazz. Chim.

Ital. 1991, 121, 483

The condensation of arylsulfonyl acetonitriles 369a– c with 22 a proceeds viaaddition of the in-situ formed anion 370 to the arylsulfonyl acetonitriles 369 to af-ford the dimers 371, in 69–94% yield, and hexamethyldisiloxane 7 [136]. Further-more, �-dicarbonyl compounds such as ethyl acetoacetate 372a or ethyl benzoyl-acetate 372b are O-silylated by 22 a or 22 c to rather stable alkyl 3-O-trimethylsilyl-oxycrotonoate 373a and alkyl 3-O-trimethylsilyloxy-3-phenyl acrylate 373 b [130].Aliphatic nitro compounds such as nitromethane are O-trimethylsilylated andfurther transformed into oligomers [132] (cf. Section 7.6) and are thus unsuitablereactants for silylation-C-substitutions (Scheme 4.50).


Scheme 4.49

[136] V. M. Neplyuev, I.M. Bazavova, M.O. Lozinskii, L.A. Lazukina, V. P. Kukhar, Zh.Org. Khim. 1984, 20, 1451; Chem. Abstr. 1985, 102, 45570

Scheme 4.50

Barbituric acid 374 condenses at 125–145 �C with N,N-bis(trimethylsilyl)formamide22 c in unspecified yield [137] to give 375, which is, however, also obtained, in quan-titative yield, by heating free barbituric acid 374 in formamide for 1 h at 130 �C [137a].N-Ethylrhodanines 376 and 2-methyl-N-ethyl-benzothiazole tosylate 378 react with22 c to give the dimers 377 and 379 in 55 and 75% yields, respectively [137](Scheme 4.51).

Instead of employing persilylated amide systems such as 22a- c and silylated n-alkyl-amides such as 363, one can generate such activated amide, lactam, or imidesystems in situ. Thus, on heating succinimide with HMDS 2 and ethyl cyanoace-tate and catalytic amounts of (NH4)2SO4 in abs. acetonitrile the intermediate N-(trimethylsilyl)succinimide 201 is obtained (cf. Section 4.2.2); this can be assumedto be in equilibrium with the reactive O-trimethylsilyl compound 202a. The lattercondenses with a slight excess of ethyl cyanoacetate via 202 a in, as yet, only 17%yield [138] to the known [139] crystalline mono-substituted product 380 and, via380 and 381, in 3% yield to the likewise known [139] crystalline chelated bis-prod-uct 382, and, apparently, the trimer 368 b and HMDSO 7 [139] (Scheme 4.52). Asalready described in Section 4.2.2, these reactions with silylated succinimides 201and 202a, and with 381, which are apparently in equilibrium with O-silylated pyr-roles such as 202 b, should be performed with strict exclusion of oxygen, under ar-gon, to avoid the formation of dark colored side-products which reduce the yieldof 380 and 382 [138].

The bis(substituted) product 382 has previously been obtained in ca 53% yieldvia the bis-imino intermediate 383 on boiling succinodinitrile with ethyl sodiocya-


Scheme 4.51

[137] L.A. Lazukina, I. L. Mushkalo, V. M. Neplyuev, V. P. Kukhar, Zh. Org. Khim. 1983, 19,2417; Chem. Abstr. 1984, 100, 53185

[137a] S. Hünig, Liebigs Ann. Chem. 1951, 574, 107[138] D. Song, H. Vorbrüggen, unpublished work[139] J. A. Elvidge, J. S. Fitt, R. P. Linstead, J. Chem. Soc. 1956, 235

noacetate in ethanol and subsequent work-up with ice-cold HCl [139], whereas themonosubstitution product 380 is formed in quantitative yield on boiling O-ethyl-succinimide with ethyl cyanoacetate in ethanol [140] (Scheme 4.53).

Imino ethers and, in particular, lactim ethers [141] such as O-ethylpyrrolidone384 a [142] or O-trimethylsilylcaprolactam 384 b, which is formed, in equilibriumwith N-trimethylsilylcaprolactam, on treatment of caprolactam with HMDS 2, con-dense readily with activated methylene compounds such as methyl or ethyl cya-noacetate to the �-enamino esters 385 a and 385 b [140] whereas O-alkylureas suchas 2-methoxyimidazoline 386 [143–146] afford products such as 387.

In a related reaction N-trimethylsilylpyrrolidone 388 a, which is assumed to bein equilibrium with the O-trimethylsilyl form 389 a, reacts with methyl-, butyl-, or


Scheme 4.52

Scheme 4.53

[140] T. Yamazaki, K. Matoba, S. Imoto, M. Twerashima, Chem. Pharm. Bull. 1976, 24, 3011[141] R.G. Glusgkov, V.G. Granik, Russ. Chem. Rev. 1970, 12, 185[142] Y. Yamada, D. Miljkovic, P. Wehrli, B. Golding, P. Löliger, R. Keese, K. Müller, A.

Eschenmoser, Angew. Chem. 1969, 81, 301[143] S. Henmi, T. Katsurayama, JP 09 20,756; Chem. Abstr. 1997, 126, 186083c[144] P. Delbecq, J.-P. Celerier, G. Lhommet, Tetrahedron Lett. 1990, 31, 4873[145] D. Fasseur, B. Rigo, C. Leduc, P. Cauliez, D. Coutourier, J. Heterocycl. Chem. 1992,

29, 1285[146] G. Dannhardt, A. Bauer, Pharmazie 1996, 51, 805

phenyllithium to give cyclic Schiff bases such as 390a [147–150], in high yields,and Me3SiOLi 98.

All these results indicate that silylated amides and, in particular, silylated lac-tams such as 388 will react with methyl or ethyl cyanoacetate or malonate andmalodinitrile in the presence of HMDS 2 (to convert the leaving group Me3SiOH4 into HMDSO 7) via the O-silylated forms such as 384 b or 389 to give similarproducts such as 385 and HMDSO 7 (Scheme 4.54).


Tetrahydrofuran-2-carboxylic acid 167 (3.48 g, 30 mmol), N-methyl-1,3-diamino-propane 168 (5.28 g, 60 mmol), and (12.65 mL, 60 mmol) HMDS 2 (b.p. 126 �C)are heated for 8 h under nitrogen at 110 �C in a flask connected to a smallVigreux column to enable removal by distillation of HMDSO 7 (b.p. 100 �C) or theazeotrope of Me3SiOH 2 and HMDSO 7 (b.p. 89–91 �C) during the reaction. Aftercooling, addition of chloroform, and shaking of the mixture with sat. NaHCO3 so-lution, the organic phase is washed with water, dried (Na2SO4), and chromato-


Scheme 4.54

[147] D.H. Hua, S.W. Miao, S. N. Bharathi, T. Katsuhira, A.A. Bravo, J. Org. Chem. 1990,55, 3682

[148] M.A. Brindle, S. Gorsuch, Aust. J. Chem. 1999, 52, 965[149] C. Coindet, A. Comel, G. Kirsch, Tetrahedron Lett. 2001, 42, 6101[150] Y. Ahn, G. I. Cardenas, J. Yang, D. Romo, Org. Lett. 2001, 3, 751

Scheme 4.55

graphed on a SiO2 column with EtOAc–MeOH–NEt3 (7:3:1) to give ca. 85% of theoily basic amide 169 [6] (Scheme 4.55).

A mixture of 2-indolinone 187 (6.66 g, 50 mmol), pyrrolidine (12.52 mL,150 mmol), and HMDS 2 (15.5 mL, 75 mmol) is heated under reflux for 3 h withTsOH·H2O (0.475 g, 2.5 mmol) under argon in an oil-bath at 125–130 �C. After1 h 188 starts to crystallize. After cooling to 24 �C the crystals of 2-pyrrolidino-3H-indole 188 are isolated by filtration and washed with acetone to give 7.07 g (76%)sand-colored crystals, m.p. 140–142 �C, which can be readily recrystallized fromboiling acetone under argon [27] (Scheme 4.56).

Me2SiCl2 48 (0.267 mL, 2 mmol) is added to a suspension of (330 mg, 2 mmol)l-phenylalanine in abs. pyridine (10 mL), whereupon the reaction temperaturerises from 23 �C to 28 �C and a clear solution results. After 2 min abs. benzyla-mine (0.65 mL, 6 mmol) is added and the resulting suspension is stirred for 16 hwith exclusion of humidity. Evaporation of the mixture in vacuo and chromatogra-phy with CH2Cl2–MeOH–NEt3 (94:5:1) on a column of SiO2 gives (Me2SiO)n oli-gomers 54–56 and 98% l-phenylalanine-N-benzylamide [12a] (Scheme 4.57).

A mixture of inosine 235a (5.346 g, 20mmol), HMDS 2 (16.77 mL, 80 mmol),dopamine-hydrochloride (7.586 g, 40 mmol), and (NH4)2SO4 (0.264 g, 2 mmol) isboiled under reflux with magnetic stirring in an oil bath at 145 �C for 20 h, where-upon most of the NH4Cl formed sublimes into the lower part of the reflux-con-denser. The cooled mixture is transsilylated for 3 h with 400 mL boiling methanol,


Scheme 4.56

Scheme 4.57

Scheme 4.58

the dark solution is evaporated, and the residue is dissolved in 150 mL H2O. Thesolution is then chromatographed on a column of 150 g cellulose powder (MN300; Macherey–Nagel, Düren, Germany) which has previously been equilibratedwith H2O for 24 h. The first 750 mL aqueous eluate contain traces of inosine 235and dark-colored impurities whereas the next 1500 mL affords, on evaporation,homogeneous amination product 237a (7.15 g, 84.6%). Recrystallization from200 mL methanol with some charcoal gives the analytically pure hydrate 237a,m.p. 166–168 �C [64, 65] (Scheme 4.58).

2,3-Dihydro-1,4-phthalazindione 248 (4.68 g, 30 mmol), benzylamine (16.07 mL,150 mmol), HMDS 2 (22 mL, 105 mmol), and (NH4)2SO4 (0.79 g, 6 mmol) areheated, with stirring, in a round-bottomed flask with a small Vigreux-column con-nected to a cooler, in an oil-bath at 155 �C. NH3 is evolved and 248 rapidly dissolveswithin 10 min. During 13 h at 155–165 �C 11 mL of an azeotropic mixture ofMe3SiOH 2 and HMDSO 7 (b.p. 89–91 �C) are removed by distillation; on continuedheating for 11 h another 4 mL distillate are obtained. After cooling and addition of25 mL methanol, evaporation gives 19.7 g crude product, which is extracted with150 mL ether. After filtration and evaporation of the ether phase 11.1 g crude yellow-ish oil is obtained, which crystallizes from EtOAc to give, in two crops, 8.85g (87%)pure 1,4-dibenzylaminophthalazine 249, m.p. 122 �C [27] (Scheme 4.59).

A mixture of 2-methylpyrido[3,4-d]pyrimidine-4-one 261 (1 mmol), benzylamine(3 mmol), HMDS 2 (3 mmol), and (NH4)2SO4 (0.1 mmol) is heated under refluxfor 4–5 h. After cooling, addition of 10 mL ethanol, and evaporation, the residueis recrystallized from water or aqueous methanol to give 97% 2-methyl-4-benzyla-minopyrido[3,4-d]pyrimidine 262, m.p. 156–160 �C [74] (Scheme 4.60).

2,4(1H,3H)-quinazoline 250 (3.24 g, 20 mmol), N-(2-hydroxyethyl) piperazine251 (13.02 g, 100 mmol), p-toluenesulfonic acid hydrate (0.38 g, 2 mmol), and octa-methylcyclotetrasilazane (OMCTS) 52 (11.71 g, 40 mmol) are heated for 48 h at


Scheme 4.59

Scheme 4.60

190–200 �C in an oil bath (temperature inside the reaction mixture 175–180 �C),whereupon NH3 is evolved. The dark mixture is cooled, dissolved in 250 mLmethanol, and the solution is boiled for 4 h. After evaporation, ca. 7.6 g excess N-(2-hydroxy-ethyl)piperazine 251 is removed by distillation, by heating to 130 �C/11 mm. The dark brown residue is dissolved in 300 mL hot water and charcoal isadded. Filtration and evaporation give 8 g crude product, which is chromato-graphed on a column of 240 g neutral alumina (A II) with CH2Cl2 as mobilephase. Elution with 1 L CH2Cl2 is followed by elution with ethyl acetate saturatedwith water (2500 mL). The first 1000 mL gives only impurities, whereas the next1250 mL affords 1.3 g (24%) 253a. Because this would not crystallize it was acety-lated with acetic anhydride–pyridine for 18 h at room temperature and for 1 h at70 �C and co-distilled repeatedly with toluene to give, after chromatography on acolumn of neutral alumina (AII) with toluene–ethyl acetate (1:1) as mobile phase,and subsequent recrystallization from cyclohexane, pure crystalline 253b(m.p. 107.5 �C). The subsequent 2500 mL water-saturated ethyl acetate eluted 4.3 g(56%) of the desired 252 [27] (Scheme 4.61).

Methyl 4-chlorobenzoate (13.65 g, 80mmol) was added in one portion to a stir-red slurry of potassium trimethylsilanolate 97 (10.26 g, 80 mmol) in 500 mL dryether at ambient temperature, under N2. After 4 h the white slurry is filtered un-der N2, washed with ether, and dried under a stream of N2 to afford 13.1 g (84%)analytically pure potassium 4-chlorobenzoate [119] (Scheme 4.62).

Succinimide (9.9 g, 100 mmol), ethyl cyanoacetate (21.28 mL, 200 mmol),HMDS 2 (42.2 mL, 200 mmol), and (NH4)2SO4 (0.7 g, 5 mmol) are heated for34 h under reflux with magnetic stirring. After cooling the colored residue is chro-matographed on a silica gel column (25 cm�6 cm i.d.) with hexane–ethyl acetate(1:1) as mobile phase. The first fractions contain ca 3% pure bis-product 382,


Scheme 4.61

Scheme 4.62

m.p. 202 �C (Lit. [139] m.p. 205 �C) and subsequent fractions give 3.4 g (17%)slightly greenish crystals of 380, which are recrystallized from ethanol to givenearly colorless needles of pure 380 m.p. 145 �C (Lit. [140] m.p. 140–150 �C)(Scheme 4.63).


Scheme 4.63

5.1Conversion of Carbonyl Groups into Acetals and Analogous Reactions

5.1.1Conversion of Carbonyl Groups into O,O-Acetals and Analogous Reactions

Aldehydes and ketones react with trimethylsilylated alcohols or glycols at –78 �Cin 3–20 h in CH2Cl2, in the presence of trimethylsilyl triflate (TMSOTf) 20, togive the corresponding acetals and hexamethyldisiloxane 7 in high yields [1]. Thuswith silylated alcohols 13 or silylated glycol cyclohexanone affords the acetals 391aand 391b and the ethylene acetal 392 (Scheme 5.1). 2-Cyclohexenone gives, analo-gously, on reaction with silylated glycol, without shift of the double bond, the ace-tal 393, whereas benzaldehyde reacts with methoxytrimethylsilane 13 a to give thedimethyl acetal 121 (Scheme 5.1) (cf. also an alternative preparation of 121 by re-action of benzaldehyde with Si(OMe)4 58 in Scheme 3.9).

This very mild Noyori acetalization has found wide application for the prepara-tion of dialkyl or ethylene acetals of aldehydes and ketones, affording, e.g. with

83

5

Reactions of Aldehydes and Ketones


Scheme 5.1

[1] T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1980, 21, 1357

steroidal 3,20-diketones, selective monoacetalization of the less hindered 3-ketogroup [2] and succeeds also with very sensitive silylated hydroperoxides such as394 and 396 to give the corresponding 1,2,4-trioxanes-5-ones 395 [3, 4] and 1,2,5,6-tetraoxacycloheptanes 397 [5, 5 a] (Scheme 5.2).

For further applications of this Noyori ketalization compare, e.g. Refs. [6–15].Interesting also are the reactions of silylated 1,3-diols and 1,3,5-triols with l-

5 Reactions of Aldehydes and Ketones84

Scheme 5.2

[2] H.R. Hwu, J. M. Wetzel, J. Org. Chem. 1985, 50, 3946[3] C.W. Jefford, J. Currie, G. D. Richardson, J.-C. Rossier, Helv. Chim. Acta 1991, 74,

1239[4] C.W. Jefford, S.-J. Jin, G. Bernardinelli, Helv. Chim. Acta, 1997, 80, 2440[5] K. J. McCullough, Y. Nonami, A. Masuyama, M. Nojima, H.-S. Kim, Y. Wataya, Tetra-

hedron Lett. 1999, 40, 9151[5a] H.-S. Kim, K. Begum, N. Ogura, Y. Wataya, Y. Nonami, T. Ito, A. Masuayama, M. Nojima,

K. McCullough, J. Med. Chem. 2003, 46, 1957[6] J. R. Hwu, L.-C. Leu, J.A. Robl, D.A. Anderson, J. M. Wetzel, J. Org. Chem. 1987, 52,

188[7] D.A. Archer, S. M. Bromidge, P.G. Sammes, J. Chem. Soc. Perkin I 1988, 3223[7a] M. Ihara, M. Suzuki, K. Fukumoto, Heterocycles 1990, 30, 381[8] T.H. Chan, A. E. Schwerdtfeger, J. Org. Chem. 1991, 56, 3294[9] A. F. Schwerdtfeger, T. H. Chan, A. W. Thomas, G. M. Strunz, A. Salonius, M.

Chiasson, Can. J. Chem. 1993, 73, 1184[10] J. Cossey, J.-L. Ranaivosata, V. Bellosta, Tetrahedron Lett. 1994, 35, 1205[11] D. Enders, B. Jandeleit, Synthesis 1994, 1327[12] U. Berens, H.-D. Scharf, J. Org. Chem. 1995, 60, 5127[13] J. Cossey, J.-L. Ranaivosata, V. Bellosta, Tetrahedron 1996, 52, 629[14] K. C. Nicolaou, W. Qian, F. Bernal, N. Uesaka, P.M. Pihko, J. Hinrichs, Angew.

Chem. Int. Ed. 2001, 40, 4068[15] M.E. Gihani, H. Heaney, SynLett 1993, 583

menthone 398 [16, 19–23] or ethyl pyruvate [17, 18]. Thus l-menthone 398 is con-verted by 1- or 1,3-substituted silylated propane-1,3-diols 399 or 401 into the ketals400 and 402 with equatorial substituents [16, 20] (Scheme 5.3).

The use of the enolsilyl ether of l-menthone [16, 19, 21–23] and of some freetriflic acid favors the formation of the thermodynamically controlled products aswith free 2,2�-dihydroxydiphenyl [22] and only subsequently added HMDS 2 [22].On reacting silylated alcohols and carbonyl compounds with pure trimethylsilyltriflate 20 under strictly anhydrous conditions no conversion to acetals is observed[24]. Apparently, only addition of minor amounts of humidity to hydrolyzeTMSOTf 20 to the much stronger free triflic acid and hexamethyldisiloxane 7 oraddition of traces of free triflic acid [18–21, 24, 26] or HClO4 [25] leads to forma-tion of acetals.

Because of the equilibrium between silylated alcohols and free carbonyl com-pounds, the reaction between silylated alcohols ROSiMe3 13 and free enolized 1,2-dicarbonyl compounds such as 403 in the presence of 1% CF3SO3H results, at

5.1 Conversion of Carbonyl Groups into Acetals and Analogous Reactions 85

Scheme 5.3

[16] A. P. Davis, Angew. Chem. Int. Ed. 1997, 36, 591[17] A. Lipták, L. Szabó, J. Carbohydr. Chem. 1989, 8, 629[18] K. Hiruma, J.-I. Tamura, S. Horito, J. Yoshimura, H. Hashimoto, Tetrahedron 1994,

50, 12143[19] T. Harada, S. Tanaka, A. Oku, Tetrahedron 1992, 48, 8621[20] T. Harada, A. Inoue, I. Wada, J.-j. Uchimura, S. Tanaka, A. Oku, J. Am. Chem. Soc.

1993, 115, 7665[21] T. Harada, Y. Kagamihara, S. Tanaka, K. Sakamoto, A. Oku, J. Org. Chem. 1992, 57,

1637[22] T. Harada, S. Ueda, T. Yoshida, A. Inoue, S. Tanaka, K. Sakamoto, A. Oku, J. Org.

Chem. 1992, 57, 1637[23] T. Harada, T. Shintani, A. Oku, J. Am. Chem. Soc. 1995, 117, 12346[24] H.J. E. Loewenthal, “A guide for the perplexed organic experimentalist” John Wiley and

Sons, p. 42[25] A. Börner, J. Holz, A. Kless, D. Heller, U. Berens, Tetrahedron Lett. 1994, 35, 6061[26] A. A. Ponaras, Md. Y. Meah, Tetrahedron Lett. 1986, 27, 4953

20 �C in CH2Cl2, in the formation of enol ethers 404 in high yields [26](Scheme 5.4). Likewise, silylated alcohols 13 and free 1,2- and 1,3-glycols reactwith ketones in the presence of TMSOTf 20 to cyclic ketals [27].

Reaction of aldehydes and ketones with methanol or glycols at ambient tem-perature in the presence of excess trimethylchlorosilane (TCS) 14 to form acetals,hexamethyldisiloxane 7, and HCl is achieved very simply [28]. Thus cyclohexa-none and diacetyl react with free glycol and TCS 14 to give the acetals 392 and405 in 95% yield [28]. Reaction of phenylglyoxal with methanol in the presence oftrimethylchlorosilane 14 affords the acetal 406 in 83% yield [28], whereas catechol79 is converted by pivaldehyde into acetal 407 in 91% yield [29] (Scheme 5.5).

Polymer-attached 1,3-diols react with substituted benzaldehyde dimethylacetalsin the presence of Me3SiCl 14 to give 1,3-dioxanes in high yields [30].

Of special preparative interest is 2,3-bis(trimethylsilyloxy)trimethylsilylpropane408, readily obtained from allyltrimethylsilane 82 by hydroxylation and subsequentO-silylation, as a new means of protecting carbonyl groups. The silylated glycol


Scheme 5.4

[27] M. Kurihara, N. Miyata, Chem. Lett. 1995, 263[28] T.H. Chan, M.A. Brook, T. Chaly, Synthesis 1983, 203[29] Y. Nishida, M. Abe, H. Ohrui, H. Meguro, Tetrahedron Asymmetry 1993, 4, 1431[30] S.M. Sternson, J. B. Louca, J. C. Wong, S. L. Schreiber, J. Am. Chem. Soc. 2001, 123,

1740

Scheme 5.5

408 reacts readily with aldehydes and ketones such as cyclohexanone to acetalssuch as 409, which are cleaved by LiBF4 in boiling acetonitrile to recover the car-bonyl compound, for example cyclohexanone, in high yields [31] (Scheme 5.6).

Unsaturated ketones such as mesityl oxide react with glycol and Me3SiX (X = Cl,Br) with 1,4-addition of X– to the acetals 410. On employing trimethylsilyl azide19 in combination with SiCl4 57 the azide-acetal 410 (X = N3) is formed, with SiO2

and HCl [32]. The carbonyl group in protected sugar lactones such as 411 reactsanalogously with 1,3-glycols such as 412 in the presence of methoxytrimethylsi-lane 13 a and trimethylsilyl triflate 20 (with the formation of free triflic acid) togive the lactone acetals 413 in high yields [33] (Scheme 5.7).

Trimethyl ortho-benzoate 414 affords, with free 1,2- or 1,3-diols and TMSOTf, 20via 415 �-methoxy esters 416 [34] (Scheme 5.8).

Reaction of ketones such as l-menthone 398 with silylated glycolic acid 417 inthe presence of catalytic amounts of TMSOTf 20 provides an 1:1-mixture of the1,3-dioxolan-4-ones 418 and 419 [35, 36]. Likewise, other aldehydes and ketones[37, 38] and pivaldehyde [39] react with substituted silylated glycolic acids 420a, band �-hydroxy acids 420c to give, e.g., 421a, b and 421c as mixtures [37–40]. Reac-tion of pivaldehyde with the persilylated hydroxy acid 420d and TMSOTf 20 to


Scheme 5.6

[31] B. M. Lillie, M.A. Avery, Tetrahedron Lett. 1994, 35, 969[32] G. Gil, Tetahedron Lett. 1984, 35, 3805[33] H. Ohtake, T. Iimori, S. Ikegami, Tetrahedron Lett. 1997, 38, 3413[34] H. Fujioka, H. Kitagawa, M. Kondo, M. Matsunaga, S. Kitagaki, Y. Kita, Heterocycles

1993, 35, 665[35] W. H. Pearson, M.-C. Cheng, J. Org. Chem. 1986, 51, 3746[36] W. H. Pearson, M.-C. Cheng, J. Org. Chem. 1987, 52, 1353

Scheme 5.7

give 421d failed, as did conventional acetalization methodology. Acetalizationcould be achieved only by reaction of free 3-hydroxy-4-trifluorobutyric acid withTsOH or CSA in boiling benzene with in situ removal of water in the gas phaseby use of molecular sieves [40 a] (Scheme 5.9). Yet reaction of 420d with pivalde-hyde in the presence of TsOH, CSA, or TfOH in boiling xylene, with distillativeremoval of HMDSO 7 (b.p. 100 �C), might also succeed.

5.1.2Conversion of Carbonyl Groups into O,N-, N,N-, N,S-, and O,S-Acetals

O,N-Acetals of aldehydes can be readily prepared by reaction of aldehydes with tri-methylsilylated secondary amines. Thus, formaldehyde is converted by diethylami-notrimethylsilane 146, in 55% yield, into the silylated O,N-acetal 422, which reactswith a further equivalent of 86 to give 90% of the N,N-acetal 423 and 94% hexa-methyldisiloxane 7 [41, 42]. On heating of diethylamine with formaldehyde andHMDS 2, 22% 422, 70% of the N,N-acetal 423, HMDSO 7, and ammonia are ob-tained [42] (Scheme 5.10).

Heating of formaldehyde with bis(trimethylsilyl)methylamine 424 affords, viathe intermediate O,N-acetal 425, on reaction with a second equivalent of formalde-


Scheme 5.8

Scheme 5.9

[37] T. A. Hoye, B.H. Peterson, J. D. Miller, J. Org. Chem. 1987, 52, 1351[38] D. Seebach, R. Imwinkelried, G. Stucky, Helv. Chim. Acta 1987, 70, 448[39] N.A. Petasis, S.-P. Lu, Tetrahedron Lett. 1996, 37, 141[40] A. B. Smith, I.G. Safanov, R. M. Corbett, J. Am. Chem. Soc., 2001, 123, 12426[40a]A. K. Beck, M. Gautschi, D. Seebach, Chimia 1990, 44, 291[41] V. P. Kozyukov, V. P. Kozyukov, V. F. Mironov, Zh. Obshch. Khim. 1982, 52, 1386; Chem.

Abstr. 1982, 97, 163077[42] V. P. Kozyukov, V. P. Kozyukov, V. F. Mironov, Zh. Obshch. Khim. 1983, 53, 2091; Chem.

Abstr. 1984, 100, 22696

hyde, compound 426, whereas with formaldehyde at 110 �C monosilylated methyl-amine 427 gives the N-trimethylperhydrotriazine 428 in 80% yield [41, 42](Scheme 5.11).

Silylated pyrrolidone 388 reacts with formaldehyde to give 429 [41] whereas N-trimethylsilylsuccinimide 201 reacts with formaldehyde only in the presence ofMe3SiONa 96 at 100 �C to give N-trimethylsilyloxymethylenesuccinimide [42]. Thesilylating agent BSA 22 a with formaldehyde at 75 �C gives the O,N-acetal 430 [41].Hydrated ninhydrin 431 is converted by N,O-bis-(trimethylsilyl)acetamide 22 a tothe O,N-acetal 432 [43] (Scheme 5.12).

In the presence of catalytic amounts of TMSOTf 20 methyl pyruvate reacts withN,N-bis(trimethylsilyl)formamide 22 c in CCl4 to give the silylated O,N-acetal 433in 83% yield [44]; this, with allyltrimethylsilane 82 and excess TMSOTf 20, after30 h at 78 �C in CH2Cl2, affords 72% of the methyl ester of 2-allyl-N-formylala-


Scheme 5.10

[43] M. Yalpanu, G. Wilke, Chem. Ber. 1985, 118, 661

Scheme 5.11

Scheme 5.12

nine 434 [44a]. With 22 c in the presence of TMSOTf 20 benzaldehyde gives theO,N-acetal 435 in up to 99% yield [44–47] (Scheme 5.13). With alcohols ROH 11in the presence of TMSOTf 20 these silylated O,N-acetals 436 afford the O,N-ace-tals 437 [46].

Redistilled N,O-persilylated l-proline 438 reacts with pivaldehyde in pentane atambient temperature to give the O,N-acetal 439 in 78% yield; in the presence ofLDA this condenses, � to the carbonyl group, with N-alkyl-2-pyrrole aldehydes [48](Scheme 5.14).

Condensation of N-allyl-N-phenylglyoxamide 440 with silylated sarcosine 441 af-fords, on heating, via the O,N-acetal 442 and elimination of CO2 to give 443, the1,3-dipolar cycloaddition product 444 in 40% yield [49] (Scheme 5.15).

Likewise, heating of aldehyde 445 with persilylated N-benzylglycine 446 in tol-uene leads, via the O,N-acetal 447 and decarboxylation, to the intermediate 448;this cyclizes in 25% yield to the 1,3-dipolar cycloaddition product 449 [50](Scheme 5.16).

Persilylated d-ribose 450 (or other persilylated sugars such as persilylated d-glu-cose) reacts as the O,O-acetal with excess persilylated bases such as persilylateduracil 451, in the presence of TMSOTf 20 in acetonitrile, possibly via 452 and for-


Scheme 5.13

Scheme 5.14

[44] A. P. Johnson, R. W. A. Luke, R.W. Steele, J. Chem. Soc. Chem. Commun. 1986, 1658[44a] E.C. Roos, M.C. Lopez, M.A. Brook, H. Hiemstra, W. N. Speckamp, B. Kaptein,

J. Kamphuis, H.S. Schoemaker, J. Org. Chem. 1994, 58, 3259[45] A. P. Johnson, R. W. A. Luke, R.W. Steele, A. N. Boa, J. Chem. Soc. Perkin I. 1996, 883[46] A. P. Johnson, R. W. A. Luke, A.N. Boa, J. Chem. Soc. Perkin I. 1996, 895[47] A. P. Johnson, R. W. A. Luke, G. Singh, A. N. Boa, J. Chem. Soc. Perkin I. 1996, 907[48] R. Annunciata, M. Ferrari, G. Papeo, M. Resmini, M. Sisti, Synth. Commun. 1997,

27, 23

mation of HMDSO 7, to give persilylated nucleosides (which are O,N-acetals)such as persilylated uridine 3 in moderate yields [51]; these must be transsilylatedin boiling methanol and subsequently purified by preparative HPLC to obtainpure free uridine 1 [52] (Scheme 5.17). An important side reaction, which has stillto be investigated, is apparently the glycoside-forming reaction between the rela-tively unhindered 5-trimethylsilyloxy groups in 450 and the 1-trimethylsilyloxygroups in 450 in the presence of TMSOTf 20 [52a].

O,N-Acetals such as 429 react with silylated amines such as 294 at ambienttemperature or on gentle heating in the presence of trimethylsilyl iodide 17 indiethyl ether to afford, e.g., the N,N-acetal 453 in 88% yield and HMDSO 7 [53].The silylated tetrazole 454 reacts on heating to 160 �C with the O,N-acetal 422 to


Scheme 5.15

Scheme 5.16

[49] M.A. Marx, A.-L. Grillot, C.T. Louer, K. A. Beaver, P.A. Bartlett, J. Am. Chem. Soc.1997, 119, 6153

[50] C.-L. J. Wang, W. C. Ripka, P.N. Confalone, Tetrahedron Lett. 1984, 25, 4613[51] B. Bennua-Skalmowski, K. Krolikiewicz, H. Vorbrüggen, Tetrahedron Lett. 1995, 43,

7845[52] H. Vorbrüggen, I. Retzko, D. Song, W. Münch, unpublished work[52 a] E.M. Nashed, C.P. J. Glaudemans, J. Org. Chem. 1989, 54, 6116[53] N.A. Orlova, I. Yu. Belavin, V. N. Sergeev, A. G. Shipov, Yu. I. Baukov, Zh. Obshch.

Khim. 1984, 54, 717; Chem. Abstr. 1984, 101, 110668

give 70% of the N,N-acetal 455 [54]. More acidic triazoles, for example benzotria-zole 456, or tetrazoles react with the O,N-acetal 457 at room temperature to fur-nish 92% of a mixture of the N,N-acetals 458 [54]. Thus the silylated 1,2,3,4-tetra-zole 459 converts the N-nitro derivative 460 to the N,N-acetal 461 and TCS 14 [55,56] (Scheme 5.18; cf. also Scheme 5.10).

A large range of aromatic and heteroaromatic aldehydes, for example benzalde-hyde 462 a or pyridine-2-aldehyde 462b, condense with two equivalents of N-silyl-ated dimethylamine 463, piperidine, or morpholine 294 in the presence of


Scheme 5.17

[54] A. V. Kalinin, E. T. Apasov, S. L. Ioffe, V.P. Kozyukov, Vik. P. Kozyukov, Izv. Akad.Nauk SSSR, Ser. Khim. 1985, 1447; Chem. Abstr. 1986, 104, 168415

[55] A. V. Apasov, A.V. Kalinin, S. L. Ioffe, V. A. Tartakovskii, Izv. Akad. Nauk SSSR, Ser.Khim. 1993, 1319; Chem. Abstr. 1996, 125, 142840

[56] A. V. Apasov, A.V. Kalinin, S. L. Ioffe, V. A. Tartakovskii, Izv. Akad. Nauk SSSR, Ser.Khim. 1993, 1666; Chem. Abstr. 1996, 125, 221716

Scheme 5.18

TMSOTf 20 in CCl4 via the O,N-acetals 464 a, to give the N,N-acetals 465a and465b in nearly quantitative yields [57] (Scheme 5.19).

Likewise, enolizable aldehydes such as isobutyraldehyde or 2-phenacetaldehyde areconverted by silylated morpholine 294, in the presence of TMSOTf 20, into N,N-acet-als such as 466 in nearly quantitative yield [57]. The thermal and, in particular, Lewisacid-catalyzed conversion of O,N-acetals such as 124 into N,N-acetals such as 464aobviously proceeds via the intermediate 467 and iminium salts such as 468, whichreadily add nucleophiles, as discussed in Sections 5.1.3 and 5.2 (Scheme 5.20).

Benzaldehyde reacts with formamide and Me3SiCl 14 on heating to give, via435, the N,N-acetal 469, which reacts in situ with p-toluenesulfinic acid, in highyields, to give 470 [58]. The analogous reaction of excess �,�-unsaturated aliphaticprimary amide with aliphatic aldehydes in the presence of TMSOTf 20 in 1,2-di-chloroethane at 25 �C affords the unsaturated N,N-acetals in high yield [58a].Benzaldehyde also condenses with excess HMDS 2, in the presence of catalyticamounts of ZnCl2, via 471, to 472 and HMDSO 7 [59] (Scheme 5.21).

With alkyl-, allyl-, benzyl-, or aryl-Grignard or lithium reagents 72 O,N-acetals473 give the N,N-bis-silylated primary amines 474 in high yields; these are con-verted by methanol into the free primary amines 44 and MeOSiMe3 13a [60](Scheme 5.22).

Aromatic aldehydes such as benzaldehyde, anisaldehyde, or 4-pyridinealdehydereact with neat N,S-silylated 2-mercaptoethylamines 475 at 20 �C to give the N,S-


Scheme 5.19

Scheme 5.20

[57] P. Aube, I. Christot, J.-C. Combret, J.-L. Klein, Bull. Soc. Chim. Fr. 1988, 1009[58] J. Sisko, M. Mellingar, P.W. Sheldrake, N.H. Baine, Org. Synth. 77, 198[58a] K. C. Nicolaou, D.W. Kim, R. Baati, Angew. Chem. Int. Ed. 2002, 41, 3701[59] K. Nishiyama, M. Sato, M. Oba, Bull. Chem. Soc. Jpn. 1988, 61, 609

acetals 476 in 88% yield [61]. With benzylmercaptan in the presence of Me3SiCl14 in pyridine butyraldehyde affords the O,S-acetal 477, which is converted in situby Me3SiI 17, in 90% overall yield, into the �-iodomercaptan 478 and HMDSO 7[62] (Scheme 5.23). Alternatively, aldehydes condense with silylated alcoholsMe3SiOR 13 and silylated mercaptans, in the presence of TMSOTf 20 in CH2Cl2at 78 �C, to give the corresponding O,S-acetals in high yields [63].

The penicillin-N,S-acetal 479 reacts with N,N-bis(trimethylsilyl)formamide 22cand Hg(OAc)2, apparently via the iminium salt 480, to give the penicillin-N,N-acetal 481 in 65% yield [64]. On treatment of racemic �-ketoesters such as 482with chiral silylated 1,3-mercaptoalcohols such as 483, in the presence of TMSOTf20, at room temperature a kinetically controlled 2 : 1 mixture of the O,S-acetals484 and 485 is obtained in 90% yield [65]. Triflic acid-catalyzed equilibrium of this2:1 mixture of 484 and 485 in CDCl3 leads, however, to a 9:1 mixture of 484 and485 [65] (Scheme 5.24; cf. the formation of O,S- and, primarily, S,S-acetals in Sec-tion 5.1.5).


Scheme 5.21

Scheme 5.22

Scheme 5.23

[60] T. Morimoto, T. Takahashi, M. Sekiya, J. Chem. Soc. Chem. Commun. 1984, 794[61] L.A. Pavlova, Yu. A. Davidovich, S. V. Rogozhin, Izv. Akad. Nauk SSSR, Ser. Khim.

1986, 228; Chem. Abstr. 1986, 104, 224849[62] T. Aida, D. N. Harpp, T. H. Chan, Tetrahedron Lett. 1980, 21, 3247[63] A. Kusche, R. Hoffmann, P. Keiner, R. Brückner, Tetrahedron Lett. 1991, 32, 467[64] P. Milner, A. W. Guest, F.P. Harrington, R. J. Ponsford, T. C. Smale, A.V. Stachulski, J.

Chem. Soc. Chem. Commun. 1984, 1335

Finally, the silylated O,S-acetal of formaldehyde Me3SiOCH2SMe 1275 is formedas intermediate in the treatment of alcohols or glycols with DMSO and TCS 14;the final products are O,O-acetals such as (n-BuO)2CH2 1280 (cf. Section 8.2.1).

5.1.3Conversion of Carbonyl Groups into Schiff Bases, Iminium Salts, and Enamines

N-Silylated Schiff bases are important synthetic intermediates in preparations ofsubstituted primary and secondary amines, �-lactams, amino acids, etc. The N-silylated Schiff bases of non-enolizable carbonyl groups, for example those ofbenzaldehyde, benzophenone, or p-quinone, are prepared on reaction with the so-dium salt 486 of hexamethyldisilazane 2 (Na-HMDS) to afford hexamethyldisilox-ane 7 and the silylated imines 487, 489, and 490, which can be readily hydrolyzedto the free imines such as 488 on addition of water or methanol [66–68]. An ana-logous reaction is that of quinone with N,N �-bis(trimethylsilyl)carbodiimide 328,probably via N-bis(trimethylsilyl)cyanamide 553, to the N,N �-bis(cyano)imine 556(cf. also the subsequent reaction with p-quinone to give 490). It should be notedhere, however, that compounds such as 487 are also accessible by addition ofphenyllithium to benzonitrile then quenching with trimethylchlorosilane (TCS) 14[67]; 489 can also be obtained by selective reduction of benzonitrile withLi[HAl(OEt)3] then quenching with TCS 14 [69]. In another recent procedure N-tert-butyldimethylsilyl-substituted primary amines are N-chlorinated withMe3COCl followed by treatment with DBU to give N-silylated imines in high yield[70]. The reactions of carbonyl groups with salts of HMDS have subsequently


Scheme 5.24

[65] M. Nishida, K. Nakaoka, S. Ono, O. Yonemitsu, A. Nishida, N. Kawahara, H. Takayama,

J. Org. Chem. 1993, 58, 5870[66] C. Krüger, E.R. Rochow, U. Wannagat, Chem. Ber. 1963, 96, 2132[67] L.-H. Chan, E .G. Rochow, J. Organomet. Chem. 1967, 9, 231[68] K. Rühlmann, H. Schilling, H. Frey, J. Organomet. Chem. 1985, 290, 277[69] P. Andreoli, G. Cainelli, M. Contento, D. Giacomini, G. Martelli, M. Panuncio,

Tetrahedron Lett. 1986, 27, 1695

found many applications; sodium-HMDS 486 has, however, been replaced by Li-HMDS 492 [70–72, 74–76], which is readily accessible in situ by adding butyl-lithium to a solution of HMDS 2 in hexane at –78� (Scheme 5.25).

The substituted benzaldehyde 491 reacts readily with Li-HMDS 492 to give, onsubsequent addition of allylmagnesium bromide to the intermediate N-silylatedSchiff base, the amine 493 in high yield [71]. Analogous additions of allylmagne-sium bromides, lithium acetylides, or Zn reagents to give iminum salts are de-scribed elsewhere [72–74]. In contrast with previously described reactions of non-enolizable carbonyl compounds, enolizable aldehydes such as n-octanal 494 af-ford, after treatment with 492 then with allyl Grignard reagents, amines such as495 in 10% yield only [74]. Later studies demonstrated, however, that, e.g., reac-tion of acetaldehyde with Li-HMDS 492 gives a high yield of the N-silylatedSchiff-base; this reacts in situ with the lithium ester enolate of tert-butyl butyrate496 to afford 46% of the �-lactam 497 [75]. Substituted propionaldehydes reactreadily with Li-HMDS 492 to give, on subsequent treatment with LDA and ethyln-butyrate, �-lactams in moderate yields [76]. Whereas N-silylated benzaldehydeimine 489 reacts with diphenylketene to furnish only 12% of the corresponding �-lactam [77] it was subsequently demonstrated that 489 gives, on addition of thelithium enolate of methyl isobutyrate 498, the �-lactam 499 in 72% yield [78, 79].Equilibria between N-silylated Schiff bases and N-silylated enamines of enolizablecarbonyl compounds are discussed elsewhere [67] (Scheme 5.26).


Scheme 5.25

[70] E.W. Colvin, D. McGarry, M.J. Nugent, Tetrahedron 1998, 44, 4157[71] D.J. Hart, K.-I. Kanai, J. Org. Chem. 1982, 47, 1555[72] M.R. Saidi, M. Mojtahedi, M. Bolourtchian, Tetrahedron Lett. 1997, 38, 8071[73] M.R. Saidi, H.R. Khalaji, J. Chem. Res. (S) 1997, 340[74] D.J. Hart, K.-i. Kanai, D. G. Thomas, T.-K. Yang, J. Org. Chem. 1983, 48, 289[75] G. Cainelli, D. Giacomini, M. Panunzio, G. Martelli, G. Spunta, Tetrahedron Lett.

1987, 28, 5369[76] J. C. Chabala, J. V. Heck, K. L. Thompson, Y.-C.P. Chiang, S. S. Yang, Eur. Pat. EP

462,667; Chem. Abstr. 1992, 116, 194133[77] L. Birkofer, J. Schramm, Liebigs Ann. Chem. 1977, 760

By analogy, the acetylene aldehyde 500 gives, on addition of the chiral Li-enolate501 [79–82], the chiral �-lactams 502 and 503 in 75% yield [80–82]. Similar �-lac-tam-forming reactions are discussed elsewhere [70, 83–88]. The ketone 504 af-fords, with the lithium salt of the silylated lithium amide 505, the Schiff base 506,in 74% yield (Scheme 5.27). The Schiff base 506 is also obtained in 25% yield byheating ketone 504 with (C6H5)3P=N-C6H4Me 507 in boiling toluene for 7 days[89] (Scheme 5.27).

Additions of aryl- or alkyllithium reagents to N-silylated formamides 508 givethe imines 509 in 55–80% yield [90, 91]; some of these imines can subsequentlybe converted into the corresponding �-lactams by reaction with enolates of alkylbutyrates [92]. Conversion of N-silylated butyrolactam 388 into cyclic Schiff basessuch as 390, by reaction with methyl- or butyllithium, via O-silylated butyrolactam389, is discussed in Section 4.8 (Scheme 5.28).


Scheme 5.26

[78] D.-C. Ha, D. J. Hart, T.-K. Yang, J. Am. Chem. Soc. 1984, 106, 4819[79] D.J. Hart, D.-C. Ha, Tetrahedron Lett. 1985, 26, 5493[80] T. Chiba, M. Nagatsuma, T. Nakai, Chem. Lett. 1984, 1927[81] T. Chiba, T. Nakai, Chem. Lett. 1985, 651[82] T. Chiba, T. Nakai, Tetrahedron Lett. 1985, 26, 4647[83] E.W. Colvin, D.G. McGarry, J. Chem. Soc. Chem. Commun. 1985, 539[84] G. Cainelli, M. Contento, D. Giacomini, M. Panunzio, Tetrahedron Lett. 1985, 26, 937[85] G. Cainelli, M. Panunzio, D. Giacomini, G. Martelli, G. Spunta, J. Am. Chem. Soc.

1988, 110, 6879[86] N. Oguni, Y. Ohkawa, J. Chem. Soc. Chem. Commun. 1988, 1376[87] G. Cainelli, D. Giacomini, P. Galletti, A. Gaiba, SynLett 1996, 657[88] G. Cainelli, M. Panunzio, E. Bandini, G. Martelli, G. Spunta, Tetrahedron 1996, 52,

1685[89] W. Verboom, M.R. J. Hamzink, D. N. Reinhoudt, R. Visser, Tetrahedron Lett. 1984, 25,

4309[90] B. L. Feringa, J. F. G.A. Jansen, Tetrahedron Lett. 1986, 27, 507[91] B. L. Feringa, J. F. G.A. Jansen, Synthesis 1988, 184

N-silylated imines 509 react with the Li salts of tosylmethylisonitriles to give4,5-disubstituted imidazoles in moderate yields [93]. Acetylation of N-trimethylsilylimines 509 with acetyl chloride and triethylamine affords 72–80% of the aza-dienes 510; these undergo readily Diels–Alder reactions, e.g. with maleic anhy-dride at 24 �C to give 511 [94] or with dimethyl acetylenedicarboxylate to give di-methyl pyridine-3,4-dicarboxylates [94] (Scheme 5.29).

On reaction with Li-HMDS 492 and subsequent treatment with Me3SiCl 14 �-ketoesters such as 512 afford N-silylated Schiff bases such as 513, which can bereduced to amino acids 514 or amino alcohols 515 and dimerized with methanolor H2O to give the imidazolone 516 [95]. Analogous treatment of benzil with Li-HMDS 492 and quenching with Me3SiCl 14 gives 517, which reacts with the Li-enolate of methyl isobutyrate 498 at 78 �C in THF to give the adduct 518 in 75%


Scheme 5.27

Scheme 5.28

[92] T. Uyehara, I. Suzuki, Y. Yamamoto, Tetrahedron Lett. 1989, 30, 4275[93] N.-Y. Shih, Tetrahedron Lett. 1993, 34, 595[94] L. Ghosez, P. Bayard, P. Nshimyumukiza, V. Gouverneur, F. Sainte, R. Beaudegnies,

M. Rivera, A.-M. Frisque-Hesbain, C. Wynants, Tetrahedron 1995, 51, 11021

Scheme 5.29

yield, whereas warming to 24 �C affords 60% of the pyrroline 519 [96](Scheme 5.30).

Excess Na-HMDS 486 followed by TCS 14, however, converts benzil (or 9,10-phenanthrenequinone) into its silylated bis-imine in high yield; this is readilytranssilylated by abs. ethanol to the free benzil bis(imine) 520 [97]. In the pres-ence of humidity, 520 fragments to benzonitrile and benzaldehydeimine, whichcondenses with 520 to give 2,4,5-triphenylimidazole 521 in 30% yield [97]. Benzal-dehyde 462a or 2-pyridylaldehyde 462b condense with HMDS 2 in DMSO, in thepresence of NaBr, via 522, to give 2,4,5-tris(aryl)imidazoles 523 in high yields [98](Scheme 5.31).

The carbonyl group of methyl benzoate condenses with Na-HMDS 486 to givemethoxytrimethylsilane 13 a and 51% yield of N,O-bis(trimethylsilyl)benzamide296 [99], which is also accessible by silylation of benzamide with TCS 14/triethyla-mine. Benzamide or N-silylated benzamide, however, are converted by Na-HMDS486 in benzene and subsequent quenching with Me3SiCl 14 into 34% N,O-bis(trimethylsilyl)benzamide 296, 24% crystalline N-silylated benzamidine 524,and HMDSO 7 [99] (Scheme 5.32).

Heating of aldehydes and ketones with N-alkylated hexamethyldisilazanesHMDS 525 in the presence of ZnCl2 affords N-alkyl-Schiff bases in 45–95% yield[100, 101]. Whereas acetone reacts with heptamethyldisilazane 525a to give only45% N-methylimine 526a, use of N-phenyl-hexamethyldisilazane 525b affords65% N-phenylimine 526b [100]. Analogously, adamantan-2-one is converted byheptamethyldisilazane 525a, in 95% yield, into the imine 527a and HMDSO 7


Scheme 5.30

[95] Y. Matsuda, S. Tanimoto, T. Okamoto, S. M. Ali, J. Chem. Soc. Perkin I 1989, 279[96] B. Alcaide, J. Rodriguez-Lópes, J. Chem. Soc. Perkin I 1990, 2451[97] G. Tuchtenhagen, K. Rühlmann, Liebigs Ann. Chem. 1968, 711, 174[98] E.A. Mistryukov, Mendeleev Commun. 2001, 29[99] C. Krüger, E.G. Rochow, U. Wannagat, Chem. Ber. 1963, 96, 2138

[100] N. Dauffaut, J.-P. Dupin, Bull. Soc. Chim. Fr. 1966, 3205[101] E. Oliveros-Desherces, M. Riviere, J. Parello, A. Lattes, Synthesis 1974, 812

[101]. Condensation of heptamethyldisilazane 525a (= 424) with ketones or alde-hydes such as benzaldehyde, in the presence of catalytic amounts of trimethylsilyltriflate 20, in CH2Cl2 or Cl(CH2)2Cl, at room temperature or on gentle heating,gives imines such as 528 in nearly quantitative yield [102] (Scheme 5.33).

Fluoride-catalyzed condensations of aldehydes and ketones such as benzalde-hyde with N,N-bis(trimethylsilyl)sulfenamide 529 furnish sulfenimides such as530 in 82–96% yield [103] (Scheme 5.34).


Scheme 5.31

Scheme 5.32

Scheme 5.33

[102] T. Morimoto, M. Sekiya, Chem. Lett. 1985, 1371

Recent review articles on the synthesis and use of N-(trimethylsilyl)imines [104] orN-(trimethylstannyl)imines [105] focus primarily on the preparation of �-lactams.

N,N-bis(Silylated) enamines or dienamines such as 531, 533, or 535 react withbenzaldehyde in DMF, in the presence of CsF or sodium methylate, to give theazadienes 532, 534, 536, and 537 in moderate to good yields [106–110](Scheme 5.35).

It is interesting to note that condensation of the N,N-bis(silylated) enamine 538with a variety of chalcones such as benzalacetophenone 735 proceeds, via 539 andsubsequent cyclization and oxidation, to pyridines such as 540 [106, 108] whereaspersilylated �-amino ketones such as the 2-substituted pyridine 541 cyclize, via542, in 29% yield, to the pyrrole 543 [109] (Scheme 5.36).

Heating of cyclohexanone with N,N-dialkyltrimethylsilyl carbamates 544a and544b affords the enamines 545a and 545b in 55% and 50% yield, respectively[111]. More efficient, however, is the reaction of aldehydes such as n- or iso-butyr-aldehyde and ketones such as cyclopentanone or cyclohexanone with two equiva-lents of N-trimethylsilyldimethylamine 463 to give, either on heating [112] or at


Scheme 5.34

Scheme 5.35

[103] T. Moromoto, Y. Nezu, K. Achiwa, M. Sekiya, J. Chem. Soc. Chem. Commun. 1985,1584

[104] M. Panuncio, P. Zarantonello, Org. Proc. Res. Dev. 1998, 2, 49[105] C. Scolastico, G. Poli, Chemtracts-Org. Chem. 1990, 450[106] R. J.P. Corriu, V. Huynh, J. J.E. Moreau, M. Pataud-Sat, Tetrahedron Lett. 1982, 23,

3257[107] R. J.P. Corriu, V. Huynh, J. J.E. Moreau, M. Pataud-Sat, J. Metalorg. Chem. 1983,

255, 359[108] R. J.P. Corriu, J. J. E. Moreau, M. Pataud-Sat, J. Org. Chem. 1990, 55, 2878[109] R. J.P. Corriu, V. Huynh, J. Iqbal, J. J.E. Moreau, C. Vernhet, Tetrahedron 1992, 48,

6231

room temperature in the presence of TsOH [113], the enamines 546 and 545a inhigh yields, with evolution of dimethylamine and HMDSO 7 [112, 113](Scheme 5.37).

This method fails, however, with bicyclic ketones such as 1-tetralones even inthe presence of TsOH, affording only enol trimethylsilyl ethers such as 107a [114,115]. A subsequent investigation revealed that cyclohexanone reacts with equiva-lent amounts of N-trimethylsilyldimethylamine 463 in the presence of TMSOTf20 at –30 �C to give the enol silyl ether 107a, whereas reaction of cyclohexanone,benzaldehyde, and chlorodimethyl ether with 463 and TMSOTf 20 or TCS 14 at+20 �C afforded the iminium salts 547, 548, and 549 in high yield [116–118].Analogously, N-trimethylsilylpyrrolidine 550 and N-trimethylsilylmorpholine 294convert aldehydes such as benzaldehyde, at ambient temperature in the presence


Scheme 5.36

Scheme 5.37

[110] A. Degl’Innocenti, A. Mordini, D. Pinzani, G. Reginato, A. Ricci, SynLett 1991,712

[111] F. Kardon, M. Mörtl, D. Knausz, Tetrahedron Lett. 2000, 41, 8937[112] T.G. Selin, ‘US Patent 3,621,060; Chem. Abstr. 1972, 76, 45258a[113] R. Comi, R.W. Franck, M. Reitano, S.M. Weinreb, Tetrahedron Lett. 1973, 3107[114] M. Uemura, N. Nishikawa, S. Tokuyama, Y. Hayashi, Bull. Chem. Soc. Jpn. 1980, 53,

293[115] L.H. Hellberg, A. Juarez, Tetrahedron Lett. 1974, 3553

of TCS 14 [116] (or TMSOTf 20 [117, 119] and LiClO4 [120]), into the iminiumchlorides (or triflates or perchlorates) 551 and 552 (Scheme 5.38). These reactionshave recently been reviewed [118].

Alternatively, iminium salts such as 549 or 551 can also be synthesized by reac-tion of aldehydes and ketones with O,N- or N,N-acetals in the presence ofTMSOTf 20 [121], Me3SiCl 14 [122], Me2SiCl2 48, or MeSiCl3 [123]. The reactions[123] and the rate constants [121] for reaction of different electrophilic iminiumsalts R1R2C=NR3R4

+ X– with nucleophilic aromatic systems were recently dis-cussed.

N,N-Bis(trimethylsilyl)carbodiimide 328, which is readily accessible in 81% yieldon silylation of cyanamide with TCS 14/triethylamine [124] and which is appar-ently in equilibrium with N,N-bis(trimethylsilyl)cyanamide 553, reacts readily withnon-enolizable ketones such as 554 or 2,5-dimethyl-p-quinone in the presence ofCsF or TiCl4, probably via 553, to N-cyanoimines such as 555 or 556, in 47 and89% yield, respectively, and HMDSO 7 [125, 126] whereas the enolizable ketone


Scheme 5.38

[116] U. Jahn, W. Schroth, Tetrahedron Lett. 1993, 34, 5863[117] W. Schroth, U. Jahn, S. Ströhl, Chem. Ber. 1994, 127, 2013[118] W. Schroth, U. Jahn, J. Prakt. Chem. 1998, 340, 287[119] A. Armstrong, G. Ahmed, I. Garnett, K. Goacolou, SynLett 1997, 1075[120] M.R. Naimi-Jamal, M.M. Mojtahedi, J. Ipaktschi, M.R. Saidi, J. Chem. Soc. Perkin I

1999, 3709[121] H. Mayr, A.R. Ofial, Tetrahedron Lett. 1997, 38, 3503[122] V.P. Kozyukov, Vik. P. Kozyukov, V.F. Mironov, Zh. Obshch. Khim. 1983, 53, 119;

Chem. Abstr. 1983, 98, 179461[123] H. Heaney, G. Papageorgiou, R. F. Wilkins, Tetrahedron 1997, 53, 2941[124] L. Birkofer, A. Ritter, P. Richter, Tetrahedron Lett. 1962, 195

acetophenone affords only 23% of the N-cyanoimine [125]. The reaction has sub-sequently been applied to other quinoid systems [126–128] (Scheme 5.39).

4-tert-Butylbenzaldehyde condenses with a 5–20-fold excess of urea in the presenceof TCS 14 to give, mainly, the mono-condensation products, which are reduced insitu by NaBH4 to give, in 88–94% overall yield, N-substituted ureas such as 557and HMDSO 7 [129] (Scheme 5.40).

Fluoride-catalyzed condensation of cyclohexanone with tetra(isothiocyanate)silane558 in the presence of Bu4NF or Bu3SnF and (Me3Si)2SO4 559 affords, in 98% yield,the unsaturated isothiocyanate 560 and SiO2 [130].

Finally, because of the close relationship between silicon and tin, carbonyl com-pounds such as phenylacetaldehyde afford with the commercially availablebis[bis(trimethylsilyl)amino]tin(II) 561, which is prepared by reaction of Li-HMDS492 with SnCl2, the N,N-bis(trimethylsilylated)enamine 562, in 85% yield, andSnO [131, 132] (Scheme 5.41).


Scheme 5.39

Scheme 5.40

[125] A. Aumüller, S. Hünig, Angew. Chem. Int. Ed. 1984, 96, 437[126] A. Aumüller, S. Hünig, Liebigs Ann. Chem. 1986, 142[127] E. Günther, S. Hünig, K. Peters, H. Rieder, H.G. von Schnering, J.-U. von

Schütz, S. Söderholm, H.-P. Werner, H.C. Wolf, Angew. Chem. 1990, 102, 220[128] K. Takahashi, K. Kobayashi, J. Org. Chem. 2000, 65, 2577[129] D. Xu, L. Ciszewski, T. Li, O. Repic, T. J. Blacklock, Tetrahedron Lett. 1998, 39, 1107[130] I. Mori, K. Oshima, H. Nozaki, Tetrahedron Lett. 1984, 25, 4683[131] C. Burnell-Curty, E. J. Roskamp, J. Org. Chem. 1992, 57, 5063[132] C. Burnell-Curty, E. J. Roskamp, Synlett. 1993, 131

5.1.4Conversion of Formaldehyde into N-Chloromethyl Lactams, Amides, and Ureas

N-(Chloromethyl)lactams such as 565 [133], N-(Chloromethyl)ureas [134], and N-chloromethyl-amides 566 [135], which are usually prepared in a two-step proce-dure via condensation of lactams, N,N-trimethylurea [134], or secondary amideswith formaldehyde then treatment with thionyl chloride, can be readily obtainedin one step from lactams such as 563 via 564 (cf. also formation of 429 in Sec-tion 5.1.1) or secondary amides such as N-methylbenzamide [135, 136], in up to90% yield, on treatment with formaldehyde and TCS 14, with formation ofHMDSO 7. The resulting N-chloromethylamides such as 566 react with ethyl di-phenylphosphite 567 to give phosphonates such as 568 [135] and with sodium car-boxylates to give the N-acyloxymethylene compounds [136]. Analogously, trimethyl-silylated N,N �-diethyl-N-methylurea 569 with formaldehyde and TCS 14 in THFgives, on heating to 40–60 �C, via the O,N-acetal, the chloromethyl urea 570 andHMDSO 7 in high yield [134]. In a related process, secondary amines such as 4-phenylpiperidine 571 react with DMF in the presence of TCS 14 and imidazole togive, via 572, hexamethyldisiloxane 7 and the iminium chloride 573, which isreadily hydrolyzed by ice water to the N-formylamine 574 in 92% yield [137]. Itshould, however, be emphasized here that DMF is decomposed on heating withTCS 14 at 153 �C, e.g. to Me2NH·HCl, HMDSO 7, and CO [138] (Scheme 5.42)(cf. also the formation of O,S-acetals 484 and 485 in Section 5.1.2).

5.1.5Conversion of Carbonyl Compounds into S,S-Acetals

Whereas aldehydes such as benzaldehyde or ketones are converted by trimethyl-silylated alkyl- or aryl-mercaptans such as 575, in the presence of catalyticamounts of cyanide, to give high yields to O-trimethylsilyl-hemithioketals such as


Scheme 5.41

[133] A. G. Shipov, N. A. Orlova, Yu. I. Baukov, Zh. Obshch. Khim. 1984, 54, 2645; Chem.Abstr. 1985, 102, 78704

[134] V. P. Kozyukov, Vik. F. Mironov, G. I. Orlov, V.F. Mironov, Zh. Obshch. Khim. 1984,54, 230; Chem. Abstr. 1984, 100, 174907

[135] A. Couture, E. Deniau, P. Grandclaudon, Synth. Commun. 1992, 22, 2381[136] R. Moreira, E. Mendes, T. Calheiros, M.J. Bacelo, J. Iley, Tetrahedron Lett. 1994, 35,

7107[137] M.B. Berry, J. Blagg, D. Haig, M.C. Willis, SynLett 1992, 659[138] E.E . Rochow, K. Gingold, J. Am. Chem. Soc. 1954, 76, 4852

576, reaction in the presence of Lewis Acids such as ZnI2, such as ZnI2 [139] orSiCl4 57 [139 a] gives rise to thioacetals and hexamethyldisiloxane 7. Silylated alkylthiols such as ethylthiol 575 or 1,3-propylenedithiol 578, which are prepared fromthiols either with HMDS 2/Me3SiCl 14 [140], butyllithium/Me3SiCl 14 [139], orwith HMDS 2 and imidazole [139], and from lead mercaptides with Me3SiCl 14[141], react with cyclohexanone or diethyl ketone to afford the thio ketals 577 and579 in high yields [139] (Scheme 5.43). Free mercaptans such as benzylmercaptan,1,2-ethanedithiol, or 1,3-propanedithiol, however, react with aldehydes such asbenzaldehyde or furfural and with ketones such as cyclopentanone, in the pres-ence of equivalent amounts of SiCl4 57 in CH2Cl2 at –10 �C, to give thioketals, in70–98% yield, and SiO2 and HCl [139 a].


Scheme 5.42

Scheme 5.43

[139] D.A. Evans, L.K. Truesdale, K.G. Grimm, S.L. Nesbitt, J. Am. Chem. Soc. 1977, 99,5009

[139a] B. Ku, D.Y. Oh, Synth. Commun. 1989, 19, 433

The dimethylketals of �,�-unsaturated ketones, for example 580 a and 580 b, areconverted by 578, in the presence of catalytic amounts of triphenylmethyl perchlo-rate, either into pure 581 a or into mixtures of the 1,2- and 1,4-products 581b and582 b [142], whereas steroidal �4-3-ketones give exclusively the �4-3-thioketals withMe3SiS(CH2)2SSiMe [139]. Reaction of cyclohexenones with 578, in the presenceof ZnI2 in CHCl3, affords, however, 1,1-thioacetals without shift of the olefinicbond [143] (Scheme 5.44).

2-Phenylpropanal 583 reacts with phenylthiotrimethylsilane 584 in the presenceof TiCl4, via the O,S-acetal 585, to give the S,S-acetal 586 [144]. Conducting the re-action in the presence of allyltrimethylsilane 82 and SnCl4 furnishes the allylicsulfides 587 and 588 in 3:1 ratio and 56% yield [144] (Scheme 5.45).

On reacting aldehydes such as propionic aldehyde, however, with a 1:1-mixtureof a silylated allyl- or benzyl alcohol such as 589 and phenylthiotrimethylsilane584 in the presence of TMSOTf 20 O,S-acetals such as 591 are obtained, via theprobable intermediate 590, in high yields [63]. The �-ketoamide 592 is convertedby methylthiotrimethylsilane 593/F3B·OEt2 into the bisthioketal 594 in 81% yield[145]. Ethylenethioketals such as 595 are cleaved by Me3SiBr 16 or Me3SiI 17 in


Scheme 5.44

Scheme 5.45

[140] S.H. Langer, S. Connell, I. Wender, J. Org. Chem. 1958, 23, 50[141] E.W. Abel, J. Chem. Soc. 1960, 4406[142] T. Soga, H. Takenoshita, M. Yamada, J. S. Han, T. Mukaiyama, Bull. Chem. Soc. Jpn.

1991, 64, 1108[143] E. J. Corey, M.A. Tius, J. Das, J. Am. Chem. Soc. 1980, 102, 1742[144] I. Mori, P.A. Bartlett, C.H. Heathcock, J. Org. Chem. 1990, 55, 5966[145] E.K. Mantus, J. Clardy, Tetrahedron Lett. 1993, 34, 1085

combination with DMSO in high yields to the free ketones such as cyclopenta-none [146] (Scheme 5.46).

5.1.6Conversion of Carbonyl Compounds into Thio- and Selenoaldehydes and Ketones

Reaction of aliphatic aldehydes with H2S and TCS 14 at room temperature in thepresence of pyridine leads to the adducts 596, which can be converted by NaH inDMF, via the adducts 597 and the intermediate thioaldehydes 598, into their so-dium salts 599. These sodium salts 599 can be trapped by alkyl- or allyl halides inup to 91% yield to give the vinyl sulfides 600 [147] (Scheme 5.47).

Free intermediate thioaldehydes 598 or 602 and the selenoaldehydes 605 andHMDSO 7 are obtained in THF at 0 �C on treatment of aliphatic and aromatic alde-hydes with bis(trimethylsilyl)thiane 601 or bis(trimethylsilyl)selenide 604 in the pres-ence of traces of butyllithium, while trapping the sensitive intermediate thio- orselenoaldehydes 602 and 605 with cyclopentadiene or cyclohexadiene to furnishmixtures of endo and exo Diels–Alder adducts such as 603a and 606a and 603band 603b [148–150], the exo/endo ratio of which can be controlled [150](Scheme 5.48). Analogous reaction of ketones such as 2-adamantanone or acetyleneketones with Me3SiXSiMe3 608 (a. X= S (601); b. X= Se (604)) in the presence of


Scheme 5.46

[146] G. A. Olah, S.C. Narang, A. K. Mehrotra, Synthesis 1982, 965[147] D.N. Harpp, T. Aida, T.H. Chan, Tetrahedron Lett. 1985, 26, 1795[148] M. Segi, T. Nakajima, S. Suga, S. Murai, I. Ryu, A. Ogawa, N. Sonoda, J. Am. Chem.

Soc. 1988, 110, 1976[149] A. Ricci, A. Degl’Innocenti, A. Capperucci, G. Reginato, J. Org. Chem. 1989, 54, 19[150] A. Capperucci, A. Degl’Innocenti, A. Ricci, A. Mordini, G. Reginato, J. Org. Chem.

1991, 56, 7323

CoCl2·6H2O [149] or TMSOTf 20 [150–152] in acetonitrile afford Diels–Alderadducts in yields of up to 85%. The dienals 607 are converted by bis(trimethyl-silyl)thiane 601 or bis(trimethylsilyl)selenide 604 and catalytic amounts of BuLi,via 609, to the intramolecular Diels–Alder products 610 in up to 70% yield [153,154].

In the presence of catalytic amounts of BF3.OEt2 aromatic aldehydes such asbenzaldehyde are converted by bis(trimethylsilyl)selenide 604 into hexamethyldi-siloxane 7 and the corresponding trimers, for example 611 in up to 90% yield. Onheating with 1,3-dienes such as 2,3-dimethylbutadiene trimers such as 611 reactto give the Diels–Alder product 612 [155] (Scheme 5.49).


Scheme 5.47

Scheme 5.48

[151] A. Degl’Innocenti, A. Capperucci, A. Mordini, G. Reginato, A. Ricci, F. Cerreta,

Tetrahedron Lett. 1993, 34, 873[152] A. Degl’Innocenti, A. Capperucci, P. Scafato, T. Mecca, G. Reginato, A. Mordini,

SynLett 1999, 1739[153] M. Segi, M. Takahashi, T. Nakajima, S. Suga, S. Murai, N. Sonoda, Tetrahedron Lett.

1988, 29, 6965[154] M. Segi, M. Takahashi, T. Nakajima, S. Suga, N. Sonoda, Synth. Commun. 1989, 19,

2431[155] Y. Takikawa, A. Uwano, H. Watanabe, M. Asanuma, K. Shimada, Tetrahedron Lett.

1989, 30, 6047

3-Azido-2-formylbenzo[b]-thiophene 613 is thiated and cyclized by 601 and HClto give benzothieno[3,2-c]isothiazole 614 in 50% yield whereas 613 is reduced ontreatment with 601, in the absence of HCl, to give 3-amino-2-formyl-ben-zo[b]thiophene 615; this reacts with excess 601 and HCl to give 3-amino-2-thiofor-myl-benzo[b] thiophene 616 [156] (Scheme 5.50).

Amides such as DMF or ureas such as N,N-tetramethylurea react withbis(trimethylsilyl)selenide 604 in the presence of BF3·OEt2 to give selenoamides,for example 617, or selenoureas whereas esters such as n-butyl benzoate reactwith 604 in the presence of BF3·Et2O and 2,3-dimethylbutadiene to give 619 via618 [157]. On heating with P4S10/sulfur and hexamethyldisiloxane 7 �-ketoesterssuch as ethyl acetoacetate are converted to 3H-1,2-dithiole-3-thiones such as 620in high yields [158] (Scheme 5.51; cf. also Section 8.6).


Scheme 5.49

Scheme 5.50

[156] A. Degl’Innocenti, M. Funicello, P. Scafato, P. Spagnolo, Chem. Lett. 1994, 1873[157] Y. Takikawa, H. Watanabe, R. Sasaki, K. Shimada, Bull. Chem. Soc Jpn. 1994, 67, 876[158] T. J. Curphey, Tetrahedron Lett. 2000, 41, 9963

Scheme 5.51

5.2Conversion of Carbonyl Groups, their O,O- and O,N-Acetals, O-Silylenoethers,and Iminium Salts into C-Substitution Products

Although some examples of C-substitutions of silylated Schiff bases and iminiumsalts, in particular the formation of �-lactams, have already been mentioned inSections 5.1.3 and 5.1.5 (cf. also C-substitutions of lactones and amides in Sec-tion 4.8) in this section several additional and typical C-substitutions of O,O- andO,N-acetals and of iminium salts derived from carbonyl groups are discussed.

With tetramethoxysilane 58 and allyltrimethylsilane 82, in the presence of10 mol% Me3SiI 17, cyclohexanone affords 1-methoxy-1-(2-propenyl)cyclohexane621 in 90% yield [159]. Isobutyraldehyde reacts with the lithium salt of (S)-(–)-2-phenylethanol 622a and allyltrimethylsilane 82, in the presence of TiCl4 inCH2Cl2, to give the chiral allylic ether 623 [160], whereas benzaldehyde [161], withsilylated (S)-(–)-2-phenyl-ethanol 622b and allyltrimethylsilane 82, in the presenceof Ph2BOTf in toluene, gives chiral ethers such as 624 in high yield [161, 162]. Inanalogous reactions with silylated benzyl alcohol [164] or O-silylated (1R,2R)-N-tri-fluoroacetylnorpseudoephedrine [166] and allyltrimethylsilane 82, in the presenceof diphenylboryl triflate [161], Ph3CClO4 [162], TMSOTf 20 [163, 164, 166], triflicacid [165], or fluorosulfonic acid [15], benzaldehyde affords benzylhomoallylethers. Benzaldehyde also condenses with benzyloxycarbonyl amide 625 andtrimethylpropargylsilane 626 to give the aminoallene 627 [167], which cyclizes inthe presence of AgBF4 to give �3-dihydropyrrole [167]. In contrast with all theLewis acid-catalyzed reactions, benzaldehyde condenses with allyltrimethylsilane82, in the presence of catalytic amounts of the strong phosphine-baseP(i-PrNCH2CH2)3N, in THF after 3 days at room temperature, to give 74% of thesilylated homoallylic ether [168] (Scheme 5.52).

Dimethyl acetals of aldehydes and ketones, for example benzaldehyde dimethylacetal 121, and hemiacetals, react with allyltrimethylsilane 82 at –78 �C in CH2Cl2,in the presence of TMSOTf 20 [169], trimethyliodosilane TIS 17 [159, 170],

5.2 Conversion of Carbonyl Groups, their O,O- and O,N-Acetals, O-Silylenoethers 111

[159] H. Sakurai, K. Sasaki, J. Hayashi, A. Hosomi, J. Org. Chem. 1984, 49, 2808[160] R. Imwinkelreid, D. Seebach, Angew. Chem. Int. Ed. 1985, 97, 781[161] T. Mukaiyama, M. Oshima, N. Miyoshi, Chem. Lett. 1987, 1121[162] T. Mukaiyama, H. Nagaoka, M. Murakami, M. Oshima, Chem. Lett. 1985, 977[163] J. Cossrow, S.D. Rychnowsky, Org. Lett. 2002, 4, 147[164] A. Mekhalfia, I.E. Markó, Tetrahedron Lett. 1991, 32, 4779[165] M. El Giani, H. Heaney, SynLett 1993, 433[166] L.F. Tietze, A. Dölle, K. Schiemann, Angew. Chem. 1992, 104, 1366[167] M. Billet, A. Schoenfelder, P. Klotz, A. Mann, Tetrahedron Lett. 2002, 43, 1453[168] C. Wang, P. Kisanga, J. K. Verkade, J. Org. Chem. 1999, 64, 6459[169] T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1980, 21, 71[169a] A. Ishii, G. Kotera, T. Saeki, K. Mikami, SynLett 1997, 1145[170] H. Sakurai, K. Sasaki, A. Hosomi, Tetrahedron Lett. 1981, 22, 745

Ph3COTf [171], Ph3CClO4 [162, 171], ZnCl2 [172], Ph2BOTf [162], or fluorosulfonicacid combined with bis(trimethylsilyl)acetamide (BSA) 22 a [15] to give methoxyole-fins such as 628 in 81–85% yield and methoxytrimethylsilane 13 a (Scheme 5.53). Inthe presence of TMSOTf 20 in CH2Cl2 cyclohexanone dimethyl acetal is converted byallyltrimethylsilane 82 into the previously described methoxyolefin 621, in 81% yield,and 13a [169], whereas 4-tert-butylcyclohexanone dimethyl acetal affords 89% of amixture in which the stereoisomer with the equatorial allyl group predominatesover the axial isomer 93:7 [169]. On using the stronger Lewis acidMe3SiN(OSO2CF3)2 as catalyst instead of TMSOTf 20 91% yield of 621 and 13 a isobtained [169 a]. In addition to the dimethyl acetals of ketones, ethoxy and benzyloxyderivatives of aldehydes and ketones also give homoallylic ethers [15]. Likewise, avariety of 1-methoxy, 1-alkoxy, or 1-acyloxy derivatives of protected reducing sugarshave been transformed under the action of Lewis acid catalysis with allyl-trimethylsilane 82 and Lewis acids into 1-allyl derivatives.

The diacetal 629, prepared from the carbonyl compound and O-silylated allylicalcohols in the presence of TMSOTf 20, reacts with (E)-1-trimethylsilyl-2,4-penta-diene 630, in the presence of TMSOTf 20 in CH2Cl2 at –78 �C, to afford 60% 631;this undergoes Diels–Alder-cyclization at 170 �C in toluene to give a substituted


Scheme 5.52

Scheme 5.53

[171] T.K. Hollis, B. Bosnich, J. Am. Chem. Soc. 1995, 117, 4570[172] P.M. O’Neill, M. Pugh, A. Stachulski, S.A. Ward, J. Davies, B.K. Park, J. Chem.

Soc. Perkin I 2001, 2682

unsaturated oxadecalin derivative [173]. Several Lewis acid catalysts were tested inthe reaction of the dimethyl acetal of 3-phenylpropionaldehyde 632 with trimethyl-silylethynyl-benzene 633; SnCl4–ZnCl2 afforded the highest yield of 85% 634 andmethoxytrimethylsilane 13 a [174]. Dimethyl acetals of chalcones such as 635 reactwith trimethylsilylcyanide 18 to give, depending on the Lewis acid, the products636 or 637 and 13 a [142]. Likewise, reaction of �-alkoxy- or �-trimethylsilyloxyurethanes with Me3SiCN 18 and F3B.OEt2 or TMSOTf 20 affords �-cyano com-pounds in high yield [175]. Reaction of 635 with PhSSiMe3 584 in acetonitrile, inthe presence of TiCl4, gives the 1,4 adduct 639 only, yet with Ph3CClO4 in ben-zene only the bis adduct 538 and methoxytrimethylsilane 13a are formed [142](Scheme 5.54).

Additions of silylated ketene acetals to lactones such as valerolactone in the pres-ence of triphenylmethyl perchlorate in combination with either allyltrimethylsilane82, trimethylsilyl cyanide 18, or triethylsilane 84b, to afford substituted cyclic ethersin high yields have already been discussed in Section 4.8. Aldehydes or ketones suchas cyclohexanone condense in a modified Sakurai-cyclization with the silylatedhomoallylic alcohol 640 in the presence of TMSOTf 20, via 641, to give unsaturatedcyclic spiro ethers 642 and HMDSO 7, whereas the O,O-diethyllactone acetal 643gives, with 640, the spiroacetal 644 and ethoxytrimethylsilane 13 b [176–181]


Scheme 5.54

[173] D. Craig, J.C. Reader, SynLett 1992, 757[174] M. Hayashi, A. Inubushi, T. Mukaiyama, Chem. Lett. 1987, 1975[175] J.-G. Suh, D.-Y. Shin, J.-K. Jung, S.-H. Kim, J. Chem. Soc. Chem. Commun. 2002,

1064

(Scheme 5.55). Isomerization of the exocyclic double bonds in 642 and 644, by tracesof free triflic acid formed by hydrolysis of TMSOTf 20, to give the endocyclic isomersis effectively prevented by addition of small amounts of collidine [176].

Benzaldehyde dimethyl acetal 121 reacts, for example, with the silylated allylicalcohol 645, in the presence of SnCl2–MeCOCl, via an intermediate analogous to641, to the 3-methylenetetrahydrofuran 646 and methoxytrimethylsilane 13 a [182],whereas benzaldehyde dimethyl acetal 121 reacts with the silylated homoallylalco-hol 640 in the presence of TMSOTf 20 to afford exclusively the cis 4-vinyltetrahy-drofuran 647 and 13 a [183]. A related cyclization of an �-acetoxy urethane 648containing an allyltrimethylsilane moiety gives the 3-vinylpyrrolidine 649 in 88%yield and trimethylsilyl acetate 142 [184, 185]. Likewise, methyl 2-formylamido-2-trimethylsilyloxypropionate reacts with allyltrimethylsilane 82 or other allyltri-methylsilanes to give methyl 2-formamido-2-allyl-propionate and some �2–unsatu-rated amino acid esters and HMDSO 7 [186] (Scheme 5.56).


Scheme 5.55

[176] A. Mekhalfia, I.E. Markó, H. Adams, Tetrahedron Lett. 1991, 32, 4783[177] I.E. Markó, A. Mekhalfia, Tetrahedron Lett. 1992, 33, 1799[178] I.E. Markó, D. J. Bayston, A. Mekhalfia, H. Adams, Bull. Soc. Chim. Belg. 1993, 102,

655[179] I.E. Markó, A. Mekhalfia, F. Murphy, D. J. Bayston, M. Bailey, Z. Janousek, S. Dolan,

Pure Appl. Chem. 1997, 69, 565[180] I.E. Markó, M. Bailey, F. Murphy, J.-P. Declercq, B. Tinant, J. Feneau-Dupont, A.

Krief, W. Dumont, SynLett 1995, 123[181] A. Krief, W. Dumont, I.E. Markó, F. Murphy, J.-C. Vanherck, R. Duval, T. Ollevier,

U. Abel, SynLett 1998, 1219[182] T. Oriyama, A. Ishiwata, T. Sano, T. Matsuda, M. Takahashi, G. Koga, Tetrahedron

Lett. 1995, 34, 5581[183] T. Sano, T. Oriyama, SynLett 1997, 716[184] H.H. Mooiweer, H. Hiemstra, H.P. Fortgens, W. N. Speckamp, Tetrahedron Lett.

1987, 28, 3285[185] H.H. Mooiweer, H. Hiemstra, W. N. Speckamp, Tetrahedron 1989, 45, 4627[186] E.C. Roos, H. Hiemstra, W. N. Speckamp, B. Kaptein, J. Kamphuis, H.E. Schoe-

maker, SynLett 1992, 451

Whereas enol silyl ethers of cyclohexanones 650 condense with dimethyl acetalsof aldehydes and ketones, for example benzaldehyde dimethylacetal 121 [15, 187],in the presence of TMSOTf 20 or fluorosulfonic acid to give a 93:7 mixture of con-densation products such as 651 and its isomer and methoxytrimethylsilane 13 a,reaction of 650 a (= 107a) and 650b with trimethyl orthoformate affords the pro-tected �-formylcyclohexanones 652a [187] and 652b [188], in high yields, andmethoxytrimethylsilane 13a (Scheme 5.57). In acetal 402, in which both R groupsare equatorial, only the equatorial C–O bond is cleaved by TiCl4 to give a cationwhich reacts with the silylenol ether 653 of acetophenone to give, after work-up,products 654 in high yields [189, 190] (cf. also Ref. [169]). Trimethylsilyl enolethers such as 650a or 653 and, in particular, tert-butyldimethylsilylenol ethers un-dergo the Mukaiyama-aldol synthesis, e.g. with benzaldehyde in the presence ofMe3SiN(Tf)2 or t-BuMe2SiN(Tf)2, in high yields [187a].

Analogously, the silylated �-hydroxyallylsilane 655 condenses with excess dihy-drocinnamaldehyde in the presence of TMSOTf 20 at –78 �C to afford, via 656, thedihydropyran 657 in 82% yield [191] (Scheme 5.58). Condensation of benzalde-hyde with methoxytrimethylsilane 13 a and 1-trimethylsilyl-2-butyne 658 in thepresence of TMSOTf 20 in CH2Cl2 affords the allenyl compound 659 in 97% yieldand HMDSO 7 [192].

Treatment of ninhydrin 431 with excess allyltrimethylsilane 82 and triflic acid inacetonitrile affords dehydrated ninhydrin 660 in 55% yield and the O-silylatedproduct 661 in 18% yield [43] (Scheme 5.59).


Scheme 5.56

[187] S. Murata, M. Suzuki, R. Noyori, J. Am. Chem. Soc. 1980, 102, 3248[187a] K. Ishihara, Y. Hiraiwa, H. Yamamoto, J. Chem. Soc. Chem. Commun. 2002, 1564[188] G. A. Molander, S. C. Jeffrey, Tetrahedron Lett. 2002, 43, 359[189] T. Harada, H. Kurokowa, A. Oku, Tetrahedron Lett. 1987, 28, 4847[190] T. Harada, T. Shintani, A. Oku, J. Am. Chem. Soc. 1995, 117, 12346[191] W. R. Roush, G. J. Dilley, SynLett 2001, 955[192] L. Niimi, K. Shiino, S. Hiraoka, T. Yokozawa, Tetrahedron Lett. 2001, 42, 1721

As already emphasized in Section 5.1.2, the Lewis acid-catalyzed conversions ofO,N-acetals such as 464b into N,N-acetals 465b proceed via iminium salts such as662, which readily adds the O-silylated ketene acetal 663 at room temperature inCCl4 to give the C-substitution product 664 in 85% yield [57] (Scheme 5.60). Imi-nium salts, which are formed from ammonium trifluoroacetates and formalde-hyde in aqueous solution, add allyltrimethylsilane 82 to give intermediates suchas 665 which cyclize in water to give 666 [193]. Analogously, N-methyl-N-benzyl-ammonium trifluoroacetate adds formaldehyde and allyltrimethylsilane 82 to give


Scheme 5.57

Scheme 5.58

Scheme 5.59

667 [193, 194]. Free aldehydes such as benzaldehyde are directly converted by 663,excess silylation reagent 463, and TMSOTf 20 to give high yields of C-substitutionproducts such as 668 [57].

In Section 5.1.3 the conversion of aldehydes 491 and 494 into N-silylated Schiffbases and their in-situ reaction with allylmagnesium bromide into unsaturatedsecondary amines 493 and 495 is described. Likewise, reactions of the N-silylatedSchiff bases such as 489 with the lithium enolate of methyl isobutyrate 498 togive �-lactams such as 499 are also discussed in Section 5.1.3.

With trimethylsilyl iodide 17 the O,N-acetal 457 gives the iminium iodide as re-active intermediate; this converts the enol silyl ether 107a in situ into the Man-nich-base 669, in 81% yield, and hexamethyldisiloxane 7 [195]. On treatment ofthe O,N-acetal 473 (or the N-silylated Schiff base 489) with TMSOTf 20 (or ZnI2),the intermediate iminium triflate adds to the ketene acetal 663 to give methoxytri-methylsilane 13 a and silylated �-amino esters such as 670, which are readilytranssilylated by methanol to give the free �-aminoester [70, 196] (Scheme 5.61).

Benzaldehyde can be condensed with the N-silylated urethane 671 and allyltri-methylsilane 82 in the presence of trityl perchlorate to give, via an intermediateO,N-acetal, the substituted urethane 672 in high yield [197]. O,N-Acetals such as673 condense with the enol silyl ether of acetophenone 653 in the presence ofTMSOTf 20 to give the �-hydroxyurethane 674 in 94% yield [198] (Scheme 5.62).


Scheme 5.60

[193] S.D. Larsen, P.A. Grieco, W.F. Fobare, J. Am. Chem. Soc. 1986, 108, 3512[194] A. R. Ofial, H. Mayr, J. Org. Chem. 1996, 61, 5823[195] V. P. Kozyukov, Vik. P. Kozyukov, V.F. Mironov, Zh. Obshch. Khim. 1985, 55, 467;

Chem. Abstr. 1985, 103, 70961[196] K. Okano, T. Morimoto, M. Sekiya, J. Chem. Soc. Chem. Commun. 1984, 883[197] L. Niimi, K.-I. Serita, S. Hiraoka, T. Yokozawa, Tetrahedron Lett. 2000, 41, 7075[198] M. Sugiara, H. Hagio, R. Hirabayashi, S. Kobayashi, J. Am. Chem. Soc. 2001, 123,

12510

Aliphatic or aromatic aldehydes RCHO can be transformed, in situ, via theiriminium iodides, on reaction with enamines of ketones, to give �-aminoketones.Thus, 4-methoxybenzaldehyde reacts with dimethylammonium chloride, triethyla-mine and in situ generated trimethyliodosilane, TIS, 17 via the iminium iodide, togive, on addition of the pyrrolidine-enamine of cyclohexanone 675, the �-aminoke-tone 676 in 86% yield [199] (Scheme 5.63). Aldehydes such as benzaldehyde com-bine with dimethylaminotrimethylsilane 463 in the presence of LiClO4 in diethylether to give the N,N-dimethyliminium perchlorate, which reacts in situ with Znreagents such as BrZn(CH2)2CO2Et 677, in yields of up to 86%, to give 3-, 4-, or5-aminoesters such as 678 [200].

Methyl levulinate 679 condenses with silylated �-alanine 680 in the presence ofcatalytic amounts of TsOH·H2O to give hexamethyldisiloxane 7 and the Schiff-base 681, whose O-trimethylsilyl groups are saponified by water (derived fromTsOH·H2O) to give, via 682, the intermediate enamine 683. Subsequent conden-sation of 683 with the Schiff base 681 affords, via 684, and subsequent saponifica-tion, a 4 : 1 mixture of olefins 685 and 686 [201, 202] (Scheme 5.64).

The N,N-bis(formylamido)acetal of cinnamaldehyde 687 condenses with theenol silyl ether of ethyl acetoacetate 724a, in the presence of TiCl4, to give 79%


Scheme 5.61

Scheme 5.62

[199] M. Arend, N. Risch, SynLett 1997, 974[200] M.R. Saidi, H.R. Khalaji, J. Ipaktschi, J. Chem. Soc. Perkin I 1997, 1983[201] H. Wegmann, Diploma Thesis, University of Bonn, 1977[202] G. Schulz, Ph.D. Thesis, University of Bonn, 1979


Scheme 5.63

Scheme 5.64

Scheme 5.65

yield of a 4:1 mixture of isomers of 688 [203]. 1,4-bis(Trimethylsilyl)-1,4-dihydro-pyridine 689, which is readily available from pyridine on reduction with lithium/Me3SiCl 14 in THF, reacts with benzaldehyde in the presence of catalyticamounts of Bu4NF·2–3H2O in THF to give, via 690 and 691, 3-benzylpyridine692 in 72% yield and HMDSO 7 [204] (Scheme 5.65).

5.3Conversion of Carbonyl Groups and their O,O- or O,N-Acetals into �-Halo, �-Azido,�-Alkinyl, and �-Phosphono Ethers

Aldehydes such as formaldehyde, acetaldehyde, paraformaldehyde, 1,3,5-trioxane,or acetaldehyde-trimer react with trimethyliodosilane (TIS) 17 to give 2,2-di-iodoethers such as 693 and 694 in up to 97% yield [205] (Scheme 5.66).

Whereas 1,3-dioxane is converted by TIS 17 into 83% 695, 12% 696, and 81%HMDSO 7 [206], reaction of 1,4-dioxane with TIS 17 gives 95% 1,2-diiodoethane,53% 1,2-bis-(trimethylsilyloxy)ethane, and 32% of HMDSO 7 [205] (Scheme 5.67).

Cyclic acetals such as the ethyleneacetal of benzaldehyde are cleaved by TIS 17to give 79% benzyl iodide, 99% 1,2-diiodoethane, 98% 2-benzoyloxy-1-iodoethane697, and 99% of HMDSO 7 [206]. Reaction of the ethylene acetal of acetophenone698 with TCS 14, however, affords, besides 1,2-dichloroethane, 8% 699, 17% 700,and 9% 701 [207]. The formation of esters 697 and 700 is similar to conversion ofortho ester 414, via 415, to 416 in Section 5.1.1. Electrophilic anhydrous chloraladds TIS 17 to give 702 [208] (Scheme 5.68) (cf. also Chapter 6, Scheme 6.13).


Scheme 5.66

[203] G. Cainelli, M. Contento, A. Drusiani, M. Panunzio, L. Piessi, J. Chem. Soc. Chem.Commun. 1985, 240

[204] O. Tsuge, S. Kanemasa, T. Naritomi, J. Tanaka, Chem. Lett. 1984, 1255[205] M.G. Voronkov, V. G. Komarov, A. I. Albanov, I.M. Korotaeva, E. I. Dubinskaya, Izvest.

Akad. Nauk. SSSR, Ser. Khim. 1981, 1391; Chem. Abstr. 1981, 95, 133006[206] M.G. Voronkov, E. I. Dubinskaya, V. G. Komarov, Zh. Obshch. Khim. 1990, 60, 1355;

Chem. Abstr. 1991, 114, 9722k[207] R. S. Musavirov, Z. F. Mullakhmetova, E. P. Nedogrei, E.A. Kantor, D.L. Rakmanku-

lov, Khim. Geterosikl. Soed. 1985, 1571; Chem. Abstr. 1986, 106, 4614

�-Iodosulfides such as 704 and 478 can be readily prepared in high yields by treat-ment of silylated O,S-acetals such as 703 or 477 (cf. also Section 5.1.3) with TIS17 [62]. Addition of triethylamine to 478 gives E vinylsulfides such as 705 in 86–95% yield [62]. Aldehydes such as propionaldehyde react with TIS 17 in diethylether at 0 �C to give, in solution, �-iodotrimethylsilyl ethers such as 706 which canbe reacted in situ with cuprates such as BuCuLi to give secondary alcohols such as707 [209] (Scheme 5.69).

Triazidochlorosilane ClSi(N3)3 708, which is readily prepared in situ by reactionof three equivalents of NaN3 with SiCl4 57 in acetonitrile, reacts with acetophe-none to give the tetrazoles 709 and 710 and with cyclohexanone to 6,7,8,9-tetrahy-dro-5H-tetrazolo[1,5-a]azepine 711, SiO2, and HCl [210] (Scheme 5.70).�,�-Unsaturated aldehydes such as cinnamaldehyde react with the triethylsilyl-

ated phosphorus reagent 712 at 0 �C, without solvents, to give �-silyloxyphospho-nates such as 713 in high yields [211]. Whereas �,�-unsaturated aldehydes such ascinnamaldehyde give nearly exclusively products from 1,2-addition of the reagent712, �,�-unsaturated ketones such as methylvinylketone 764 afford exclusively 1,4-addition-products such as 714 [211] (Scheme 5.71).

5.3 Conversion of Carbonyl Groups and their O,O- or O,N-Acetals into �-Halo, �-Azido, �-Alkinyl, 121

Scheme 5.67

Scheme 5.68

[208] M.G. Voronkov, V. G. Komarov, E. I. Dubinskaya, Izvest. Akad. Nauk. SSSR, Ser.Khim. 1982, 2182; Chem. Abstr. 1983, 98, 72219

[209] M.E. Jung, P. K. Lewis, Synth. Commun. 1983, 13, 213[210] A.-A.E. El-Aziz, S.S. Elmorsy, H. Soliman, F.A. Amer, Tetrahedron Lett. 1995, 36,

7337[211] D.A. Evans, K. M. Hurst, L.K. Truesdale, J. M. Takacs, Tetrahedron Lett. 1977, 29,

2495

–20� to +20�

Aromatic aldehydes such as benzaldehyde react with diethylhydrogen phosphite715 in the presence of HMDS 2 and acidic alumina to give the benzylidenederivatives of 1-aminoarylmethylphosphonates such as 716 in 65% yield [212](Scheme 5.72).

5.4Reduction of Carbonyl Groups and their Acetals into Ethers

Acetals of aldehydes such as benzaldehyde dimethyl acetal 121 are readily reducedby trimethylsilane 84a [213] or triethylsilane 84 b in the presence of TMSOTf 20


Scheme 5.69

Scheme 5.70

Scheme 5.71

Scheme 5.72

[212] A. R. Sardarian, B. Kaboudin, Tetrahedron Lett. 1997, 38, 2543[213] T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1979, 4679

[213, 215], trityl perchlorate [214], or a mixture of BSA 22 a with FSO3H [15], togive ethers such as 717 in high yields (Scheme 5.73). The reaction of aldehydessuch as benzaldehyde, e.g. with i-Pr2(PhCH2O)SiH/BiBr3 in acetonitrile, affordsethers such as dibenzyl ether (PhCH2)O 1817 in 90% yield [213a] (cf. alsoScheme 12.15 in Section 12.2).

On reacting aldehydes such as benzaldehyde or cyclohexanecarboxaldehyde 720with silylated alcohols such as 718 or 721, or with triethylsilane 84 b in the presenceof TMSOTf 20 at low temperatures, acetal formation and reduction is achieved inone step to afford ethers 719 and 722 in high yields [215] (Scheme 5.74).

5.5Reactions of �-Dicarbonyl or Tricarbonyl Compounds

5.5.1-Dicarbonyl or Tricarbonyl Compounds with HMDSto Give Amino Compounds or Pyridines>Reaction of �-Dicarbonyl or Tricarbonyl Compounds with HMDSto Give Amino Compounds or Pyridines

“Normal” �-dicarbonyl compounds such as ethyl acetoacetate 723a or acetylace-tone 723b are converted, as the free �-dicarbonyl compounds or as their sodiumsalts, by TCS 14, 14/pyridine, or HMDS 2/TCS 14 into their enol silyl ethers724a [216, 217, 219] and 724b [218]. Yet treatment of �-triketones such as 2-acetyl-dimedone 725 with HMDS 2 results, via the corresponding 2-enol trimethylsilyl


Scheme 5.73

Scheme 5.74

[213a] X. Jiang, J. S. Bajwa, J. Slade, K. Prasad, O. Repic, T. J. Blacklock, Tetrahedron Lett.2002, 43, 9225

[214] T. Kato, N. Iwasawa, T. Mukaiyama, Chem. Lett. 1985, 743[215] S. Hatakeyama, H. Mori, K. Kitano, H. Yamada, M. Nishizawa, Tetrahedron Lett.

1994, 35, 4367[216] H. Gilman, R. N. Clark, J. Am. Chem. Soc. 1947, 69, 967[217] R. West, J. Org. Chem. 1953, 23, 1552[218] R. West, J. Am. Chem. Soc. 1958, 80, 3246[219] D.T. W. Chu, S. N. Huckin, Can. J. Chem. 1980, 58, 138

ether, in quantitative formation of 2-aminoacetyldimedone 726 and hexamethyldi-siloxane 7 [219]. 1,5-Diacetyl-1,3-cyclopentadiene 727 reacts with heptamethyldisi-lazane 525 a as �-triketone to give the amino compound 728 in 94% yield [220](Scheme 5.75)

Whereas heating of the hydrochloride of the enaminone 729 for 4 h at tempera-tures up to 135 �C affords 2,4,6-trimethyl-3-acetylpyridine 732 in 90% yield [221],heating of the free enaminone 729 with 0.5–1.0 equiv. TCS 14 at 125 �C proceeds,probably via 730 and 731, to give 97% 732 [222] (Scheme 5.76).

If the enaminone contains one N-methyl group as in 733a, a mixture of thepyridine 732 and the substituted benzene 735 is obtained, whereas with two N-al-


Scheme 5.75

Scheme 5.76

[220] K. Hatke, A. Kohl, T. Kämpchen, Chem. Ber. 1983, 116, 2653[221] S. Auricchio, R. Bernardi, A. Ricca, Tetrahedron Lett. 1976, 4831[222] C. Kashima, Y. Yamamoto, J. Heterocycl. Chem. 1980, 17, 1141

kyl groups such as in 733b only the benzene derivative 734 is formed [222]. Reac-tion of benzalacetophenone 735 with N-propenylhexamethyldisilazane 538 in thepresence of CsF in DMF affords, via 736 and 737 and subsequent air oxidation,67% yield of the pyridine 540 [106] (Scheme 5.77). On the basis of these results �-dicarbonyl compounds such as acetylacetone 723 b might be converted directly, inhigh yield, into pyridines such as 732 on heating with HMDS 2/TCS 14 or octa-methylcyclotetrasilazane (OMCTS) 52/(NH4)2SO4.

On reaction of 2H-pyran-2-ones 738 with HMDS 2 and catalytic amounts ofDBU, pyridine derivatives 741 are obtained via 739 and 740 in yields of 40–97%[223] (Scheme 5.78).


Scheme 5.77

Scheme 5.78

[223] V. Kvita, Synthesis 1991, 883

40% 20%

5.5.2Reactions of Alkyl 4-Chloro-3-trimethylsilyloxycrotonates with Amidinesto Give Alkyl Imidazole(4,5)-acetates

Because free or esterified imidazole(4,5)-acetates 745 are currently accessible onlyvia a rather tedious multistep synthesis via (4,5)hydroxymethylimidazole [224–226], it seemed obvious to react amidines such as isobutyraminidine·HCl 742with commercially available methyl or ethyl 4-chloroacetoacetates 743a, b to obtain745 directly in one step. Because of the low reactivity of the 4-chlorine in 743,however, reaction of 743, e.g. with isobutyramidine·HCl 742 in the presence of so-dium methylate in methanol, affords exclusively 2-isopropyl-6-chloromethyl-pyri-midin-4-one 744 [227], whereas treatment of 743b with NaOEt in EtOH gives, inthe absence of amidines, 2,5-bis(ethoxycarbonyl)cyclohexane-1,4-dione in nearlyquantitative yield [228, 229].

Because silylation with HMDS 2/TCS 14 in acetonitrile at ambient temperatureconverts the unreactive �-chloroketone moiety of 743 into an E/Z-mixture of reac-tive alkyl 4-chloro-3-trimethylsilyloxycrotonates 746a, b [230, 231] which can be iso-lated and distilled, if humidity is excluded, silylation of 743a, b in the presence ofamidine salts such as 745 gives the desired ethyl or methyl imidazole(4,5)-acetates748a, b via 747a and 747b. The reaction of formamidine acetate with 746a,baffords 745 (with R = H) in up to 70% yield [232, 233] (Scheme 5.79). As side reac-tions one must, e.g., take into account the reaction of 746 with ammonia to give755 which subsequently dimerizes to the pyrazine 756, as discussed in Sec-tion 5.5.3.

Because esters 745a, b of imidazole-acetic acid are unstable when stored forlong periods, owing to intramolecular catalysis by the imidazole moiety, the estersshould be converted into their salts or free acids and stored as such. Only tert-butyl imidazole-(4,5)acetates derived from tert-butyl 4-chloroacetoacetate seemto be stable [232, 233]. N-alkyl-substituted amidines give rise to a mixture of alkylN-alkylimidazole-4- and 5-acetates [232, 233].


[224] F. L. Pyman, J. Chem. Soc. 1911, 99, 668[225] I. Antonini, G. Christalli, P. Franchetti, M. Grifantini, S. Martelli, Synthesis

1983, 47[226] R. Steffens, W. Schunack, Arch. Pharm. (Weinheim) 1987, 320, 135[227] C. O’Murchu, German Pat. Appl. 2,120,247; Chem. Abstr. 1972, 76, 72539[228] E. Greth, German Pat. Appl. 2,317,266; Chem. Abstr. 1973, 83, 113768[229] A. L. Vereshchagin, A. A. Semenov, Zh. Org. Khim. 1982, 18, 1722; Chem. Abstr. 1982,

97, 181793[230] G. Anderson, D. W. Cameron, G. I. Feutrill, R.W. Read, Tetrahedron Lett. 1981, 22,

4347[231] T.H. Chan, M.A. Brook, Tetrahedron Lett. 1985, 26, 2943[232] H. Vorbrüggen, N. Schwarz, Eur. Pat. Appl. 59,156; Chem. Abstr. 1983, 98, 53895[233] N. Schwarz, V.D. Joachim, H. Rehwinkel, H. Vorbrüggen, unpublished work

5.5.3Reactions of Alkyl 4-Chloro-3-trimethylsilyloxycrotonates with Amines and Enamines

Reaction of ethyl 4-chloroacetoacetate 743b with o-phenylenediamine in the pres-ence of HMDS 2/TCS 14 in acetonitrile affords, via 746b, 83% alkyl 2-(2,3-dihy-droquinoxaline) acetate 749, which can be oxidized by air or by MnO2 in CH2Cl2,in 71% yield, to give ethyl 2-quinoxaline acetate 751 [234] (Scheme 5.80). Ethyl2,4-dichloroacetoacetate 750, which is obtained in high yield from ethyl 4-chloroa-cetoacetate 743b on chlorination with SO2Cl2 in CH2Cl2 at ambient temperature[235], reacts with o-phenylenediamine in the presence of HMDS 2/TCS 14, viaethyl 2,4-di-chloro-3-trimethylsilyloxycrotonate, in one reaction step, to give 58%ethyl quinazoline-2-acetate 751 [234].

Reaction of methyl 4-chloroacetoacetate 743a with benzylamine in the presenceof HMDS 2/TCS 14 at ambient temperature in acetonitrile gives 34% of the de-sired butyrolactam 752a, 11% 753a, probably formed by reaction of the enami-none 752a with 746a, 16% 754a, and hexamethyldisiloxane 7 [236] (Scheme 5.81).Whereas 753a is probably formed by electrophilic attack of methyl 4-chloro-3-tri-methylsilyl-oxycrotonate 746 on the enaminone moiety of the butyrolactam 752a,the formation of 754a is apparently a consequence of nucleophilic attack of ben-zylammonium carbonate on the reactive 4-chloro group in 746a. Consequently,the yield of 754a is increased to 31% on introduction of CO2 to the reaction mix-ture [236]. On reaction of the E/Z mixture of 746 with NH3 17% 753b, 1% 754b,and ca. 15% methyl pyrazin-2,5-diacetate 756 are isolated. The pyrazine 756 isprobably formed by dimerization of methyl 4-amino-3-trimethylsilyloxycrotonate


Scheme 5.79

[234] W. Bühler, Ph.D. Dissertation, Free University, Berlin, 1989[235] T. Meul, L. Tenud, A. Huwiler, EP 153,615; Chem. Abstr. 1986, 104, 148723[236] B. Bennua-Skalmowski, H. Vorbrüggen, unpublished work

755 to the dihydropyrazine derivative and subsequent in situ air oxidation to 756[236]. On reaction of the E/Z-mixture 746 with benzylamine in the presence ofCS2, the cyclic thiocarbonates 757 and 758 are formed by attack of benzylammo-nium thiocarbonate on 747, N,N�-thiourea 759 is also formed [236] (Scheme 5.81).

The pyrrolidine enamine of cyclohexanone 675 react, with 746 in THF/acetoni-trile to form, via 760, the bicyclic ketoester 761 in, as yet, only ca 30–40% yield[237] (Scheme 5.82).

Reaction of commercially available 3-chlorotetronic acid 762, obtained by pyroly-sis of methyl 2,4-dichloroacetoacetate at 140 �C in vacuo [235], with o-phenylene-diamine affords, after cyclization–oxidation with AgOAc, the quinoxaline lactone763 in 69% yield [234] (Scheme 5.83).


Scheme 5.80

Scheme 5.81

[237] H. Vorbrüggen, Acc. Chem. Res. 1995, 28, 509

5.5.41,4-Additions of Amines to �,�-Unsaturated Ketones

�,�-Unsaturated ketones such as methyl vinyl ketone 764, cyclohexenone, or ben-zalacetophenone 735 add N-silylated secondary amines such as N-trimethylsilyldi-methylamine 463, N-trimethylsilylmorpholine 294, or N-trimethylsilyldimethyla-mine 463 to afford the corresponding �-aminoenol silyl ethers 765–768 in highyields [238] (Scheme 5.84).

5.6Aminations of Silylated �-Hydroxyaldehydes or �-Hydroxyketones

Whereas condensation of �-hydroxy ketones such as benzoin and acetoin on heat-ing with formamide [240] or ureas in acetic acid [239, 242] to form imidazolessuch as 769 or 770 is a well known reaction, only two publications have yet dis-cussed the amination of silylated enediols, prepared by Rühlmann-acyloin conden-sation of diesters [241], by sodium, in toluene, in the presence of TCS 14 [241,242]. Thus the silylated acyloins 771 and higher homologues, derived from Rühl-

5.6 Aminations of Silylated �-Hydroxyaldehydes or �-Hydroxyketones 129

Scheme 5.82

Scheme 5.83

[238] J.-C. Combret, J.-L. Klein, M. Mousalouhouddine, Tetrahedron Lett. 1984, 25, 3449[239] B. B. Corson, E. Freeborn, Org. Synth. Coll. Vol. II, 1943, 231[240] H. Bredereck, G. Theilig, Chem. Ber. 1953, 86, 88[241] K. Rühlmann, Synthesis 1971, 236[242] J. Akester, J. Cui, G. Fraenkel, J. Org. Chem. 1997, 62, 431

mann-acyloin condensations of methyl adipate, diethyl pimelate, diethyl suberate,or diethyl azelate, are converted by N,N �-dimethylurea in 56–77% yield into theimidazolones 772 and hexamethyldisiloxane 7 [241] (Scheme 5.85) (cf. also the dis-cussion of such Rühlmann-acyloin condensations in Section 12.4).


Scheme 5.84

Scheme 5.85


Methoxytrimethylsilane 13 a (2.11 g, 20 mmol) and benzaldehyde (1.07 g, 10 mmol)are added at –78 �C, in an argon atmosphere, to a solution of (0.022 g, 0.1 mmol)trimethylsilyl triflate 20 in CH2Cl2. The mixture is stirred at –78 �C for an additional3 h, quenched by addition of 0.2 mL dry pyridine at –78 �C, poured into 15 mL of asaturated aqueous solution of NaHCO3 and extracted with ether (3�15 mL). Thecombined extracts are dried over a 1:1 mixture of Na2CO3 and Na2SO4 and evapo-rated. Bulb-to-bulb distillation of the residue gives 1.45 g (94%) benzaldehyde di-methyl acetal 121 as a colorless oil (b.p. 125–135 �C/51 mm) [1] (Scheme 5.86).

Cyclohexanone (0.52 g, 5.3 mmol) is added, under a nitrogen atmosphere, to amixture of dry ethylene glycol (3 mL, 54 mmol) and dry methanol (20 mL). Tri-methylchlorosilane 14 (1.4 mL, 11 mmol) is added and the mixture stirred for16 h at room temperature. The mixture is neutralized to pH 6 by addition of a 5%solution of sodium methoxide in methanol and the solvent is removed under re-duced pressure. The residue is dissolved in 20 mL ether and filtered through 5 gsilica gel, which is then washed with 2�10 mL ether. The combined ether eluatesare evaporated and the crude residue submitted to flash chromatography on silicagel with ethyl acetate–hexane (1:10) to give 0.63 g (83%) cyclohexanoneethyleneketal 392 [28] (Scheme 5.87).

A suspension of l-proline (15 g, 130.3 mmol) and HMDS 2 (85.14 g, 527.5 mmol)containing three drops of conc. H2SO4 is heated under reflux for 45 min under anitrogen atmosphere, whereupon a homogenous solution is obtained. The mixtureis cooled to room temperature and Me3SiCl 14 (22.28 g, 205.1 mmol) is added drop-wise. After 3 h the reaction is complete, according to 1H NMR, and excess silylatingreagent is removed by evaporation in vacuo and the residue distilled (b.p. 76 �C/3 mmHg) to give 27 g (80%) N,O-bis(trimethylsilyl)-l-proline 438, which can bestored at –25 �C. Pivaldehyde (8.93 g, 103.8 mmol) is slowly added at room tempera-ture under nitrogen to 438 (26.83 g, 103.5 mmol) in 20 mL anhydrous n-pentane.After 30 min the N,O-bis(trimethylsilyl)-l-proline 438 is completely transformedinto the oxazolidinone 439 according to 1H NMR. The pentane is evaporated andthe residue purified by distillation to give 14.77 g (78%) pure 439 [48] (Scheme 5.88).


Scheme 5.86

Scheme 5.87

A mixture of sarcosine (45 mg, 0.5 mmol) and bis(trimethylsilyl)acetamide 22 a(272 �L, 1.1 mmol) in 0.5 mL acetonitrile is stirred at room temperature for 1 hand at 40 �C for 30 min to give 441, which is then combined with a solution ofthe glyoxamide 440 in 1 mL abs. toluene. The resulting mixture is heated underreflux for 18 h, cooled, diluted with CH2Cl2, washed with 1 M NaOH, and theaqueous layer is extracted with CH2Cl2. The combined organic layers are washedwith brine, dried, concentrated, and purified by chromatography to give 40 mg(40%) 444 as a yellowish oil [49] (Scheme 5.89).

A solution of redistilled benzaldehyde (4.2 g, 41 mmol) in 10 mL ether is addeddropwise at 0 �C, with magnetic stirring, to Li-HMDS 492 (10 g, 41 mmol) in100 mL abs. ether in a 500 mL round-bottomed flask. The mixture is kept for 1 hat 0 �C then triethylamine (4 mL, 41 mmol) is added followed at once by dropwiseaddition of a solution of acetyl chloride (2.95 mL, 41 mmol) in 10 mL ether. Thecooling bath is then removed and the reaction stirred for two further hours atroom temperature. The triethylamine hydrochloride is removed by filtrationthrough a layer of Celite and the filtrate evaporated in vacuo. The residue is puri-fied by bulb-to-bulb distillation at 80 �C/0.03 mm Hg to give 4.53 g (50%) 510[94a], which reacts readily in CHCl3 at 20 �C with maleic anhydride in 92% yieldto give the bicyclic Diels–Alder adduct 511 [94] (Scheme 5.90).

Trimethyliodosilane 17 (0.02 g, 0.10 mmol) is added, with a syringe, to a cooledsolution of 1 mmol cyclohexanone, 1.1 mmol tetramethoxsilane 58, and 1.2 mmol


Scheme 5.88

Scheme 5.89

Scheme 5.90

allyltrimethylsilane 82 in 2 mL CH2Cl2 at 40 �C. After 0.5 h at 40 �C and 4 h at 0 �Cthe reaction is worked up with ice-cold aqueous sat. NaHCO3 solution, extractedwith ether, and separated and identified by TLC to give 90% 621 [159] (Scheme 5.91).

A suspension of 0.11 mmol SnCl4 and 0.11 mmol ZnCl2 in 4 mL CH2Cl2 is stir-red for 30 min at room temperature under an argon atmosphere. Solutions of theacetal 632 (1.0 mmol) in 2 mL CH2Cl2 and acetylene 633 (1.5 mmol) in 3 mLCH2Cl2 are then added successively. After 3.0 h at room temperature the reactionis worked up with ice-cold aqueous NaHCO3 solution. The combined CH2Cl2 ex-tracts are dried with MgSO4, and separated by preparative TLC to afford0.85 mmol (85%) 634 [174] (Scheme 5.92).

A solution of TMSOTf 20 (3 �L, 0.017 mmol) in 1 mL acetonitrile is added at–20 �C under an argon atmosphere to a solution of benzaldehyde dimethyl acetal121 (0.34 mmol, 51.7 mg) and (Z)-(5-trimethylsilyloxy-2-pentenyl)trimethylsilane640 (94.9 mg, 0.412 mmol) in 3 mL acetonitrile. After 20 min at 20 �C the reactionis quenched with phosphate buffer (pH 7). The combined CH2Cl2 extracts arewashed with brine and dried (Na2SO4) to give, after evaporation, 59.2 mg (99%)647 [183] (Scheme 5.93).

Trimethyl orthoformate, HC(OMe)3 (0.58 g, 5.57 mmol) in 15 mL dry CH2Cl2are added to a mixture of 1-trimethylsilyloxycyclohexene 107a (= 650a) (0.873 g,5.12 mmol), which can be prepared in situ by reaction of cyclohexanone withHMDS 2, Me3SiCl 14, and C4F9SO3K [243]. The mixture is then cooled to –78 �Cand a 0.1 M solution of TMSOTf 20 in CH2Cl2 (0.5 mL, 0.05 mmol) is added un-


Scheme 5.91

Scheme 5.92

Scheme 5.93

[243] H. Vorbrüggen, K. Krolikiewicz, Synthesis 1979, 35

der argon. After 8 h at 78 �C the reaction is quenched with an ice-cold aqueoussolution of NaHCO3 and extracted with CH2Cl2. After the usual work-up andchromatography on SiO2, elution with pentane–ether and ether gives acetal 652 in89% yield [187] (Scheme 5.94).

A catalytic amount of TMSOTf 20 (0.1 mmol) is added to a stirred ice-cold solu-tion of 1.2 mmol benzaldehyde and 1 mmol �-benzyloxy-�-butyrolactone 718 in10 mL CH2Cl2. After 1 h at 0 �C, 1 mmol triethylsilane 84b is added at 0 �C andthe mixture is left to warm to room temperature. After 12 h the reaction mixtureis diluted with ether, washed with aqueous NaHCO3 solution, dried over MgSO4,evaporated, and chromatographed on a SiO2 column with pentane–ether andether to give the benzyl ether 719 in 89% yield [215] (Scheme 5.95).

A Dean–Stark trap is attached to a 1.5-L round-bottomed flask with side arm.A Friederich condenser is attached to the mouth of the trap, a septum is placedover the mouth of the condenser, and the system is flame-dried under vacuumand then purged twice with argon. A stirring bar, freshly distilled cumene(700 mL; b.p. 152–154 �C), dry 1,3-dimethylurea (8.81 g, 0.1 mol), 1,2-bis(trimethyl-silyloxy)cyclohexene 771a (25.85 g, 0.1 mol), and dry p-toluenesulfonic acid-mono-hydrate ((1.97 g, 0.01 mol)) are placed in the flask and the reaction mixture isheated under reflux at 152 �C for 12 h under argon, whereupon 1.9 mL HMDSO 7or H2O has separated in the trap. The cumene is removed by distillation and theremaining 60 mL dark red oil is distilled (b.p. 116–121 �C/0.07 Torr) to give 9.77 g(0.058 mol= 58%) 772a [242] (Scheme 5.96).


Scheme 5.94

Scheme 5.95

Scheme 5.96

6.1Conversion of Alcohols, Esters, and Silyl Ethers into their Corresponding Halides,Azides, and Ethers

Trimethylsilyl iodide 17, which can be generated in situ by reaction of trimethyl-silyl chloride (TCS) 14 with NaI in acetonitrile [1], converts alcohols 11, in highyields at room temperature, into their iodides 773a, HI, and hexamethyldisiloxane(HMDSO) 7 [1–8, 12]. Likewise esters such as benzyl benzoate are cleaved byMe3SiCl 14/NaI in acetonitrile under reflux [1]. Reactions of alcohols 11 with tri-methylsilyl bromide 16 in chloroform or, for in situ synthesis of 16 from LiBr andTCS 14 in acetonitrile and with HMDS 2 and pyridinium bromide perbromide,proceed only on heating in acetonitrile or chloroform to give the bromides 773b;in nearly quantitative yield [3, 8, 12] (Scheme 6.1).

135

6

Reactions of Alcohols, Esters, Silyl Ethers, Epoxides,and Haloalkanes


Scheme 6.1

[1] G. A. Olah, S.C. Narang, B. G. B. Gupta, R. Malhotra, J. Org. Chem. 1979, 44, 1247[2] G. A. Olah, S. C. Narang, B. G. B. Gupta, R. Malhotra, Angew. Chem. Int. Ed. 1979,

18, 612[3] G. A. Olah, B. G.B. Gupta, R. Malhotra, S. C. Narang, J. Org. Chem. 1980, 45, 1639[4] G. A. Olah, S.C. Narang, Tetrahedron 1982, 38, 2225[5] M.G. Voronkov, E. I. Dubinskaya, J. Organomet. Chem. 1991, 410, 13[6] M. Arend, J. Prakt. Chem. 1998, 340, 760[7] M.E. Jung, P. L. Ornstein, Tetrahedron Lett. 1977, 2659[8] M.E. Jung, G. L. Hatfield, Tetrahedron Lett. 1978, 4483[9] M. Lissel, K. Drechsler, Synthesis 1983, 314

[9a] A. V. Malkov, P. Spoor, V. Vinader, P. Kocovsky, J. Org. Chem. 1999, 64, 5308[10] J. G. Lee, K.K. Kang, J. Org. Chem. 1988, 53, 3634[11] M. Labroullière, C. Le Roux, J. Dubac, SynLett 1994, 723[12] M. Labroullière, C. Le Roux, A. Oussaid, H. Gaspard-Iloughmane, J. Dubac, Bull.

Soc. Chim. Fr. 1995, 132, 522

Allylic alcohols such as geraniol 774 and linalool 777 also react with TCS 14 inthe presence of K2CO3 at 0 �C to produce, via 775 or 778, the allylic chlorides 776or 781 in 97% or 89% yield, respectively, and HMDSO 7 [9]. Cinnamyl alcohol779 likewise affords, via its O-trimethylsilylated intermediate cinnamyl chloride,780 in 91% yield [9] and HMDSO 7 whereas 779 reacts with Me3SiN3 19, in thepresence of (acac)2Mo(OTf)2 as Lewis acid, to allylic azides such as 781, in 65%yield, and 7 [9a]. Saturated alcohols do not react with TCS 14 under these condi-tions, however (Scheme 6.2).

Addition of catalytic amounts of SeO2 was subsequently found to catalyze the re-action of saturated alcohols 11 with TCS 14 in CCl4 to give the corresponding chlorocompounds, via intermediate formation of SeOCl2 782, which can be prepared in74% yield from SeO2 and TCS 14 [10]. Whereas benzyl alcohol or neopentyl alcoholare readily converted, after 1–2 h at 25 �C, into benzyl chloride and neopentyl chlo-ride 783 in high yields, cyclohexanol affords 93% chlorocyclohexane 784 only after7 h at 50 �C [10] (Scheme 6.3). It is interesting to note that neither ethylene glycolnor 1,4-butanediol is converted to any of either 1,2-dichloroethane or 1,4-dichlorobu-tane, respectively [10], because of the formation of cyclic selenites.

Secondary alcohols such as cyclohexanol or 2-butanol also react on heating for 20–120 min at 80 �C with TCS 14 in the presence of BiCl3 to give the chloro compoundscyclohexyl chloride 784 and 2-chlorobutane in 93 and 90% yield, respectively, HCl,and HMDSO 7 [11, 12]. Benzyl alcohol is transformed likewise by Me3SiCl 14 after120 min. at 80 �C into benzyl chloride in quantitative yield. Analogously, esters suchas 2-acetoxypropane 785 are also converted by TCS 14 in 100% yield into chloro com-pounds such as 786 and trimethylsilyl acetate 142. The �-lactone 787 gives rise to 788

6 Reactions of Alcohols, Esters, Silyl Ethers, Epoxides, and Haloalkanes136

Scheme 6.2

[12] (Scheme 6.4). The more reactive Me2SiCl2 48 (compared with TCS 14) (orMeSiCl3) converts alcohols likewise into chloro compounds and to oligomers orpolymers (Me2SiO)n 56 instead of the volatile HMDSO 7 [10, 11].

Finally, reaction of primary, secondary, or tertiary alcohols 11 with Me3SiCl 14 inthe presence of equivalent amounts of DMSO leads via 789 and 790 to the chlorocompounds 791 [13]. n-Pentanol, benzyl alcohol, �-phenylethanol or tert-butanolare readily converted, after 10 min reaction time, into their chloro compounds, in89–95% yield, yet cyclohexanol affords after reflux for 4 h cyclohexyl chloride 784in only 6% yield [13] (Scheme 6.5). 1,4-Butanediol is cyclized to tetrahydrofuran(THF) [13 a], whereas other primary alcohols are converted in 90–95% yield intoformaldehyde acetals on heating with TCS 14 and DMSO in benzene [13b] (cf. alsothe preparation of formaldehyde di(n-butyl)acetal 1280 in Section 8.2.1).

Trimethylsilylated alcohols, phenols, or carboxylic acids 13 react with trimethyl-silylated triphenylcarbinol 792 in the presence of TMSOTf 20 to give the tritylethers 793, in 73–98% yield, and HMDSO 7 [14] (Scheme 6.6).

6.1 Conversion of Alcohols, Esters, and Silyl Ethers into their Corresponding Halides, Azides, and 137

Scheme 6.3

Scheme 6.4

[13] D.C. Snyder, J. Org. Chem. 1995, 60, 2638[14] S. Murata, R. Noyori, Tetrahedron Lett. 1981, 22, 2107

Scheme 6.5

6.2Conversion of Allyl alcohols into their Corresponding Thiols or Diallyl Sulfides

Whereas allylic alcohols 794 react with one equivalent of hexamethyldisilathiane601 in the presence of BF3·Et2O, via 795, to give the thiols 796 in 43–99% yield[15, 15 a], use of only 0.55 equivalents of 601 affords, via 797, the diallyl sulfides798 in 81–96% yield [15, 15 a, 16] (Scheme 6.7). Cyclohexenol 799 gives, analo-gously, 90% of the sulfide 800, whereas 3-methyl-2- butene-1-ol 801 affords 60%of 802 and 779 affords 70% of 803 [16].

6.3C-Substitution Reactions of Silylated Allyl or Benzyl Alcohols

Trimethylsilylated allylic alcohols such as 804 react readily with allyltrimethyl-silane 82 in the presence of ZnCl2 in CH2Cl2 to give, after 1.5 h at 25 �C, an ap-proximately ca. 22 : 78 mixture of 805 and 806 in 94% yield, and HMDSO 7 [17].


Scheme 6.6

Scheme 6.7

[15] S.-C. Tsay, L.C. Lin, P.A. Furth, C.C. Shum, D.B. King, S.F. Yu, B.-L. Chen, J. R.

Hwu, Synthesis 1993, 329[15a] L.V. Dunkerton, N.K. Adair, J. M. Euske, K. T. Brady, P. D. Robinson, J. Org. Chem.

1988, 53, 845[16] S.-C. Tsay, G.L. Yep, B.-L. Chen, L.C. Lin, J.R. Hwu, 1993, 49, 8969[17] T. Yokozawa, K. Furuhashi, H. Natsune, Tetrahedron Lett. 1995, 36, 5243

The weaker Lewis acid TMSOTf 20 as catalyst gives, after 2 h at 0 �C in CH2Cl2, a20 : 80 mixture of 805 and 806 in only 23% yield (Scheme 6.8). But this yield willprobably increase either on longer reaction time at 0 �C or on shorter reactiontime at 25 �C! On replacing one of the methyl groups in 804 by an acetylene sub-stituent the resulting enyne adds allyltrimethylsilane 82 or anisole in the presenceof TMSOTf 20 to give allenes [18]. Substituted allyltrimethylsilanes such as 808 re-act with the allylic silylether 807 after 70 h at 25 �C in 62% yield to a 41 :59 mix-ture of 809 and 810 as well as 7 [17]. Closely related additions of 82 to allylicethers or O-acetates are discussed in Refs. 17 a–c.

Free allyl alcohols and some benzyl alcohols react likewise with excess allyltri-methylsilane 82 in the presence of HN(SO2F)2 to give 1,5-dienes [19]. Thus treat-ment of 1,3-diphenylpropenol 811 with 82 at –78 �C in CH2Cl2 in the presence ofHN(SO2F)2 affords the C,C-coupling product 812 in 82% yield, whereas the allylicalcohol 813 gives a 91 : 9 mixture of 814 and 815 in 92% yield [19] (Scheme 6.9). Di-phenylcarbinol is converted readily by 82 into the alcohol 816 in 96% yield. Whereasp-methoxybenzyl alcohol 817 reacts with 82 to give 818 in 90% yield, benzyl alcohol or1-phenylethanol do not give any C-substitution product [20]. Asymmetric allylationsof O-silylated benzhydrols with 82 and a titanium complex have been described [19a].

Reaction of benzhydrols such as 819a and 819 b; with HMDS 2 in the presence oftriflic acid in CH2Cl2 at 80 �C leads to the silylated compounds 820 a and 820 b; andammonium triflate. 4,4-Dimethoxydiphenylcarbinol 819 c, however, disproportionatesvia 821 c, which can be isolated, to give, at 60 �C in CHCl3, 50% of 4,4-dimethoxyben-zophenone 822 and 4,4-dimethoxydiphenylmethane 823, and HMDSO 7(Scheme 6.10). Treatment of pure benzhydrol 819a with triflic acid at 0 �C affords,likewise, the bis-benzhydryl ether 821 a in 98% yield and HMDSO 7 [20] (Scheme 6.10).

6.3 C-Substitution Reactions of Silylated Allyl or Benzyl Alcohols 139

Scheme 6.8

[17a] A. Hosomi, T. Imai, M. Endo, H. Sakurai, J. Organomet. Chem. 1985, 95, 285[17b] Y. Morizawa, S. Kanemoto, K. Oshima, H. Nozaki, Tetrahedron Lett. 1982, 23, 2953[17c] T. Fujisawa, M. Kawashima, S. Ando, Tetrahedron Lett. 1984, 25, 3213[18] T. Ishikawa, M. Okano, T. Aikawa, S. Saito, J. Org. Chem. 2001, 66, 4635[19] G. Kaur, M. Kaushik, S. Trehan, Tetrahedron Lett. 1997, 38, 2521[19a] M. Braun, W. Kotter, Angew. Chem. Int. Ed. 2004, 43, 514[20] P. Gautret, S. El-Ghammarti, A. Legrand, D. Couturier, B. Rigo, Synth. Com. 1996,

26, 707

2,5-Dihydro-2,5-dimethoxyfuran 824 reacts neat at 24 �C with TCS 14 via the in-termediate 825, the 2-trimethylsilyloxyfuran 826 (which can also be readily pre-pared from 5H-furan-2-one), and 827–829 to give the crystalline trimer 830 in20% yield [21]. In the presence of aldehydes such as thiophen-2-aldehyde 831a orbenzaldehyde 831 b, however, 824 reacts via 832 to give the condensation products833 a and 833 b, which are obtained in 30 and 62% yield, respectively [22, 23](Scheme 6.11). Because it is postulated 2-trimethylsilyloxyfuran 826 is a intermedi-


Scheme 6.9

Scheme 6.10

[21] J. Reisch, Z. Mester, Liebigs Ann. Chem. 1982, 2096[22] J. Reisch, Z. Mester, Monatsh. Chem. 1983, 114, 635[23] J. Reisch, Z. Mester, Arch. Pharm. 1985, 318, 459

ate in the formation of 830 and 833 from 832, it should be pointed out here that826 or 2-(tert-butyldimethylsilyloxy)furan, 2-(tert-butyldimethylsilyloxy)thiophene,and N-BOC-2-(tert-butyldimethylsilyloxy)pyrrole, which can be readily prepared bysilylation of 5H-furan-2-one, 5H-thiophen-2-one, and N-BOC-1,5-dihydropyrrol-2-one, have, in recent years, frequently been employed as synthons in the prepara-tion of 5-substituted �2-substituted butyrolactones such as 833, 5-substitutedbutyrothiolactones, and 5-substituted butyrolactams [24, 24 a, 25], and have beenreviewed [24, 24a].

6.4Conversion of Ethers and Ketals into Iodides, Bromides, Chlorides, and �-Iodo Ethers

Because trimethylsilyl iodide 17 can be regarded as a combination of the “hard”trimethylsilyl cation and the “soft” iodide anion, the “hard” trimethylsilyl cationwill complex with the “hard” ether or ester oxygen, thus weakening the bond be-tween oxygen and the adjoining carbon. This adjoining carbon is attacked by the“soft” iodide anion leading to cleavage of this O–C bond under very mild reactionconditions with formation of trimethylsilylated oxygen and the alkyl iodide. Thesecleavage reactions can, furthermore, be simplified by generating the rather sensi-tive trimethylsilyl iodide 17 in situ by reacting the ether or ester with NaI and tri-methylchlorosilane TCS 14 in acetonitrile [1].

6.4 Conversion of Ethers and Ketals into Iodides, Bromides, Chlorides, and �Iodo Ethers 141

Scheme 6.11

[24] G. Rassu, F. Zanardi, L. Batistini, G. Casiraghi, Chem. Soc. Rev. 2000, 29, 109[24a] S.K. Bur, S.F. Martin, Tetrahedron 2001, 57, 3221[25] D.A. DeGoy , H.-J. Chen, W. J. Flosi, D. J. Grampovnik, C.M. Yeung, L.L. Klein, D. J.

Kempf, J. Org. Chem. 2002, 67, 5445

Whereas cleavage of cyclic ethers such as tetrahydrofuran with trimethylsilyliodide 17 proceeds very rapidly at 60 �C in quantitative yield to give 834 a [2–7] thereaction with trimethylsilyl bromide 16 to give 834b; takes several days [4, 5, 8].The analogous cleavage of other ethers, including epoxides or aromatic ethers,with Me3SiI 17 has been documented and discussed in several reviews [2, 4–7].The rather unstable 1-trimethylsilyloxy-4-iodobutane 834a [8] can be converted byexcess 17, in 85% yield, to 1,4-diiodobutane 835 and HMDSO 7 [5]. In the pres-ence of sodium THF reacts with 17 to afford 1,8-bis(trimethylsiloxy)octane 836 in50% yield and 10% 1-trimethylsilyl-4-(trimethylsilyloxy)butane 837 [5]. The lattersubstance 837 can also be obtained on a preparative scale by treatment of THFwith TCS 14 in the presence of Mg and MgI2 [5]. Whereas THF reacts very rapid-ly with 17 at 25 �C to give 834a, the reaction of THF with trimethylsilyl bromide16 requires several days at 25 �C to give 1-trimethylsilyloxy-4-bromobutane 834b;[8]. Tetrahydropyran is cleaved by Me3SiI 17 at 90 �C to give (5-iodopentyl-oxy)trimethylsilane [26]. Perhydrofurfurol 838 is converted by NaI/TCS 14 in ace-tonitrile, in 71% yield, to 1-iodo-4,5-dihydroxypentane 839 [27]. It is interesting tonote that aromatic methyl ethers are cleaved selectively by 17 in preference tomethylenedioxy groups in the presence of quinoline [4, 28] (Scheme 6.12).

1,4-Dioxane reacts with trimethylsilyl iodide 17 to give 96% 1,2-bis-iodoethane,53% 1,2-bis(trimethylsilyloxy)ethane, and 32% HMDSO 7 [5, 29]. 1,3-Dioxolane840 furnishes, via 841, iodomethyl-2-iodoethyl ether 842 and HMDSO 7 [5, 30](Scheme 6.13). 2-Substituted 1,3-dioxolanes 843 are converted by trimethylsilyliodide 17, via a series of postulated intermediates, into 1,2-diiodoethane, the ester844, the alkyl iodide 845, and HMDSO 7 [5] (cf. also Chapter 5, Scheme 5.67).

Whereas ethylene oxide gives with 17 at ambient temperature a quantitativeyield of 1-trimethylsilyloxy-2-iodoethane [5, 31], substituted epoxides such as 846 breact with 17 to give 848 as the main product [32]. Excess 17, however, leads tothe bis-iodo compounds 849 and HMDSO 7 [4, 5]. In the presence of DBU the ep-oxides 850 are converted by 17, which is generated in situ from hexamethyl-disilane 857 and I2, into the allyl alcohols 851 [4, 32] (Scheme 6.14). Cycloctene ep-oxide 852 is opened by SiCl4 at –78 �C in the presence of catalytic amounts of theasymmetric catalyst 853 to give 61% of the chlorohydrin 854 in 98% ee [33].


[26] M.G. Voronkov, E. I. Dubinskaya, V. Komarov, S.F. Pavlov, Zh. Obshch. Khim. 1976,46, 1908; Chem. Abstr. 1976, 85, 192810p

[27] M. Jatzak, R. Amouroux, M. Chastrette, Tetrahedron Lett. 1985, 26, 2315[28] J. Minamikawa, A. Brossi, Tetrahedron Lett. 1978, 3085[29] M.G. Voronkov, V.G. Komarov, A. I. Albanov, I.M. Korotaeva, E. I. Dubinskaya, Izv.

Akad. Nauk, SSSR, Ser. Khim 1981, 1391; Chem. Abstr. 1981, 95, 133006q[30] M.G. Voronkov, E. I. Dubinskaya, V.G. Komarov, Zh. Obshch. Khim. 1990, 60, 1355;

Chem. Abstr. 1991, 114, 5772k[31] M.G. Voronkov, V. G. Komarov, A. I. Albanov, E. I. Dubinskaya, Izv. Akad. Nauk,

SSSR, Ser. Khim, 1978, 2623; Chem. Abstr. 1979, 90, 72270u[32] H. Sakurai, K. Sasaki, A. Hosomi, Tetrahedron Lett. 1980, 2329[33] J. M. Brunel, O. Legrand, S. Reymand, G. Buono, Angew. Chem. Int. Ed. 2000, 39,

2554

6.4 Conversion of Ethers and Ketals into Iodides, Bromides, Chlorides, and �Iodo Ethers 143

Scheme 6.12

Scheme 6.13

Scheme 6.14

1,3-Dioxolane [34] or 1,4- and 1,5-dialkoxy-2-oxacycloalkanes 855a and 855 b; aretransformed by trimethylsilyl iodide 17 into 1-trimethylsilyloxy-3-oxa-�-iodoalkanes[34] or �,�-dimethoxydiiodoalkanes 856a and 856 b; and HMDSO 7 [5], whereas�-butyrolactone affords with 17 98% I(CH2)3CO2SiMe3 [5, 35] (Scheme 6.15).

6.5C–C Bond-formation from Haloalkanes with Allyltrimethylsilane

Preparative amounts of a commercial solution of Bu4NF·2–3H2O in THF can bedehydrated at temperatures between 0 and ca 10 �C by slow addition of hexa-methyldisilane 857 during ca. 24–36 h to give a highly active solution of almostanhydrous Bu4NF in THF, which can be stored for several months at –28 �C[36, 37]. (For more detailed discussion of the dehydration of salts such as Bu4NF·2–3H2O, see also Section 13.1.)

Allyltrimethylsilane 82 is converted by equivalent amounts of “anhydrous” Bu4NFin THF to the intermediate allyl anion, which reacts in situ with benzyl chloride to give53% 4-phenyl-1-butene 858 and the volatile Me3SiF 71 (b.p. 17 �C) and a precipitate ofBu4NCl [35, 36]. Likewise, a large excess of 82 reacts with benzyloxytrimethylsilane13 c; in the presence of trityl tetrakis[3,5-bis(trifluoromethyl)phenyl]borate in CH2Cl2to give 70% 4-phenyl-1-butene 858 [37 a,b, c]. At least two equivalents of allyltrimethyl-silane 82 react with 1,6-dibromohexane in the presence of two equivalents of “anhy-drous” Bu4NF to afford 61% 1,11-dodecadiene 859 and Bu4NBr [36, 37] (Scheme 6.16).Benzyltrimethylsilane 83 reacts in the same way as allyltrimethylsilane 82. For moredetailed discussion of the conversion of allyltrimethylsilane 82 into the anhydrousallyl tetrabutylammonium salt 2078 and its reaction with Br(CH2)6Br to give 859and 2079 see Schemes 13.4 and 13.5. Similar C–C bond-forming reactions employ-ing anhydrous phosphazenium fluoride instead of anhydrous Bu4NF have also beenreported [38].


Scheme 6.15

[34] G. E. Keyser, D. E. Jerry, J.R. Barrio, Tetrahedron Lett. 1979, 35, 263[35] M.G. Voronkov, V. G. Komarov, A. I. Albanov, E. I. Kositsina, E. I. Dubinskaya, Izv.

Akad. Nauk, USSR, 1978, 1692; Chem. Abstr. 1978, 89, 146971b[36] M. Marschner, Ph.D. Dissertation, Technical University, Berlin, 1984[37] H. Vorbrüggen, Acc. Chem. Res. 1995, 28, 509[38] R. Schwesinger, R. Link, G. Thiele, H. Rotter, D. Honerl, H.H. Limbach, F.

Mäusle, Angew. Chem. Int. Ed. 1991, 30, 1372


Me3SiCl 14 (40 mmol) is added with stirring to a solution of 20 mmol benzylbenzoate and 40 mmol NaI in 20 mL abs. acetonitrile. The reaction mixture isthen heated under reflux for 4 h, cooled to room temperature, and 50 mL H2O isadded to saponify the trimethylsilyl benzoate. The reaction mixture is then takenup in 2 � 50 mL ether, which is washed successively with H2O and aqueous thio-sulfate solution to remove inorganic salts and iodine. The benzoic acid is then ex-tracted with 2 � 15 mL aqueous 15% NaHCO3 solution, leaving benzyl iodide andtraces of unreacted benzyl benzoate in the ether layer. On acidification of theaqueous NaHCO3 extract 80% benzoic acid is recovered [1] (Scheme 6.17).

Me3SiCl 14 (10 g, 0.18 mol), SeO2 (0.2 g, 2 mol%), and 5 mL CCl4 are placed ina 50-mL round-bottomed flask equipped with a dropping funnel and a condenserconnected to an oil bubbler. After stirring for several minutes at room tempera-ture benzyl alcohol (5 g, 0.0925 mol) is added slowly, whereupon evolution of HClbegins. The resulting mixture is heated under reflux for 2 h. The flask is thenconnected to a distillation apparatus. After removal of HMDSO 7 and CCl4 the re-sidue is distilled to give 5.5 g (95%) benzyl chloride [10] (Scheme 6.18).


Scheme 6.16

Scheme 6.17

Scheme 6.18

A solution of 1 equiv. 811 in CH2Cl2 is added over a period of 15–20 min to amixture of 1.5 equivalents of allyltrimethylsilane 82 and 10 mol% HN(SO2F)2 at–78 �C. The reaction is complete less than 5 min after addition, as indicated byTLC. After the usual aqueous work up the product 812 is obtained in 82% yield[19] (Scheme 6.19).


Scheme 6.19

7.1Reactions of Heterocyclic N-Oxides with Trimethylsilyl Cyanide, Trimethylsilyl Azide,Trimethylsilyl Isothiocyanate, and Trimethylsilyl Halides

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can beconverted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40–70% yield, in a Reissert–Henze reaction, byactivation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followedby treatment with aqueous alkali metal cyanide in H2O or dioxane.

As described briefly in a lecture [4] and a patent application [5] in 1982 and in thefull paper in 1983 [6], activation of the N-oxide function and subsequent cyanationcan be combined in a one-step procedure by heating the N-oxides of pyridines, qui-nolines, and isoquinolines in acetonitrile with 3–4 equivalents of trimethylsilyl cya-nide 18 in the presence of triethylamine; this affords 2-cyanopyridines, 2-cyanoqui-nolines, and 1-cyanoisoquinolines in 80–90% yield [4–6]. Thus, pyridine N-oxide 860adds 18 in the presence of triethylamine to form the postulated intermediates 861and 863 in boiling abs. acetonitrile, giving, after elimination of trimethylsilanol 4,more than 80% of 2-cyanopyridine 862 and traces of 4-cyanopyridine 864. The leav-ing group trimethylsilanol 4 reacts with a second equivalent of trimethylsilyl cyanide18 to give hexamethyldisiloxane (HMDSO) 7 and hydrogen cyanide, which is neutra-lized by triethylamine. Without the added triethylamine the reaction of pyridine-N-oxide 860 with 18 stops on heating in acetonitrile after ca. 40–50% conversion intothe desired 2-cyanopyridine 862 [6] (Scheme 7.1).

The strong affinity of the “hard” potential trimethylsilyl cation for the “hard” N-oxide moiety and of the “soft” cyanide anion (or the “soft” iodide anion) for the ad-

147

7

Reactions of N–O Systems


[1] M. Henze, Ber. Dtsch. Chem. Ges. 1936, 69, 1566[2] T. Okamoto, H. Tani, Chem. Pharm. Bull. 1959, 7, 925, 930[3] W.E. Feely, E.M. Beavers,. J. Am. Chem. Soc. 1959, 81, 4004[4] H. Vorbrüggen, in “Current Trends in Organic Synthesis”, H. Nozaki, ed., Pergamon

Press, Oxford 1983, p. 331[5] H. Vorbrüggen, Germ. PCT Int Appl. WO 8,301,446; Chem. Abstr. 1983, 99, 105129w

DOS 3231072 Germ. Appl. 19.8.1982[6] H. Vorbrüggen, K. Krolikiewicz, Synthesis 1983, 316

jacent “soft” � carbon atom is apparently the driving force for the selective �-additionof Me3SiCN 18 (or of Me3SiI 17) to heterocyclic N-oxides such as pyridine-N-oxide860 (or picoline-N-oxides 865 or 867 a) to give, via intermediates such as 861 and863 and subsequent elimination of trimethylsilanol 4, the 2-cyano compounds 862(or the later described 2-iodopicolines 1779 in Scheme 12.8) and traces of 864.

Whereas 4-picoline N-oxide 865 is converted by 18 and triethylamine, in boilingacetonitrile, into 2-cyano-4-methylpyridine 866 in 89% yield, 3-picoline N-oxide867 a affords 40% 2-cyano-3-methylpyridine 868a and 40% 2-cyano-5-methylpyri-dine 869a. Analogously, 3-cyanopyridine N-oxide 867 b gives rise to 53% 2,3-dicya-nopyridine 868b and 28% of 2,5-dicyanopyridine 869b, but 3-carboxypyridine N-oxide 867c, which is silylated in situ to the bulky 3-trimethylsilyloxycarbonylpyri-dine N-oxide, affords, with TCS 14 and NaCN in DMF at 110 �C and subsequenttranssilylation with boiling methanol, 2-cyano-5-carboxy-pyridine 869c in 76%yield. In contrast, 3-hydroxypyridine N-oxide 870 reacts with excess 18 and triethyl-amine in boiling acetonitrile or with TCS 14, NaCN, and triethylamine at 100–110 �C in DMF to give exclusively the 2,3-substituted 871. Transsilylation of 871with boiling methanol (cf. Section 2.3) gives the free crystalline 2-cyano-3-hydroxy-pyridine 872 in 73% or 90% overall yield, respectively [6] (Scheme 7.2).

Thus the somewhat unstable, toxic, and relatively expensive trimethylsilyl cyanide18 can be generated in situ [7] by reaction of trimethylsilyl chloride (TCS) 14 with aDMF-solution of KCN or preferably of NaCN, which is much more soluble in DMFthan KCN [8] (cf. the use of KCN/TCS 14/NEt3/DMF [24]) to give, on subsequentheating with heterocyclic N-oxides such as 3-carboxypyridine N-oxide 867c, 3-carbox-amidopyridine N-oxide 867d, 3-hydroxypyridine N-oxide 870, and quinoline N-oxide879, in DMF, to 100–110 �C, 2-cyano-5-carboxypyridine 869c, 2-cyano-5-carboxamido-pyridine 869d, 2-cyano-3-hydroxy-pyridine 872, and 2-cyanoquinoline 880 in highyields [6]. During this in-situ preparation of 18 from TCS 14 and NaCN in DMFin the presence of triethylamine, the subsequently generated trimethylsilanol 4 re-acts with excess TCS 14 to give HMDSO 7 and triethylamine hydrochloride [6].

7 Reactions of N–O Systems148

Scheme 7.1

[7] J. K. Rasmussen, S.M. Heilmann, Synthesis 1978, 219[8] Du Pont Inc. booklet on DMF. Solubilities in DMF: NaCN 0.76 g/100 ml DMF; KCN

0.22 g/100 ml DMF

After work up with H2O and subsequent filtration of any crystalline end product orextraction of the H2O–DMF mixture with Et2O or CH2Cl2, the slight excess of NaCNin the DMF–H2O mother liquor can be readily oxidized by 3–10% H2O2 to non-toxicNaCNO, which might be of practical importance in larger scale synthesis.

Reaction of N-oxides such as 3-cyanopyridine-N-oxide 867 b with excess trimethyl-silyl cyanide 18 and triethylamine can, furthermore, be conducted at + 5 �C in THFon addition of catalytic amounts of Bu4NF·2–3H2O to afford, via 873 and 874, afterwork-up, about the same yields of 2,3-dicyanopyridine 868 b and 2,5-dicyanopyridine869 b as on heating of 867 b with 18/NEt3 [6]. The fluoride-catalyzed procedure mightfail, however, with heterocyclic N-oxides containing trimethylsilylated functionalgroups such as hydroxyl or carboxyl groups, because these O-trimethylsilylated func-tional groups will be immediately desilylated by the fluoride ion.

Subsequently, other authors reacted a series of 3-substituted pyridine N-oxideswith 18/NEt3 or with TCS 14/NaCN in DMF producing, in high yields, the corre-sponding 2-cyano (or 6-cyano) pyridines [9–17]. In particular compounds 867e, f,

7.1 Reactions of Heterocyclic N-Oxides with Trimethylsilyl Cyanide, Trimethylsilyl Azide 149

Scheme 7.2

[9] R. N. Misra, D.S. Karanewsky, US Patent 4,555,520; Chem. Abstr. 1996, 104, 186314[10] T. Sakamoto, S. Kaneda, S. Nishimura, H. Yamanaka, Chem. Pharm. Bull. 1985, 33, 565[11] H. Hilpert, Helv. Chim. Acta 1987, 70, 1307[12] A. L. Hadri, G. Leclerc, J. Heterocycl. Chem. 1993, 30, 631[13] R. J. Bergeron, C.Z. Liu, J. S. McManis, M.X.B. Xia, S. E. Algee, J. Wiegand, J. Med.

Chem. 1994, 37, 1411[14] K. Umemura, H. Noda, J. Yoshimura, A. Konn, Y. Yonazawa, C. Shin, Tetrahedron

Lett. 1997, 38, 3639[15] F. Leroy, M. Bigan, D. Blondeau, Synth. Commun. 1997, 27, 2905[16] K. Umemura, S. Ikeda, J. Yoshimura, K. Okumura, H. Saito, C. Shin, Chem. Lett. 1997, 1203[17] N.M. Kolyadina, A. T. Soldatenkov, O.M. Baktibaev, N. S. Prostakov, Khim. Geterots.

Soed. 1998, 1088

with chelating substituents such R= OMe or R = NMe2, and 871, afford nearly ex-clusively the 2-cyano-3-substituted compounds 868e, f or 872 [10]. It was thus pos-tulated that the N-oxides 867e, f react initially with excess trimethylsilyl cyanide 18via the intermediates 875 and 876 and elimination of trimethylsilanol 4 to give 3-substituted 2-cyanopyridines 868e, f and 875 and very small amounts of the 2,5-substituted pyridines 869 e, f [10] (Scheme 7.3). Subsequently described reactionsof other heterocyclic N-oxides (cf. reactions of pyrimidine N-oxides 891, 894, 896,and 898) seem to indicate, however, that these reactions are probably much morecomplicated, because the bulk of the 3-substituent (cf. also the reactions of867 c,d) also seems to be a major influence.

Cyanations of quinoline 877 and isoquinoline N-oxide 879 in DMF or N-methyl-pyrrolidone provides the cyano compounds 878 and 880 in 90 and 79% yield,respectively (Scheme 7.4); it was expected, e. g., that pyrimidine N-oxides wouldreact analogously [6].

Whereas 2-methylpyridine-N-oxide 881a reacts rather slowly with TCS 14/NaCN/NEt3 in DMF at 100–110 �C, sterically hindered 2-methoxycarbonyl- 881b,2-isopropyl- 881 c, or 2-tert-butylpyridine-N-oxide 881d have not yet been reacted inthe presence of NEt3 or DBU in DMF with the much less bulky but apparently asyet unknown dimethylsilyl cyanide Me2HSiCN 883 (which can probably be gener-


Scheme 7.3

Scheme 7.4

ated readily in situ on addition of the rather cheap, commercially available di-methylchlorosilane Me2HSiCl 882 to a solution in DMF of sodium or potassiumcyanide and triethylamine) to give the 6-cyanopyridines 885b, 885c, or 885 d withformation of Me2HSiOH 884 and (Me2HSi)2O 886 (cf. also the preparation of107b in Section 3.2). Neither have pyridine-N-oxide 860, 2-substituted pyridine-N-oxides 881, or 3-substituted pyridine-N-oxides such as 867 yet been reacted in thepresence of NEt3 or DBU with much more bulky silyl cyanides such as triisopro-pylsilyl cyanide 888, which can probably be prepared in situ by reaction of com-mercial triisopropylsilyl chloride 91 with sodium cyanide in DMF. Such reactionsof 888 with pyridine-N-oxides might proceed via intermediate 889, in which thebulky O-triisopropylsilyl group might block attack of the cyanide ion on the hin-dered 2- or 6-position in 889, in the nearly exclusive formation of the 4-cyanopyri-dines 890 and tris(isopropyl)silanol 92 and the corresponding disiloxane 95(Scheme 7.5).

Analogously, quinoline-N-oxide 877 should be converted by triisopropylsilylcyanide 888/triethylamine into 4-cyanoquinoline while most other heterocyclic N-oxides should be transformed analogously into �-cyanoheterocycles. Although ithas been assumed that, e.g., for Me3SiCN 18 or i-Pr3SiCN 888 prepared in situfrom trialkylsilyl halides (or triflates) and sodium cyanide in DMF (or acetonitrile)the trialkylsilyl cyanides generated add to pyridine N-oxides to give intermediatessuch as 861, the pyridine-N-oxides might react first with trialkylsilyl halides (or tri-flates) to give O-trialkylsilyl pyridinium halides (or triflates) such as 889 (cf. alsothe subsequently described intermediate 932) followed by reaction with cyanideanion to give intermediate addition products such as 861 which furnish, afterelimination of Me3SiOH 4, the desired 2-cyano-pyridines. Consequently, unreac-tive pyridine N-oxides or other heterocyclic N-oxides might nevertheless react withmixtures of Me3SiOSO2CF3 (TMSOTf) 20 or Me3SiSO2C4F9 (TMSONf) 21 withMe3SiCN 18 to give, via heterocyclic N-OSiMe3 pyridinium triflates or nonaflates(analogous to 889) on addition of cyanide anion (generated by attack of the triflateor nonaflate anion on Me3SiCN 18 with reformation of TMSOTf 20 and TMSONf21), the desired 2-cyanopyridines, 2-cyanoquinolines, or 1-cyanoisoquinolines.


Scheme 7.5

Alternatively, unreactive heterocyclic N-oxides might also be readily convertedinto their �-cyano heterocycles on reaction with the strongly electrophilic Cl3SiCN,Cl2Si(CN)2, or ClSi(CN)3, which should be formed in situ on addition of SiCl4 to asolution or suspension of sodium or potassium cyanide in acetonitrile or DMF(cf. the analogous formation of ClSi(N3)3 708 in Scheme 5.70).

4-Substituted pyrimidine N-oxides such as 891 are converted analogously intotheir corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 affordthe 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6).The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines900 are formed nearly exclusively, combination of a 4-methoxy substituent with a5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive for-mation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimi-dine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formedby reaction of the amino group in 902 with DMF in the presence of TCS 14 [23](Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides reactwith 18 under a variety of conditions, e. g. in the presence of ZnBr2 [22].

Analogously 3-hydroxyquinoline N-oxide is converted in 64% yield into 2-cyano-3-hydroxyquinoline [24] whereas substituted isoquinoline N-oxides are trans-formed into their 1-cyanoisoquinolines [25, 26].

1-Ethoxycarbonylpyrrolo[3,4-b] N-oxide 904 furnishes 42% of the 5-cyano product905 and 32% of the saponified 5-cyanoproduct 906, whereas the N-oxides of 2-methyl-or 2-cyanofuropyridines 907a, b, 909a,b, and 911a,b afford 2-methyl- or 2-cyanofur-opyridines 908 a, b, 910a, b, and 912a,b in 84 to 99% yield [27–29a] (Scheme 7.8).


[18] H. Yamanaka, S. Nishimura, S. Kaneda, T. Sakamoto, Synthesis 1984, 681[19] H. Yamanaka, T. Sakamoto, S. Nishmura, M. Sagi, Chem. Pharm. Bull. 1987, 35, 3119[20] H. Yamanaka, T. Sakamoto, S. Niitsuma, Heterocycles 1990, 31, 923[21] N. Sato, J. Heterocycl. Chem. 1989, 26, 817[22] N. Sato, Y. Shimomura, Y. Ohwaki, R. Takeuchi, J. Chem. Soc. Perkin I 1991, 2877[23] E.G. Rochow, K. Gingold, J. Am. Chem. Soc. 1954, 76, 4852[24] R. J. Bergeron, J. Wiegand, W.R. Weimar, J. R. T. Vinson, J. Bussenius, G. W. Yao, J. S.

McManis, J. Med. Chem. 1999, 42, 95[25] Y. Kitahara, T. Nakai, S. Nakahara, M. Akazawa, M. Shimizu, A. Kubo, Chem.

Pharm. Bull. 1991, 39, 2256[26] D.F. Ortwine, T. C. Malone, C.F. Bigge, J.T. Drummond, C. Humblet, G. Johnson,

G. W. Pinter, J. Med. Chem. 1992, 35, 1345[27] J. E. Marcor, R. Post, K. Ryan, J. Heterocycl. Chem. 1992, 29, 1465[28] S. Shiotani, K. Tanigichi, J. Heterocycl. Chem. 1997, 34, 493[29] S. Yamaguchi, M. Kurosaki, K. Orito, H. Yokoyama, Y. Hirai, S. Shiotani, J. Hetero-

cycl. Chem. 1998, 35, 1237[29a] S. Yamaguchi, K. Awajima, Y. Hirai, H. Yokoyama, S. Shiotami, J. Heterocycl. Chem.

1998, 35, 1249


Scheme 7.6

Scheme 7.7

Scheme 7.8

Analogous reactions of furopyridines have been reviewed [30]. It is interestingto note that the N-oxides of several furopyridines such as 907a, 909a, and 911 agive much higher yields of the cyano derivatives 908 a, 910a, and 912a on boilingwith Me3SiCN 18/NEt3/MeCN than with Me3SiCN 18/BzCl/CH2Cl2 or with BzCl/KCN [28, 30].

Analogously, the 2-butyl-7-methyl-imidazo[4,5-c]pyridine N-oxide 913 is con-verted in 84% yield into the 4-cyano compound 914 [31]. Reaction of 3-substitutedquinoxaline N-oxides 915 with 18/DBU gives rise to the expected 2-cyano-3-substi-tuted quinoxalines 916 [32]. Whereas heating of 915a for 3 h with 18/NEt3 inTHF affords only 64% 916a, treatment of 915a with 18 and DBU in THF for 30min at ambient temperature furnishes 95% 916a. Similar effects are observedwith 915b (R = OMe) and 915c (R = CMe3) [32] (Scheme 7.9). The authors do not,however, report whether heating of 915a with 18/NEt3 in acetonitrile for morethan 3 h improves yields of 916a.

The much stronger base DBU apparently assists in the removal of the hydrogenatom in the 2-position of intermediate 861, which thus seems to be an additionalfunction of the added bases triethylamine or DBU, besides neutralization of thegenerated HCN.

In a subsequent paper [33] the authors used both 18/NEt3 and 18/DBU in boil-ing THF to, e.g., acridine N-oxide 917. Whereas combination of 18 with DBUgives, after 60 min boiling, 77% nitrile 918, no 918 is obtained after boiling 917in THF with 18/NEt3 for 60 min – and only 65% 917 is recovered [33] Similarly,phenanthridine N-oxide 919 affords 65% nitrile 920 after 60 min boiling in THFwith 18/DBU whereas heating of 919 for 120 min with 18/NEt3/THF furnishes


Scheme 7.9

[30] S. Shiotani, Heterocycles, 1997, 45, 975[31] N. Cho, K. Kubo, S. Furuya, Y. Sugiura, T. Yasuma, Y. Kohara, M. Ojima, Y. Inada, K.

Nishikawa, T. Naka, Bioorg. Med. Chem. Lett. 1994, 4, 35[32] C. Iijima, A. Miyashita, Chem. Pharm. Bull, 1990, 38, 661[33] A. Miyashita, T. Kawashima, C. Iijima, T. Higashino, Heterocycles 1992, 33, 211

only 18% 920 and 45% recovered 919 [33] (Scheme 7.10). Again, the combination18/NEt3 might succeed, although in boiling acetonitrile.

Quinazoline N-oxide 921 affords only 32% nitrile 922 and 22% amide 923 after10 min. boiling with 18/DBU in THF, yet boiling of 921 with 18/NEt3 for 1 hgives 86% nitrile 922. It thus appears, if humidity has not interfered, thatMe3SiOH 4 might have added, as the nucleophilic DBU salt, to the reactive nitrilegroup in 922 to give the N,O-bis(trimethylsilyl)amide R–C(OSiMe3)=NSiMe3,which affords, on aqueous work-up, the corresponding free amide 923 andHMDSO 7 (Scheme 7.11). If this interpretation is correct, addition of Me3SiO–

H·DBU+ to activated nitriles, which will lead, via their N,O-bis(trimethylsilyl)-amides such as 22 or 296 then desilylation with methanol or H2O, to primaryamides, might be an attractive alternative to presently used methods for hydrationof nitriles to primary amides.

Finally, reaction of 1-phenylphthalazine 3-N-oxide 924 with 18/DBU gives, onboiling in THF for 40 min, 76% nitrile 925 whereas combination 18/NEt3 pro-vides, after 180 min boiling in THF, only 37% nitrile 925 and 37% starting N-ox-ide 924 [33].

It is obvious that the combination of trimethylsilyl cyanide 18/DBU reacts fasterthan the combination 18/NEt3. The higher boiling and more polar acetonitrile is,


Scheme 7.10

Scheme 7.11

however, a more suitable solvent than THF for reaction of N-oxides with the com-bination 18/NEt3, which might, on longer heating in acetonitrile, give as highyields as the more expensive combination 18/DBU. Last, but not least, on usingacetonitrile as solvent, any potential DBU-induced addition of Me3SiOH 4 to acti-vated nitriles to result in the formation of primary amides such as 923 will beminimized, because of competition from the large excess of acetonitrile, whichwill give acetamide via BSA 22 a and desilylation with methanol or H2O.

Two reports have appeared on the reaction of imidazole N-oxides with 18/NEt3

[34, 35]. N-Substituted imidazole-N-oxides 926 react with 18/NEt3 in CHCl3 to af-ford the three nitriles – 927, 928, and 929 [34]. Reaction of 926a (R = C6H11) for96 h at room temperature gives only 5% 2-cyanoimidazole 927 a, 68% 4-cyanoim-idazole 928 a, and 27% 5-cyano compound 929a. Heating of 926a with 18/NEt3

for 17h at 60 �C in CHCl3 results, however, in 59% 2-cyanoimidazole 927a and19% 4-cyanoimidazole 928a, whereas the amount of the 5-cyanoimidazole 929aremains constant. In contrast, reaction of 926b with 18/NEt3 in CHCl3 is nottemperature-dependent, and provides the 2-cyanoimidazole 927b in ca. 30% yield.After 24 h at 20 �C in acetonitrile, however, 74% of the desired 2-cyanoimidazole927b, 5% 928 b, and 21% 929b are obtained, supporting the assumption thatacetonitrile might usually be the optimum solvent for cyanation of heterocyclicN-oxides. Finally, it should also be mentioned that reactions of heterocyclicN-oxides with excess Me3SiCN 18/NEt3 without any solvent have been described[26, 27] (Scheme 7.12).

Reaction of trisubstituted imidazole N-oxides such as 1,4,5-trimethylimidazole-3-oxide 930 with 18/NEt3 in CH2Cl2 at 0–5 �C affords the 1,4,5-trimethyl-2-cyano-imidazole 931 in 78% yield [35].


[34] J. Alcázar, M. Begtrup, A. de la Hoz, J. Org. Chem. 1996, 61, 6971[35] G. Mloston, M. Celeda, G. K.S. Prekash, G. A. Olah, Helv. Chim. Acta 2000, 83, 728

Scheme 7.12

In two publications [36, 37] and a subsequent review [38], a closely related alter-native procedure for conversion of pyridine-N-oxides into cyanopyridines was re-ported in 1983. This used a combination of the mild Lewis acid Me2NCOCl andtrimethylsilyl cyanide 18 for the cyanation of pyridine N-oxides such as 860, af-fording, in CH2Cl2, via 932 and 933, 2-cyanopyridine 862 in 94% yield and appar-ently no 4-cyanopyridine 864 [36–38] (Scheme 7.13). With 3-substituted pyridineN-oxides such as methyl nicotinate N-oxide a mixture of 40% methyl 2-cyanonico-tinate and 60% methyl 6-cyanonicotinate is obtained.

The Me3SiCN 18/Me2NCOCl procedure has been applied successfully to a se-ries of pyridine, bipyridine, and terpyridine N-oxides [37–49]. Pyridine-N-oxides[50] and 1H-pyrrolo[2,3-b]-pyridine N-oxide [51] also react with trimethylsilyl cya-nide 18 in combination with benzoyl chloride instead of Me2NCOCl to give 75–90% 2-cyanopyridines or 39% of 1-benzoyl-6-cyano-1H-pyrrolo[2,3-b]pyridine. Thereactions, already discussed, of N-oxides 907 a, 909a, and 911a with Me3SiCN 18/NEt3 to give 908a, 910a, and 912a are also effected with benzoyl chloride andMe3SiCN 18 in CH2Cl2 [28, 30].

The question of whether the commercially available benzoyl cyanide (PhCOCN),methyl cyanoformate (MeOCOCN), and R2NCOCN are formed (cf., however, Ref.


Scheme 7.13

[36] W. K. Fife, J. Org. Chem. 1983, 48, 1375[37] W. K. Fife, B.D. Boyer, Heterocycles 1984, 22, 1121[38] W. K. Fife, E.F. V. Scriven, Heterocycles 1984, 22, 2375[39] E. Bisagni, M. Rautureau, C. Huel, Heterocycles 1989, 29, 1815[40] P.A. Goodson, A. R. Oki, J. Glerup, D. J. Hodgson, J. Am. Chem. Soc. 1990, 112, 6248[41] R. T. Shuman, P.L. Ornstein, J. W. Pashcal, P.D. Gesellchen, J. Org. Chem. 1990, 55,

738[42] P.L. Ornstein, D.D. Schoepp, M.B. Arnold, J.D. Leander, D. Lodge, J. W. Pashcal, T.

Elzey, J. Med. Chem. 1991, 34, 90[43] G. Chelucci, Synth. Commun. 1992, 22, 2645[44] G. Chelucci, Synth. Commun. 1993, 23, 1897[45] M. Horikawa, K. Hashimoto, H. Shirahama, Tetrahedron Lett. 1993, 34, 331[46] V.-M. Mukkala, M. Kwiatkowski, J. Kankare, H. Takalo, Helv. Chim. Acta 1993, 76, 893[47] V.-M. Mukkala, M. Hellenius, I. Hemmilä, J. Kankare, H. Takalo, Helv. Chim. Acta

1993, 76, 1361[48] G. Chelucci, M.A. Cabras, A. Saba, J. Heterocycl. Chem. 1994, 31, 1289[49] S. de la Moya Cereo, M. Böhme, M. Nieger, F. Vögtle, Liebigs Ann. Chem. 1997, 1221[50] F.R. Heirtzler, SynLett 1999, 1203[51] S. Minakata, M. Komatsu, Y. Ohshiro, Synthesis 1992, 661

[54]) in these reactions, in situ, as reactive intermediates, which could be used assuch in combination with triethylamine to convert heterocyclic N-oxides into theircorresponding cyano heterocycles, has, apparently, not yet been addressed.Whereas a substituted quinoline N-oxide affords with 18/Me2NCOCl 95% 2-cyano-quinoline [52], isoquinoline N-oxide 879 gives rise to 98% 1-cyanoisoquinoline 880[53]. Quinoxaline N-oxide reacts with the combination 18/benzoyl chloride inCH2Cl2 to give 2-cyanoquinoxaline in 72% yield [54].

In a critical comparison [8] of the reagent combinations Me3SiCN/18/NEt3/MeCN, Me3SiCN 18/Me2NCOCl/CH2Cl2 [27], or of Me3SiCN 18/PhCOCl inCH2Cl2 for cyanation of a variety of heterocyclic N-oxides, the first method wasdeemed to be more convenient [8, 28, 30]. Furthermore, as will be described inthe reaction of 1H-pyrrolo-[2,3-b]pyridine 936 with MeOCOCl/Me3SiNCS 937, anyfree NH or NH2 group in the heterocyclic N-oxide might be acylated by PhCOClor MeOCOCl [51]. Such N-acylation could also occur by reaction with the combi-nation of the less electrophilic Me2NCOCl with Me3SiCN 18. Finally, the presenceof chloride ions in the reaction might lead to formation of 2-chloroheterocycliccompounds, for example the subsequently discussed formation of the 6-chloropyr-rolo[2,3-b]pyridine 939.

Whereas our experiments failed to convert pyridine-N-oxide 860, on heatingwith excess trimethylsilyl azide 19, in which the azide is neither “hard” nor “soft”,in combination with triethylamine in MeCN, into 2-azidopyridine, combination ofMe3SiN3 19/Et2NCOCl/CH2Cl2 (or in situ-formed Et2NCON3) converts the muchmore reactive 3-aminopyrazine N-oxide 934 in boiling acetonitrile, in 99% yield,into 2-azido-3-aminopyrazine 935 [55, 56] (Scheme 7.14). Other substituted pyra-zine-N-oxides give, likewise, 2-azidopyrazines in 45–100% yield [56]. BecauseMe3SiN3 19 can also be readily prepared in situ from Me3SiCl 14 and NaN3 inDMF [57], introduction of azide groups into reactive heterocyclic N-oxides canprobably be simplified, although it has still to be established which heterocyclicN-oxides do react with 19 to give 2-or 4-azidoheterocycles. Less reactive N-oxidesmight also be converted into their azides by the much more electrophilic Cl3SiN3,Cl2Si(N3)2, or ClSi(N3)3 708, which are formed in situ on addition of SiCl4 to a so-lution of sodium azide in DMF (cf. Chapter 5, Scheme 5.70).

The N-oxide of 1-pyrrolo[2,3-b]pyridine 936 is converted by the combination tri-methylsilylisothiocyanate Me3SiNCS 937/MeOCOCl to 21% 6-isothiocyanato-1-methoxycarbonyl-pyrrolo[2,3-b]pyridine 938 and 18% 6-chloro-1-methoxycarbonyl-pyrrolo[2,3-b]pyridine 939 [51] (Scheme 7.14). To avoid formation of the chlorocompound 939 a reagent combination of Me3SiNCS 937 with triethylamine orDBU, which lacks any competing chloride ion, might give much higher yields of


[52] S.A. Shiba, Indian J. Chem. 1995, 34b, 895[53] B. Elman, C. Moberg, Tetrahedron 1986, 42, 223[54] J. Nasielski, S. Heilporn, R. Nasielski-Hinkens, B. Tinant, J. P. Declercq, Tetrahe-

dron 1989, 45, 7795[55] N. Sato, N. Miwa, N. Hirokawa, J. Chem. Soc. Perkin I, 1994, 885[56] N. Sato, T. Matsuura, N. Miwa, Synthesis 1994, 931[57] H. Vorbrüggen, K. Krolikiewicz, Synthesis, 1979, 35

the desired 2-isothiocyanato heterocycle 938, if isomerization of any equilibriumbetween Me3SiNCS 937 and Me3SiSCN 940 does not depend on the presence of aLewis acid such as Me2NCOCl or MeOCOCl. The more electrophilic reagentsCl3SiNCS, Cl2Si(NCS)2, ClSi(NCS)3, or Si(NCS)4 558 might also be generated insitu on addition of SiCl4 to a solution of KSCN in DMF.

The partial conversion of 936 into the 2-chloro heterocycle 939 [51] and intro-duction of chloro groups into 2,3-diphenylquinoxaline-N-oxide [54] indicates that itmight be possible to convert reactive heterocyclic N-oxides into 2-chloro- or bro-mo-N-heterocycles by use of Me3SiCl 14 or Me3SiBr 16 or, much more simply,with the stronger electrophiles SiCl4 and SiBr4, whereas the much more reactiveMe3SiI 17 readily gives labile 2-iodo N-heterocycles such as the 2-iodopicolines1779 described later (Scheme 12.8). In a related reaction N-oxides of methyl-sub-stituted pyrazoles 941a or triazoles 941b are converted by Me3SiI 17 and1,2,2,6,6,-pentamethylpiperidine, via 942, into the iodomethyl heterocycles 943and HMDSO 7 [58] (Scheme 7.15). Likewise, the 5-methylpyrazole-2-N-oxides 944afford a mixture of the iodomethyl compounds 945 and the trimethylsilyloxy-methyl compounds 946 [58]. Reaction of related methyl-substituted azole-N-oxideswith trimethylsilyl triflate (TMSOTf) 20 leads to the introduction of C-trimethylsi-lyl groups [59].

7.2Additions of Allyl- and Benzyltrimethylsilanes to Aromatic Heterocyclic N-Oxides

Because allyltrimethylsilane 82 or benzyltrimethylsilane 83 can be regarded ascombinations of the “hard” trimethylsilyl cation and the “soft” allyl or benzyl an-ions, pyridine N-oxide 860 reacts with excess 82 or 83 in the presence of catalyticamounts of tetrabutylammonium fluoride di- or trihydrate in THF to give 2-allyl-or 2-benzylpyridines 948 and 950 [60]. The general reaction of silicon reagentssuch as 82 and 83 or of trimethylsilyl cyanide 18 with fluoride to generate allyl or

7.2 Additions of Allyl- and Benzyltrimethylsilanes to Aromatic Heterocyclic N-Oxides 159

Scheme 7.14

[58] M. Begtrup, P. Vedsø, Poster, Belg. Org. Synth. Symp. May 5, 1992[59] M. Begtrup, P. Vedsø, J. Chem. Soc. Perkin I 1993, 625[60] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1983, 24, 889

benzyl and cyanide anions and trimethylsilyl fluoride 71 as reactive intermediateshas already been discussed in Section 2.4 (Scheme 2.12) and, briefly, in Sec-tion 7.1.

Reaction of pyridine N-oxide 860 with excess allyltrimethylsilane 82 affords, via947, 2-propenylpyridine 948 in 53% yield as the only reaction product which canbe isolated. Elimination of trimethylsilanol 4 from 947 is apparently followed byfluoride-catalyzed isomerization of 2-allylpyridine into 2-propenylpyridine 948. 3-Methylpyridine-N-oxide 867 a is converted into 2-propenyl-3-methylpyridine in69% yield. Likewise, fluoride-catalyzed addition of excess benzyltrimethylsilane 83to 860 furnishes, via 949, 2-benzylpyridine 950 in 70% yield. The generated leav-ing group trimethylsilanol 4 reacts with excess allyltrimethylsilane 82 or benzyl-trimethylsilane 83 in the presence of fluoride to give hexamethyldisiloxane(HMDSO) 7 and propylene or toluene, respectively [60] (Scheme 7.16).


Scheme 7.15

Scheme 7.16

Analogously, reaction of quinoline N-oxide 877 with benzyltrimethylsilane 83 af-fords 65% 2-benzylquinoline 951 and HMDSO 7 and toluene (Scheme 7.17) [60].

Although these reactions are formulated as ionic reactions via 947 and 949, be-cause of the apparent partial formation of polymers and inhibition of the fluoride-catalyzed reaction of pyridine N-oxide 860 with allyl 82 or benzyltrimethylsilane83 by sulfur or galvinoxyl yet not by Tempo, a radical mechanism cannot be ex-cluded [61, 62]. The closely related additions of allyltrimethylsilane 82 (cf. Section7.3) to nitrones 976 are catalyzed by TMSOTf 20 to give, via 977, either �-unsatu-rated hydroxylamines 978 or isoxazolidines 979 (cf. also the additions of 965 to962a and 969 in schemes 7.20 and 7.21).

7.3Reactions of Nitrones and Aliphatic N-Oxides with Trimethylsilyl Cyanide,Allyltrimethylsilane, Enolsilyl Ethers, and other Nucleophiles

Because there is quite a similarity between heterocyclic N-oxides and nitrones, thetendency of nitrone adducts to eliminate leaving groups to give Schiff bases is muchless pronounced than for addition products to aromatic heterocyclic N-oxides, forwhich the tendency for re-aromatization is the strong driving force for eliminationof Me3SiOH 4. Nitrone adducts such as 953 can be readily prepared in high yieldby addition of persilylated N-methylhydroxylamine 952 to benzaldehyde. �5-Hexe-nal 954 reacts with 952, via a nitrone adduct analogous to 953 and subsequent elim-ination of HMDSO 7 in a 1,3-dipolar cycloaddition, to the bicycle 955 [63, 64, 64a](Scheme 7.18). Whereas addition of Me3SiCN 18 to N-(4-diethylaminophenyl)-�-phe-nylnitrone 956 at room temperature in benzene leads, via 957 and elimination ofMe3SiOH 4, in 87% yield, to the Schiff base 958, N-phenyl-�-diphenylnitrone 959does not react with 18 at room temperature (Scheme 7.18), although heating of959 with 18 at 120 �C, without solvent, affords, via a radical reaction, a mixture of41% tetraphenylsuccinonitrile 960 and 45% azoxybenzene 961 [65].

7.3 Reactions of Nitrones and Aliphatic N-Oxides with Trimethylsilyl Cyanide 161

Scheme 7.17

[61] J. Kitteringham, M.R. Mitchel, Tetrahedron Lett. 1988, 29, 3319[62] N. Lewis, M.B. Mitchel, Chem. Ind. 1991, 374[63] J. A. Robl, J.R. Hwu, J. Org. Chem. 1985, 50, 5913[64] J. R. Hwu, J. A. Robl, N. Wang, D.A. Anderson, J. Ku, E. Chen, J. Chem. Soc. Perkin

I, 1989, 1823[64a] J. R. Hwu, K. P. Khoudary, S.-C. Tsay, J. Organomet. Chem. 1990, 399, C13[64b] S.-C. Tsai, H.V. Patel,. J. R. Hwu, Acc. Chem. Res. 1998, 939[65] O. Tsuge, S. Urano, T. Iwasaki, Bull. Chem. Soc. Jpn. 1980, 53, 485

N-Phenyl-�-phenyl-nitrone 962a or N-methyl-�-phenyl-nitrone 962b react witheither trimethylsilyl cyanide 18/NEt3 in DMF or with NaCN/TCS 14/NEt3/DMF[66] at room temperature to afford, via 963 and elimination of Me3SiOH 4, theSchiff bases 964a and 964b in 90 or 75% yield, respectively [66] (Scheme 7.19). Itwas recently observed that N,N-bis(3,5-bis-trifluoromethylphenyl)thiourea catalyzesthe addition of Me3SiCN 18 to a large variety of nitrones, at 0–24 �C, in goodyields [66a]. In a subsequent study trimethylsilyl cyanide 18 was added to 962band 962c, in the presence of ZnI2 at 80 �C, to give 963b and 963c, which elimi-nate LiOSiMe3 98 on treatment with lithium di(isopropyl)amide (LDA) at –78 �Cto provide 964b and 964c in 95% yield [67]. All attempts to trap the intermediateanion, generated from 963 by LDA, by use of electrophiles, failed, however [67](Scheme 7.19).

Additions of silyl-substituted synthons 965 to nitrones such as 962a in the pres-ence of LDA result in the products 966 which eliminate the lithium salt of O-tri-methylsilyl-N-phenylhydroxylamine 968 to give the olefins 967 a or 967b in 72 and39% yield, respectively [68, 69] (Scheme 7.20). The intermediate lithium salt 968dimerizes with elimination of LiOSiMe3 98 to form azobenzene and azoxybenzene961 [68, 69].

Addition of 965a to cyclic nitrones such as 3,4-dihydroquinoline N-oxide 969 af-fords 36% 970 and 20% of the dimer 971 whereas addition of 965b to 969 gives11% 972 and 9.5% of the lactone 973 and Me3SiOLi 98 [69] (Scheme 7.21). Reac-

162

Scheme 7.18

[66] D.K. Dutta, D. Prajapati, J. S. Sandhu, J. N. Baruah, Synth. Commun. 1985, 15, 335[66a] T. Okino, Y. Hoashi, Y. Takemoto, Tetrahedron Lett. 2003, 44, 2817[67] A. Padwa, K. F. Koehler, J. Chem. Soc. Chem. Commun. 1986, 789[68] O. Tsuge, K. Sone, S. Urano, Chem. Lett. 1980, 977[69] O. Tsuge, K. Sone, S. Urano, K. Matsuda, J. Org. Chem. 1982, 47, 5171

tion of 965a with 4,5,5-trimethyl-1-pyrroline N-oxide 974 affords 975 in 30% yieldwith elimination of Me3SiOLi 98 and 28% unchanged 974 [69].

Trimethylsilyl triflate (TMSOTf) 20-catalyzed additions of allyltrimethylsilane 82to nitrones such as 976a (= 962b) and 976b in CH2Cl2 proceed via 977 and prob-ably via 979 and Peterson olefin-formation to afford, after aqueous work-up, theallylhydroxylamines 978 a and 978 b in 86% and 13% yield and 59% of a mixtureof 979b [70, 71]. The intermediate O-trimethylsilylated hydroxylamines are cy-clized in situ by N-iodosuccinimide (NIS) to give the iodomethylisooxalidines [71],

7.3 Reactions of Nitrones and Aliphatic N-Oxides with Trimethylsilyl Cyanide 163

Scheme 7.19

Scheme 7.20

Scheme 7.21

[70] P.G. M. Wuts, Y.-W. Jung, J. Chem. Soc. 1988, 53, 1957[71] M. Gianotti, M. Lombardo, C. Trombini, Tetrahedron Lett. 1998, 39, 1643

Compound 976c, however, gives, after addition of allyltrimethylsilane 82, via ex-clusive 1,3-dipolar cycloaddition of allyltrimethylsilane 82, only 5-trimethylsilyl-methylisoxazolidine 979c [71, 72] (Scheme 7.22).

Addition of allyltrimethylsilane 82 to 3,4,5,6-tetrahydropyridine-N-oxide (readilyaccessible, primarily as the dimer, on HgO-oxidation of N-hydroxypiperidine) inthe presence of Bu4NF·2–3H2O in THFaffords 2-propenyl-N-hydroxypiperidine [72a].

Likewise, addition of enol silyl ethers such as 980 to the intermediate 977a fur-nish the 5-trimethylsilylmethylisoxazolidine 981 in 61% yield and 15% isoxazoline982 [73, 74] whereas addition of 2-trimethylsilyloxyfuran 827 to 977a affords, viathe intermediates 983, on work-up with CF3CO2H, 96% yield of a mixture of lac-tones 984 and 985 [75] (Scheme 7.23). More recently it has also been reported thatDanishefsky (trimethylsilyloxy)dienes add to intermediates such as 977 to give thecorresponding products [76].

N-Oxides 986 are transformed by tert-butyldimethylsilyl triflate 987 into the reac-tive intermediates 988, which rearrange in the presence of methyllithium in THF,followed by PhMgBr in toluene via 989, to 990 [77, 77a]. Subsequent work demon-strated that the intermediates 989 react with Me3SiCN 18 in the presence of TiCl4to give the �-cyanoamines 991 [78]. Likewise, the N-oxide 992 affords, with 18 inthe presence of 986, the �-cyanoamine 993 in 63% yield. The N-oxide 994 is,furthermore, converted by Me3SiCN 18 in 61% yield into the �-cyanoamine 995,whereas the N-oxide of tribenzylamine 996 is converted by 18, 78% yield, into the�-cyanoamine 997 [78, 79] (Scheme 7.24).


Scheme 7.22

[72] D. Dhavale, C. Trombini, Heterocycles 1992, 34, 2253[72a] K. Krolikiewicz, H. Vorbrueggen, unpublished work[73] D.D. Dhavale, C. Trombini, J. Chem. Soc. Chem. Commun. 1992, 1268[74] C. Camiletti, D. D. Dhavale, L. Gentilucci, C. Trombini, J. Chem. Soc. Perkin I

1993, 3157[75] C. Camiletti, L. Poletti, C. Trombini, J. Org. Chem. 1994, 59, 6843[76] C. Camiletti, D.D. Dhavale, F. Donati, C. Trombini, Tetrahedron Lett. 1995, 36, 7293[77] R. Okazaki, N. Tokitoh, J. Chem. Soc. Chem. Commun. 1984, 192[77a] N. Tokitoh, R. Okazaki, Tetrahedron Lett. 1984, 25, 4677[78] N. Tokitoh, R. Okazaki, Chem. Lett. 1985, 241[79] N. Tokitoh, R. Okazaki, Bull. Chem. Soc. Jpn. 1988, 61, 735

7.4Reductions of Heterocyclic N-Oxides and Aromatic Nitro Groups

Hexamethyldisilane 857, which is produced on a large scale, can be regarded as acombination of the “soft” trimethylsilyl cation with the “hard” trimethylsilyl anion.We expected, therefore, that hexamethyldisilane 857 might add to pyridine N-oxide860 to give intermediates such as 998 which should eliminate hexamethyldisiloxane(HMDSO) 7 to give pyridine. We thus treated pyridine N-oxide and hexa-methyldisilane 857 in THF at room temperature with 0.01–0.1 equivalents of a com-mercial solution of Bu4NF·2–3H2O (as catalyst) in THF. After ca 30 min stirring atambient temperature the colorless reaction mixture suddenly turned dark and ex-ploded [80]. Because the explosion might have been caused by gradual removal ofwater from Bu4NF·2–3H2O to result, after an induction period, in a very reactive

7.4 Reductions of Heterocyclic N-Oxides and Aromatic Nitro Groups 165

Scheme 7.23

Scheme 7.24

[80] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1983, 24, 5337

fluoride catalyst and rapid onset of the reaction, we added a solution of ca 1.5 equiva-lents of hexamethyldisilane 857 slowly, over a period of 2–3 h, to a solution of pyr-idine N-oxide 860 (R = H) and the fluoride catalyst in THF. This resulted, via 998and subsequent elimination of HMDSO 7, in the formation of pyridine 999a, whichwas isolated in 90% yield as its picrate [80] (Scheme 7.25). This smooth reduction wasextended to a variety of pyridine-N-oxides, for example �-picoline-N-oxide and 4-di-methylaminopyridine N-oxide (DMAP-N-oxide), to afford the pyridines 999b and999c as crystalline picrates in yields of up to 84%. Quinoline and isoquinoline N-oxide were reduced to quinoline or isoquinoline in 72 and 91% yield, respectively[80]. Subsequently, reduction of such aromatic heterocyclic N-oxides by hexamethyl-disilane 857 in HMPA–THF was induced by methyllithium as catalyst to generate, insitu, Me3SiLi 1883 and afford the corresponding pyridines in similar yields [81, 82]. Ina related reaction, pyridine N-oxides and quinoline-N-oxide are reduced to pyridinesand quinoline, in 45–95% yield, by the combination TCS 14/NaI/Zn in MeCN [83].

Reduction of nitrones such as N,�-diphenylnitrone 962a with equivalent amountsof methyllithium/857 in HMPA/THF, again generating Me3SiLi 1883, affords thecorresponding Schiff bases such as 964a in 84% yield [82] (Scheme 7.25).

Because aromatic nitro compounds such as nitrobenzene had been reduced byhexamethyldisilane 857 at 240 �C to give azobenzene and aniline [84], we slowlyadded hexamethyldisilane 857 in THF to a solution of nitrobenzene and 0.05equivalents of Bu4NF·2–3H2O and obtained, via the probable intermediates 1000–1002, azobenzene in 84% yield [85]. Because azoxybenzene 961 affords azoben-zene in 95% yield, azoxybenzene 961 is a probable intermediate in the reductionof nitrobenzene [85] (Scheme 7.26).

Because reduction of 2-nitrodiphenyl with hexamethyldisilane 857 does not giveany carbazole, nitrene intermediates can probably be excluded. The very polar 4-nitropyridine N-oxide 1003 can be reduced by 857 only in the polar solvent N,N-di-


Scheme 7.25

[81] J. R. Hwu, J. M. Wetzel, J. Org. Chem. 1985, 50, 400[82] J. R. Hwu, W. N. Tseng, H.V. Patel, F. F. Wong, D.-N. Horng, B.R. Liaw, L.C. Lin, J.

Org. Chem. 1990, 64, 2211[83] T. Morita, K. Kuroda, Y. Okamoto, H. Sakurai, Chem. Lett. 1981, 921[84] F.-P. Tsui, T. M. Vogel, G. Zon, J. Org. Chem. 1975, 40, 761[85] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1984, 25, 1259

methylimidazolin-2-one, to give 52% precipitated azoxypyridine-N-oxide 1004 and12% of a mixture of 1005 and 1006 [85]. Thus the nitro group in 1003 is appar-ently reduced faster by 857 than is the N-oxide moiety (Scheme 7.27).

A similar reduction of nitrobenzene with (Me3Si)2Hg to give azobenzene andazoxybenzene has been described [86]. The dehydration of tetrabutylammoniumfluoride di- or trihydrate by hexamethyldisilane 857 is discussed in Chapter 13.

7.5Additions of Active Methylene Groups to Aromatic and Unsaturated Aliphatic NitroCompounds

Nitrobenzene reacts with the O-trimethylsilyl ketene acetal 663 in the presence oftris(dimethylamino)sulfur(trimethylsilyl)difluoride (Me2N)3S(Me3SiF2) (TASF) togive the O-silylated adduct 1007a, which can be oxidized in situ, e.g. by bromine,to give the 4-substituted nitrobenzene 1008 in an overall yield of 79% [87](Scheme 7.28). With less hindered ketene-acetals, however, mixtures of ortho- andpara-substituted nitrobenzenes are obtained. Yet, on reaction of 4-fluoronitroben-zene with the cyclic O-trimethylsilyl ketene acetal 1009 the ortho-substitutionproduct 1010 is obtained in 79% yield [87].

The 2-alkylene-substituted aromatic nitro compound 1011, which is readily ac-cessible via “vicarious nucleophilic substitution” (VNS) [88–90] of 4-fluoronitroben-

7.5 Additions of Active Methylene Groups to Aromatic and Unsaturated Aliphatic Nitro Compounds 167

Scheme 7.26

Scheme 7.27

[86] K. Reuter, W.P. Neumann, Tetrahedron Lett. 1978, 5235[87] T.V. RajanBabu, T. Fukunaga, J. Org. Chem. 1984, 49, 4571[88] M. Makosza, Russ. Chem. Rev. 1996, 45, 491[89] M. Makosza, Pure Appl. Chem. 1997, 69, 559[90] M. Makosza, K. Wojciechowski, Heterocycles 2001, 54, 445

zene and subsequent Knoevenagel condensation with acetaldehyde, cyclizes, viaO-silylation with TCS 14/triethylamine in DMF to give 1012, cyclization of this to1013 then, in 89% yield, to 4-cyano-6-fluoroquinoline N-oxide 1014; HMDSO 7and NEt3·HCl are also formed [91, 92]. On treatment of 1011 with 1 M NaOH inMeOH/H2O 60% 4-cyano-6-quinoline N-oxide 1014, 26% N-hydroxyindole 1015,and 5% N-hydroxyindole 1016 are obtained whereas 0.05 M potassium carbonatein MeOH–H2O converts 1011, after 3 days at 24 �C, into 74% 1016 and 5% 1015[92] (Scheme 7.29) (cf. the intermediate 1018 in Scheme 7.30).

Alkylation of 2-cyanomethylenenitrobenzenes with allylbromides in the pres-ence of K2CO3 and Bu4NI afford allylic compounds such as 1017, which cyclizeson treatment with excess TCS 14/NEt3 in DMF at room temperature, via 1018, tothe N-hydroxyindole 1019, in 91% yield, and to HMDSO 7 and Et3N·HCl [93, 94](Scheme 7.30).

Whereas o-tosylmethylnitrobenzene 1020a cyclizes with TCS 14/NEt3 in DMF,via 1021a, to give the 2,1-benzisoxazole (anthranil) 1022a in 20% yield only, re-placement of the tosyl group by a tert-butoxycarbonyl group, as in 1020b , leads,via 1021b, to 1022b in 71% yield [95]. On replacing the tosyl group by a cyanidegroup, as in 1020c, the analogue 1023 is isolated in THF in 40% yield, whereasin DMF the dimeric compound 1025c is obtained in 48% yield (Scheme 7.31).The formation of 1025 c can be rationalized to occur either via 1023 or via cycload-dition of the N-trimethylsilylketenimine derived from 1020c to the anthranil1022c to give 1025c via 1024 [95]. Because both mechanisms are concentration-de-pendant, higher dilution might reduce the side reaction which leads to 1025c.

All these reactions also occur readily with naphthalenes or quinolines, espe-cially in the presence of DBU as base [95].


Scheme 7.28

[91] Z. Wrobel, A. Kwast, M. Makosza, Synthesis 1993, 31[92] Z. Wrobel, M. Makosza, Tetrahedron 1993, 49, 5315[93] Z. Wrobel, M. Makosza, SynLett 1993, 597[94] Z. Wrobel, M. Makosza, Tetrahedron 1997, 53, 5501[95] Z. Wrobel, Synthesis 1997, 753

1-Nitronaphthalene 1026a or 5-nitroquinoline 1026 b are converted with cinna-myl phenyl sulfone 1027, via “vicarious nucleophilic substitution” in the presenceof excess Me3CSi(Me)2Cl 85 a/DBU in DMF at ambient temperature via 1028,1029, and 1030, to give 94 a and the benzo- or pyridinoquinolines 1031 a or 1031b

7.5 Additions of Active Methylene Groups to Aromatic and Unsaturated Aliphatic Nitro Compounds 169

Scheme 7.29

Scheme 7.30

Scheme 7.31

in 69 or 87% yields, respectively [96, 97]. It is interesting to note that the combi-nation t-BuSiMe2Cl 85a/DBU gives higher yields than the combination Me3SiCl14/DBU. The combination BSA 22 a/DBU/1027 in acetonitrile converts 1026aafter 24 h at 24 �C into 1031a, in 82% yield, and HMDSO 7 [97] (Scheme 7.32).

By analogy with aromatic nitro compounds, nitroolefins such as �-nitrostyrene1032 react with the O-silylketene acetal 1033 at –78 �C, in the presence of the se-lective Lewis acid MAD, in toluene, to give a 6.3:1 syn/anti mixture of the �-nitroester 1034 and 94 a [98] (Scheme 7.33).

7.6Reactions of Silylated Aliphatic Nitro Compounds

Aliphatic nitro compounds 1035 with an �-hydrogen atom are readily O-silylatedby N-trimethylsilyl-N,N�-diphenylurea 23 b to give a mixture of 1036 or 1037 [99].This silylation works in particularly well if R1 and or R2 are activating nitro or car-


Scheme 7.32

Scheme 7.33

[96] Z. Wrobel, Tetrahedron Lett. 1997, 38, 4913[97] Z. Wrobel, Tetrahedron 1998, 54, 2607[98] J. A. Tucker, T. L. Clayton, D.M. Mordas, J. Org. Chem. 1997, 62, 4370[99] J. F. Klebe, J. Am. Chem. Soc. 1964, 86, 3399

bomethoxy groups [100–102]. In the absence of such activating groups R1 or R2

other silylating agents such as 23 b [99, 101], BSA 22 a [103–109], BSTFA 22 b[104], TCS 14/HMDS 2, or TCS 14/triethylamine [104–107, 109–129], TMSBr 16/


[100] S.L. Ioffe, M.V. Kashutina, V. M. Shitkin, A.Z. Yankelevich, A.A. Levin, V. A. Tar-

takovskii, Izv. Akad. Nauk, SSSR, Ser. Khim. 1972, 1341; Chem. Abstr. 1972, 77, 88586[101] M.V. Kashutina, S. L. Ioffe, V.M. Shitkin, N.O. Cherskaya, V. A. Korenevskii, V. A.

Tartakovskii, Zh. Obshch. Khim. 1973, 1715; Chem. Abstr. 1973, 79, 126558[102] S.L. Ioffe, M.V. Kashutina, V.M. Shitkin, A. A. Levin, V. A. Tartakovskii, Zh. Org.

Khim. 1973, 896; Chem. Abstr. 1973, 79, 53425[103] M.V. Kashutina, S.L. Ioffe, V. A. Tartakovskii, Doklady Akad. Nauk, SSSR, 1974, 218,

109; Chem. Abstr. 1975, 82, 43227[104] S.C. Sharma, K. Torssell, Acta Chem. Scand. 1979, B33, 379[105] S.H. Andersen, N. B. Das, R. D. Joergenson, G. Kjeldsen, J.S. Knudsen, S.C. Shar-

ma, K. B.G. Torssell, Acta Chem. Scand. 1982, B 36, 1[106] V. M. Danilenko, S. L. Ioffe, Yu. A. Strelenko, V. A. Tartakovskii, Izv. Akad. Nauk,

SSSR, Ser. Khim. 1986, 2399; Chem. Abstr. 1987, 107, 217699[107] S.L. Ioffe, I.M. Lyapkalo, A.A. Tishkov, V. M. Danilenko, Y. A. Strelenko, V. A. Tar-

takovsky, Tetrahedron 1997, 53, 13085[108] A. A. Tishkov, I.M. Lyapkalo, S.L. Ioffe, Y. A. Strelenko, V. A. Tartakovsky, Org. Lett.

2000, 2, 1323[109] I.M. Lyapkalo, S.L. Ioffe, Russ. Chem. Rev. 1998, 67, 467[110] K. Torssell, O. Zeuthen, Acta Chem. Scand. 1978, B32, 118[111] S.K. Mukerji, K. Torssell, Acta Chem. Scand. 1981, B 35, 643[112] M. Asaoka, T. Mukuta, H. Nakai, Tetrahedron Lett. 1981, 22, 735[113] M. Asaoka, M. Abe, T. Mukuta, H. Nakai, Chem. Lett. 1982, 215[114] N.B. Das, K. Torssell, Tetrahedron 1983, 39, 2227[115] N.B. Das, K. Torssell, Tetrahedron 1983, 39, 2247[116] K. Torssell, A.C. Hazell, R. G. Hazell, Tetrahedron 1985, 41, 5569[117] W. R. Ewing, B. D. Harris, K. L. Bhat, M.M. Joullie, Tetrahedron, 1986, 42, 2421[118] V. M. Danilenko, Yu. A. Strelenko, N.F. Karpenko, S. L. Ioffe, V.A. Tartakovskii,

Izv. Akad. Nauk, SSSR, Ser. Khim. 1989, 1212; Chem. Abstr. 1990, 112, 35956[119] W. Dehaen, A. Hassner, Tetrahedron Lett. 1990, 31, 743[120] A. Hassner, O. Friedman, W. Dehaen, Liebigs Ann. Chem. 1997, 587[121] P. Isager, L. Thomsen, K.B. G. Trossell, Acta Chem. Scand. 1990, 44, 806

Scheme 7.34

NEt3 [131–135], TMSBr 16/DBU [135, 147], TMSOTf 20/NEt3 [130, 132, 133, 136,137], LDA/TCS [104, 138–140], or TCS 14/Li2S [141] are employed to convert 1035to the O-trimethylsilyl nitronates 1036 or 1037 in high yields as intermediates,some of which can be purified by distillation in vacuo [99, 103–104, 110, 136]. Re-active silylating reagents such as TMSOTf 20/NEt3 and BSA 22 a or TMSBr 16/NEt3 silylate free or substituted nitroethanes or nitropropanes to the unsaturatedN,N-bis-O-trimethylsilyl- or free unsaturated nitroso compounds (cf. the subse-quently discussed reactions of 1085 to 1086). Because of the mobility of the O-tri-methylsilyl group the structure of the O-trimethylsilyl nitronates 1036–1037 can-not be assigned (Scheme 7.34). The free O-trimethylsilyl nitronate 1038 derivedfrom nitromethane, e.g. with N-trimethylsilyl-N,N�-diphenylurea 23 b at 35 �C, can,


[122] A. V. Belyankin, V. V. Veselovskii, A. M. Moiseenkov, Izv. Akad. Nauk, SSSR, Ser.Khim. 1991, 2406; Chem. Abstr. 1992, 116, 20697

[123] B. H. Kim, J.Y. Lee, K. Kim, D. Whang, Tetrahedron Asymmetry 1991, 2, 26[124] B. H. Kim, J.Y. Lee, Tetrahedron Asymmetry 1991, 2, 1359[125] C.-L. J. Wang, J.C. Calabrese, J. Org. Chem. 1991, 56, 4341[126] M. Ohno, A. Yashiro, S. Eguchi, SynLett 1996 , 815[127] J. L. Duffy, M.J. Kurth, J. Org. Chem. 1994, 59, 3783[128] J. Chen, C.M. Hu, J. Chem. Soc. Chem. Commun. 1995, 267[129] A. D. Dilman, I.M. Lyapkalo, Y.A. Strelenko, S. L. Ioffe V. A. Tartakovskii, Mende-

leev Commun. 1997, 133[130] H. Feger, G. Simchen, Synthesis 1981, 378[131] A. A. Tishkov, I.M. Lyapkalo, S.L. Ioffe, Y. A. Strelenko, V.A. Tartakovskii, Izv.

Akad. Nauk, Ser. Khim. 1997, 46, 205; Chem. Abstr. 1997, 127, 135839[132] A. A. Tishkov, A. V. Kozintsev, I.M. Lyapkalo, S. L. Ioffe, V. V. Katchala, Y.A. Tarta-

kovskii, Tetrahedron Lett. 1999, 40, 5075[133] A. A. Tishkov, I. M. Lyapkalo, A. V. Kozintsev, S. L. Ioffe, Y. A. Strelenko, Y.A. Tarta-

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ko, Y. A. Tartakovskii, J. Chem. Soc. Chem. Commun. 2000, 2926[135] A. D. Dilman, A.A. Tishkov, I. M. Lyapkalo, S.L. Ioffe, Y.A. Strelenko, Y. A. Tarta-

kovskii, Synthesis 1998, 181[136] H. Feger, G. Simchen, Liebigs Ann. Chem. 1986, 428[137] H. Feger, G. Simchen, Liebigs Ann. Chem. 1986, 1456[138] E.D. Colvin, D. Seebach, J. Chem. Soc. Chem. Commun. 1978, 689[139] E.D. Colvin, A.K. Beck, B. Bastani, D. Seebach, Y. Kai, J. D. Dunitz, Helv. Chim.

Acta 1980, 63, 697[140] C. Li, C. Yuan, Synthesis 1993, 471[141] G. A. Olah, B. G.B. Gupta, S.C. Narang, R. Malhotra, J. Org. Chem. 1979, 44, 4272[142] G. A. Olah, B. G.B. Gupta, Synthesis 1980, 44[143] K. B.G. Torssell, “Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis” in Syn-

thesis of Silyl Nitronates, Verlag Chemie (VCH) 1988, p. 113[143a] Ref. 143 “Applications of Nitrile Oxides, Nitronates, and Intermediate Isoxazoles, Isoxa-

zolines in Synthesis”, p. 128[144] E.W. Colvin, A. D. Robertson, D. Seebach, A. K. Beck, J. Chem. Soc. Chem. Com-

mun. 1981, 952[145] T.H. Keller, L. J. Yelland, M.H. Benn, Can. J. Chem. 1984, 62, 437[146] D. Seebach, I.M. Lyapkalo, R. Dahinden, Helv. Chim. Acta 1999, 82, 1833[147] A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Y. A. Strelenko, Y.A. Tartakovskii, Synthesis

1999, 1767

however, not be isolated but reacts with nitromethane to give the labile compound1039 [99, 110, 143a] or in situ with methyl acrylate or acrylonitrile [110] (cf.Schemes 7.37 and 7.42). Nitroethane gives, on silylation with TCS 14/NEt3, crudetrimethylsilyl nitronate 1040 [135], which can be purified, and thus stabilized, bydistillation in vacuo [110]. Crude 1040, however, eliminates trimethylsilanol 4 onstanding to give acetonitrile oxide 1041, which dimerizes to 3,4-dimethylisooxadia-zole-N-oxide 1042 [110] (Scheme 7.34).

The liberated trimethylsilanol 4, however, reacts with the trimethylsilyl nitronate1040 to give nitroethane and hexamethyldisiloxane 7 [110, 114]. On addition ofhexamethyldisilazane (HMDS) 2 or BSA 22 a the liberated trimethylsilanol 4would probably be silylated in situ to hexamethyldisiloxane 7, resulting in higheryields of 1042.

On treatment of trialkylsilyl nitronates 1043 with MeLi, LiBr, or BuLi in THFthe resulting nitrile oxide intermediates 1044 afford, in dilute THF solution(R = Me) the ketoximes 1045 in ca 50–60% yield, whereas in concentrated THF so-lution the O-silylated hydroxamic acids 1046 are obtained as major products [144](Scheme 7.35). Analogously, the silyl nitronate 1047 reacts with the 2,3,4,6-tetra-O-acetyl-�-d-glucopyranosyl thiol/triethylamine mixture to afford, via the thiohydroxi-mate 1048, in high yield, a mixture of oximes 1049 which are intermediates inthe synthesis of glucosinolate [145] (Scheme 7.35).

If an electron-attracting group is present in the position � to the nitro moiety,formation of trimethylsilyl nitronates from, for example 1050, leads, via 1051, tothe oximes 1052 in 73–78% yield [106]. Subsequent transsilylations of 1052 withmethanol give the free oximes in high yield [106] (Scheme 7.36).

Because of the relative instability of many trimethylsilyl nitronates 1036, 1037,they should be reacted in situ with olefins 1053 [103–105] or acetylenes [127] togenerate the isooxazolidines 1054 [103–105, 107–117, 119–133] or isoxazoles [127](Scheme 7.37) The isoxazolidines 1054 with R2 = H readily eliminate trimethylsila-nol 4 in the presence of acids such as TsOH to form the isoxazolines 1055 inhigh yields [104, 105] (Scheme 7.37; cf. also the cycloadditions with acrylonitrilein Scheme 7.42).


Scheme 7.35

Whereas “normal” olefins such as cyclohexene do not react with O-trimethylsilylnitronates, the entropically favored cyclizations of �-nitroolefins give, via 1,3-dipo-lar cycloaddition, bicyclic compounds, often in high yields. Thus the �-nitroole-fins 1056a and 1056b afford, via 1057a, b, the bicyclic compounds 1058a [104,105] and 1059 b [104], whereas 1056 c and 1056d furnish, via 1057 and subsequentfluoride catalyzed elimination of Me3SiOH 4, the bicyclic compounds 1059 c and1059d in 74 and 89% yield, respectively [119, 120]. The �-nitroolefin 1056ecyclizes in 51–67% yield to give 1060 [113], whereas the �-nitroacetylene 1061cyclizes to 1062, which, on treatment with aqueous HCl, eliminates Me3SiOH 4and HNO to give the unsaturated aldehyde 1063 [127] (Scheme 7.38).


Scheme 7.36

Scheme 7.37

Scheme 7.38

The diolefin 1064 gives rise to the isoxazoline 1065, which cannot eliminate tri-methylsilanol 4 [122]. Cyclization of the �-nitroolefin 1066 with trimethylchloro-silane (TCS) 14/triethylamine at –35 �C then HCl-induced removal of trimethyl-silanol 4 leads, in 85% yield, to the dimer 1067, which is converted in two moresteps into racemic pyrenophorin 1068 [112] (Scheme 7.39). Further cyclizations of�-nitroolefins [109] to monomeric or dimeric isoxazolines have been described.Conjugated dienes such as butadiene afford a mixture of the mono or bis adducts[115–117].

The nitro compound 1069 is converted by BSA 22 a and diisopropylethylamine(DIPEA) (Hünig’s base), via 1070, via a 1,3-dipolar cycloaddition, into 1071 in67% yield [146] (Scheme 7.40).

The unsaturated “Oppolzer” amide 1072 adds O-trimethylsilyl nitronates 1073to give a 9:1 mixture of isoxazolines 1074 and 1075 in 96% yield [123, 124](Scheme 7.41).

On reacting nitromethane and acrylonitrile in the presence of TCS 14/triethyla-mine in benzene (cf. also Scheme 7.42) the oxazolidine 1076, which is obtainedin 85% yield, eliminates trimethylsilanol 4 in the presence of TsOH to give 40%�2-oxazoline 1077 [104]. Heating of 1076, however, or treatment of 1076 with solidKF leads, via ring opening, elimination of HCN, and rearrangement to �-iso-oxazolidine 1078 in 82% yield; this is converted by TsOH, with elimination of 4,into 83% isooxazole 1079 [104]. In contrast with 1076 the isooxazolidine 1080 de-


Scheme 7.39

Scheme 7.40

rived from 2-nitropropane and acrylonitrile affords, on heating with KF, via 1081,senecioaldehyde 1082 and HNO [111] (Scheme 7.42).

Treatment of aliphatic nitro compounds 1083 with TMSBr 16/NEt3 [135–139],with BSA 20 a [107], or with TMSOTf 18/NEt3 or DBU [131–135] leads, via the tri-methylsilyl nitronates 1084, to the N,N-bis(trimethylsilyloxy)enamines 1085 in upto 97% yield [132–134, 136, 137]. On elimination of hexamethyldisiloxane 7 thesegive the unsaturated nitroso compounds 1086 [107–109] (cf. a review on conju-gated nitrosoalkenes [109]). Methyl �-nitropropionate 1087 reacts with BSA 20ainitially to give the O-trimethylsilyl derivative 1088 [107], which adds methyl acry-late to give 1089. Elimination of trimethylsilanol 4 from the oxazolidine 1089 inbenzene is induced by dry HCl, to afford 50% 1090 [107]. In the presence of alarge excess of ethyl vinyl ether instead of methyl acrylate the intermediate 1088loses trimethylsilanol 4 to give the unsaturated nitroso compound 1092, whichadds ethyl vinyl ether to give, after treatment with methanol, ca. 60% 1093 [107].Reaction of 1087 with cyclopentadiene in the presence of BSA 22 a affords, via1092, the bicyclic derivative 1094 in 57% yield [108] (Scheme 7.43).


Scheme 7.41

Scheme 7.42

[148] A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Y. A. Strelenko, Y. A. Tartakovskii, J. Org.Chem. 2000, 65, 8826

[149] A. D. Dilman, S. L. Ioffe, H. Mayr, J. Org. Chem. 2001, 66, 3196

DBU-salts of nitro compounds such as 1095 react with bis-trimethylsilyloxyena-mines such as 1096 to give, via 1097 after subsequent treatment with Bu4NF, ni-tro oximes such as 1098 in 78% yield [147]. The nucleophilicity of N,N-bis(silyloxy)enamines such as 1096 in reactions with benzyl cations has been mea-sured and compared [149] (Scheme 7.44).

Methyl 4-nitrobutyrate 1099, on treatment with Me3SiBr 16/NEt3, affords theunsaturated O-trimethylsilylated oxime 1101, in 71% yield, via the O-trimethylsilylnitronate 1100 and elimination of trimethylsilanol 7 [107, 131] whereas the nitrocompound 1102 is converted by TCS 14/NEt3, via 1103, into the �-chlorooxime1104, in 39% yield [107] (Scheme 7.45).

Silylation of ethyl 2-nitropropionate 1105 to the N,N-bis(silyloxy)enamine 1106followed by addition of triethylamine affords the triethylammonium bromide 1107in 45% yield [135]. Migration of the trimethylsilyloxy group in 1108 gives 68%1109 and, after transsilylation with methanol, 71% of the free 2-hydroxycyclohexa-none-oxime 1110 [135] (Scheme 7.46).

Bis-O-trimethylsilylated enamine intermediates without an activating electron-at-tracting group � to the nitro group, for example 1085, can be readily prepared inone step in high yields on reaction of 1035 with exactly two equivalents ofMe3SiBr 16/NEt3 or TMSOTf 20/NEt3 at –10 �C to +5 �C in CH2Cl2 [134, 135].


Scheme 7.43

Scheme 7.44

Reactive unsaturated nitroso compounds such as 1112 can also be readily pre-pared from �-halooximes such as 1111 on treatment with powdered Na2CO3 indiethyl ether to give, in the presence of enoltrimethylsilyl ether 1113 or strainedolefins such as norbornene and other dienophiles, hetero-Diels–Alder adductssuch as 1114 and 1115 in moderate yields [150–155] (Scheme 7.47).

O-Trimethylsilyl nitronates 1036 have been used in fluoride-catalyzed aldol-typecondensations with aldehydes and ketones to give �-trimethylsilyloxy-nitro com-


Scheme 7.45

Scheme 7.46

Scheme 7.47

[150] C. Hippeli, H.-U. Reissig, Liebigs Ann. Chem. 1990, 217[151] R. Zimmer, H.-U. Reissig, J. Org. Chem. 1992, 57, 339[152] R. Zimmer, M. Collas, M. Roth, H.-U. Reissig, Liebigs Ann. Chem. 1992, 709[153] T. Arnold, B. Orschel, H.-U. Reissig, Angew. Chem. Int. Ed. 1992, 31, 1033[154] R. Zimmer, J. Angermann, U. Hain, F. Hillwer, H.-U. Reissig, Synthesis 1997, 1467[155] K. Homann, J. Angermann, R. Zimmer, H.-U. Reissig, J. Prakt. Chem. 1998, 340, 649

pounds such as 1116, which can be reduced by LiAlH4 to give the 2-aminoalco-hols 1117 [156, 157] (Scheme 7.48).

The synthesis of O-trimethylsilyl nitronates [143 a], the many synthetic applica-tions of O-trimethylsilyl nitronates [143 b, 158, 159], and the chemistry of conju-gated nitrosoalkenes have been reviewed [109].

The closely related tributylstannyl nitronates 1120, which can be expected to re-act in the same way as O-silylnitronates, have been prepared by treatment of ali-phatic nitro compounds 1035 with tributylstannylamine 1118 at 24 �C or by heat-ing of 1035 with tributylstannyl oxide 1119 in toluene with azeotropic removal ofH2O [160] (Scheme 7.49).

7.7Reactions of N,O-Bis(trimethylsilylated) Hydroxylamines

Silylation of hydroxylamine or N-alkyl or N-ethoxycarbonylhydroxylamines is usuallyaccomplished, in 52–84% yield, by silylation with TCS 14/NEt3 [63, 161, 162].Whereas the reaction of N,O-bis(trimethylsilyl)methylhydroxylamine 952 with alde-hydes such as benzaldehyde, or with ketones, with to adducts such as 953, has al-ready been mentioned at the beginning of Section 7.3; thermal and other reactionsof N,O-bis(trimethylsilyl)hydroxylamine 1141 or N-substituted N,O-bis(trimethylsi-lyl)hydroxylamines 1121, 1128, 1131 are discussed in this section.


Scheme 7.48

Scheme 7.49

[156] E.W. Colvin, A.K. Beck, D. Seebach, Helv. Chim. Acta 1981, 64, 2264[157] D. Seebach, A. K. Beck, T. Mukhopadhyay, E. Thomas, Helv. Chim. Acta 1982, 65,

1101[158] V. A. Tartakovskii, Izv. Akad. Nauk, SSSR, Ser. Khim. 1984, 165; Chem. Abstr. 1984,

100, 174225[159] V. O. Rudchenko, F. Huet, J. Metalorg. Chem. 1987, 320, 171[161] O. Smrekar, U. Wannagat, Monatsh. Chem. 1969, 100, 760[162] R. West, P. Boudjouk, J. Am. Chem. Soc. 1968, 93, 5901

On treatment with butyllithium followed by addition of Me3SiCl 14 at 40 �C inEt2O N-phenylhydroxylamine is silylated in ca. –20% yield to N,O-bis(trimethyl-silyl)phenylhydroxylamine 1121, which decomposes at ca. 100 �C to phenylnitrene1122 and HMDSO 7 [163, 164] (cf. Scheme 7.57). In cyclohexane as solvent ani-line and N-cyclohexylaniline 1123 are obtained in 20 and 5% yield, respectively,whereas in cyclohexene as solvent at 100 �C N,O-bis(trimethylsilyl)phenylhydroxyl-amine 1121 affords 20% aniline, 2% aziridine 1124, 4% N-cyclohexenylaniline1125, azobenzene, imine 1126, and traces of bicyclohexyldiene 1127 [163, 164](Scheme 7.50). The electron-induced fragmentation of 1121 to 1122 and HMDSO7 has also been investigated [165–167]. Persilylated N-ethoxycarbonylhydroxyla-mine 1128, which is readily obtained in ca 90% yield by treatment with Me3SiCl14/triethylamine in Et2O, decomposes at 100 �C to the nitrene 1129, which reactswith cyclohexene to give 42% the aziridine 1130 [168]. On the basis of NMRmeasurements persilylated benzhydroxamic acid, obtained either by treatment ofbenzoyl chloride with N,O-bis(trimethylsilyl)hydroxylamine [169] or by silylation ofphenylhydroxamic acid with HMDS 2 in MeCN at 24 �C [170], has the structure1132 and not 1131 [170] (cf. also the structures of BSA 22 a or of 296= 312b);1132 decomposes on heating in cyclohexene to phenyl isocyanate and 10% 3-ben-zamidocyclohexene 1133 [169, 170].


Scheme 7.50

[163] F. P. Tsui, T.M. Vogel, G. Zon, J. Am. Chem. Soc. 1974, 96, 7144[164] F. P. Tsui, Y.H. Chang, T. M. Vogel, G. Zon, J. Org. Chem. 1976, 41, 3381[165] H. Schwarz, G. Zon, F.-P. Tsui, Org. Mass Spectrosc. 1975, 10, 1160[166] H. Schwarz, B. Steiner, G. Zon, Y. H. Chang, 1978, Z. Naturforsch. 1978, 33b, 129[167] B. Ciommer, H. Schwarz, A. Maaroufi, M.T. Reetz, K. Levsen, Z. Naturforsch. 1981,

36b, 771[168] Y.H. Chang, F.-T. Chiu, G. Zon, J. Org. Chem. 1981, 46, 342[169] F. D. King, S. Pike, D. R.M. Walton, J. Chem. Soc. Chem. Commun. 1978, 351[170] J. Rigaudy, E. Lytwyn, P. Wallach, N.K. Cuong, Tetrahedron Lett. 1980, 21, 3367

On heating persilylated N-ethoxycarbonylhydroxylamine 1128 with the silylke-tene acetal 1134 the resulting aziridine 1135 rearranges on work-up, in situ, toethyl N-ethoxycarbonylaminopropionate 1136 [171]. N-Ethoxycarbonylhydroxyla-mine 1128 adds to 2-trimethylsilyloxyfuran 826 to give, via 1137, the cyclic car-bamate 1138 [172]. As discussed in Section 4.5, persilylated N-trimethylsilyloxy-carbonylhydroxylamine 317 decomposes on heating to trimethylsilyloxyisocyanate318, with an isocyanate IR band at 2270 cm–1, which reacts with diethylamine togive the trimethylsilyl N,N-diethylcarbamate 1139 and N,N-tetraethylurea [173](Scheme 7.51).

O-Trimethylsilyl phenylhydroxylamine 1140 with LDA eliminates Me3SiOLi 98to give phenylnitrene 1122; this combines with 1140 to give azoxybenzene 961and azobenzene [68, 69]. N,O-Bis(trimethylsilyl) hydroxylamine 1141 adds to �,�-unsaturated malonates such 1142 in the presence of catalytic amounts of the Le-wis acid Yb(OTf)3 to give, on subsequent mild hydrolysis, O-silylated adducts suchas 1143, which cyclizes with Me3COK in CH2Cl2 to the aziridine 1144 andMe3SiOK 97 [174] (Scheme 7.52). O-Silylated alkylhydroxylamines 1145, which areobtained by silylation of the free hydroxylamines with N-trimethylsilylimidazole1219 react with lithium aryl or heteroaryl cyanocuprates 1146 to give the alkylami-noaryl or heteroaryl compounds 1147 and Me3SiOLi 98 [175].

Finally, the TMSOTf 20-catalyzed Beckmann reaction of cyclohexanone withN,N-dimethoxyamine HN(OMe)2 1148 [176] affords, via 1149, N-methoxycaprolac-


Scheme 7.51

[171] M.A. Loretto, L. Pellacani, P.A. Tardella, J. Chem. Res. (S) 1988, 304[172] M.A. Loretto, L. Pellacani, P.A. Tardella, Tetrahedron Lett. 1989, 30, 5025[173] V. D. Sheludyakov, A. B. Lebedeva, A.V. Kisin, I.S. Nikishina, A. V. Lebedev, A.D.

Kirilin, Zh. Obshch. Khim. 1986, 56, 1525; Chem. Abstr. 1986, 106, 156554[174] G. Cardillo, L. Gentilucci, M. Gianotti, R. Perciaccante, A. Tolomelli, J. Org.

Chem. 2001, 66, 8657[175] P. Bernardi, O.P. Dembech, G. Fabbri, A. Ricci, G. Seconi, J. Org. Chem. 1999, 64,

641[176] V. F. Rudchenko, S.M. Ignatov, R.G. Kostyanvsky, J. Chem. Soc. Chem. Commun.

1990, 261

tam 1150 in 84% yield [177]. Olefins such as cyclooctene react with HN(OMe)2

1148/TMSOTf 20 in CH2Cl2 to give N-methoxyaziridines such as 1151 in highyields [177] (Scheme 7.53).


(a) A mixture of 3-hydroxypyridine-N-oxide 870 (2.78 g, 25 mmol) and triethyla-mine (8.3 mL, 62.5 mmol) in abs. acetonitrile (20 mL) is heated for 8 h at100–110 �C with trimethylsilyl cyanide 18 (11 mL, 87.5 mmol). After evapora-


Scheme 7.52

[177] E. Vedejs, H. Sano, Tetrahedron Lett. 1992, 33, 3261

Scheme 7.53

Scheme 7.54

tion the crude residue is heated under reflux for 0.5 h with excessMe3SiNHSiMe3 (HMDS) 2, the excess HMDS evaporated in vacuo, and the re-sidue of crude 871 is purified by bulb-to bulb distillation at 120–130 �C/2.6Torr. On keeping the distillate in methanol 2-cyano-3-hydroxypyridine 872starts to crystallize. After evaporation of the methanol and methoxytrimethyl-silane 13 a the residue is crystallized from ethyl acetate to give, in severalcrops, 2.19 g (73%) 872, m.p. 210 �C (dec.) [6] (Scheme 7.54 ).

(b) Me3SiCl 14 (15.1 mL, 120 mmol) is added slowly, within 1 h, at room tem-perature, to a stirred suspension of 3-hydroxypyridine-N-oxide 870 (3.27 g,30 mmol), sodium cyanide (2.94 g, 60 mmol), and triethylamine (20.8 mL,150 mmol) in abs. dimethylformamide (DMF; 40 mL), whereupon the reactiontemperature rises to 35–40 �C. After subsequent heating for 12 h at 100–110 �C, the reaction mixture is left to cool, filtered at 22 �C, the inorganic saltswashed with DMF, and the filtrate evaporated in vacuo. On addition of 100 mLmethanol to desilylate the intermediate 871 to 872, the mixture becomes warmand is evaporated after 30 min. The brownish crystalline residue is recrystal-lized from 10 mL ethyl acetate to give a first crop of 2.6 g 872. On addition ofcharcoal, filtration, and concentration, a second crop of 0.61 g 872 is obtained.Total yield = 3.25 g (90%), m.p. 210 �C (dec.) [6] (Scheme 7.54b).

Dimethylcarbamyl chloride (5.35 g, 0.05 mol) is added dropwise with stirring to asolution of the N-oxide of (+)-(S)-2 (1-methylpropyl)pyridine (7.55 g, 0.05 mol) andMe3SiCN 18 (5.5 g, 0.055 mol) in CH2Cl2 (100 ml and stirring is continued for 5days at room temperature. After addition of 10% aqueous K2CO3 the mixture isstirred for 15 min, the CH2Cl2 extract is dried (Na2SO4) and evaporated, and theresidual oil distilled to give 7.6 g (95%) (+)-(S)-2-cyano-6-(1-methylpropyl)pyridine,b.p. 60�C (0.01 mmHg) [a]26D + 27.16 �C (2.6, cyclohexane) [43] (Scheme 7.55).


Scheme 7.55

Scheme 7.56

Me3SiN3 19 (0.34 mL, 2.,4 mmol) and of Et2NCOCl (0.32 mL, 2.4 mmol) areadded, in this sequence, under argon, to a solution of 3-aminopyrazine-1-oxide934 (1 mmol) in abs. MeCN (8 mL) and the reaction mixture is heated under re-flux for 18 h with exclusion of humidity. After evaporation in vacuo the residue ischromatographed with hexane–ethyl acetate (10:1 to 3:1) on a column of 20 g sili-ca gel to give almost quantitative yield of microcrystalline 2-amino-3-azidopyrazine935, m.p. 225 �C (dec.) [55] (Scheme 7.56).

A solution of Bu4NF·2–3H2O in THF (1 molar, 1 mL) which has been dilutedwith an additional 3 mL abs. THF is added slowly, with stirring, within 15 min, toan ice-cold solution of pyridine-N-oxide 860 (0.95 g, 10 mmol) and benzyltri-methylsilane 83 (3.29 g, 20 mmol) in abs. THF (25 mL). During addition of theBu4NF·2–3H2O solution in THF the color of the reaction mixture turns slowlyfrom yellow to dark red. When addition is complete TLC on silica plates (Et2O–hexane, 1:1) reveals only traces of 860 and 83 (RF = 0.8) and a new product(RF = 0.4). After warming to room temperature the reaction mixture is kept at thistemperature for 16 h and then evaporated at 30 �C/11 mm. The residue is ex-tracted with Et2O (4�25 mL) and the extracts are applied to a column of 50 g neu-tral Al2O3 (Woelm, A III). The first 200 mL eluate affords, on evaporation, 1.5 gyellowish oil, which is distilled at 140–150 �C/14 mmHg in a Kugelrohr apparatusto give 1.19 g (70.4%) pure 2-benzylpyridine 950 [60] (Scheme 7.57).

A mixture of hex-5-en-1-al 754 (65.2 mg, 0.664 mmol) and N-methyl-N,O-bis(trimethylsilyl)hydroxylamine 952 (126.7 mg, 0.662 mmol; prepared from N-methylhydroxylamine hydrochloride by silylation with Me3SiCCl 14/NEt3 [64]) inbenzene (1.7 mL) is heated for 20 h at 50 �C and then for 72 h at 80 �C. Thecooled solution is chromatographed with pentane–Et2O (1:1) on a silica gel col-


Scheme 7.57

Scheme 7.58

umn. The fractions containing 955 are pooled and the solvents are removed un-der reduced pressure at –30 �C to give 65.4 mg (0.514 mmol, 78%) 955 as a clearliquid [64] (Scheme 7.58).

TMSOTf 20 (0.11 g, 0.5 mmol) is added to a solution of �-phenyl-N-methylni-trone 976a (0.68 g, 5.0 mmol) and allyltrimethylsilane 82 (0.69 g, 6 mmol) in dryCH2Cl2 (5 mL). After 36 h at room temperature the reaction mixture is quenchedwith 3 M aqueous HCl and stirred for 1 h. After neutralization with 3 M NaOH,extraction with Et2O (2�25 mL), and evaporation the residue is purified by flashchromatography on silica gel with hexane–ethyl acetate (7 : 3) to give 0.763 g (86%)978 a as a crystalline solid, m.p. 93–95 �C [70] (Scheme 7.59).

A solution of TMSOTf 20 (11 �L, 0.062 mmol) in CH2Cl2 (2 mL) is added, at20 �C, to a stirred solution of nitrone 976a (135 mg, 1 mmol) and 2-[(trimethyl-silyl)oxy]furan 826 (0.2 mL, 1.2 mmol) in dry CH2Cl2 (8 mL). After 3 h the reac-tion mixture is quenched with a solution of 50 �L CF3CO2H in 1 mL H2O. Thetwo layers are separated and the aqueous layer is extracted with Et2O (3�10 mL).The combined organic layers are washed with 1 mL brine, dried (Na2SO4), andevaporated to dryness. Flash chromatography with cyclohexane–Et2O (1 : 1) on a(230–400 mesh) silica gel 60 column gives 0.176 g (80.6%) syn-984 (m.p. 117 �C,hexane) and 0.034 g (15.4%) oily anti-985 [75] (Scheme 7.60).


Scheme 7.59

Scheme 7.60

Scheme 7.61

A solution of Bu4NF·2–3H2O (1 M, 0.5 mL, 0.5 mmol) in THF is added to a so-lution of isoquinoline-N-oxide 879 (1.45 g, 10 mmol) in abs. THF (30 mL), where-upon the solution turns yellowish–brown. A solution of hexamethyldisilane 857(3.1 mL) in abs. THF (10 mL) is then added slowly (within 45 min), with mag-netic stirring, while cooling with cold water to maintain reaction temperature be-tween 23 and 26 �C. After stirring for a further 60 min TLC (toluene–EtOAc, 1 : 1)indicates the presence of 20–30% unreacted 879, so an additional amount of hexa-methyldisilane 857 (1.03 mL, 5 mmol) in THF (5 mL) is added slowly within30 min, whereupon starting material 879 can no longer be detected by TLC. Afterevaporation of the crude reaction mixture the brown oily residue is distilled in aKugelrohr apparatus at 145–150 �C/30 mmHg to give 1.18 g (91.5%) pure iso-quinoline [80] (Scheme 7.61).

A solution of Bu4NF·2–3H2O in THF (1 M, 0.5 mL, 0.5 mmol) is added to an(almost colorless) solution of nitrobenzene (2.04 mL, 20 mmol) in abs. THF(30 mL) whereupon the color of the solution changes to dark green. A solution ofhexamethyldisilane 857 (8 mL, 40 mmol) in abs. THF (15 mL) is then addedslowly (within 45 min) with water-cooling to maintain the reaction temperaturebetween 19 and 23 �C, whereupon the solution turns red. After 20 h, TLC onsilica plates (toluene–EtOAc, 1 : 1) indicates the presence of ca 40% unreacted ni-trobenzene so further Bu4NF·2–3H2O in THF (0.5 mL, 0.5 mmol) is added, fol-lowed by a solution of 857 (2 mL, 10 mmol) in abs. THF (20 mL) within 15 minat 23 �C. After further stirring for 1 h without cooling the reaction temperaturerises to 35 �C. Approximately 1.5 h after addition of 857 nitrobenzene can no long-er be detected by TLC. On evaporation of the solvents a crystalline red-brown resi-due (ca 2.5 g) is obtained. This is dissolved in 30 mL toluene and chromato-graphed on a column of 75 g neutral Al2O3 (Woelm, A = II). After preliminary elu-tion with 75 mL toluene the next 75 mL toluene elutes 1.57 g (84%) pure crystal-line azobenzene [85] (Scheme 7.62).


Scheme 7.62

Scheme 7.63

A solution of 1 mmol 1017 in 4 mL dry DMF is treated with Me3SiCl 14(0.63 mL, 5 mmol) then with triethylamine (0.7 mL, 5 mmol) at room tempera-ture. After stirring until completion of the reaction the mixture is poured intodilute HCl, extracted with ethyl acetate, and the product isolated by column chro-matography on silica gel with hexane–ethyl acetate (3:1) as mobile phase to give,on crystallization from ethyl acetate, 91% N-hydroxyindole 1019, m.p. 218–220 �C(dec.) [93, 94] (Scheme 7.63).

N,O-bis(trimethylsilyl)acetamide (BSA, 22 a; 2.5 mmol) is added to 1-nitro-naphthalene 1026 (1 mmol) and sulfone 1027 (1 mmol) in acetonitrile (2 mL) andthe resulting mixture is stirred until dissolution occurs. After addition of DBU(776 �L, 5 mmol, in one portion) the reaction mixture is stirred at room tempera-ture for 24 h then poured into a cold aqueous solution of NH4Cl in H2O and ex-tracted with CH2Cl2 (3�20 mL). The extracts are washed with 20 mL brine, driedwith MgSO4, and evaporated. On addition of 3 mL chloroform crystalline 1028,m.p. 227–228 �C (82%) is obtained [97] (Scheme 7.64).

Nitroalkene 1056 (1 mmol) and triethylamine (0.12 g, 1.2 mmol) are dissolvedin benzene (5 mL) followed by Me3SiCl 14 (0.119 g, 1.1 mmol). A precipitate isformed and the resulting mixture is left to stand overnight at room temperatureand subsequently treated with 5 mL 5% HCl. The benzene layer is washed with10 mL water and 10 mL brine and dried (MgSO4). Evaporation gives an oil whichis chromatographed over silica gel to yield 89% of the bicyclic isoxazolidine 1059[119] (Scheme 7.65).


Scheme 7.64

Scheme 7.65

A 50 mL flask equipped with a dropping funnel is charged with cyclooctene(2.5 mL, 19.5 mmol) and CH2Cl2 (20 mL). After cooling to –14 �C TMSOTf 20(3 mL, 15.5 mmol) is added followed slowly (within 30 min) by a solution ofHN(OMe)2 1148 (1.0 g, 13 mmol) in CH2Cl2 (5 mL) (CAUTION: only solutions of1148 can be handled safely!) When addition of 1148 is complete the solution isleft to warm to room temperature and then stirred for 1 h with NaOH (1 M,

20 mL). Extraction with CH2Cl2 (3�10 mL) then drying of the organic phase(Na2SO4) and removal of the CH2Cl2 (aspirator) affords crude 1151 in 86% yield.This is distilled at 90–93 �C/30 mmHg to give 1.28 g (64%) pure 1151. Chroma-tographic purification of crude 1151 over silica gel gives a 77% recovery of pure1151 [177] (Scheme 7.66).


Scheme 7.66

8.1Sila–Pummerer Rearrangements of Sulfoxides

8.1.1Introduction

Whereas conversion of sulfoxides to the corresponding �-acyloxysulfides by acid an-hydrides, for example acetic anhydride, the Pummerer reaction [1], has been knownfor quite a time, the conversion of sulfoxides with silylating reagents via the unstableintermediate O-silyl compounds to �-silyloxysulfides, the Sila–Pummerer reaction isa relatively new reaction, which has recently been reviewed [1–4].

At 60 �C trimethylsilylmethyl phenyl sulfoxide 1152 undergoes a Brook rearrange-ment [2, 3] to the intermediate 1153, which affords, after subsequent Sila–Pummererrearrangement, trimethylsilyloxymethylphenyl sulfide 1154 in 79% yield [5]. Alkyla-tion of 1152 with LDA/methyl iodide gives a diastereomeric mixture of sulfoxides1155. Only the isomer of 1155 which enables intramolecular 4-center rearrange-ment, as depicted in 1156, will undergo the Brook rearrangement and the sub-sequent Sila–Pummerer rearrangement at 60 �C to give 1157 [6] (Scheme 8.1). Thediastereomeric mixture of �-chlorosulfoxides 1158 affords, on alkylation withLDA/ trimethylchlorosilane 14, the intermediates 1159, which rearrange on warm-ing to 60 �C, via 1159 and 1160, to the thioesters 1161 and trimethylchlorosilane14 [7]. Reductions of sulfoxides to the sulfides, e.g. with hexamethyldisilthiane601, are discussed in Section 12.3.

189

8

Reactions of S–O and Se–O Systems


[1] O. De Lucchi, U. Miotti, G. Modena, Organic Reactions 1991, 40, 157[2] A. G. Brook, Acc. Chem. Res. 1974, 7, 77[3] W. P. Weber, Silicon Reagents for Organic Synthesis”, 1983, Springer, Berlin, New York[4] T. Bach, H. Brummerhop, J. Prakt. Chem. 1999, 341, 410[5] A. G. Brook, D.G. Anderson, Can. J. Chem. 1968, 46, 2115[6] E. Vedejs, M. Mullins, Tetrahedron Lett. 1975, 2017[7] K. M. More, J. Wemple, J. Org. Chem. 1978, 43, 2713

Because 2-trimethylsilyloxy sulfides such as 1154 and 1157 are hemiphenylthioacetals of aldehydes, they are readily hydrolyzed to aldehydes [8–12] or ketones[13]. Thus alkylation of the lithium salt 1162 with cyclohexylmethylbromide 1163,gives in nearly quantitative yield, the sulfide 1164, which, after oxidation with m-chloroperbenzoic acid and hydrolysis, rearranges in 70% yield to cyclohexylacetal-dehyde 1165 [8] (Scheme 8.2). A more detailed discussion of the formation of alde-hydes is given in Section 8.5.

Heating of bis(trimethylsilylmethyl)sulfoxide 1166 generates HMDSO 7 and, via1167, the reactive intermediate thioformaldehyde-S-methylide 1168, which can betrapped in situ, e.g. by N-methylmaleimide, to give 81% of the 1,3-dipolar cycload-dition product 1169 [14] (Scheme 8.3). Further analogous 1,3-dipolar cycloaddi-tions with acetylenes are discussed elsewhere [15].

8 Reactions of S–O and Se–O Systems190

Scheme 8.1

Scheme 8.2

[8] P. J. Kocienski, Tetrahedron Lett. 1980, 21, 1559[9] P. J. Kocienski, J. Chem. Soc. Chem. Commun. 1980, 21, 1096

[10] D.J. Ager, R. C. Cookson, Tetrahedron Lett. 1980, 21, 1677[11] D.J. Ager, Tetrahedron Lett. 1980, 21, 4759[12] I. Cutting, P. J. Parsons, Tetrahedron Lett. 1981, 22, 2021[13] T. Takeda, T. Tsuchida, K. Ando, T. Fujiwara, Chem. Lett. 1983, 549[14] M. Aono, C. Hyodo, Y. Terao, K. Achiwa, Tetrahedron Lett. 1986, 27, 4039[15] X.-S. Ye, H.N. C. Wong, J. Org. Chem. 1997, 62, 1940

8.1.2Sila–Pummerer Reactions to Vinylsulfides

Reactions of sulfoxides containing �- and �-hydrogen atoms, for example n-dibutylsulfoxide 1170, with trimethylsilyl iodide 17 in the presence of tertiary aminessuch as diisopropylethylamine (DIPEA) give, e.g., the vinylsulfide 1171 as an 1 : 1E/Z mixture in 75% yield and HMDSO 7 [16] (Scheme 8.4). Analogously, thevinyl sulfoxide 1172 or the vinyl sulfoxide 1174 furnish the 1,3-dienyl sulfides1173 and 1175 in 91 and 85% yield, respectively, and HMDSO 7 [16].

Reaction of the cyclic sulfoxide 1176 with trimethylchlorosilane (TCS) 14 inCH2Cl2 affords the unsaturated sulfide 1177, in 86% yield, and HCl and HMDSO7 whereas the ester 1178 gives rise to 72% 1179, 16% isomer 1180, and, via 1181,the chloro compounds 1182 and the ring contracted 1183 in 7% yield [17, 18](Scheme 8.5).

The thiazolidine-S-oxides 1184 are converted by Me3CSi(Me2)OTf 987/triethyla-mine, in up to 50% yield, into the thiazoline 1185 and the thiazolidine 1186,whereas reaction of 1184 (R1, R2 = (CH2)5) with trimethylsilyl iodide 17/tri-ethylamine leads to 42% 1187 and, via ring enlargement, to 14% 1188 [19, 20].


[16] R. D. Miller, D.R. McKean, Tetrahedron Lett. 1983, 24, 2619[17] S. Lane, S. J. Quick, R. J.K. Taylor, Tetrahedron Lett. 1984, 25, 1039[18] S. Lane, S. J. Quick, R. J.K. Taylor, J. Chem. Soc. Perkin I 1984, 2549[19] N. Tokitoh, Y. Igarashi, W. Ando, Tetrahedron Lett. 1987, 28, 5903[19a]M. Hori, T. Kataoka, H. Shimizu, Y. Imai, Chem. Pharm. Bull. 1979, 27, 1982[20] D. Seebach, A. Jeanguenat, J. Schmidt, T. Maetzke, Chimia 1989, 43, 314

Scheme 8.3

Scheme 8.4

Analogous ring enlargements of S-oxides of benzothiazolium compounds on heat-ing with acetic anhydride have been described elsewhere [19a] (cf. also Sec-tion 8.1.4). S-Oxides of thioketals such as 1189 are converted to the unsaturated1,3-dithiolanes such as 1190 [21] (Scheme 8.6).

Sulfoxides containing an �-chloro group 1191 or an �-trimethylsilyl group 1193rearrange on silylation with TMSOTf 20/triethylamine or with LDA followed byTCS 14 to the olefins 1192 and 1194 in 86 and 75% yield and HMDSO 7 [22, 23],whereas a sulfoxide with an �-cyano or �-carbomethoxy group as in 1195 reacts


Scheme 8.5

[21] E. Schaumann, S. Winter-Extra, K. Kummert, S. Scheiblich, Synthesis 1990, 271[22] R. D. Miller, R. Hässig, Synth. Commun. 1984, 14, 1285[23] R. D. Miller, R. Hässig, Tetrahedron Lett. 1984, 25, 5351

Scheme 8.6

with TMSOTf 20 and HMDS 2 as base to give the cyano (or carbomethoxy) vinylsulfides 1196 in 84% (or 83%) yield and HMDSO 7 [24] (Scheme 8.7).

Vinyl sulfoxides containing an �-trimethylsilyl group, for example as 1197, rear-range on heating in benzene to give the vinyl sulfoxide 1198 in up to 19% yield,the acetylene 1199 in 37% yield, and the ketene-S,O-acetal 1200 in 32% yield [25](Scheme 8.8).

Reaction of the �-ketosulfoxide 1201 with TMSOTf 20/DIPEA affords, in 100%yield, the diene 1202, which readily undergoes Diels–Alder reactions, e.g. withmethyl acrylate [26] (Scheme 8.9).

When heated in ethylene chloride at 80 �C for 3 h the �-ketosulfide 1203 reactswith the trimethylsilyl ester of polyphosphoric acid (PPSE) 195 (prepared fromP2O5 and HMDSO 7) to give 36% 1204 and 8% 1205, whereas the lactone 1206 af-fords with PPSE 195 the unsaturated sulfide 1207 in 93% yield [27] (Scheme 8.10).

Finally, sulfoxides containing an �-carbonyl group and a �-syn trimethylsilylgroup [28–30], for example 1208 or 1211, are, on heating, readily converted toalkenes such as mesityl oxide 1209 and the alkyne 1212, and to trimethylsilyl phe-nylsulfenate 1210 [29, 30] (Scheme 8.11).


Scheme 8.7

Scheme 8.8

[24] R. D. Miller, R. Hässig, Tetrahedron Lett. 1985, 26, 2395[25] D.J. Hart, Y.-M. Tsai, Tetrahedron Lett. 1983, 24, 4387[26] H. Kosugi, K. Hoshino, H. Uda, Chem. Lett. 1991, 1577[27] M. Kakimoto, Y. Imai, Chem. Lett. 1984, 1831[28] B. M. Trost, T. N. Salzmann, K. Hiroi, J. Am. Chem. Soc. 1976, 98, 4887[29] I. Fleming, D. A. Perry, Tetrahedron Lett. 1981, 22, 5095[30] I. Fleming, J. Goldhill, D.A. Perry, J. Chem. Soc. Perkin I 1982, 1563

Silylation of the 2-cyclohexanone phenylsulfoxide 1213 with the O-silylketene-acetal 1214 in the presence of ZnI2 gives 75% of the Sila–Pummerer product1215, whereas the 2-cyclooctanone phenylsulfoxide 1216 affords a ca. 1 : 1 mixtureof the Sila–Pummerer products 1217 and the olefin 1218 [31] (Scheme 8.12).

8.1.3Nucleophilic Substitutions and Cyclizations via Sila–Pummerer Reactions

On heating DMSO with 2 equivalents of imidazole and hexamethyldisilazane(HMDS) 2, or of N-trimethylsilylimidazole 1219 [32], to 140–160 �C the intermedi-ate S-ylide 1220 adds to the imidazole to give N-methylthiomethylimidazole 1221in 40–60% yield and HMDSO 7 and NH3 or imidazole [33]. The analogous reac-


Scheme 8.9

Scheme 8.10

Scheme 8.11

[31] Y. Kita, H. Yasuda, O. Tamura, F. Itoh, Y. Tamura, Tetrahedron Lett. 1984, 25, 4681[32] L. Birkofer, P. Richter, A. Ritter, Chem. Ber. 1960, 93, 2804[33] A. F. Janzen, G. N. Lypka, R.E. Wasylishen, Can. J. Chem. 1980, 58, 60

tion with 2- or 4-methylimidazoles, pyrazole or 1,2,4-triazole and benzimidazoleproduces N-methylthiomethyl derivatives [33] (Scheme 8.13).

Treatment of the sulfoxide 1222a; with tert-butyldimethylsilyl chloride 85a; andexcess imidazole in DMF at 25 �C furnishes the imidazole derivative 1223 a; in70% yield, whereas the phenyl derivative 1222 b; affords, besides 47% of 1223 b;,the cyclized product 1224 in 24% yield and 94 a; and imidazole hydrochloride [34](Scheme 8.14). Reaction of 1225 with N-(trimethylsilyl)imidazole 1219 at 170 �C af-fords 1226 in 50% yield [35].

Treatment of the allylic sulfoxide 1227 a with diisopropylethylamine (DIPEA) or of1227b with N-trimethylsilyldiethylamine 146 and TMSOTf 20 leads in ca. 90% yieldto the quaternary amino derivatives 1228 and 1229 and HMDSO 7 [36] (Scheme 8.15).Tetramethylene sulfoxide 1230 reacts with silylated thymine 1231 in the presence ofthree equivalents of TMSOTf 20 to give the 4�-thio-nucleoside analogue 1232 andHMDSO 7 [37]. Other silylated pyrimidine, pyridine, and purine bases react analo-gously with cyclic sulfoxides to give 4�-thio-nucleoside analogues [37, 37a, 38].

The �-amido-phenylsulfoxide 1233 cyclizes on reaction with TMSOTf 20/NEt3

via 1234 in 41% yield to the �-lactam 1235 as well as in 8% yield to 1236 and


Scheme 8.12

Scheme 8.13

[34] S.G. Pyne, B. Dikic, J. Chem. Res. (S) 1990, 226[35] P. Cozzi, G. Carganico, U. Branzoli, Ger. Offen. DE 3,519,432, Chem. Abstr. 1986,

104, 224894d[36] R. Hunter, C.D. Simon, Tetrahedron Lett. 1988, 29, 2257[37] I. O’Neil, K.M. Hamilton, SynLett 1992, 791[37a] D. Ikemizu, A. Matsuyama, K. Takemura, O. Mitsunobu, SynLett 1997, 1247[38] For further Pummerer reactions with silylated heterocyclic bases see Refs. 414a–414i in

“Handbook of Nucleoside Synthesis”, H. Vorbrüggen, C. Ruh-Pohlenz, Wiley–Inter-science, New York, 2001

HMDSO 7 [39]. With 20/DIPEA sulfoxide 1233 affords 76% of 1235 [40]. Analo-gous silylation of the S-oxide function in 1237 with the O-silylketene acetal 1214and subsequent cyclization with ZnCl2 or ZnI2 affords 1238, a precursor of thie-namycin [41–43] (Scheme 8.16).

Attempts to replace the phenylsulfenyl group in 1239 with benzyloxytrimethyl-silane 13 c; leads, via fragmentation of 1240 and 1241 and incorporation of aceto-nitrile in a Ritter reaction, to 82% of a 7 : 1 mixture of 1242 and 1243 [44]


Scheme 8.14

Scheme 8.15

[39] T. Kaneko, J. Am. Chem. Soc. 1985, 107, 5490[40] T. Kaneko, Y. Okamoto, K. Hatada, J. Chem. Soc. Chem. Commun. 1987, 1511[41] Y. Kita, N. Shibata, N. Kawano, T. Tohjo, C. Fujimori, K. Matsumoto, S. Fujita, J.

Chem. Soc. Perkin I 1995, 2405[42] Y. Kita, O. Tamura, N. Shibata, T. Miki, J. Chem. Soc. Perkin I 1989, 1862[43] Y. Kita, N. Shibata, T. Miki, Y. Takemura, O. Tamura, J. Chem. Soc. Chem. Commun.

1990, 727[44] Y. Kita, N. Shibata, N. Yoshida, N. Kawano, K. Matsumoto, J. Org. Chem. 1994, 59, 938

(Scheme 8.17). All these biogenic cyclizations [45] have recently been reviewed[46].

Cyclization of �-amidophenyl sulfoxides 1244 for n = 1, 2, 3 with O-silylketeneacetal 1214 affords 5-, 6-, and 7-membered lactams 1245 in 100, 54, and 57%yields, respectively, and [Me3CSi(Me)]2O 94 a; [47, 48], whereas cyclization of N-methyl-2-methylsulfenyl benzamide 1246 with silylketene acetal 1214 and ZnI2

gives 85% 3-methyl-2,3-dihydro-1,3-benzothiazine-4-one 1247 and [Me3CSi(Me)2]2O94 a; [48] (Scheme 8.18).

Cyclization of the sulfoxide 1248 with TMSOTf 20/DIPEA affords a 4 : 1 mixtureof the tetrahydroquinolines 1249 and 1250, in 97% yield, and HMDSO 7 [49]. Onheating of the sulfoxide 1251 to 80 �C Brook rearrangement then Sila–Pummererrearrangement–cyclization gives, via 1252, 17% 1253 [50] (Scheme 8.19).


Scheme 8.16

Scheme 8.17

[45] Y. Kita, O. Tamura, T. Miki, T. Tono, Tetrahedron Lett. 1989, 30, 729[46] Y. Kita, N. Shibata, Acc. Chem. Res. 1995, 289[47] Y. Kita, O. Tamura, T. Miki, Y. Tamura, Tetrahedron Lett. 1987, 28, 6479[48] Y. Kita, O. Tamura, N. Shibata, T. Miki, Chem. Pharm. Bull. 1990, 38, 1473[49] D. Craig, K. Daniels, A.R. MacKenzie, Tetrahedron Lett. 1992, 37, 7803[50] I.W.J. Still, J.R. Strautmanis, Can. J. Chem. 1990, 68, 1408

Likewise, treatment of sulfoxide 1254 with Me3CSi(Me)2OTf 987/NEt3 inducesrearrangement via 1255 to give 30% of the aspidosperma alkaloid 1256 and 25%starting material 1254 [51] (Scheme 8.20).

Sila–Pummerer reaction of the �-ketosulfoxide 1257 with the enol silyl ether ofacetophenone 653 in the presence of BSA 22 a and stannous triflate affords the C-substituted sulfide 1258 in 82% yield and HMDSO 7 [52]. The allylic sulfoxide1259 reacts with 653 in the presence of TMSOTf 20/DIPEA to give the unsatu-rated sulfide 1260 in 62% yield or, with the enol silyl ether of cyclohexanone107a;, the unsaturated sulfide 1261 in 63% yield and HMDSO 7 [53] (Scheme8.21).


Scheme 8.18

Scheme 8.19

[51] M. Dardaine, A. Chiaroni, C. Riche, N. Langlois, Tetrahedron Lett. 1992, 33, 6143[52] M. Shimizu, T. Akiyama, T. Mukaiyama, Chem. Lett. 1984, 1531[53] R. Hunter, C.D. Simon, Tetrahedron Lett. 1986, 27, 1385

In the presence of ZnI2 in acetonitrile the saturated sulfoxide 1262 is convertedby the O-trimethylsilylketene acetal 663 into the sulfide 1263 in 55% yield andHMDSO 7 [54] whereas the unsaturated sulfoxide 1264 affords with excess O-silyl-ketene acetal 663 the bis-addition product 1265 in 45% yield [55, 56] (Scheme8.22).

In the presence of TMSOTf 20 the olefin 1266 adds methyl benzene sulfenateto give the episulfonium triflate 1267, which cyclizes in 97% yield to give a ca 1 : 1mixture of epimers of 1268 [57] (Scheme 8.23).

The Sila–Pummerer reaction of �-alkoxy sulfoxides such as 1269 with excess tri-methylsilyl cyanide 18 and ZnI2 affords, in quantitative yield, the �-cyanoether1270 and trimethylsilyl methylsulfenate 1271 [58] (Scheme 8.24).


Scheme 8.20

Scheme 8.21

[54] Y. Kita, O. Tamura, H. Yasuda, F. Itoh, Y. Tamura, Chem. Pharm. Bull. 1985, 33, 4235[55] Y. Kita, O. Tamura, F. Itoh, H. Yasuda, T. Miki, Y. Tamura, Chem. Pharm. Bull. 1987,

35, 562[56] N. Shibata, C. Fujimori, S. Fujita, Y. Kita, Chem. Pharm. Bull. 1996, 44, 892[57] E.D. Edstrom, T. Livinghouse, J. Am. Chem. Soc. 1986, 108, 1334[58] J. A. Schwindeman, P.D. Magnus, Tetrahedron Lett. 1981, 22, 4925

8.1.4Sila–Morin-Rearrangement of Penicillin Sulfoxides to Cephalosporins

Whereas the acid-catalyzed Morin rearrangement of the readily available penicil-lin-S-oxides 1272 gives only moderate yields of the cephalosporins 1274 [59, 59 a],the Sila–Morin rearrangement of 1272 with TCS 14 or BSA 22 a; affords, in highyield, the ring-opened products 1273, which cyclize in the presence of methane-sulfonic acid to give the ring-expanded cephalosporins 1274 in up to 70% yield(Scheme 8.25), making this Sila–Morin rearrangement technically feasible [60–66].


Scheme 8.22

Scheme 8.23

Scheme 8.24

[59] R. A. Morin, B. G. Jackson, R.A . Mueller, E.R. Lavagnino, W. P. Scanlon, S.L. An-

drews, J. Am. Chem. Soc. 1963, 85, 1896[59a] R. A. Morin, B. G. Jackson, R.A. Mueller, E.R. Lavagnino, W. P. Scanlon, S.L. An-

drews, J. Am. Chem. Soc. 1969, 91, 1401[60] Ger. Offen. DE 210,765; Chem. Abstr. 1970, 76, 3879

(Cf. also the analogous rearrangement of the sulfoxide 1184 with trimethylsilyl io-dide 17/triethylamine, which leads to a mixture of 1187 and 1188 [19].)

8.2Reactions with DMSO

8.2.1Reaction of DMSO-Me3SiCl Reagents with Nucleophiles

DMSO or other sulfoxides react with trimethylchlorosilanes (TCS) 14 or trimethyl-silyl bromide 16, via 789, to give the Sila–Pummerer product 1275. Rearrangementof 789 and further reaction with TCS 14 affords, with elimination of HMDSO 7 andvia 1276 and 1277, methanesulfenyl chloride 1278, which is also accessible by chlor-ination of dimethyldisulfide, by treatment of DMSO with Me2SiCl2 48, with forma-tion of silicon oil 56, or by reaction of DMSO with oxalyl chloride, whereupon COand CO2 is evolved (cf. also Section 8.2.2). On heating equimolar amounts of pri-mary or secondary alcohols with DMSO and TCS 14 in benzene, formaldehyde acet-als are formed in 76–96% yield [67]. Thus reaction of n-butanol with DMSO and TCS14 gives, via intermediate 1275 and the mixed acetal 1279, formaldehyde di-n-butylacetal 1280 in 81% yield and methyl mercaptan (Scheme 8.26). Most importantly,use of DMSO-D6 furnishes acetals in which the O,O�-methylene group is deuter-ated. Benzyl alcohol, however, affords, under these reaction conditions, 93% diben-zyl ether 1817 and no acetal [67].

Furthermore, 1,3-, 1,4-, and 1,5-diols react with DMSO and Me3SiCl 14 inCH2Cl2 to give 1,3-dioxanes, 1,3-dioxacycloheptanes, and 1,3-dioxacyclooctanes in25–40% yields [68]. Because alcohols can give reactive intermediates, an �-hy-


Scheme 8.25

[61] J. de Koning, H.J. Kooreman, H.S. Tan, J. Verweij, J. Org. Chem. 1975, 40, 1346[62] P.G. Claes, G. Decoster, L.A. Kerremans, H. Vanderhaeghe, J. Antibiot. 1979, 33, 820[63] A. P. Coll, J.C. Castellvi, Span. ES. 534,646; Chem. Abstr. 1987, 106, 18248d[64] T.S. Chou, Tetrahedron Lett. 1974, 725[65] T.S. Chou, J. R. Burgtorf, A. L. Ellis, S. R. Lammert, S. P. Kukolja, J. Am. Chem. Soc.

1974, 96, 1609[66] R. Noyori, Tetrahedron 1981, 37, 3899[67] B. S. Bal, H.W. Pinnick, J. Org. Chem. 1979, 44, 3727[68] Z. Gu, L. Zeng; X.-P. Fang, T. Colman-Saizarbitoria, M. Huo, J. J. McLaughlin, J.

Org. Chem. 1994, 59, 5162

droxyl group forms a leaving group enabling cyclization to, e.g., tetrahydrofurans.Thus diol 1281 affords, in the presence of DMSO/TCS 14, via 1282, the annelatedTHF 1283 in 85% yield and up to 14% of olefins [69] (Scheme 8.27).

Ketones such as methyl cyclohexyl ketone 1284 react with DMSO/TCS 14, viatheir enol form, to give 21% of the chloroketone 1285a; and 63% of the �-methylmercaptoketone 1286 [70]. Reaction of 1284 with DMSO/Me3SiBr (TBS) 16 affords85% of the bromo compound 1285b; and 12% hexahydrophenacyl bromide 1287but no 1286 [71]. Whereas reaction of trans-4-phenyl-3-buten-2-one (benzalacetone)1288 with DMSO/TCS 14 gives 81% of the sulfonium salt 1289 [70], the �-dicar-bonyl compound ethyl acetoacetate furnishes 69% of 1290 [70]. In contrast withDMSO/TCS 14, the combination DMSO/TBS 16 effects selective monobromina-tion of �-dicarbonyl compounds [71] (Scheme 8.28).


Scheme 8.26

Scheme 8.27

[69] P.F. Vlad, N.D. Unger, Synthesis 1983, 216[70] F. Bellesia, F. Ghelfi, R. Grandi, U.M. Pagnoni, J. Chem. Res. (S) 1986, 426[71] F. Bellesia, F. Ghelfi, R. Grandi, U.M. Pagnoni, J. Chem. Res. (S) 1986, 428

Because the reactive intermediate 1277 and methanesulfenyl chloride 1278 areelectrophiles, they can react with olefins [72–75]. Thus �5-steroids give rise to 6-�-methylmercapto-�4-steroids [74]. trans-6-Phenylcyclohex-3-ene-3-carboxylic acid1291 reacts with DMSO/Me3SiBr 16 to form, via 1292, the lactone 1293 in 87%yield, whereas attempted bromolactonization of 1291 affords only 59% 1294 [75](Scheme 8.29).

When TCS 14 is added slowly to a mixture of indole or 1-methylindole inDMSO and MeCN at 0 �C the sulfonium salts 1295a; and 1295b; are isolated in87% in 71% yield, respectively [76]. If, however, TCS 14 reacts for 30 min at 0 �Cwith DMSO in MeCN before addition of indole the sulfonium salt 1295a; is iso-lated in 37% yield only, with 35% 3-chloroindole 1296a;. The authors assume thatthe initially formed intermediate 789 gives the sulfonium salt 1295, whereas on


Scheme 8.28

Scheme 8.29

[72] F. Bellesia, F. Ghelfi, U.M. Pagnoni, A. Pinetti, J. Chem. Res. (S) 1987, 238[73] F. Bellesia, F. Ghelfi, U.M. Pagnoni, J. Chem. Res. (S) 1987, 24[74] P.R. Shafiullah, P.R. Dua, R.C. Srimal, S.A. Ansari, Steroids 1991, 56, 562[75] K. Miyashita, A. Tanaka, H. Mizuno, M. Tanaka, C. Iwata, J. Chem. Soc. Perkin I 1994,

847[76] F. Bellesia, F. Ghelfi, U.M. Pagnoni, A. Pinetti, J. Chem. Res. (S) 1989, 182

standing at 0 �C Me2SCl2 1277 is formed, which chlorinates the indoles to 3-chloroindole 1296 [76] (Scheme 8.30).

Pyrroles react likewise with DMSO/TCS 14 or DMSO/TBS 16 to give sulfoniumsalts and halo derivatives [77].

8.2.2Oxidations with DMSO/Me3SiCl

Whereas the original Moffat–Pfitzner oxidation employs dicyclohexylcarbodiimideto convert DMSO into the reactive intermediate DMSO species 1297, which oxi-dizes primary or secondary alcohols via 1298 and 1299 to the carbonyl com-pounds and dicyclohexylurea [78–80], subsequent versions of the Moffat–Pfitzneroxidation used other reagents such as SO3/pyridine [80a, 83] or oxalyl chloride[81–83] to avoid the formation of dicyclohexylurea, which is often difficult to re-move. The so-called Swern oxidation, a version of the Moffat–Pfitzner oxidationemploying DMSO/oxalyl chloride at –60 �C in CH2Cl2 and generating Me2SCl21277 with formation of CO/CO2, has become a standard reaction in preparativeorganic chemistry (Scheme 8.31).

As discussed in Section 8.2.1, DMSO reacts with Me3SiCl 14 in acetonitrile, via789 and 1276, to give 1277 and HMDSO 7, which separates as a mobile colorlessupper layer [70]. One thus wonders whether the reaction conditions for oxidationswith DMSO/Me3SiCl 14, DMSO/Me2SiCl2 48, or DMSO/SiCl4 57 can be adaptedto generate Me2SCl2 1277 cleanly in acetonitrile or CH2Cl2 for in-situ or subse-quent oxidation of primary or secondary alcohols to their carbonyl compounds, be-fore decomposition of 1277 occurs to MeSCl 1278 and MeCl.

Oxidation of oximes or semicarbazones of saturated and �,�-unsaturated alde-hydes and ketones with DMSO/Me3SiCl 14 results in high recoveries of the car-


Scheme 8.30

[77] U. Pagnoni, A. Pinetti, J. Heterocycl. Chem. 1993, 30, 617[78] K. E. Pfitzner, J. A. Moffatt, J. Am. Chem. Soc. 1963, 85, 3027[79] K. E. Pfitzner, J. A. Moffatt, J. Am. Chem. Soc. 1965, 87, 5661[80] K. E. Pfitzner, J. A. Moffatt, J. Am. Chem. Soc. 1965, 87, 5670[80a] J. R. Parikh, W. von E. Doering, J. Am. Chem. Soc. 1967, 89, 5505[81] A. J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978, 43, 2480[82] A. J. Mancuso, D. S. Brownfain, D. Swern, J. Org. Chem. 1979, 44, 4148[83] A. J. Mancuso, D. Swern, Synthesis 1981, 165

bonyl compounds [84]. Thus the oxime of cinnamaldehyde 1300 gives free cin-namaldehyde, in 90% yield, and dimethyl sulfide and NOCl, whereas the tosylhy-drazone of phenethyl methyl ketone 1301 affords 98% phenethyl methyl ketone1302 [85] (Scheme 8.32). Hindered secondary alcohols such as in borneol or iso-borneol are also readily oxidized by DMSO/(F3CCO)2O in CH2Cl2 [85a].

8.3Reactions with SO2 and SO3 and their Derivatives

Treating �-trimethylsilyllithium compounds such as 1303 with SO2 results, via1304, in elimination of Me3SiOLi 98 to give the sulfines 1305 in 80% yield [86].Vinylsilanes such as 1306 add tert-butyllithium to generate the salt 1307, whichadds SO2 again to give, after rearrangement and elimination of Me3SiOLi 98, thesulfine 1308 in 51% yield [87] (Scheme 8.33).

Adding butyllithium to N-silylated amines such as N-trimethylsilylaniline 1309to form the salt 1310 and then introducing SO2 induces elimination of Me3SiOLi


Scheme 8.31

Scheme 8.32

[84] F. Ghelfi, R. Grandi, U.M. Pagnoni, Synth. Commun. 1993, 23, 2279[85] F. Ghelfi, R. Grandi, U.M. Pagnoni, Synth. Commun. 1992, 22, 1848[85a] S.L. Huang, K. Omura, D. Swern, J. Org. Chem. 1976, 41, 3329[86] M. van der Leij, P. A . T. W. Porskamp, B. H.-M. Lammerink, B. Zwanenburg, Tetrahe-

dron Lett. 1978, 811

98 and rearrangement to N-sulfinylamines such as 1311 in 74% yield [88]. Silyl-ated amides of amino acids 1312 derived from 7-aminocephalosporin give, ontreatment with SO2, via 1313, cyclization and elimination of HMDSO 7 to give1314, and subsequent elimination of Me3SiOH 4, the 3-keto-1,2,5-thiadiazoles1315 in up to 65% yield [89] (Scheme 8.34).

Heating perfluorbutylsulfonyl fluoride 1316 with HMDS 2 and CsF in DMF af-fords the N-nonaflylamidine 1317 in 62% yield, trimethylsilyl fluoride 71, andHMDSO 7 [90]. Di(fluorosulfonyl)phenoxysulfonylmethane 1318 reacts with ex-cess lithium trimethylsilanolate 98 to give, via 1319, with elimination of HMDSO7, the lithium salt 1320 in 95% yield [91] (Scheme 8.35).

Treatment of N-tert-butylsulfonylamine 1321 with Li-HMDS 492 induces elimi-nation of Me3SiOLi 98 and the formation of sulfurdiimide 1322 in 65% yield [92].The analogous reaction of tert-butyl isocyanate 1323 with Li-HMDS 492 affords N-


Scheme 8.33

Scheme 8.34

[87] M. van der Leij, B. Zwanenburg, Tetrahedron Lett. 1978, 3383[88] P.A. T. W. Porskamp, B. Zwanenburg, Synthesis 1981, 368[89] W. H.W. Lunn, J. K. Shadle, Tetrahedron 1992, 48, 8615[90] H. Niederprüm, P. Voss, V. Beyl, Liebigs Ann. Chem. 1973, 20[91] Y.L. Yagupol’skii, T. I. Savina, Z. Z. Rozhkova, Zh. Org. Khim. 1991, 27, 492; Chem.

Abstr. 1991, 115, 182740[92] I. Ruppert, V. Bastian, R. Appel, Chem. Ber. 1975, 108, 2329

tert-butyl-N �-trimethylsilylcarbodiimide 1324 in 56% yield [92]. The authors ex-clude the presence of any N-tert-butyl-N-(trimethylsilyl)cyanamide (cf. the postu-lated equilibrium between 328 and 553 in Scheme 5.38). Reaction of 1325 withtris(trimethylsilyl)amine 1326 gives rise to the sulfurdiimide 1327 and trimethyl-silyl fluoride 71 [92]. Reaction of the dichlorosulfuranylideneamino moiety 1328with methylmercapto-N,N �-trimethylsilylamine 1329 affords, analogously, the sul-furdiimides 1330 [93] (Scheme 8.36).

Bis(trimethylsilyl)sulfate 559, which is readily available from TCS 14 andH2SO4 in 76% yield [94], reacts on heating with anisole to form the trimethylsilylester of p-methoxybenzenesulfonic acid 1331 in 92% yield [95]. The hexamethyldi-siloxane (HMDSO) 7 and H2O formed are removed during the reaction by azeo-tropic distillation [95]. On heating of acetyl chloride with 559 the probable inter-mediate 1332 rearranges to give 1333 in 63% yield. The last reaction can be ex-tended to other acid chlorides [95] (Scheme 8.37).

Sulfur trioxide reacts with Me3SiCl 14 to give the trimethylsilyl ester of chloro-sulfonic acid 1334 [96], which on treatment with iodosobenzene forms iodosoben-zenedichloride 1335, HMDSO 7, and regenerated SO3 [97]. Addition of olefinssuch as cyclohexene leads to the formation of sulfones such as 1336 [97]. With


Scheme 8.35

Scheme 8.36

[93] A. Schwöbel, G. Kresze, Liebigs Ann. Chem. 1985, 453[94] N. Duffaut, R. Calas, J. Dunoguès, Bull. Soc. Chim. Fr. 1963, 512[95] P. Bourgeois, N. Duffaut, Bull. Soc. Chim. Fr. 1980, II 195[96] M. Schmidt, H. Schmidbaur, Chem. Ber. 1962, 95, 47[97] A. R. Bassindale, I. Katampe, M.G. Maesano, P. Patel, P.G. Taylor, Tetrahedron Lett.

1999, 40, 7417

silylated diethylamine 146 sulfur trioxide affords the trimethylsilyl ester of N,N-diethylamidosulfonic acid 1337 [98].

8.4Reactions of Selenoxide and SeO2 and their Derivatives

After oxidation of �-selenide 1338 with m-chloroperbenzoic acid the resultingselenoxide 1339 decomposes in CCl4 at 80 �C to give 64% 1340, PhSeOH 1341,6% 1342, acetophenone, and 6% 1343, whereas in THF as solvent at 25 �C only30% 1340 but 22% 1342, acetophenone, and 24% 1343 are formed [99]. Likewise,with 30% H2O2 in THF–Et2O the selenide 1344 affords, via the selenoxide, 40%lactol 1345 and 24% lactone 1346 [100] (Scheme 8.38).

Reaction of SeO2 with N-trimethylsilylamines 1347 affords quantitative yield ofthe corresponding trimethylsilylamidoselenites 1348, which gradually decomposeat ambient temperature to give the anhydrides 1349 and HMDSO 7 [101]. Theseanhydrides have, apparently, not yet been used as oxidants (cf., e.g., the reactionswith PhSe(O)OSe(O)Ph 1354 described below). On treatment of 1350 with SOCl2the crystalline trichloroselenomorpholine 1351 is obtained in 84% yield [101].Compound 1350 might also be converted into 1351 and HMDSO 7 on treatmentwith TCS 14. N-Silylated morpholine 1347b; reacts with dimethyl selenite 1352 togive the methyl morpholinoselenite 1353 [101] (Scheme 8.39).


Scheme 8.37

[98] M. Schmidt, H. Schmidbaur, Angew. Chem. 1958, 70, 657[99] H.J. Reich, S.K. Shah, J. Org. Chem. 1977, 42, 1773

[100] J. D. White, M.-C. Kang, B.G. Sheldon, Tetrahedron Lett. 1983, 24, 4539[101] G. G. Brashenkov, N. Y. Derkach, Zh. Org. Khim. 1978, 48, 1110; Chem. Abstr. 1978,

89, 109676p

In the presence of HMDS 2 phenol reacts with diphenylseleninic anhydride1354 to give, via 1355, 1356, which is further oxidized via 1357 to give the N-phe-nylselenoquinonimine 1358 in 45% yield [102] (Scheme 8.40).

8.4 Reactions of Selenoxide and SeO2 and their Derivatives 209

Scheme 8.38

Scheme 8.39

Scheme 8.40

[102] D.H.R. Barton, A. G. Brewster, S.V. Ley, M.N. Rosenfeld, J. Chem. Soc. Chem. Com-mun. 1977, 147

Reaction of estrone 1359 with 1354 and HMDS 2 results in 64% 1360 and 12%1361 [103]. Reduction of 1360 with Zn/acetic anhydride affords 4-acetaminoes-trone 1362 in 83% yield [103] (Scheme 8.41).

8.5Preparation of Aldehydes and Ketones from Thio- and Selenoethers

As already briefly mentioned in Section 8.1.1, �-trimethylsilylphenyl thioetherssuch as 1164 can be oxidized by m-chloroperbenzoic acid to give S-oxides such as1363, which is readily saponified in 70% overall yield to the aldehyde 1165 [8]. InSection 8.4 the conversion of the 1-trimethylsilyl-1-phenylylselenyl-pentose 1344 tothe lactol 1345 is also described. Conversion of cyclohexene oxide into the adduct1364 gives, after oxidation, rearrangement, and hydrolysis, the aldehyde 1365 in79% yield [8]. The allylic sulfoxide 1366 furnishes, after S-methylation withFSO3Me and [2,3]sigmatropic rearrangement, the sulfide 1367, which is convertedon oxidation and Sila–Pummerer rearrangement into the homoallylic aldehyde1368 [9] (Scheme 8.42).

The cyclic sulfoxide 1369 rearranges on heating in THF to give 1370 which, ontreatment with AgNO3, gives the cyclobutenone 1371 in 72% yield [13]. Unsatu-rated sulfoxides such as 1372 rearrange at 24 �C to give 1373 which, on hydrolysisin the presence of AgNO3, gives the unsaturated sennecio aldehyde 1082 in 55%yield [12] (Scheme 8.43).

The seleno derivative 1374, which can be readily prepared by reduction of di-phenyldiselenide with sodium borohydride then alkylation with chloromethyltri-methylsilane, is alkylated to 1375 to give, on oxidative hydrolysis, aldehydes 1376in high yields, PhSeO2H·H2O 1377 [104], and 7 (Scheme 8.44). Alkylation of thecommercially available methyl thiomethyl sulfoxide 1378 leads to mono- or dialkyl


Scheme 8.41

[103] J. S.E. Holker, E. O’Brian, B. K. Park, J. Chem. Soc. Perkin I, 1982, 1915[104] K. Sachdev, H.S. Sachdev, Tetrahedron Lett. 1976, 4223

derivatives such as 1379, which give, on Pummerer rearrangement with HCl inTHF and hydrolysis, aldehydes [105] or ketones such as 1380 in 54–81% yield[106]. Sila–Pummerer rearrangements, to aldehydes, of intermediates such as1379 with Me3SiCl 14 or TMSOTf 20 have, apparently, not yet been investigated.

The seleno derivative 1381 gives, via a [2,3]sigmatropic shift, 1382; eliminationof PhSeOH then gives the olefin 1383 in 68% yield [107]. Rearrangement of 1384

8.5 Preparation of Aldehydes and Ketones from Thio- and Selenoethers 211

Scheme 8.42

Scheme 8.43

[105] K. Ogura, G.-I. Tsuchihashi, Tetrahedron Lett. 1971, 3151[106] G. Schill, P.R. Jones, Synthesis 1974, 117[107] H.J. Reich, J. Org. Chem. 1975, 40, 2570

Scheme 8.44

affords the ��-unsaturated ketone 1385 in 70% yield [107]. The thio derivative1386 provides, on oxidation with m-chloroperbenzoic acid, 45% bis(trimethyl-silyl)ketone 1387 and 45% 1388 [108] (Scheme 8.45).

8.6Conversion of Carbonyl Groups into Thiocarbonyl Groups

The Lawesson reagent, the dimer of 4-MeOC6H4PS2, has become widely used forconversion of carbonyl groups into thiocarbonyl groups in esters, lactones,amides, or lactams [109, 110]. An alternative reagent is a mixture of P4S10/Me3SiOSiMe3 (HMDSO) 7, which can be considered to be the monomeric or poly-meric trimethylsilyl ester of thiophosphoric acid Me3SiO-P(=S)(SSiMe3)-S-P(=S)(SSiMe3)-OSiMe3 [111]. On heating esters, lactones, amides, or lactams withP4S10/HMDSO 7 in boiling xylene the thio compounds are obtained in yields equiva-lent to, or often superior to, yields on employing the Lawesson reagent. Thus, onheating of ethyl benzoate in boiling xylene with P4S10/HMDSO 7 for 8 h ethyl thio-benzoate 1389 is isolated in up to 81% yield [111]. In boiling acetonitrile valerolactoneis converted into the thiolactone 1390 in 82% yield whereas the Lawesson reagentgives only 71% 1390. Butyrolactam affords 91% thiolactam 1391. Interestingly, the�-ketoesters 1392 are converted into the dithiolthiones 1393 [111] (cf. also the reactionof ethyl acetoacetate with P4S10/HMDSO 7 to give 620). This class of compound canalso be prepared by condensing ketones such as acetophenone with CS2 and KH inN,N �-dimethylpropyleneurea (DMPU), to give 1394, then addition of hexamethyldi-silathiane 601 and subsequent oxidation with hexachloroethane (C2Cl6) to give, via1395, the 5-phenyl-3H-1,2-dithiol-3-thione 1393b; in 99% yield and HMDSO 7[112] (Scheme 8.46).


Scheme 8.45

[108] A. Ricci, A. Degl’Innocenti, M. Ancillotti, Tetrahedron Lett. 1986, 27, 5985[109] B. S. Pedersen, S.O. Lawesson, Tetrahedron 1979, 35, 2433[110] M.P. Cava, M.I. Levinson, Tetrahedron 1985, 41, 5061[111] T. J. Curphey, J. Org. Chem. 2002, 67, 6461[112] T. J. Curphey, A.H. Libby, Tetrahedron Lett. 2000, 41, 6977

8.7Reduction of Sulfoxides

Sulfoxides such as DMSO can be selectively reduced with the rather evil smellingcommercially available hexamethyldisilthiane 601, without solvent, to give sulfidessuch as dimethyl sulfide without affecting other reactive functional groups suchas a �-carbonyl or �-chloromethyl groups. In the reduction of DMSO the probableintermediate 1396 decomposes to HMDSO 7 and the unstable thiosulfoxide 1397which loses sulfur to give dimethyl sulfide in 97% yield [113, 115]. Chloromethylphe-nyl sulfoxide 1398 reacts with hexamethyldisilthiane 601 [114] in chloroform to give95% chloromethylphenyl sulfide 1399 [113]. Replacement of 601 by hexamethylcyc-lotrisilthiane (Me2SiS)3 [114] leads to approximately the same yields of sulfides andsulfur and hexamethylcyclotrisiloxane 54 or octamethylcyclotetrasiloxane 55 [113].Analogously, the �-ketosulfoxide 1400 is reduced by 601 in THF, in 90% yield, tothe sulfide 1401 and HMDSO 7 and sulfur [115] (Scheme 8.47). Divinylsulfoxide1402 is reductively chlorinated by Me3SiCl 14, via 1403 and 1404, to afford 54% di-chloro compound 1405 and 99% HMDSO 7 [116]. Treatment of diphenyl sulfoxide1406 with TMSOTf 20 then Grignard reagents RMgBr gives moderate yields of suchsulfonium triflates as 1407 and HMDSO 7 [117] (Scheme 8.47).

8.7 Reduction of Sulfoxides 213

Scheme 8.46

[113] H.S. D. Soysa, W. P. Weber, Tetrahedron Lett. 1978, 235[114] D.A. Armitage, M. J. Clark, A.W. Sinden, J.N. Wingfield, E. W. Abel, E. J. Louis, In-

organic Synthesis 1974, 15, 207[115] M.R. Detty, M.D. Seidler, J. Org. Chem. 1982, 47, 1354[116] B. A. Trofimov, M. Ya, Khil’ko, N.K. Gusarova, N.A. Chernysheva, A. V. Gusarov,

Zh. Org. Khim. 1993, 63, 495[117] R. D. Miller, A.F. Renaldo, H. Ito, J. Org. Chem. 1988, 53, 5571


�,��-bis(Trimethylsilyl)sulfide 1166 (1.5 equiv.) and N-methylmaleic imide (1 equiv.)are heated for 10 min in HMPA at 100 �C to give, via 1167, the tetrahydrothio-phene 1169 in 81% yield [14] (Scheme 8.48).

Treatment of 1213 (1 equiv.) for 14 h at 70 �C with silylketeneacetal 1214 (ca. 2equiv.), in abs. acetonitrile, in the presence of anhydrous ZnI2 (0.05 equiv.), givesthe �-silyloxysulfide 1215 in 75% yield [31] (Scheme 8.49).


Scheme 8.47

Scheme 8.48

Scheme 8.49

Keteneacetal 1214 (27 mg, 0.143 mmol) is added to a stirred solution of sulfoxide1244 (27 mg, 0.09 mmol) and ZnI2 (6 mg) in acetonitrile (1 mL), kept for 1 h at 25 �Cunder nitrogen, then partitioned between 20 mL CH2Cl2 and 20 mL sat. NaHCO3

solution in H2O. The aqueous layer is extracted with CH2Cl2 (4�20 mL) and thecombined extracts are washed with brine, dried over MgSO4, and concentrated un-der reduced pressure. The residue is subjected to column chromatography or TLCwith hexane–EtOAc as mobile phase to give 25.9 mg (100%) 1245 [48] (Scheme 8.50).

Me3SiCl 14 (108 mg, 1 mmol) is added to a solution of DMSO (78 mg, 1 mmol)in dry toluene (1 mL), whereupon a white product precipitates. A solution of the1,4-diol 1281 (254 mg, 1 mmol) in dry toluene (2.5 mL) is added and the reactionmixture is stirred in a water bath at 40–45 �C until the precipitate dissolves(5 min). The reaction mixture is then kept at 22 �C for 17 h, diluted with 5 mLether, and 5 mL H2O is added. The organic layer is washed with H2O (3�5 mL),sat. NaHCO3 solution (3 mL), H2O (3�5 mL), dried (Na2SO4), filtered, and evapo-rated. The residue is chromatographed on alumina (A III) with hexane–5% ethylacetate as mobile phase to give 85% 1283, m.p. 73–74 �C [69] (Scheme 8.51).

Methyl benzoate (3.73 mL, 30 mmol), P4S10 (4.45 g 10 mmol), and Me3SiOSiMe3 7(10.6 mL, 50 mmol) are heated under reflux for 10 h in 30 mL abs. xylene, with mag-netic stirring, under argon. The reaction mixture is then cooled to 0 �C, 15 mL acet-one and an aqueous solution of K2CO3 are added, and the mixture is stirred for30 min at 0 �C. Water is added and the mixture extracted with benzene. The extractsare washed with K2CO3 solution, water, and brine, and dried (Na2SO4). After evapora-tion, the residue is distilled to give 3.63 g (79%) pure methyl thiobenzoate, b.p. 62–65 �C/0.25 Torr, as an orange liquid [111] (Scheme 8.52).


Scheme 8.50

Scheme 8.51

Scheme 8.52

9.1Introduction

Because several cyclizations have already been described in previous chapters,these are usually not repeated in this chapter but only referred to by the numberof their chemical formulas, schemes, or sections.

Acetalization or ketalization with silylated glycols or 1,3-propanediols and theformation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cy-clizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal121 with �-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also thereaction of 654 to give 655 in Section 5.2) Likewise, Sila–Pummerer cyclizationshave been discussed in Chapter 8 (Schemes 8.17–8.20).

9.2Cyclizations of Aliphatic Systems

In a typical example of aliphatic cyclizations, already discussed in Section 5.2, theenamine 675 is alkylated by silylated methyl 4-chloroacetoacetate 747a [2] to give,via 760 and subsequent elimination of pyrrolidine, the unsaturated bicyclic �-ke-toester 761 in, as yet, only 30–40% yield [1]. Analogously, the bicyclic system 1408with an additional 6-keto group is silylated to 1409 and cyclized via 1410, in anoverall yield of 42%, to the tricyclic capnellene intermediate 1411 [3] (Scheme 9.1).An alternative synthesis of bicyclic compounds like 761 is given elsewhere [3a].

The 1,5-diketone 1412 either cyclizes after 16 h at 24 �C in CHCl3 with TCS 14and gaseous HCl to give the cyclohexenone 1413 in 92% yield [4] and HMDSO 7

217

9

Cyclizations and Ring Enlargements


[1] H. Vorbrüggen, Acc. Chem. Res. 1995, 28, 509[2] B. Bennua-Skalmowski, H. Vorbrüggen, unpublished work[3] M. Shibasaki, T. Mase, S. Ikegami, J. Am. Chem. Soc. 1986, 108, 2090[3a] E. Piers, B. Abeysekera, J. R. Scheffer, Tetrahedron Lett. 1979, 3279[4] W. Kreiser, P. Below, Tetrahedron Lett. 1981, 22, 429

or cyclizes on treatment with piperidine/acetic acid for 12 h in boiling benzene togive the alternative cyclization product 1414 in 75% yield [4] (Scheme 9.2).

1,2-Bis(trimethylsilyloxy)cyclobutene 1415, which is readily available via theRühlmann acyloin condensation [4a] of dialkyl succinate by sodium/Me3SiCl 14(cf. Scheme 5.84) adds to ketones such as acetophenone in CH2Cl2, in the pres-ence of BF3·OEt2 to give, via 1416, on aqueous work-up, the ring enlargementproduct 1417 in 70% yield [5] (Scheme 9.3).

Acyclic and cyclic diols can be readily cyclized on silylation (cf. Schemes 8.17–8.20in Chapter 8). Whereas 1,4-butane-diol 1418a is cyclized with TCS 14 and DMSOonly in low yields, via 1419 a, to give the tetrahydrofuran 1420 a and the unsaturatedalcohol 1421a [6], the tetramethyl analogue 1418b cyclizes readily in 75% yield, via1419b, to give 2,2,5,5-tetramethyltetrahydrofuran 1420b and 21% unsaturated alco-hol 1421b [6] (Scheme 9.4). Analogously, the terpene 1281 affords 85% cyclic ether1282 [6] and 14% of a mixture of olefins, as discussed in Section 8.1.4.

9 Cyclizations and Ring Enlargements218

Scheme 9.1

Scheme 9.2

[4 a] K. Rühlmann, Synthesis 1971, 236[5] S.N. Crane, D. J. Burnell, J. Org. Chem. 1998, 63, 1352[6] P.F. Vlad, N.D. Ungur, Synthesis 1983, 216

In MeCN/Cl(CH2)2Cl in the presence of SnCl4 silylated �-hydroxy-acetals suchas 1422 react, via cations such as 1423, with silylated 5-fluorouracil 1424 to afford,after aqueous work-up, 84% of the nucleoside analogue 1425 and MeOSiMe3 13a[7] (Scheme 9.5).

Esters of �-ketoalcohols such as 1426 cyclize on silylation with TCS 14/HMDS 2and subsequent addition of TMSOTf 20, via 1427, to give a 65:35 mixture of iso-mers of the bicyclic compound 1428 in 65% yield [8] (Scheme 9.6).


Scheme 9.3

Scheme 9.4

Scheme 9.5

Scheme 9.6

[7] T. Iwasaki, T. Nishitani, H. Horikawa, I. Inoue, Tetrahedron Lett. 1981, 22, 1029[8] U. Berens, H.D. Scharf, J. Org. Chem. 1995, 60, 5127

Silylated acetylenic alcohols such as 1429 cyclize with benzaldehyde in the pres-ence of BF3·OEt2 (or KF) to give allenyltetrahydrofurans 1430a or allenyltetrahy-dropyrans 1430b [9] (Scheme 9.7).

On transforming the cyclopentenone 1431 into the trimethylsilyloxy diene 1432the ensuing Diels–Alder cyclization gives rise to 69% tricyclic compound 1433 [10](Scheme 9.8). For Diels–Alder-reactions of thioaldehydes, selenoaldehydes, or un-saturated nitroso compounds with cyclopentadiene, see the reactions of 602 to 603and of 605 to 606 in Scheme 5.48 and of 1092 to 1093 in Scheme 7.43. For Diels–Alder-reactions of silyloxyazadienes such as 510 with maleic anhydride to give511, see Scheme 5.29.

In a related reaction, the Danishefsky diene 1434 cyclizes with ethyl pyruvate1435 in the presence of catalytic amounts of the asymmetric Lewis acid catalyst1436, at –72 �C in THF, to give the Diels–Alder adduct 1437, in 85% yield and91% ee, and the ring-opened product 1438, which cyclizes, however, with triflicacid to give 1437 [11] (Scheme 9.9).


Scheme 9.7

Scheme 9.8

Scheme 9.9

[9] J. Pornet, D. Damour, L. Miginiac, Tetrahedron 1986, 42, 2017[10] M. Ihara, K. Malkita, Y. Fujiwara, Y. Tokunago, K. Fukumoto, J. Org. Chem. 1996, 61,

6416[11] P. I. Dalko, L. Moisan, J. Cossy, Angew. Chem. Int. Ed. 2002, 41, 625

�-Unsaturated amides such as 1439 are readily silylated by TMSOTf 20/NEt3 togive the N,O-bis(silyl) compound 1440, which is cyclized by iodine in 64% overallyield to give the iodolactam 1441 [12] (Scheme 9.10).

4-Aminobutyric acid 1442 a, 5-aminovaleric acid 1442 c, and 6-aminocaproic acid1442e [13, 16] and their 2-amino derivatives 1442b, 1442 d, and 1442f cyclizespontaneously on heating with HMDS 2 or TCS 14, via their N,O-bis(trimethyl-silyl)derivatives 1443, to give, on aqueous work-up, the butyrolactams 1444a, b, the2-piperidones 1444 c, d, or the caprolactams 1444 e, f in high yields [13–17].

Substituted 4-aminobutyric acids 1445a– c cyclize likewise at 140 �C, via 1446a–c, to give substituted butyrolactams 1447a–c [13, 18]. The powdered dihydrochlo-ride of 3-hydroxylysine 1448 affords, on heating with HMDS 2 in xylene thentranssilylation of the silylated 3-hydroxy group with isopropanol, the caprolactam1449 in high yield; 1449 is an intermediate in a new total synthesis of (–)-balanol[19] (Scheme 9.11).

The silylated glycine derivative 1450 cyclizes spontaneously on heating to 85–140 �C to give the hydantoin derivative 1451 in 94% yield [20, 21]. The silylated hy-dantoin 1453 is obtained by reacting silylated N-carboxymethylglycine 1452 withtrimethylsilyl isocyanate 327 and subsequent heating to 140 �C [22] (Scheme 9.12).

Silylation of glycylglycine 1454a and analogs 1454b and c, e.g. with BSA 22aresults, at ambient temperature or on slight heating, usually via 1455, in the high-yield formation of diketopiperazines 1456a–c [17, 23]. The free N,O-bis(trimethyl-silyl)glycylglycine 1455a and insoluble Et3N·HCl can only be isolated by boiling1454a with Me3SiCl 14/NEt3 in CH2Cl2 [17]. Likewise, l-proline can be silylatedby Et2NSiMe3 146 to give N,O-bis(trimethylsilyl)proline 438, which cyclizes slowly


Scheme 9.10

[12] S. Knapp, K.E. Rodriques, A. T. Levorse, R.M. Ornaf, Tetrahedron Lett. 1985, 26, 1803[13] R. Peelegata, M. Pinza, G. Pifferi, Synthesis 1978, 614[14] V. P. Kozyukov, N.V. Mironova, Zh. Obshch. Khim. 1979, 50, 620[15] D.A. Wells, J.E. Chaney, G.A. Digenis, J. Labelled Compd. Radiopharm. 1984, 22, 367[16] H.R. Kricheldorf, Synthesis 1970, 649[17] H.R. Kricheldorf, Liebigs Ann. Chem. 1972, 763, 17[18] B. D. Harris, K.L. Bhat, M.M. Joullie, Synth. Commun. 1986, 16, 1815[19] J. W. Lampe, P.F. Hughes, C.K. Biggers, S. H. Smith, H. Hu, J. Org. Chem. 1994, 59,

5147[20] I.A. Vostokov, J. Obshch. Khim. 1984, 54, 880; Chem. Abstr. 1984, 101, 90830b[21] I.A. Vostikov, S.E. Skoboleva, E. P. Trub, Zh. Obshch. Khim. 1984, 54, 885; Chem.

Abstr. 1984, 101, 130745m[22] I.A. Vostokov, O.S. Medvedev, L.S. Mal’chikowa, E.W. Oranovskaja, Khim-Farm. Zh.

1990, 24, 36; Chem. Abstr. 1991, 114, 344n[23] L. Birkofer, A. Ritter, P. Neuhausen, Liebigs Ann. Chem. 1962, 659, 190


Scheme 9.11

Scheme 9.12

Scheme 9.13

at 24 �C to give diketopiperazine 1457 [24] (cf. the condensation of 438 with pival-dehyde to give 439 in Scheme 5.14). N-Alkylated dipeptides such as sarcosylgly-cine cyclize rapidly during silylation to give N-alkyldiketopiperazines.

3-Methylaminobenzoic acid 1458 cyclizes on heating with SiCl4 57 in pyridineto give a mixture of oligomers 1459 of which the trimer (n= 1) is the major com-pound formed in 41% yield [25] (Scheme 9.14).

Fluoride induced cleavage of silyloxy groups generates the correspondingalcoholates or phenolates, which can undergo ring closure. Thus, the tetrabutyl-ammonium phenolate moiety generated from the protected phenol 1460 withBu4NF·2–3H2O in THF replaces the adjacent O-mesyl group to afford, at 0 �C,90% of the cyclized product 1461 [26, 27] (Scheme 9.15; for cyclizations to �-lac-tams, see Schemes 5.26 and 5.27). A free or silylated hydroxyl group can also be-come a leaving group on reaction with Me3SiI 17, the iodine of which, as theiodide ion, provides the nucleophilic “push” to convert, e.g., the cyclohexanol 1462in 90% yield into the bicyclic lactone 1463 [28]. Likewise, thio ethers become leav-ing groups on reaction of Cu(ClO4)2 with silylated alcohols; an example is thecyclization of 1464 to the tricyclic compound 1465 [29].

Whereas cyclization of the �-keto-��-hydroxyamide 1466 in boiling toluene orxylene in the presence of camphorsulfonic acid (CSA) results in decomposition ofthe starting material 1466, heating of 1466 with excess TMSOTf 20 and N-methyl-morpholine in 1,2-dichloroethane affords 46% of the desired cyclization product1467 [30] (Scheme 9.16). The close relationship of product 1467 to �2-oxazolinessuggests that reaction of carboxylic acids 11 with free (or C-substituted) ethanola-mines 1468 and HMDS 2/TCS 14 might lead analogously, via the silylated inter-mediates 1469, to �2-oxazolines 1470 and HMDSO 7. As demonstrated in thesomewhat related cyclization of 1466 to 1467, combination of TMSOTf 20 with N-


[24] A. A. Prishchenko, M.V. Livantsov, D.A. Pisarnitskii, V. S. Petrosyan, Zh. Obshch.Khim. 1993, 63, 2020

[25] I. Azumaya, H. Kagechika, K. Yamaguchi, K. Shudo, Tetrahedron Lett. 1996, 37, 5003[26] G. Just, T.-J. Liak, Can J. Chem. 1978, 56, 211[27] G. Just, G. H. Hakimelahi, A. Ugolini, R. Zamboni, Synth. Commun. 1979, 9, 113[28] D.R. Walley, J. L. Belletire, Synth. Commun. 1984, 14, 401[29] J.-S. Dung, R. W. Armstrong, R. M. Williams, J. Org. Chem. 1984, 49, 3416[30] H. Vorbrüggen, B. Bennua-Skalmowski, Acc Chem. Res. 1995, 28, 509,

Scheme 9.14

methylmorpholine (instead of 2 with 14) might be an even more effective meansof oxazoline synthesis.

Finally, in another typical example of a Pummerer-type cyclization, the sulfoxide1471 is converted by TMSOTf 20/DIPEA (Hünig’s base) in 98% yield into 1472[31] (Scheme 9.17) (cf. also the cyclizations of the related sulfoxides 1233, 1237,1244, 1246, 1248, 1251, and 1266 in Section 8.1.3 to the cyclized products 1235,1238, 1245, 1247, 1249, 1253, and 1268).

On treatment of the amide 1473 with Me3SiCl 14/NaI (= Me3SiI 17) in pyri-dine/acetonitrile to give 1474, followed by addition of indole and ZnCl2, tivaline1475 is obtained in 83% overall yield [32] (Scheme 9.18).


[31] J. L.G. Ruano, C.G. Paredes, C. Hamdouchi, Tetrahedron Asymm. 1999, 10, 2935[32] S. Mori, T. Ohno, H. Harada, T. Aoyama, T. Shioiri, Tetrahedron 1991, 47, 5051

Scheme 9.15

Scheme 9.16

Terminal olefins such as 1476 react in an unusual Prins reaction [33] with form-aldehyde in F3CCO2H/Me3SiCl 14 to give in ca 75–90% yield a mixture of the cis/trans 3,4-disubstituted tetrahydrofurans 1477 and 1478 [34] (Scheme 9.19).

Pyrrolidines have been prepared by 1,3-dipolar cycloaddition of N-(benzyli-dene)trimethylsilylamine/TMSOf 20 and methyl acrylate, N-methylmaleimide, ordimethyl maleate [35]. More recently, methyl trans-3-cyanocinnamate 1479 was re-acted with N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether 1480 andtrifluoroacetic acid in CH2Cl2 at 0 �C and 24 �C to afford, via 1481, the pyrrolidinederivative 1482 in high yield and MeOSiMe3 13a [35a] (Scheme 9.20). Several


Scheme 9.17

Scheme 9.18

Scheme 9.19

[33] B. B. Snyder in “Comprehensive Org. Synthesis”, Vol 2/Part 2, page 527 Editor: C.C.

Heathcock, Pergamon Press, Oxford[34] R. F. Talipov, R.R. Muslukhov, I.M. Safarov, F. A. Yamantaev, M.G. Safarov, Khim.

Geterotsikl. Soedin. 1995, 605; Chem. Abstr. 1996, 124, 145774u[35] K. Achiwa, M. Sekiya, Tetrahedron Lett. 1982, 23, 2589[35a] J. M. Fewig, M.L. Quan, PCT Int. Appl, WO 98 06,694; Chem. Abstr. 1998, 128,

192644u

other 1,3-dipolar cycloadditions have already been described in Sections 5.1.1. and5.1.2 (reaction of 440 with 441 to give 444, and of 445 with 446 to give 449) andin Section 7.6 (cyclizations of 1056, 1061, 1064, and 1069).

9.3Cyclizations to Aromatic Systems

The cyclization of acyclic precursors to aromatic compounds has been investigatedfor a long time and has been reviewed [36]. The trimerization of ketones to substi-tuted benzenes with the formation of three equivalents of water can be achievedin the presence of silylating agents. Thus, acetophenone is cyclized in ethanol byexcess SiCl4 57 to afford, probably via 1483 (cf. the formation of the trichloroenol-silylether of cyclohexanone 116 in Scheme 3.8), 1,3,5-triphenylbenzene 1484 in86% yield and three equivalents of the hypothetical leaving group Cl3SiOH [37,38], which is converted on work-up, via Cl3SiOSiCl3 119, into SiO2 and HCl.Cyclopentanone and cyclohexanone are, likewise, cyclized by excess TCS 14 inethanol giving triannullated benzenes 1485, in 65% and 46% yield, respectively,and HMDSO 7 and ethoxytrimethylsilane 13 b [37] (Scheme 9.21). 9-Acetylphenan-threne is cyclized by SiCl4 57, giving 1,3,6-tris(9-phenanthryl)benzene in 54%yield [39] (cf., furthermore, the cyclizations of malonitrile or ethyl cyanoacetate,via their N-silylated ketenimines, to 2,4,6-trisubstituted-1,3,5-triaminobenzenes368 in Scheme 4.50, and the synthesis of pyridines 540 from N-silylated enamines538 and �,�-unsaturated ketones in Section 5.1.3).

Although the most recent modifications of the Prelog condensation of 1,3-dike-tones and 1,3,5-triketones, for example that of acetylacetone with dimethyl 1,3-acetonedicarboxylate in the presence of NaOH in H2O, afford substituted ben-zenes such as 1486 in up to 94% yield (Scheme 9.22) and coumarins [40], thesecondensations of highly substituted polyketones with the corresponding aromaticsystems might also be effected in the presence of HMDS 2/TCS 14 or TMSOTf


Scheme 9.20

[36] P. Bamfield, P.F. Gordon, Chem. Soc. Rev. 1984, 13, 441[37] S.S. Elmorsey, A. Pelter, K. Smith, Tetrahedron Lett. 1991, 32, 4175[38] J. Pang, E. J.-P. Marcotte, C. Seward, R.S. Brown, S. Wang, Angew. Chem Int. Ed.

2001, 40, 4042[39] M.J. Plater, J. Chem. Soc. Perkin I 1997, 2897[40] S.H. Bertz, Synthesis 1980, 708

20/NEt3 or DBU in acetonitrile. Similar condensations of O-silylated �-dicarbonylcompounds with 1,3-bis(trimethylsilyloxy)-1-methoxybutadiene (which is readilyobtained by quenching of the anion of methyl 3-trimethylsilyloxybut-2-enoate withMe3SiCl 14, at –78 �C in CH2Cl2, in the presence of Lewis acids such as TiCl4)likewise afford O-silylated methyl salicylates in high yields [40a–d].

9.4Cyclizations to 5-Membered Aromatic Heterocycles

Heating of hexane-2,5-dione 1487 with TCS 14, NaI, and triethylamine for 36 h, toform 1488, followed by addition of triflic acid and heating to 140 �C affords, ondistillation, a mixture of 2,5-dimethylfuran 1489 and HMDSO 7 containing 90%1489 [41, 41a] (Scheme 9.23).

In the presence of TsOH·H2O N-benzoylaminobutanone 1490 condenses withexcess persilylated �-alanine 680 to give, via 1491 and 1492, the pyrrole 1493 in75% yield [42, 42 a] (Scheme 9.24).


Scheme 9.21

Scheme 9.22

[40a] T.-H. Chan, P. Brownbridge, J. Am. Chem. Soc. 1980, 102, 3534[40b] P. Brownbridge, T.-H. Chan, M.A. Brook, G. J. Kang, Can. J. Chem. 1983, 61, 688[40c] P. Langer, Synthesis 2002, 441[40d] P. Langer, G. Bose, Angew. Chem. Int. Ed. 2003, 42, 4033[41] B. Rigo, D. Valligny, S. Taisne, D. Couturier, Synth. Commun. 1988, 18, 167[41a] J. Julien, J. M. Pechine, M. Perez, J. J. Piade, Tetrahedron 1982, 38, 1413[42] G. Schulz, W. Steglich, Angew. Chem. 1977, 89, 255[42a] G. Schulz, W. Steglich, Angew. Chem. 1977, 89, 256

2,5-Diketohexane 1487 reacts with HMDS 2 in the presence of either CF3SO3H[41] or alumina [43] to give 2,5-dimethylpyrrole 1494 in 81% yield. The analogousreaction of the diketone 1495 with HMDS 2/Al2O3 furnishes the aza-prostacyclinderivative 1496 in 80% yield [44] (Scheme 9.25).

Pyrroles can also be prepared by 1,3-dipolar cycloaddition of C-trimethylsilylamides such as 1497 with dimethyl acetylenedicarboxylate in boiling toluene togive, via the azomethinimide 1498, 78% 1499 [45]. On employing a threefold ex-cess of dimethyl acetylenedicarboxylate the cycloadduct 1499 is obtained in nearlyquantitative yield [45] (Scheme 9.26).

Silylated acetylenic alcohols such as 1500 cyclize on treatment with HMDS-Li togive, via 1501 and 1502, 2-phenylpyrrole 1503 [46] (Scheme 9.27; compare also theformation of 2-pyridyl-2-pyrrole 543 in Chapter 5).

The N-silylated brominated o-toluidine 1504 reacts with Zn and subsequentlywith CuCN/LiCl to give the intermediate 1505 which reacts with a variety of acidchlorides to give, via 1506, 2-substituted indoles 1507 [47] (Scheme 9.28).

As already discussed in Section 5.5.2, amidine hydrochlorides 743 react with O-silylated methyl (or ethyl) 4-chloroacetoacetate 746, in which the 4-chlorine atom


Scheme 9.23

Scheme 9.24

[43] F. Texier-Boullet, B. Klein, J. Hamelin, Synthesis 1986, 409[44] B. Rousseau, F. Nydegger, A. Gossauer, B. Bennua-Skalmowski, H. Vorbrüggen,

Synthesis 1996, 1336[45] M. Ohno, M. Komatsu, H. Miyata, Y. Oshiro, Tetrahedron Lett. 1991, 32, 5831[46] R. J.P. Corriu, V. Huynh, J. Iqbal, J. J.E. Moreau, C. Vernhet, Tetrahedron 1992, 48,

6231[47] H.G. Chen, C. Hoechstetter, P. Knochel, Tetrahedron Lett. 1989, 30, 4795


Scheme 9.25

Scheme 9.26

Scheme 9.27

Scheme 9.28

Scheme 9.29

has become allylic and thus reactive, to give the methyl (or ethyl) imidazole ace-tates 746 in yields of up to 80% [48] (Scheme 9.29).

The silylated bis-imine of benzil 1508 reacts with benzaldehyde in benzene, at90 �C, in the presence of catalytic amounts of AlCl3, to afford 2,4,6-triphenylimida-zole 521 in 83% yield [49] (Scheme 9.30).

Thioamides 1509 cyclize with TMSOTf 20/triethylamine and with TCS 14/triethylamine in CH2Cl2 to give mercaptoimidazoles 1510 [50, 51] (Scheme 9.31).

The N-bis-silylated o-phenylenediamine 1511 reacts with DMF at 120 �C to givebenzimidazole, in 97% yield, and dimethylamine and hexamethyldisiloxane 7,whereas reaction of benzaldehyde with 1511 gives only 29% 2-phenylbenzimida-zole 1513, because the intermediate benzimidazoline 1512 is only rather slowlydehydrogenated to 1513 [52]. Heating of N,N �-bis(trimethylsilyl)ethylenediamine1514 with DMF affords imidazoline 1515 and dimethylamine and HMDSO 7 [52](Scheme 9.32). The lactam 1516 cyclizes analogously with SiCl4 57/triethylaminein 63% yield to give 1517 [53].

Whereas the substituted N-hydroxyuracil 1518 cyclizes on heating for 30 minwith excess HMDS to give the N-hydroxyxanthine 1519 in 22% yield [54], reactionof the uracil derivative 1520 with HMDS 2/TCS 14 in pyridine affords 8-methyl-2-thioxo-2,3-dihydro-1H-imidazo[1,5a]1,3,5-triazine-4-one 1522 in 85% yield, via1521, and subsequent ring opening and ring closure [55] (Scheme 9.33). An analo-gous ring-opening, ring-closure rearrangement is described elsewhere [56].


[48] H. Vorbrüggen, K. Joachim, K. Krolikiewicz, H. Rehwinkel, unpublished work[49] I. Matsuda, T. Takahashi, Y. Ishii, Chem. Lett. 1977, 1457[50] A. Spaltenstein, T. P. Holler, P. B. Hopkins, J. Org. Chem. 1987, 52, 2977[51] V. Zoete, F. Bailly, J.-P. Catteau, J.-L. Bernier, J. Chem. Soc. Perkin I 1997, 2983[52] H. Suzuki, M. Ohashi, I. Matsuda, Y. Ishii, Bull. Chem. Soc. Jpn. 1975, 48, 1922[53] L. Désaubry, C.G. Wermuth, J.-J. Bourguignon, Tetrahedron Lett. 1995, 36, 4249[54] U. Wölcke, G. B. Brown, J. Org. Chem. 1969, 34, 978[55] J. B. Holtwick, B. Golankiewicz, B. N. Holmes, N. J. Leonard, J. Org. Chem. 1979, 44,

3835[56] J. B. Holtwick, N. J. Leonard, J. Org. Chem. 1981, 46, 3681

Scheme 9.30

Scheme 9.31

The N-silylated enol acetate 1523 is cyclized by TMSOTf 20 in CHCl3, in 95%yield, giving the oxazole 1524 [57]. The dimeric derivative 1525 affords the 2,2�-bis-oxazole 1526 in 46% yield [57]. 2-Benzoylamino-3-chloropyridine 1527 is cyclizedby polyphosphoric acid trimethylsilyl ester (PPSE) 195 on heating for 15 h in boil-ing 1,2-dichlorobenzene to give 40–60% 2-phenyloxazolo[5,4-b]pyridine 1528 [58](Scheme 9.34).

Phenyl N-acetylcarbazate 1529 cyclizes on boiling with excess TCS 14/tri-ethylamine in toluene to give 5-methyl-1,3,4-oxadiazoline-2-one 1530 in 65–70%yield [41, 59, 60]. The same type of cyclization was subsequently described for re-


Scheme 9.32

Scheme 9.33

[57] R. F. Cunico, C.P. Kuan, J. Org. Chem. 1992, 57, 3331[58] C. Flouzat, G. Guillaumet, J. Heterocycl. Chem. 1991, 28, 899[59] H.J. Kricheldorf, Liebigs Ann. Chem. 1973, 1816[60] H.J. Kricheldorf, R. Stilke, Chem. Ber. 1974, 107, 3717

action of N,N �-diacylhydrazines 1531 with HMDS 2/Bu4NF [61–63] or withMe2SiCl2 48/CF3SO3H to give 1532 [64] (Scheme 9.35).

On reaction of N-thioformylphenylhydrazine 1533 with aldehydes such as benz-aldehyde (or ketones such as acetophenone) in the presence of TCS 14 inbenzene 2,3-dihydro-1,3,4-thiadiazoles such as 1535 are formed in high yields via1534 [65, 66] (Scheme 9.36).

Heating of N-acetylsemicarbazide 1536 with HMDS 2 and triflic acid in chloro-benzene to 100 �C affords 5-methyl-1,2,4-triazole-2-one 1537 [41]. Likewise, the


Scheme 9.34

Scheme 9.35

[61] B. Rigo, P. Cauliez, D. Fasseur, D. Couturier, Synth. Commun. 1986, 16, 1665[62] B. Rigo, D. Fasseur, P. Cauliez, D. Couturier, Synth. Commun. 1989, 19, 2321[63] D. Fasseur, P. Cauliez, D. Coutourier, B. Rigo, S. Defretin, J. Heterocycl. Chem.

1996, 33, 1951[64] B. Rigo, P. Cauliez, Synth. Commun. 1988, 18, 1247[65] Y. Matsubara, K. Kitano, A. Tsutsumi, M. Yoshihara, T. Maeshima, Chem. Pharm.

Bull. 1994, 42, 373[66] K. Kitano, Y. Matsubara, M. Yoshihara, T. Maeshima, Chem. Pharm. Bull. 1994, 42,

1912

protected seco nucleoside 1538 is cyclized with HMDS 2/TCS 14 in pyridine togive the protected 1,2,4-triazole nucleoside 1539 in 71% yield [67] (Scheme 9.37).

On silylation with TCS 14/triethylamine then heating in chlorobenzene in thepresence of triflic acid the amidrazone 1540 cyclizes to the fused 1,2,4-triazole1541 in nearly quantitative yield [68] (Scheme 9.38).

Addition of the Li anion of trimethylsilyldiazomethane 1542 to phenyl iso-cyanate affords, via 1543 and 1544, the 1,2,3-triazole 1545 in 79% yield [69](Scheme 9.39).

Reaction of amides such as 1546 with PPh3/CCl4 and NaN3, or with PPh3/azo-ester then addition of Me3SiN3 17, affords, via 1547 and 1548, 1,2,3,4-tetrazoles


Scheme 9.36

Scheme 9.37

Scheme 9.38

[67] D.R. Haines, N. J. Leonard, D .F. Wiemer, J. Org. Chem. 1982, 47, 474[68] B. Rigo, I. Gouni, S.E. Gammarti, P. Gautret, D. Couturier, Synth. Commun. 1994,

24, 3055[69] T. Aoyama, M. Kabeya, A. Fukushima, T. Shioiri, Heterocycles 1985, 23, 2363

such as 1549 in 19% yield [70, 71] (Scheme 9.40). Treatment with aqueous alkalithen acidification removes the cyanoethyl protecting group from 1549 [71].

Cyclizations of intermediates to heterophospholes are dealt with in Chapter 11.

9.5Cyclizations to 6-Membered Aromatic Heterocycles

At 25 �C in acetonitrile, in the presence of DBU, pyran-2-ones 1550 add HMDS 2 togive pyridin-2-ones 1553, in up to 96% yield, via 1552 and 1551 [72] (Scheme 9.41).

Reaction of the N,O-acetal 1554 with the silylenol ether of cyclohexanone 107ain the presence of TiCl4 generates the cation 1555, which affords 43% of the cycli-zation product 1556 and 27% of the seco product 1557 [73] (Scheme 9.42).

The N-silylated amide 1558 reacts with diketene via the O-silylated intermediate1559 to give the pyrone 1560, which rearranges when treated with 10% HCl togive pyridin-2-one 1561 [74] (Scheme 9.43).

Treatment of benzoylisocyanate 1562 with trimethylsilyl ketene 1563 gives theoxazine 1564 which reacts, e.g., with enamines 1565 to give pyridine-2-ones 1567,


Scheme 9.39

Scheme 9.40

[70] J. V. Duncia, M. . Pierce, J. P. Santella, J. Org. Chem. 1991, 56, 2395[71] S.B. Christensen, A. Guider, C. J. Forster, J. G. Gleason, P. E. Bender, J. P. Karpinski,

W. E. DeWolf, M.S. Barnette, D.C. Underwood, D. E. Griswold, L.B. Cieslinski, M.

Burman, S. Bochnowicz, R.R. Osborn, C.D. Manning, M. Grous, M.L. Hillegas, J.

O’Leary Bartus, M.D. Ryan, D.S. Eggleston, R. C. Haltiwanger, T. J. Torphy, J. Med.Chem. 1996, 41, 821

[72] Y. Kvita, Synthesis 1991, 883[73] T. Fuchigami, Y. Nakagawa, T. Nonaka, J. Org. Chem. 1987, 52, 5489[74] Y. Yamamoto, H. Kimura, Chem. Pharm. Bull. 1967, 24, 1236

in 61–73% yield, via 1566 [75] (Scheme 9.44). On heating with TMSOTf 20 the di-ketene adduct 1568 reacts to give the intermediate 1569, which undergoes 1,4-di-polar cycloaddition to afford the dihydropyridine-2-one 1570 in 53% yield [76](Scheme 9.45). Replacing the �-olefin by a �-acetylene moiety gives rise to pyri-dine-2-ones [76].

The amide 1571 cyclizes when treated with TCS 14/HMDS 2/pyridine to givethe protected pyrimidine-C-nucleoside 1572 in 96% yield [77] (Scheme 9.46).


Scheme 9.41

Scheme 9.42

Scheme 9.43

[75] K. Takaoka, T. Aoyama, T. Shioiri, Tetrahedron Lett. 1996, 37, 4977[76] A. Padwa, S.R. Harring, M.A. Semones, J. Org. Chem. 1998, 63, 44[77] N. Katagiri, N. Tabei, S. Atsuumi, T. Haneda, T. Kato, Chem. Pharm. Bull. 1985, 33,

102


Scheme 9.44

Scheme 9.45

Scheme 9.46

Scheme 9.47

Formamide is silylated on heating with HMDS 2 to give N,N-bis(trimethyl-silyl)formamide 22 c, which trimerizes on continued heating to 140 �C to gives-triazine 1575, via 1573 and 1574, in 83% yield [78] (Scheme 9.47).

Heating of N,O-bis(trimethylsilyl)acetamide, BSA, 22a for 3 h at 80–100 �C withtwo equivalents of phenyl isocyanate affords the s-triazinone 1577 in 87% yield,via 1576 [79] (Scheme 9.48).


Me3SiCl 14 (2.5 mL) is added to a solution of 2 g �-ketoester 1412 in 20 mL dryCHCl3. The solution is cooled with ice–water and HCl gas introduced until satura-tion occurs. After 16 h at room temperature the volatile constituents are removedin vacuo and the residue distilled in a Kugelrohr apparatus to give 1.7 g (93%)1413 as a slightly yellowish oil, b.p. 95 �C/0.2 Torr [4] (Scheme 9.49).

A two-necked reaction flask, equipped with a magnetic stirrer, efficient reflux con-denser carrying a calcium chloride valve, and gas inlet tube, is charged with l-lysine1442f (5 g, 34 mmol), xylene (450 mL), HMDS 2 (50 mL, 240 mmol), and a fewdrops of Me3SiCl 14. The mixture is heated under reflux under a gentle stream of


Scheme 9.48

[78] G. Schirawski, U. Wannagat, Monatshefte 1969, 100, 1901[79] W. Kantlehner, P. Fischer, W. Kugel, E. Möhring, H. Bredereck, Liebigs Ann. Chem.

1978, 512

Scheme 9.49

Scheme 9.50

dry nitrogen for 48 h (complete solution occurs after 3–5 h) then cooled and pouredinto 1000 mL abs. ethanol and evaporated to dryness under vacuum. The residue isdissolved in chloroform, filtered through a Celite pad on a sintered glass funnel, andthe filtrate is evaporated under reduced pressure. The residue is dissolved in 70 mLdioxane and treated with 13.7 mL 2.5 M HCl solution in isopropanol and the preci-pitate of 4.61 g (82%) hydrochloride 1444f is collected [13] (Scheme 9.50).

TMSOTf 20 (0.056 mL, 0.29 mmol) is added to 1466 (0.50 g, 0.14 mmol) and N-methylmorpholine (0.03 mL, 0.28 mmol) in 8 mL abs. 1,2-dichloroethane and themixture is stirred for 2 h at room temperature then heated under reflux for 8 hwhile removing most of the 1,2-dichloroethane by distillation. The residue is dis-solved in toluene, further amounts of N-methylmorpholine (0.03 mL) andTMSOTf 20 (0.056 mL) are added, and the mixture is heated under reflux for 1 h,with exclusion of humidity, while removing the toluene by distillation. The resi-due is taken up in CH2Cl2, washed with sat. NaHCO3 solution, dried, and evapo-rated to give 0.47 g crude product, which is chromatographed in toluene on 5 g si-lica gel. After a pre-run of 175 mL toluene, the next 250 mL toluene elute 21 mg(45.7%) pure 1467, identified by MS (m/e= 421) and NMR [30] (Scheme 9.51).

CF3CO2H (0.041 mL) is added at 0 �C to a stirred and cooled solution of 0.99 g1479 and 1.64 g 1480 in 20 mL CH2Cl2. The mixture is stirred for 2 h at roomtemperature, diluted with CH2Cl2, washed, and dried to give 1.67 g (98%) 1482and methoxytrimethylsilane 11a [35a] (Scheme 9.52).


Scheme 9.51

Scheme 9.52

Scheme 9.53

SiCl4 57 (1.2 mL, 10 mmol) is added slowly by syringe, at 20 �C, to a stirred so-lution of 4-methoxyacetophenone (1.5 g, 10 mmol) in 10 mL dry ethanol. Afterstirring for 6 h the mixture is poured into 20 mL water, extracted with CH2Cl2(2�25 mL), dried (MgSO4), filtered, and concentrated. Crystallization from ethanolgives 1.162 g (88%) 1484, m.p. 142 �C [37] (Scheme 9.53).

Me3SiCl 14 (279.1 mL, 1.875 mol) is added dropwise to a stirred mixture of 2,5-hexanedione 1487 (100 mL, 0.854 mol), triethylamine (261 mL, 1.875 mol), and so-dium iodide (12.8 g, 0.085 mol). After the exothermic reaction subsides the mix-ture is heated under reflux for 36 h and the solid is then removed by filtrationand washed with abs. ether. After evaporation of the solvent the residue is dis-tilled at 114 �C/13 mmHg to give 83% pure 1488. A mixture of 1488 (9.45 g, 0.037mol) and triflic acid (0.040 g) is heated to 140 �C, whereupon a mixture of 2,5-di-methylfuran 1489 and HMDSO 7 is distilled via a short-path distillation head,heated to 120 �C, to give 90% 2,5-dimethylfuran 1489 [41] (Scheme 9.54).

Triflic acid (0.032 g) is added through a septum to a stirred mixture of 2,5-hex-andione 1487 (1.95 g, 0.017 mol) and HMDS 2 (7.4 mL, 0.035 mol) whereupon anexothermic reaction results and hexamethyldisiloxane 7 is removed by distillationthrough a short-path distillation head. When the reaction subsides (15 min) 81%pure 2,5-dimethylpyrrole 1494, b.p. 165 �C, is isolated by distillation [41].

Reaction of 1487 with HMDS 2 with Al2O3 as acidic catalyst instead of triflicacid also gives ca. 81% pure distilled 1494, b.p. 68 �C/18 Torr [44] (Scheme 9.55).


Scheme 9.54

Scheme 9.55

Scheme 9.56

Trimethylsilyl triflate (TMSOTf) 20 (12.2 g, 54.8 mmol) is added dropwise over30 min, at –10 �C to –5 �C, to a solution of thioamide 1509b (2 g, 13.7 mmol) andtriethylamine (8.32 g, 82.3 mmol) in 140 mL CH2Cl2. After 2 h at –5 �C to 0 �C,the mixture is washed with water, dried and evaporated in vacuo. The residue isflash-chromatographed with 4:1 CH2Cl2–MeOH to give 0.79 g (45%) 1510b as a yel-low oil [51] (Scheme 9.56).


Because of the large number of publications in this field, this chapter will be lim-ited to giving an idea of developments in this area. Because the Peterson reactioncan be viewed as a special case of base-catalyzed reaction, this reaction will be dis-cussed in Section 10.2 after general base-catalyzed eliminations of trimethylsilanolin Section 10.1.

10.1Base Catalyzed Eliminations of Trimethylsilanol

On treatment of O-trimethylsilylated 2,4,6-trimethoxybenzylacohol 1578 with ethyl-magnesium bromide in Et2O, 2,4,6-trimethoxypropylbenzene 1579 is obtained inca 50–60% yield [1]. The trimethylsilyloxy leaving group in the silylated allyl alco-hol 1580 is likewise replaced by isopropyl magnesium bromide in the presence of(�5 C5Me5)2TiCl2 to furnish olefin 1581 in 83% yield [2]. The rates of base cleav-age of other benzyltrimethylsilanes in different solvents were measured and com-pared with those for the corresponding benzylstannanes [2]. Replacement of thetrimethylsilyl group in benzoyltrimethylsilane 1582 by alkali leads, via the transi-ent acyl anion 1583, to benzaldehyde and trimethylsilanol 4 [3]. Anhydrous fluor-ide anion converts benzoyltrimethylsilane 1582 into trimethylsilyl fluoride 78 andthe acyl anion 1583, which can be hydrolyzed to benzaldehyde or trapped underspecial conditions by electrophiles, for example methyl iodide, to give the ketones1584; benzaldehyde gives benzoin in 50% yield [4] (Scheme 10.1).

On treatment of the silylated dichloromethyl alcohols 1585 with butyllithium,lithium trimethylsilanolate, Me3SiOLi, 98 is eliminated and the 1,1-dichloroolefins1586 are formed in 40–82% yields [5, 6]. Likewise, treatment of sulfoxide 1587 at–30 �C with excess LDA results in elimination of trimethylsilanol 4 to afford nearly

241

10

Base-catalyzed, Acid-catalyzed and Thermal Eliminationsof Trimethylsilanol. Peterson Reactions


[1] J. M. Midgley, J. S. Millership, W. . Whalley, J. Chem. Soc. Perkin I 1976, 1384[2] M. Akita, H. Yasuda, A. Nakamura, Bull. Chem. Soc. Jpn. 1984, 57, 480[3] D. Pietropaolo, M. Fiorenza, A. Ricci, M. Taddei, J. Organomet. Chem. 1980, 197, 7[4] D. Schinzer, C. H. Heathcock, Tetrahedron Lett. 1981, 22, 1881[5] J. Villieras, C. Bacquet, J.F. Normant, J. Organomet. Chem. 1975, 97, 355[6] P. Entmayr, G. Köbrich, Chem. Ber. 1976, 109, 2175

quantitative yield of the unsaturated sulfoxide 1588 and Me3SiOLi 98 [7] (Scheme10.2).

The silylated acetylene alcohol 1589, however, is converted by ethyllithium in 87%yield into the 1,2,3-butatriene system 1590 and Me3SiOLi 98 [8] (Scheme 10.2).

On treatment of the ylide 1591 with HMDS-Na 486, the resulting sodium salt1592 reacts with valeric aldehyde and subsequently with TCS 14 to give 1593,which eliminates trimethylsilanol 4 to give the ylide 1594. This ylide 1594 con-verts aldehydes such as butyraldehyde into dienes such as 1595 in up to 48%yield [9]. The ylide 1596 reacts with CO2 to give the ylide 1597 which, on heatingto 110–120 �C, eliminates HMDSO 7 to give (oxovinyliden)phosphorane 1598 [10](Scheme 10.3).

Silylated primary amines such as N-silylated aniline 1599 are transformed by so-dium methoxide into silylated methanol and amine salts such as 1600, which are

10 Base-catalyzed, Acid-catalyzed and Thermal Eliminations of Trimethylsilanol. Peterson Reactions242

Scheme 10.1

Scheme 10.2

[7] R. W. Hoffmann, S. Goldmann, N. Maak, R. Gerlach, F. Frickel, G. Steinbach, Chem.Ber. 1980, 113, 819

[8] R. G. Visser, H.J. T. Bos, L. Brandsma, Recl. Trav. Chim. Pays-Bas, 1981, 100, 34[9] H.J. Bestmann, M. Schmidt, Angew. Chem. Int. Ed. 1987, 26, 64

[10] H.J. Bestmann, R. Dostalek, R. Zimmermann, Chem. Ber. 1992, 125, 2081

readily alkylated, e.g. by allyl-bromide, to give N-allylaniline 1601 in 72% yield[11]. Boiling of N-trimethylsilyl-o-toluidine 1602 with excess n-BuLi in hexanegives the intermediate dilithium compound 1603, which reacts in situ with esterssuch as ethyl benzoate in THF at –78 �C to give, via 1604, Me3SiOLi 98 and 2-phe-nylindole 1605 in 65% yield [12] (Scheme 10.4).

10.2Peterson Reactions

Because the mechanisms of the Peterson reaction, a synthetic alternative to theWittig reaction, have recently been reviewed [13, 14], this section will try only tosummarize recent developments and trends concerning the Peterson reaction.

Trimethylsilylmethyl Grignard or lithium reagents 1606 add to ketones such ascyclohexanone to give, via the intermediates 1607, the olefins 1608, often in highyields (Scheme 10.5).


Scheme 10.3

[11] W. Ando, H. Tsumaki, Chem. Lett. 1981, 693[12] A. B. Smith, M. Visnick, Tetrahedron Lett. 1985, 26, 3757[13] W. Ager, Synthesis 1984, 384; Org. React. 1990, 38, 1[14] L.F. van Staden, D. Gravestock, W. Ager, Chem. Soc. Rev. 2002, 31, 195

Scheme 10.4

Excess Peterson reagent 1606a reacts with methyl benzoate, via the intermediates1609 and 1610, to give, on work-up, some �-trimethylsilylacetophenone 1609 and49% phenylallylsilane 1611 [15], whereas with 1606a ethyl cyclohexanecarboxylateaffords only the �-trimethylsilyl-ketone 1612 [16, 17] (Scheme 10.6).

The trimethylsilyl ester of �-trimethylsilyacetic acid 1613 is converted by LDAand TCS 14 into the C,O,O-tris(trimethylsilyl)ketene acetal 1614 in 91% yield. Re-action of 1614 with benzaldehyde in the presence of ZnBr2 proceeds via 1615 toafford a high yield of trimethylsilyl cinnamate 1616 [18], which gives on work-upfree (E)-cinnamic acid in nearly quantitative yield (Scheme 10.7). In contrast, reac-tion of the lithium salt of 1613 with benzaldehyde then acidic hydrolysis affords a1 :1 mixture of (E)- and (Z)-cinnamic acid in 86% yield [18].

In a recent synthesis of (+)-discodermolide, Nozaki–Hiyama reaction of the alde-hyde 1617 with the unsaturated Peterson reagent 1618 then treatment with KH inTHF gave the diene 1619 in 74% yield [19] (Scheme 10.8).

The Peterson reactions of amides of bis(trimethylsilyl)methylamines such as1620 with TBAF in THF afford HMDSO 7 and the 1,2-dihydroisoquinolines 1621


Scheme 10.5

Scheme 10.6

[15] I. Fleming, A. Pearce, J. Chem. Soc. Perkin I 1981, 251[16] R. A. Ruden, B. L. Gaffney, Synth. Commun. 1975, 5, 15[17] M. Demuth, Helv. Chim. Acta 1978, 61, 3136[18] M. Bellassoued, M. Gaudemar, Tetrahedron Lett. 1988, 29, 4551[19] I. Paterson, G. J. Florence, K. Gerlach, J. P. Scott, Angew. Chem. Int. Ed. 2000, 39,

377

in up to 66% yield [20]. The reactions of �-bis(trimethylsilyl)methylamines such as1620 were recently reviewed [21] (Scheme 10.9).

Other nitrogen-containing Peterson-type reagents such as 2-trimethylsilylmethyl-pyridine 1622, in the presence of LDA, convert Schiff bases such as 1623 into ole-fins such as 1624 in 84% yield [22]. The Peterson-type Schiff base reagent 1625condenses with the bicyclic ketone 1626 in the presence of LDA to give the unsa-turated aldehyde 1627 in 67% yield [23]. Finally, aldehydes such as benzaldehydeare transformed by tris(trimethylsilyl)ketenimine 1628, in the presence ofBF3·OEt2, via 1629, into the unsaturated nitrile 1630, from which the remainingtrimethylsilyl group is readily removed by treatment with methanolic NaOH [24](Scheme 10.10).


Scheme 10.7

Scheme 10.8

[20] C. Palomo, J. M. Aizpurua, M. Legido, J. P. Picard, J. Dunogues, T. Constantieux, Tetra-hedron Lett. 1992, 33, 3903

[21] J. P. Picard, Can. J. Chem. 2000, 78, 1363[22] T. Konakahara, Y. Takagi, Tetrahedron Lett. 1980, 21, 2073[23] J.-H. Shau, W. Reusch, J. Org. Chem. 1980, 45, 2013[24] Y. Sato, J. Niinomi, J. Chem. Soc. Chem. Commun. 1982, 56

Scheme 10.9

Reaction of tris(trimethylsilyl)methyllithium 1631 with styrene oxide affords, via1632 and 1633, the cyclopropane 1634 in 69% yield [25] (Scheme 10.11). The reac-tions of tris(trimethylsilyl)methyllithium 1631 have been reviewed [26].

10.3Lewis Acid-catalyzed Elimination of Trimethylsilanol

The addition products of Me3SiCN 18 to carbonyl groups eliminate trimethylsila-nol 4, in the presence of phosphoryl chloride in pyridine or of AlCl3 in benzene,to give unsaturated nitriles. Thus ketone 1635 adds 18 and is subsequently con-verted, in a one-pot procedure, in 82% overall yield, into the olefin 1636 [27],whereas the adduct 1637 gives a mixture of the unsaturated nitriles 1638 [28] andketone 1639 adds Me3SiCN 18 and eliminates Me3SiOH 4 or HMDSO 7, in onestep, to give the �,�-unsaturated nitrile 1640 [29] (Scheme 10.12).


Scheme 10.10

Scheme 10.11

[25] I. Fleming, C.D. Floyd, J. Chem. Soc. Perkin I 1981, 969[26] R. Wustrack, H. Oehme, J. Organomet. Chem. 1988, 353, 95[27] M. Oda, A. Yamamoto, T. Watabe, Chem. Lett. 1979, 1427[28] H. Quast, Y. Görlach, G. Meichsner, K. Peters, E.-M. Peters, H.G. von Schnering,

Tetrahedron Lett. 1982, 23, 4677[29] J. F. DeBernardis, J. J. Kyncl, F. Z. Basha, D.L. Arendsen, Y.C. Martin, M. Winn, D. J.

Kerkman, J. Med. Chem. 1986, 29, 463

The silylated �-hydroxy esters 1641 and 1643 eliminate trimethylsilanol 4 in thepresence of CF3SO3H or (MeSO2)2O/DMAP in nitromethane to afford the unsatu-rated �-enamido esters 1642 [30] and 1644 [31, 32] in high yields (Scheme 10.13).

Diels–Alder reaction between the diene 1645 and the dienophile 1646 affords1647, which eliminates Me3SiOH 4 on heating with glycol and TsOH in benzeneto give 1648 in 84% yield [33] (Scheme 10.14).

The furanone 1649 eliminates Me3SiOH 4 and HMDSO 7 on treatment withTCS 14 to afford 1650 in 80% yield [34] (Scheme 10.15).

Pentacarbonyl(1-ethoxyethyliden)chromium 1651 condenses readily with aro-matic or heteroaromatic aldehydes such as benzaldehyde [35, 37] in the presenceof TCS 14 and triethylamine to give chromabutadiene 1652 in 30–82% yield andHMDSO 7 (Scheme 10.16). Condensation of pentacarbonyl(1-methoxyethyli-

10.3 Lewis Acid-catalyzed Elimination of Trimethylsilanol 247

Scheme 10.12

Scheme 10.13

[30] G. Simchen, D. Schulz, T. Seethaler, Synthesis 1988, 127[31] T. Seethaler, G. Simchen, Synthesis 1986, 390[32] T. Seethaler, G. Simchen, Liebigs Ann. Chem. 1991, 11[33] T. Ibuka, G.-Namg Chu, F. Yoneda, J. Chem. Soc. Chem. Commun. 1984, 597[34] T. Sakai, K. Kohda, S. Tsuboi, M. Utaka, A. Takeda, Bull. Chem. Soc Jpn. 1987, 60, 2911[35] R. Aumann, H. Heinen, Chem. Ber. 1987, 120, 537[36] K. H. Dötz, R. Noack, K. Harms, G. Müller, Tetrahedron 1990, 46, 1235[37] A. Wienand, H.-U. Reissig, Chem. Ber. 1991, 124, 957

dene)tungsten with cinnamaldehyde in the presence of Me3SiCl 14/triethylamineproceeds analogously in 70% yield [36].

The chiral bimetallic complex 1653 reacts with TMSOTf 20 in the presence ofexcess styrene, via 1654, to give the cyclopropane complex 1655 in high yield [38].The chromium can be readily removed from 1655 by treatment with I2 in Et2O.Analogously, the complex 1656 reacts with styrene in 90% yield, via 1657, to giveMe3SiOH 4 and phenylcyclopropane 1658 [39] (Scheme 10.17).


Scheme 10.14

Scheme 10.15

Scheme 10.16

Scheme 10.17

[38] R. D. Theys, M.M. Hossain, Tetrahedron Lett. 1995, 36, 5113[39] H. Du, F. Yang, M.M. Hossain, Synth. Commun. 1996, 26, 1371

10.4Thermal Elimination of Trimethylsilanol

Diels–Alder reaction between the Danishefsky triene 1659 and excess dimethyl-acetylene dicarboxylate or methylpropiolate in boiling benzene proceeds, via 1660and 1661, with loss of trimethylsilanol 4, to give 1662a and 1662b in 51 and 37%yield, respectively; these are transsilylated with methanol to give 1663 a and 1663b[40] (Scheme 10.18).

On thermolysis of the fluorenene derivative 1664 at 200 �C, �-elimination of tri-methylsilanol 4 leads in 88% yield to the olefin 1665 [41]. Likewise, �-eliminationof trimethylsilanol 4 from the homologue 1666 furnishes, at 190 �C, 85% of theolefin 1667 [42] (Scheme 10.19).

Pyrolysis of bis(trimethylsilyl)phenyl methanol 1668 at 500 �C leads, via elimina-tion of trimethylsilanol 4, to the carbene intermediate 1669, which rearranges, viathe carbene intermediate 1670, to give 1,2-dimethyl-2,3-benzo-1-silacyclopent-2-ene1671, in 25% yield, or rearranges via olefin 1672 and adds 4 to give the siloxane1673 in 29% yield and smaller amounts of benzyltrimethylsilane 83 and styrene[43, 44]. Pyrolysis of 1,1-bis(trimethylsilyl) cyclohexylalcohol 1674 furnishes, viathe carbene intermediate 1675, 90% of olefin 1676 [43, 44] (Scheme 10.20).

Pyrolysis of the disilane 1677 at 680 �C affords, via the carbene intermediate1678 or the diene 1679, 25% 1-methylsilitene 1680 and 68% Me3SiOMe [45](Scheme 10.21).

10.4 Thermal Elimination of Trimethylsilanol 249

Scheme 10.18

[40] O. Tsuge, E. Wada, S. Kanemasa, Chem. Lett. 1983, 239[41] M.T. Reetz, M. Kliment, N. Greif, Chem. Ber. 1978, 111, 1083[42] M.T. Reetz, N. Greif, M. Kliment, Chem. Ber. 1978, 111, 1095[43] A. Sekiguchi, W. Ando, Tetrahedron Lett. 1979, 42, 4077[44] A. Sekiguchi, W. Ando, J. Org. Chem. 1980, 45, 5286[45] G. T. Burns, T. J. Barton, J. Am. Chem. Soc. 1983, 105, 2006

Thermal elimination of HMDSO 7 from phosphorus compounds is discussedin Chapter 11.


A mixture of 1 g 2,4,6-trimethoxybenzyl trimethylsilyl ether 1578 and ethylmagne-sium bromide, prepared from 1 g ethyl bromide and 0.2 g Mg in 90 mL Et2O, isheated under reflux for 30 min to give, on filtration through a layer of silica gel


Scheme 10.19

Scheme 10.20

Scheme 10.21

and evaporation, 0.7 g (60%) 2,4,6-trimethoxypropylbenzene 1579, m.p. 47 �C [1](Scheme 10.22).

Anilinotrimethylsilane 1599 (1.65 g, 10 mmol), NaOMe (0.54 g, 10 mmol), andallyl bromide (1.21 g, 10 mmol) are stirred in 25 mL abs. THF and 5 mL diglymefor 18 h at 40 �C. The mixture is quenched with water and extracted with hexane.The organic layer is washed several times with water, dried over MgSO4, the sol-vent is evaporated, and the residue is chromatographed in benzene over a columnof silica gel to afford 0.95 g (72%) pure N-allylaniline 1601 [11] (Scheme 10.23).

A solution of n-BuLi in hexane (2.5 M, 980 L, 2.2 mmol) is added dropwise to amixture of N-trimethylsilyl-o-toluidine 1602 (200 mg, 1.12 mmol) in 10 mL dryhexane. The resulting yellow solution is heated under reflux for 6 h and then leftto cool to room temperature. The dianion 1603 is then added via a cannula to aprecooled solution of ethyl benzoate (176 mg, 1.17 mmol) in 4 mL THF. The reac-tion mixture is then warmed to room temperature and partitioned between 10 mLeach of ether and ice–water. The aqueous layer is extracted with ether (4�10 mL)and the combined organic extracts are washed with 10 mL brine, dried (MgSO4),and concentrated in vacuo. Flash chromatography with 95:5 hexane–EtOAc gives140 mg (65%) 2-phenylindole 1605, m.p. 182–184 �C [12] (Scheme 10.24).


Scheme 10.22

Scheme 10.23

Scheme 10.24

Me3SiCl 14 (136 mg, 1.25 mmol) is added to a solution of 0.5 mmol 1649 in1 mL abs. acetonitrile as well as 29 mg EtOH and the mixture is stirred at roomtemperature for 12 h to give, after dilution with Et2O and washing with sat. NaH-CO3, 80% 1650 [34] (Scheme 10.25).


Scheme 10.25

11.1Formation of Carbon–Phosphorus Double Bonds

The field of carbon–phosphorus double or triple bonds has been covered in sev-eral recent reviews [1–4 a].

Bis(trimethylsilyl)phosphines 1681, whose chemistry has been reviewed [5], con-dense with DMF and eliminate HMDSO 7 to give, e.g., the phosphaalkene 1682[6]. Bis(trimethylsilyl)phosphines 1681 react with bis(dialkylamino)difluoro-methanes 1683 with elimination of Me3SiF 71 to give the phosphaalkenes 1684 [7,8], whereas acid chlorides such as Me3CCOCl afford, with elimination of TCS 14,the O-trimethylsilylphosphaalkenes 1685 [9]. Bis(trimethylsilyl)phosphines 1681condense with CO2 to the phosphacarbamates 1686 [10] whereas CS2 furnishesthe methylenephosphanes 1687 [11, 12] (Scheme 11.1).

253

11

Formation of Carbon–Phosphorus Double Bonds


[1] Phosphaalkynes: M. Regitz on “Multiple Bonds and Low Coordination in PhosphorusChemistry”. In: M. Regitz and O.J. Scherer (Ed.) Houben–Weyl, Methoden der Organi-schen Chemie, G. Thieme, Stuttgart, New York, 1990, p. 58

[2] Phosphaalkenes: R. Appel on “Multiple Bonds and Low Coordination in PhosphorusChemistry”. In: M. Regitz and O.J. Scherer (Ed.) Houben–Weyl, Methoden der Organi-schen Chemie, G. Thieme, Stuttgart, New York, 1990, p. 157

[3] Heterophospholes: A. Schmidpeter, K. Karaghiosoff on “Multiple Bonds and Low Co-ordination in Phosphorus Chemistry”. In: M. Regitz and O.J. Scherer (Ed.) Houben–Weyl, Methoden der Organischen Chemie, G. Thieme, Stuttgart, New York, 1990, p. 258

[4] M. Regitz, Chem Rev. 1990, 90, 191[4 a] F. Mathey, Angew. Chem. Int. Ed. 2003, 42, 1578[5] R. Appel, F. Knoll, I. Ruppert, Angew. Chem. Int. Ed. 1981, 20, 731[6] G. Becker, M. Mundt, Z. Anorg. Allg. Chem. 1989, 462, 130[7] L.N. Markovskii, V. D. Romanenko, T. I. Pidvarko, J. Gen. Chem. 1982, 52, 1925;

Chem. Abstr. 1982, 97, 216330[8] L.N. Markovski, V.D. Romanenko, A. V. Kirsanov, Phosphorus Sulfur 1983, 18, 31[9] G. Becker, Z. Anorg. Allg. Chem. 1976, 423, 242

[10] R. Appel, B. Laubach, M. Siray, Tetrahedron Lett. 1984, 25, 4447[11] R. Appel, P. Fölling, L. Krieger, M. Siray, F. Knoch, Angew. Chem. Int. Ed. 1984, 23,

970[12] G. Becker, G. Gresser, W. Uhl, Z. Anorg. Allg. Chem. 1980, 463, 144

Bis(trimethylsilyl)-tert-butylphosphine 1688 was recently condensed with 2,3-di(tert-butyl)-cyclopropenone 1689 in the presence of BF3.OEt2 to give the phos-phaalkene 1690 in 79% yield [13] (Scheme 11.2).

Carbon–phosphorus double bonds are also formed in addition reactions oftris(trimethylsilyl)phosphine 1692 (which can be readily prepared from white phos-phorus, sodium, and TCS 14 [13 a,b, c]) to give oxazolium fluorides 1691 which thengive the azaphospholes 1694, via 1693 [3, 14]. On addition of 1692 to 1695, thediazaphosphole 1696 [3, 15] is prepared, whereas 1,3-azaphospholo[1,2a]pyridines1698 [16] are formed from 1692 and 1697, and 1,3-thiaphospholes 1700 are formedfrom the dithiolium fluorides 1699 [17]. 1,3-Benzodiphospholyl anions 1703 are gen-erated by reaction of acid chlorides with the dilithium salts 1701, via 1702 [18](Scheme 11.3).

11 Formation of Carbon–Phosphorus Double Bonds254

Scheme 11.1

Scheme 11.2

[13] M.A. Hoffmann, U. Bergsträßer, G. J. Reiß, L. Nyulaszi, M. Regitz, Angew. Chem.Int. Ed. 2000, 39, 1261

[13a] A. J. Leffler, E. G. Teach, J. Am. Chem. Soc. 1960, 82, 2710[13b] G. W. Parshall, R. U. Lindsey, J. Am. Chem. Soc. 1959, 81, 6273[13c] A. B. Bruker, L.D. Balashova, L.Z. Soborwskii, Isv. Akad. Naukk SSSR, 1960, 135, 843;

Chem. Abstr. 1961, 55, 13301[14] G. Märkl, G. Dorfmeister, Tetrahedron Lett. 1986, 27, 4419[15] G. Märkl, S. Pflaum, Tetrahedron Lett. 1986, 27, 4415[16] G. Märkl, S. Pflaum, Tetrahedron Lett. 1987, 28, 1511[17] G. Märkl, G. Dorfmeister, Tetrahedron Lett. 1987, 28, 1089[18] H. Schmidt, K. Issleib, E. Leissring, Phosphorus, Sulfur, Silicon 1990, 49/50, 355

Pyrylium salts such as 1704 a and 3-azapyrylium salts 1704b react withP(SiMe3)3 1692 to give �3-phosphorines 1706 a [19] and 1706b [20], via 1705(Scheme 11.4).

On addition of NaOH P-silylated compounds such as 1707 or 1709 eliminateHMDSO 7 to give the (iminomethylidene)phosphines 1708 [21] or 1710 [22], thelatter of which dimerizes to the dimer 1711 [22]. The C-silylated Wittig reagent1712 adds trimethylsilyl propionate to give, with elimination of HMDSO 7, theWittig reagent 1713 [23] whereas reaction of 1714 with acetic anhydride affordsthe Wittig reagent 1515 and reaction with trimethylsilyl succinate 1716 gives theWittig reagent 1717 [23]. Pyrolysis of the C,O-bis(trimethylsilylated) Wittig reagent1718 at 120 �C furnishes the cummulene Wittig reagent 1719 in 91% yield [24](Scheme 11.5).

11.1 Formation of Carbon–Phosphorus Double Bonds 255

Scheme 11.3

[19] G. Märkl, F. Lieb, A. Merz, Angew. Chem. Int. Ed. 1967, 6, 458[20] G. Märkl, G. Dorfmeister, Tetrahedron Lett. 1987, 28, 1093[21] J. L. Kolodiazhnji, Tetrahedron Lett. 1982, 23, 4933[22] C. Wentrup, H. Briehl, G. Becker, G. Uhl, H.-J. Wessely, A. Maquestiau, R. Flam-

mang, J. Am. Chem. Soc. 1983, 105, 7195[23] H.J. Bestmann, A. Bomhard, R. Dostalek, R. Pichl, R. Riemer, R. Zimmermann, Syn-

thesis 1992, 787[24] H.J. Bestmann, R. Dostalek, R. Zimmermann, Chem. Ber. 1992, 125, 2081

Finally, the bis(trimethylsilyl) phenylarsine 1720 reacts with DMF in the presenceof catalytic amounts of NaOH to give 1721, with a related As=C bond, andHMDSO 7 [25] (Scheme 11.6).


Scheme 11.4

Scheme 11.5

[25] G. Becker, A. Münch, H.J. Wessely, Z. Naturforsch. 1981, 36b, 1080

Scheme 11.6

11.2Preparation of Carbon–Phosphorus Triple Bonds

The preparation of phosphaalkynes, which has been reviewed [1, 4], usually im-plies elimination of trimethylchlorosilane (TCS) 14 or of hexamethyldisiloxane(HMDSO) 7. Thus pyrolysis of the chloro compounds 1722 and 1723 at 750 or630 �C, respectively, affords the trimethylsilylphosphaacetylene 1724 and TCS 14.In the most versatile preparation of phosphaalkynes, acid chlorides such aspivaloyl chloride [27] are reacted either with P(SiMe3)3 1692, with formation ofTCS 14, or with (Me3Si)2PLi 1725 [26] to give the phosphides 1726 [28, 29], whicheliminate hexamethyldisiloxane (HMDSO) 7 in the presence of catalytic amountsof NaOH [28] either in a solvent or more efficiently without a solvent at 120–200 �C [29, 30] to afford, via 1727, the corresponding phosphaalkynes 1728 andHMDSO 7 [1, 4] (Scheme 11.7).

Finally, it should be noted that phosphaalkynes such as 1728 undergo several in-teresting reactions, for example 1,3-dipolar cycloadditions with diphenylnitrili-mine, nitrile oxides [28], diazo compounds [30, 31], or 1,3-dipolar compounds [31](which have been reviewed [3, 4]). At 225 �C in vacuo precursor 1726c eliminatesHMDSO 7 to give, apparently, first the phosphaalkyne 1728c; this undergoes 1,3-dipolar cycloaddition with another intermediate, 1729c, apparently formed by theelimination of hexamethyldisilane Me3SiSiMe3 857 from 1727c. The eventual re-sult is 20% of the 3,5-dimesityl-1,2,4-oxadiphosphole 1730 [32]. 1,3-Dipolar cyclo-

11.2 Preparation of Carbon–Phosphorus Triple Bonds 257

Scheme 11.7

[26] G. Fritz, W. Hölderich, Z. Anorg. Allg. Chem. 1976, 422, 104[27] G. Becker, Z. Anorg. Allg. Chem. 1977, 430, 66[28] T. Allsprach, M. Regitz, G. Becker, W. Becker, Synthesis 1986, 31[29] G. Becker, G. Gresser, W. Uhl, Z. Naturforsch. 1981, 36b, 16[30] W. Rösch, U. Hees, M. Regitz, Chem. Ber. 1987, 120, 1645[31] W. Rösch, U. Vogelbacher, T. Allspach, M. Regitz, J. Organomet. Chem. 1986, 306,

39[32] A. Mack, U. Berggräßer, G. J. Reiß, M. Regitz, Eur. J. Org. Chem. 1999, 587

addition of the phosphotriafulvene 1731 to 1728a affords 71% of the 1,3-diphos-phinine 1732 [33] (Scheme 11.8).

It should be emphasized here that the potentially interesting pharmacologicalproperties of phosphaheterocycles such as 1694, 1696, 1698, 1700, 1706, 1730, and1732 (cf. also the second experimental example in Section 11.3), and in particulartheir substituted derivatives, have, apparently, not yet been investigated.


Tris(trimethylsilyl)phosphine (0.7 g, 2.8 mmol) 1692 is added to 2,4,6-triphenylpyr-ylium iodide 1704a (1.1 g, 2.5 mmol) in 15 mL acetonitrile under purified nitro-gen and the reaction mixture is heated under reflux under purified nitrogen for20 h. After evaporation in vacuo the residue is chromatographed in benzene on acolumn of alumina to give 0.7 g (45%) 1706a which is recrystallized from etha-nol–chloroform (3 : 1); m.p. 172–173 �C [19]. The analogous conversion of 1704bwith 1692 via 1705b affords the 1,3-azaphosphinine�3 1706b in 26% yield [20](Scheme 11.9).


Scheme 11.8

[33] M.A. Hofmann, H. Heydt, M. Regitz, Synthesis 2001, 463

Scheme 11.9

A solution of 5 mmol diazomethane, prepared from N-methyl-N-nitrosourea(0.62 g, 6 mmol), in 5 mL pentane is added to 1728a (0.5 g, 5 mmol) [4] at 0 �Cand the reaction mixture warmed to room temperature. After 30 min the yellowcolor of CH2N2 has disappeared and the reaction mixture is evaporated. The resi-due is extracted with boiling pentane to give 0.66 g (93%) 3-tert-butyl-1H-1,2,4-di-azaphosphol, m.p. 74 �C [30] (Scheme 11.10).


Scheme 11.10

12.1Reductions with Trimethylsilyl Iodide, Trimethylsilyl Azide, and Trimethylsilyl Cyanide

Because Me3SiI (TIS) 17 is relatively expensive and very sensitive to light, air, andhumidity, it is usually prepared in situ from TCS 14 and NaI in acetonitrile [1–6],although other solvents such as CH2Cl2, DMF, benzene, or hexane have also beenused [5, 6] (Scheme 12.1). It is assumed that TIS 17 forms, in situ, with MeCN, a�-complex 1733 [2, 3–6], yet Me3SiI 17 can also be prepared by treatment of hex-amethyldisilane 857 with iodine in organic solvents [4–6]. The chemistry of TIS17 has been reviewed [4–6].

Whereas benzylic hydroxyl functions such as in benzyl alcohol are converted byTIS 17 into benzyl iodide 1734 [2, 7] and HMDSO 7 and I2, 1-phenylethanol 1735[8] is reduced in high yields on longer reaction times with excess TIS 17 via theiodide 1736 to give ethylbenzene 1737 [7–11] (Scheme 12.2). Ether cleavage of1738 with TIS 17 affords, via 1739a and 1739b, the bicyclic compound 1740 in

261

12

Reductions and Oxidations


Scheme 12.1

[1] A. Schmidt, M. Russ, Chem. Ztg. 1978, 102, 26[2] G. A. Olah, S.C. Narang, B. G. B. Gupta, R. Malhotra, J. Org. Chem. 1979, 44, 1247[3] R. A. Benkeser, E.C. Mozdzen, C.L. Muth, J. Org. Chem. 1979, 44, 2185[4] W. C. Groutas, D. Felker, Synthesis 1980, 861[5] G. A. Olah, S.C. Narang, Tetrahedron 1982, 38, 2225[6] M. Arend, J. Prakt. Chem. 1998, 340, 760[7] M.E. Jung, P. L. Ornstein, Tetrahedron Lett. 1977, 2659[8] T. Sakai, K. Miyata, M. Utaka, A. Takeda, Tetrahedron Lett. 1987, 28, 3817[9] E. J. Stoner, D. A. Cothron, M.K. Balmer, B.A. Roden, Tetrahedron 1995, 41, 11043

[10] P. J. Perry, V.H. Pavlidis, I. G.C. Coutts, Synth. Commun. 1996, 26, 101[11] W. A. Ayer, P.P. Singer, Phytochemistry 1980, 19, 2717

30% yield [11]. An alternative is reaction of O-silylated alcohols with silica chlo-ride/NaI in acetonitrile to give iodides in high yields [11a].

Likewise, benzhydrols such as 1741 or 1743a, b are readily reduced to 1742 [9],1744a [9] or 1744b [10] in 90, 79, and 98% yield, respectively (Scheme 12.3). Thesame type of reduction with similar yields has also been observed on employingMe2SiI2 1745 in CH2Cl2 at room temperature, reducing �-hydroxyketones such asbenzoin to phenyl benzyl ketone in 45% yield [12]. Whereas diethyl ketone is re-duced by Me2SiI2 1745/Zn powder to give 70% of the ketone 1746, methyl-tert-butyl ketone affords 86% 1747 [13]. Allylic alcohols such as 1748 condense with

12 Reductions and Oxidations262

Scheme 12.2

Scheme 12.3

[11a] H. Firouzabadi, N. Iranpoor, H. Hazarkhani, Tetrahedron Lett. 2002, 43, 7139[12] W. Ando, M. Ikano, Tetrahedron Lett. 1979, 4941[13] W. Ando, M. Ikano, Chem. Lett. 1980, 1255

butyric aldehyde in the presence of Me3SiCl 14/NaI/Sn powder to give a mixtureof the homoallylic alcohols 1749 and 1750 [14].

Reaction of 1,2-glycol systems, such as in the hemiacetal sesquiterpene 1751,with Me3SiCl/NaI in acetonitrile for 5 min at ambient temperature affords morethan 80% of the corresponding olefin 1752 [15, 16] (Scheme 12.4). On reacting ac-tive methylene groups such as in ethyl acetoacetate or acetylacetone with benzal-dehyde in the presence of TCS14/NaI in acetonitrile, the intermediate unsaturatedketones 1753 and 1755 are reduced to ethyl 2-benzylacetoacetate 1754 [17] or 2-benzylacetylacetone 1756 [18] in 82% and 80% yield, respectively.

Sulfoxides 1757 are reduced by TIS 17 in CCl4 to give the sulfides 1758 in 52–91% yield [19–21] (cf. also Scheme 8.4 in Section 8.1.2; for reduction of cyclic sulf-oxides and their potential ring contractions or ring enlargements during reductionwith Me3SiI 17, see Schemes 8.5 and 8.6). Whereas di(n-butyl) sulfoxide 1170 isreduced by Me3SiI 17 in the presence of HMDS 2 as base to di(n-butyl)sulfide1759, the same reduction in the presence of Hünig’s base DIPEA gives 86% of a1 :1 mixture of the Pummerer product vinylsulfides 1171 (Scheme 12.5). The phe-nyl-n-octyl sulfoxide 1760 is converted into the unsaturated sulfide 1761 [21], yetonly the linear n-butyl substituent in the partially branched sulfoxide 1762 istransformed into an olefin in 1763 [21].

12.1 Reductions with Trimethylsilyl Iodide, Trimethylsilyl Azide, and Trimethylsilyl Cyanide 263

Scheme 12.4

[14] Y. Kanagawa, Y. Nishiyama, Y. Ishii, J. Org. Chem. 1992, 57, 6988[15] N.C. Barua, R. P. Sharma, Tet. Lett. 1982, 23, 1365[16] J. C. Sarma, N.C. Barua, R.P. Sharma, J. N. Barua, Tetrahedron 1983, 39, 2843[17] T. Sakai, K. Miyata, S. Tsuboi, M. Utaka, Bull. Chem. Soc. Jpn 1989, 62, 4072[18] G. Dräger, W. Solodenko, J. Messinger, U. Schön, A. Kirschning, Tetrahedron Lett.

2002, 43, 1401[19] G. A. Olah, B. G.B. Gupta, S.C. Narang, Synthesis 1977, 583[20] G. A. Olah, S.C. Narang, B. G. B. Gupta, R. Malhotra, Synthesis 1979, 61[21] R. D. Miller, D.R. McKean, Tetrahedron Lett. 1983, 24, 2619

Analogously, sulfonyl halides such as benzenesulfonyl chloride 1764 are reducedby excess TIS 17 to disulfides such as diphenyl sulfide 1765 [22, 23] (Scheme 12.5).

Whereas secondary nitroalkanes such as 1-nitrocyclohexane 1766 are reduced tothe corresponding oximes, for example 1767 [24], primary nitro compounds suchas �-nitro-o-xylene 1768 or unsaturated nitro compounds such as 1770 are trans-formed into nitriles such as 1769 and 1771 [24] (Scheme 12.6).

O-Acylated or mesylated oximes such as the ethyl carbonate of acetophenone-oxime 1772 react with TIS 17, with Beckmann rearrangement to the imidoyl io-dide 1773, which adds phenylmagnesium bromide in situ to give 61% of the sec-


Scheme 12.5

Scheme 12.6

[22] G. A. Olah, S.C. Narang, L. D. Field, G. F. Salem, J. Org. Chem. 1980, 45, 4792[23] P. Kielbasinski, J. Drabowicz, M. Mikolajczik, J. Org. Chem. 1982, 47, 4806[24] G. A. Olah, S.C. Narang, L. D. Field, A. P. Fung, J. Org. Chem. 1983, 48, 2766

ondary amine 1774 [25] (Scheme 12.7). The O-mesyl oxime of cyclohexanone 1775is converted by treatment with diethylaluminum iodide then addition of phenyl-Grignard reagent and finally by reduction with DIBAL into 81% 2-phenylhexa-methylenimine 1776 [25].

Epoxides such as cyclohexene epoxide are converted by Me3SiSiMe3 857/I2 orTMS 14/NaI, via O-silylated-2-iodocyclohexanol 1777 [26], into cyclohexene [27, 28](cf. also Ref. [33]). Pyridine-N-oxides such as 2-, 3-, or 4-methylpyridine-N-oxides1778 are reduced by Me3SiI 17/Zn in acetonitrile, probably via 2-iodopyridines1779, to picolines in 80–92% yield [29] (Scheme 12.8).

Triphenylphosphine oxide (and Ph3AsO or Ph2SeO) are reduced by Me3SiN3 19,via the labile diazidophosphines 1780, to triphenylphosphine (triphenylarsine ordiphenylselenide), nitrogen, and HMDSO 7, whereas iodosobenzene gives, via1781, iodobenzene, nitrogen, and HMDSO 7 [30] (Scheme 12.9).

Benziodoxol 1782 can be readily converted by Me3SiCN 18 into HMDSO 7 and 1-cyanobenziodoxol 1783, which oxidizes N,N-dimethylaniline in 96% yield into N-cya-

12.1 Reductions with Trimethylsilyl Iodide, Trimethylsilyl Azide, and Trimethylsilyl Cyanide 265

Scheme 12.7

Scheme 12.8

[25] Y. Ishida, S. Sasatani, K. Maruoka, H. Yamamoto, Tetrahedron Lett. 1983, 24, 3255[26] H. Sakurai, Tetrahedron Lett. 1980, 21, 2329[27] J. N. Denis, R. Magnane, M. van Eenoo, A. Krief, Nouv. J. Chim. 1981, 22, 355[28] R. Caputo, L. Mangini, O. Neri, G. Palumbo, Tetrahedron Lett. 1981, 22, 3551[29] T. Morita, K. Kuroda, Y. Okamoto, H. Sakurai, Chem. Lett. 1981, 921[30] P. Magnus, J. Lacour, P.A. Evans, M.B. Roe, C. Hulme, J. Am. Chem. Soc. 1996, 118,

3406

nomethyl-N-methylaniline 1784 [31]. 1-Di(trifluoroacetoxy)-2,2,2-trifluoroethane 1785reacts with TsOH·H2O to give the O-tosylate 1786, which oxidizes enol silyl ethers suchas acetophenone 653 to �-tosyloxyacetophenone 1787 [32] (Scheme 12.10).

Finally, an alternative in situ preparation of the silyl iodide 1789 from tetramethyl-disiloxane 1788 has been described. The silyl iodide 1789 reduces aromatic aldehydes,such as benzaldehyde 1790a, or ketones such as acetophenone, 1790b, into the io-dides 1791a, b, and quinones 1792 into the hydroquinones 1793 [33] (Scheme 12.11).


Scheme 12.9

Scheme 12.10

Scheme 12.11

[31] V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J.T. Bolz, B. Mismash, J. K. Woodward,

A. J. Simonsen, Tetrahedron Lett. 1995, 44, 7075[32] V. V. Zhdankin, C. J. Kuehl, A. J. Simonsen, Tetrahedron Lett. 1995, 36, 2203[33] B. Lecka, J.M. Aizpura, C. Palomo, Tetrahedron Lett. 1985, 41, 4657

12.2Reduction with Silanes

Benzylic or allylic oxygen functions react with Lewis acids such as trifluoroaceticacid to generate allyl or benzylic cations which abstract a hydride from silanessuch as triethylsilane 84b to result in the removal of the oxygen function in a pro-cess which has been called “ionic hydrogenation” and which has been reviewed[34–38].

Some reductions with silanes have already been described in previous chapters(in Section 4.8 reaction of 356 to give 359; in Section 5.4 reaction of 121 to give717, 718 to 719; in Section 12.1 reaction of 1790 to give 1791). Because of themany applications of such reductions with silanes in the chemical literature onlya selected number of examples can be given in this chapter.

Aldehydes such as p-tolualdehyde or ketones such as acetophenone or benzophe-none are reduced cleanly by triethylsilane 84 b in trifluoroacetic acid. Thus benzo-phenone is reduced by 84b via benzhydrol in 100% yield to give diphenylmethaneand hexaethyldisiloxane 65 [39, 40]. Reduction of alcohols such as 1-methylcyclohex-anol 1794a with triethylsilane 84 b in the presence of CF3CO2H, AlCl3, or B(C6F5)3

[40a] gives, via the cation 1795 a, the hydrocarbon 1796a in quantitative yield,whereas reduction of cyclohexanol 1794b is only effective with larger amounts ofAlCl3 to give 70% cyclohexane 1796b and, via rearrangement and ring contractionof the intermediate cation 1795 b to the more stable tertiary cation 1797, 7% ofmethylcyclopentane 1798 [39, 40, 40a]. Likewise, phenyl cyclobutyl ketone 1799 iseither reduced via 1800 to 25% 1801 or by ring-enlargement of 1800 via 1802 to43% methylcyclopentane 1803 and 7% 1804 [39] (Scheme 12.12).

It should be remarked here that trimethylsilane 84a or triethylsilane 84b andmost other known silanes, for example tetramethyldisiloxane 1788, are quite ex-pensive for any large-scale reduction, whereas the subsequently described poly-methylhydrosiloxane 1856 (cf. reductions of an azide moiety in 1855 and a carbo-benzoxy moiety in 1859) is available as large-scale orders for ca $ 15 kg–1, which isonly a fraction of the cost of any other silane.

It has been known since 1954 that aldehydes or ketones are reduced by silanesto give silylated primary or secondary alcohols [41]. Reduction of aliphatic alde-


[34] K. Rühlmann, Z . Chemie 1965, 130[35] D.N. Kursanov, Z.N. Parnes, Russ. Chem. Rev. 1969, 38, 812[36] D.N. Kursanov, Z.N. Parnes, N.M. Loin, Synthesis 1974, 633[37] I. Ojima, in S. Patai, Z. Rapoport (Eds) “The Chemistry of Organo-Silicon Com-

pounds”, Vol II, Wiley 1998, Chapter 25, p. 1479[38] D.N. Kursanov, Z.N. Parnes, Tetrahedron 1967, 23, 2235[39] C.T. West, S. J. Donelly, D.A. Kooistra, M.P. Doyle, J. Org. Chem. 1973, 38, 2675[40] D.N. Kursanov, G. I. Bolestova, U.G. Ibatullin, E. A. Kuramshina, Z.N. Parnes, Zh.

Org. Khim. 1985, 21, 2274, Chem. Abstr. 1986, 104, 185623[40a] V. Gevorgyan, J.-X. Liu, M. Rubin, S. Benson, Y. Yamamoto, Tetrahedron Lett. 1999,

40, 8919[41] H. Kautsky, H. Keck, H. Kunze, Z. Naturforsch. 1953, 8 b, 165

hydes and ketones with triethylsilane 84b in the presence of BF3·OEt2 results inthe formation of the boranates 1805 and Et3SiF. On reducing the amount of BF3,however, the ethers 1806, Et3SiF 1807, and B2O3 are obtained nearly exclusively[42]. Aromatic aldehydes or ketones, however, are reduced to hydrocarbons [35–38,43] (cf. Scheme 12.12). Thus m-nitroacetophenone is reduced selectively bytriethylsilane 84b in the presence of BF3 into 92% m-nitroethylbenzene 1808 [44].A Ruthenium-cluster catalyzes the hydrosilylation of CO2 to give triethylsilyl for-mate 1809 in 81% yield [45]. The combination of 1,1,3,3-tetramethyldisiloxane1788 with Me3SiCl 14/NaI (= Me3SiI 17) converts aromatic aldehydes such asbenzaldehyde into iodo compounds such as benzyl iodide in 91% yield [46](Scheme 12.13).

Highly enantioselective hydrosilylation of aliphatic and aromatic carbonyl com-pounds such as acetophenone, methyl phenethyl ketone 1813, or deuterobenz-aldehyde 1815 can be readily achieved with sterically hindered silanes such aso-tolyl2SiH2 or phenyl mesityl silane 1810 in the presence of the rhodium–ferro-cene catalyst 1811 to give alcohols such as 1812, 1814, and 1816 in high chemicaland optical yield [47] (Scheme 12.14). More recently, hydrosilylations of aldehydes


Scheme 12.12

[42] M.P. Doyle, C.T. West, S. J. Donnelly, C.C. McOsker, J. Organomet. Chem. 1976, 117,129

[43] J. L. Fry, M. Orfanopoulos, M.G. Adlington, W. R. Dittman, S. B. Silverman, J. Org.Chem. 1978, 43, 374

[44] J. L. Fry, S.B. Silverman, Org. Synth. 1981, 60, 108[45] G. Süss-Fink, J. Reiner, J. Organomet. Chem. 1981, 221, C36[46] J. M. Aizpura, C. Palomo, Tetrahedron Lett. 1984, 25, 1103[47] B. Tao, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 3892

or ketones with, e.g., R3SiH have been achieved with rhenium catalysts such asIReO2(PPh3)2 [47 a,b].

The formation of ethers such as 1806 by Et3SiH 84b can also be catalyzed by tritylperchlorate to convert, e.g., benzaldehyde in 84% yield into dibenzyl ether 1817 [48].The combination of methyl phenethyl ketone 1813 with O-silylated 3-phenyl-n-pro-panol 1818, in the presence of trityl perchlorate, leads to the mixed ether 1819 in68% yield [48] (Scheme 12.15). Instead of trityl perchlorate, the combination of tritylchloride with Me3SiH 84 a or Et3SiH 84b and sodium tetrakis[3,5-bis-(trifluoro-methyl)phenyl]borane as catalyst reduces carbonyl groups to ethers or olefins [49].Employing TMSOTf 20 as catalyst gives very high yields of ethers. Thus benzalde-hyde reacts with O-silylated allyl alcohol or O-silylated cyclohexanol to give the


Scheme 12.13

Scheme 12.14

[47a] J. J. Kennedy-Smith, K. A. Nolin, H.P. Gunterman, F. D. Toste, J. Am. Chem. Soc. 2003,125, 4056

[47b] W. R. Thiel, Angew. Chem. Int. Ed. 2003, 42, 5390[48] J.-I. Kato, N. Iwaswa, T. Mukaiyama, Chem. Lett. 1985, 743[49] M. Kira, T. Hino, H. Sakurai, Chem. Lett. 1992, 555

ethers 1820 or 1821 in 99% yield [50]. Aldehydes, for example benzaldehyde, andketones have recently been reacted with butoxydimethylsilane 1822 in the presenceof TMSOTf 20 to give, generally, very high yields of ethers such as 1823 [51].

As already discussed briefly in Section 5.4, ketals such as 1824 are reduced bytriethylsilane 84b/ZnCl2 at 100 �C to give ethers 1825 in yields of 60–92%,whereas ethylene ketals such as 1826 undergo ring opening to give the diethers1827 in moderate yields [52, 53]. Much higher yields of ethers are obtained withTMSOTf 20 as catalyst [54]. Thus reaction of benzaldehyde dimethyl acetal 121with trimethylsilane 84 a/TMSOTf 20 affords benzyl methyl ether 717 in nearlyquantitative yield and MeOSiMe3 13 a [54] (cf. also Scheme 5.72). The silylated 3-hydroxy group in the protected d-glucose 1828 reacts selectively with benzalde-hyde and Et3SiH 84 b in the presence of TMSOTf 20 to give the 3-benzylether1829 in 94% yield [55] (Scheme 12.16). In the presence of Et3SiH 84a andTMSOTf 20 in CH2Cl2 1-O-methyl-2,3,4-O-benzyl-protected glucopyranoses with afree 6-hydroxy group couple readily with analogous pyranoses containing a free 6-aldehyde group to give, via the acetal, 6,6-ethers in high yields [55 a].

With TMSOTf 20 as catalyst instead, reduction of acetals or ketals has also beenachieved with triethylsilane 84 b in the presence of triflic acid/BSA 22 a [56] orwith triethylsilane 84b/Nafion-H, which can be readily recovered [57].


Scheme 12.15

[50] S. Hatakeyama, H. Mori, K. Kitano, H. Yamada, M. Nishizawa, Tetrahedron Lett. 1994,25, 4367

[51] K. Miura, K. Ootsuka, S. Suda, H. Nishikori, A. Hosomi, SynLett 2002, 313[52] E. Frainnet, R. Calas, A. Bazouin, Bull. Soc. Chim. Fr. 1960, 1480[53] E. Frainnet, C. Esclamadon, C. R. Acad. Sci. 1962, 1814[54] T. Tsunoda, M. Susuki, R. Noyori, Tetrahedron Lett. 1979, 4679[55] C.C. Wang, J.-C. Lee, S.-Y. Luo, H.-F. Fan, C.-L. Pai, W.-C. Yang, L.-D. Lu, S.-C. Hung,

Angew. Chem. Int. Ed. 2002, 41, 2360[55a]H. Takahashi, T. Fukuda, H. Mitsuzuka, R. Namme, H. Miyamoto, Y. Ohkura, S. Ike-

gami, Angew. Chem. Int. Ed. 2003, 42, 5069[56] M.E. Gihani, H. Heaney, SynLett 1993, 433[57] G. A. Olah, T. Yamoto, P. S. Iyer, G.K. S. Prakash, J. Org. Chem. 1986, 51, 2826

In subsequent investigations [58–60] Me3SiI 17 was employed as catalyst for di-rect transformation of ketones such as cyclohexanone with Me3SiH 84a or Et3SiH84b into the ethers. Thus, benzaldehyde reacts with silylated tert-butanol 1830 inthe presence of Me3SiH 84a and Me3SiI 17 to give benzyl tert-butyl ether 1831 in67% yield [59]. Whereas heating of lactones such as butyrolactone with twoequivalents of triethylsilane 84 and catalytic amounts of ZnCl2 at 120–130 �C leadsonly to small amounts of THF but 76% 1,4-bis(triethylsilyloxy)butane 1832 andsome hexaethyldisiloxane 65 [61], reaction of lactols such as 1833 and 1835 (whichare readily obtained by reduction of lactones with DIBAL) with triethylsilane 84b/BF3·OEt2 at 78 �C in CH2Cl2 affords the cyclic ethers 1834 and 1836 in 72 and75% yield, respectively [62] (Scheme 12.17).

These reductions of lactols with Et3SiH 84 b in combination of BF3·OEt2,TfOH, or TMSOTf 20 have become standard reactions for synthesis of cyclicethers [62–69]. Thus even �-hydroxyketones such as 1837 cyclize readily with ex-cess Et3SiH 84b in the presence of TMSOTf 20, in high yields, via the lactols1838, to give cyclic ethers such as the substituted oxepane 1839 in 90% yield [65](Scheme 12.18).


Scheme 12.16

[58] M.B. Sassaman, K. D. Kotian, S.K. S. Prakash, G. A. Olah, J. Org. Chem. 1987, 52, 4314[59] N. Hartz, G. K. S. Prakash, G. A. Olah, SynLett 1992, 569[60] C. Ahern, R. Darcy, Synth. Commun. 1998, 28, 971[61] E. Frainnet, R. Calas, A. Berthault, C. R. Acad. Sci. 1964, 613[62] G. A. Kraus, K. A. Fraizier, B. D. Roth, M.J. Taschner, K. Neuenschwander, J. Org.

Chem. 1981, 46, 2417[63] C. Brückner, H. Lorey, H.-U. Reissig, Angew. Chem. Int. Ed. 1986, 25, 556[64] A. Schmitt, H.-U. Reissig, Eur. J. Chem. 2000, 3893[65] K. C. Nicolaou, C.-K. Hwang, D. A. Nugiel, J. Am. Chem. Soc. 1989, 111, 4136[66] I.C. González, C. J. Forsyth, J. Am. Chem. Soc. 2000, 122, 9099[67] A. B. Smith, N. Kanoh, H. Ishiyama, R. A. Hartz, J. Am. Chem. Soc. 2000, 122, 11254[68] D.A. Evans, V. J. Cee, T. E. Smith, D.M. Fitch, P.S. Cho, Angew. Chem. Int. Ed. 2000,

39, 2533[69] D.A. Evans, D.M. Fitch, Angew. Chem. Int. Ed. 2000, 39, 2536

Addition of Grignard or lithium reagents such as allylmagnesium bromide tolactones such as 1840 followed by reduction with Et3SiH 84b/BF3·OEt2 [70–72] af-fords �-substituted cyclic ethers such as 1841 in 85% overall yield [70]. Unsatu-rated ethers such as 3,4,6-tri-O-acetyl-d-glucal 1842 undergo a Ferrier-type reduc-tion with Et3SiH 84b/BF3·OEt2 in CH2Cl2 to give, via 1843, 95% 1844 andEt3SiOSiEt3 65 [73]. In the presence of TiCl4 at –78 �C in CH2Cl2 enol ethers suchas dihydrofuran or dihydropyran add �-ketoesters such as methyl pyruvate to givethe intermediate 1845 which is reduced in situ by triethylsilane 84 b to give 82%of 1846 [74] (Scheme 12.19).

Esters are reduced by PhSiH3, in the presence of Ph3P·(CO)4MnC(O)Me 1847as catalyst in benzene at room temperature, to give the ethers 1848 [75]. Caprolac-tone gives rise to 69% oxepane [75] (Scheme 12.20). Ethylthio esters such as 1849and 1851 are reduced in high yields by triethylsilane 84 b and 10% Pd/C in ace-


Scheme 12.17

Scheme 12.18

[70] M.D. Lewis, J. K. Cha, Y. Kishi, J. Am. Chem. Soc. 1982, 104, 4976[71] G. A. Kraus, M.T. Molina, J. A. Walling, J. Chem. Soc. Chem. Commun. 1986, 1568[72] G. A. Kraus, M.T. Molina, J. Org. Chem. 1988, 53, 752[73] G. Grynkiewicz, Carbohydr. Res. 1984, 128, C9[74] A. K. Gosh, R. Kawahama, D. Wink, Tetrahedron Lett. 2000, 41, 8425[75] Z. Mao, B. T. Gregg, A .R. Cutler, J. Am. Chem. Soc. 1995, 117, 10139

tone to give aldehydes such as 1850 and 1852 and EtSSiMe3 [76]. This aldehydesynthesis has been successfully applied recently [77, 78].

Whereas primary amides such as butyric acid amide, on heating to 140–150 �Cwith triethylsilane 84b and ZnCl2, give, e.g., 78% butyronitrile 1853 and 95%HMDSO 7 [79], the secondary amide benzanilide is readily converted into 90% O-triethylsilyl imino ether 1854 [80] whereas the tertiary amide N,N-diethylacetamide


Scheme 12.19

Scheme 12.20

[76] T. Fukuyama, S.-C. Lin, L. Li, J. Am. Chem. Soc. 1990, 112, 7050[77] D.A. Evans, H.A. Rajapakse, D. Stenkamp, Angew. Chem. Int. Ed. 2002, 41, 4569[78] D.A. Evans, H.A. Rajapakse, A. Chiu, D. Stenkamp, Angew. Chem. Int. Ed. 2002, 41,

4573[79] R. Calas, E. Frainnet, A. Bazouin, C. R. Acad. Sc. 1962, 2357[80] E. Frainnet, A. Bazouin, R. Calas, C. R. Acad. Sc. 1963, 1304

gives, with triethylsilane 84b/ZnCl2 at 140–155 �C, 85% triethylamine and 90–93% Et3SiOSiEt3 65 [79] (Scheme 12.21).

Benzyl azide 1855 and N-benzyloxycarbonylbenzylamine 1859 are both trans-formed by the cheap polymethylhydrosiloxane (PMHS) 1856, in the presence of(BOC)2O and Pd/C, into 92–94% N-BOC-benzylamine 1857 and the polymer 1858[81]. (Scheme 12.22). Aromatic and aliphatic amine oxides are readily reduced by1856/Pd/C into their corresponding amines. Thus, e.g., pyridine-N-oxide 860 andquinoline-N-oxide 877 give pyridine and quinoline in 90 and 92% yield, respec-tively. Analogously, benzyldimethylamine-N-oxide is converted in 88% yield intofree benzyldimethylamine [82].

On bubbling trimethylsilane 84 a into pyridine in the presence of catalyticamounts of Pd/C at different temperatures and for different reaction times fourmain products 1860–1863 and small amounts of three further products are ob-tained [83] (Scheme 12.23).

Because �-hydroxy- or �-alkoxyamides are readily transformed by Lewis acidsinto the corresponding reactive imminium ions, N-hydroxymethylamides, lactams,or ureas such as N-hydroxymethylbenzamide 1864 are readily reduced by triethyl-


Scheme 12.21

Scheme 12.22

[81] S. Chandrasekhar, L. Chandraiah, C.R. Reddy, M.V. Reddy, Chem. Lett. 2000, 780[82] S. Chandrasekhar, M.V. Reddy, R. J. Rao, M. Rao, SynLett 2002, 349[83] N.C. Cook, J.E. Lyons, J. Am. Chem. Soc. 1966, 88, 3396

silane 84b/trifluoroacetic acid to N-methylamide lactams and ureas such as N-methylbenzamide 1865 in 86% yield [84]. Likewise, the bicyclic lactam 1866 is re-duced by triethylsilane 84b/TiCl4 to the monocyclic lactam 1867 [85] whereas reac-tion of the �-lactam 1868 with Et3SiH/TiCl4 affords the lactams 1869 and 1870 in93% and 86% yield, respectively [86] (Scheme 12.24).

Nitromethane is reduced by triethylsilane 84 b and excess Me3SiI 17 for 2 h at–5 �C and 5 h at 30 �C, in a stream of argon to remove the fulminic acid HCNOformed in situ, to afford 80% methylamine·HI and 64 and 65 [87] (Scheme 12.25).

Diiodosilane I2SiH2 1872, prepared by treatment of phenylsilane PhSiH3 with io-dine, via PhSiH2I, in the presence of catalytic amounts of ethyl acetate at –20 �C, ismuch more electrophilic than Me3SiI 17 and therefore converts secondary alcoholssuch as 2-octanol 1871, at room temperature with Walden inversion, into iodidessuch as 1873 in 93% yield whereas the diol 1874 is nearly quantitatively convertedinto the monoiodobutane 1875 and only traces of the diiodobutane 1876 [88, 89](Scheme 12.26).


Scheme 12.23

Scheme 12.24

[84] J. Auerbach, M. Zamore, S. M. Weinreb, J. Org. Chem. 1976, 41, 725[85] K. Oda, A. I. Meyers, Tetrahedron Lett. 2000, 41, 8193[86] Y. Koseki, S. Kusano, D. Ichi, K. Yoshida, T. Nagasaka, Tetrahedron 2000, 56, 8855[87] M.G. Voronkov, E. I. Dubinskaya, M.V. Sigalov, V. Yu. Vitkovskii, Zh Org. Khim.

1989, 59, 1055; Chem. Abstr. 1990, 112, 77304[88] E. Keinan, D. Perez, J. Org. Chem. 1987, 52, 4846[89] E. Keinan, Pure Appl. Chem. 1989, 61, 1737

Ketones such as p-nitroacetophenone 1877 are reduced by dimethylchlorosilaneMe2HSiCl 882/In(OH)3, in high yields, to chloro compounds such as 1878 [90](Scheme 12.26).

Reductions with silanes are catalyzed by Lewis acids [34–40, 50, 53–55, 90], bytransition metal catalysts [34–40a, 45, 47] such as Mo(CO)6 [89] or (PPh3)3RhCl[94], by KF, by CsF [91, 92], by CsF/Si(OEt)4 [92], by Bu4NF [93], or by (Et3NBn)F[91]. Thus reduction of the aminoketone 1879 with PhMe2SiH in hexamethylphos-phoric triamide (HMPA) with catalytic amounts of Bu4NF in THF proceeds atroom temperature to give the diastereocontrolled exclusively anti product 1880 in83% yield [93] (Scheme 12.27). Recently, polystyrenediethylsilane has been used toreduce carbonyl groups in the presence of Wilkinson’s catalyst (PPh3)3RhCl [94].


Scheme 12.25

Scheme 12.26

Scheme 12.27

[90] Y. Onishi, D. Ogawa, M. Yasuda, A. Baba, J. Am. Chem. Soc. 2002, 124, 13690[91] J. Boyer, R. J.P. Corriu, R. Perz, C. Reye, J. Organomet. Chem. 1979, 172, 143[92] R. J.P. Corriu, R. Perz, C. Reye, Tetrahedron 1983, 39, 999[93] M. Fujita, T. Hiyama, J. Am. Chem. Soc. 1984, 106, 4629[94] Y. Hu, J.A. Porco, Tetrahedron Lett. 1998, 39, 2711

12.3Reductions with Hexamethyldisilane, Hexamethyldisilthianeand Phenylthiotrimethylsilane

As already discussed in Section 7.4, hexamethyldisilane 857 (which is producedon a technical scale), in the presence of catalytic amounts of tetrabutylammoniumfluoride di- or trihydrate in THF, reduces aromatic heterocyclic N-oxides such aspyridine N-oxide 860, quinoline N-oxide 877, or isoquinoline N-oxide 879 to theheterocycles [95] and nitrones to Schiff-bases. Aromatic nitro compounds such asnitrobenzene are reduced analogously to azo compounds such as azobenzene [96].As mentioned in Section 7.5, secondary aliphatic nitro groups are reduced to oxi-mes.

Hexamethyldisilane 857 also reduces peroxy acids 1881 while being oxidized toHMDSO 7 [97–99]; by analogy TiCl4 is reduced to TiCl3 and Me3SiCl 14 is formed[100]. 857 reacts with iodine to give Me3SiI 17 [101, 102]; this is and alternativeand useful method of preparing 17, because reaction of Me3SiCl 14 with NaI isonly effective in acetonitrile as solvent [2]. On heating hexamethyldisilane 857with potassium methoxide in HMPA at 65 �C trimethylsilylpotassium 1882 andpotassium trimethylsilanolate 97 are generated [103], whereas hexamethyldisilane857 is cleaved by methyllithium or butyllithium in HMPA at 0 �C to generate tri-methylsilyllithium 1883 [104]. In the reaction of hexamethyldisilane 857 with “an-hydrous” Bu4NF the volatile Me3SiF 71 and the tetrabutylammonium salt 1884 ofthe trimethylsilyl anion are formed in the equilibrium; 1884 reacts in situ withMeI to give tetramethylsilane [105] (Scheme 12.28).

When epoxides such as trans-3-hexene-epoxide 1885 are heated to 65 �C withhexamethyldisilane 857 and potassium methoxide in anhydrous HMPA, trimethyl-silyl potassium 1882 is generated in situ to open the epoxide rings and give 1886,which subsequently looses potassium trimethylsilanolate 97 to afford olefins withinverted stereochemistry, for example as cis-3-hexene 1887, in high yield [103]. Thereaction also proceeds at 65 �C in THF, rather than HMPA, if 18-crown-6 is added[103 a] (Scheme 12.29).

12.3 Reductions with Hexamethyldisilane, Hexamethyldisilthiane and Phenylthiotrimethylsilane 277

[95] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1983, 24, 5337[96] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1984, 25, 1259[97] H. Sakurai, T. Imoto, N. Hayashi, M. Kumada, J. Am. Chem. Soc. 1965, 87, 4001[98] H. Sakurai, Y. Kamiyama, J. Am. Chem. Soc. 1974, 96, 6192[99] G. A. Razumaev, T.N. Brevnova, V. V. Semenov, A. N. Kornev, M.A. Lopatin, G.V. Be-

lysheva, A.N. Egorochkin, Izv. Akad. Nauk SSR, Ser. Khim. 1985, 2177; Chem. Abstr.1986, 105, 153117

[100] A. R. Hermes, G. S. Girolami, R. A. Andersen, Inorg. Synth. 1998, 32, 309[101] G. A. Olah, S.C. Narang, B. G. Balaram, B. G.B. Gupta, R. Malhotra, Angew. Chem.

Int. Ed. 1979, 18, 612[102] H. Sakurai, A. Shirahata, K. Sakasaki, A. Hosomi, Synthesis 1979, 740[103] P.B. Dervan, M.A. Shippey, J. Am. Chem. Soc. 1976, 98, 1265[103a] G. W. Gokel, D. J. Cram, C.L. Liotta, H.P. Harris, F. L. Cook, J. Org. Chem. 1974, 39,

2445

Whereas aliphatic ketones such as 4-tert-butylcyclohexanone add the intermedi-ate Me3SiLi 1883 [104], aldehydes such as undecanal 1888 react with hexamethyl-disilane 857 in the presence of Bu4NF in HMPA to afford 67% of adducts such as1889 and 26% of 1-undecanol 1890 [105]. Aromatic aldehydes such as benzalde-hyde, however, are dimerized in 94% yield to an 1 : 1 mixture of the d,l and mesopinacols 1891 [105] (Scheme 12.30). Use of the stable and non-hygroscopicBu4NF·2HF in the same reaction instead of the labile “anhydrous” Bu4NF affords89% of the pinacol 1891 [106]. On using stoichiometric amounts of Bu4NF·2–3H2O, however, benzaldehyde is reduced to benzyl alcohol in 65% yield [106]. Cata-lytic amounts of “anhydrous” Bu4NF also effect 1,4-addition of hexamethyldisilane857 to 1,3-dienes such as butadiene and isoprene in HMPA–THF to give 75% (E)-1,4-bis-(trimethylsilyl)-2-butene 1892a [105, 106]. Likewise Bu4NF·2HF catalyzesthe addition of hexamethyldisilane 857 to butadiene or to isoprene to afford 1892ain 78% yield and 1892b in 83% yield [105, 106]. Allyl acetates such as 1893 and1895 add hexamethyldisilane 857 in the presence of Pd(DBA)2 in DMF to give theallylsilanes 1894, 1896, and 1897 in high yields [107].

Sulfoxides such as methyl phenyl sulfoxide 1898 are readily reduced by hexa-methyldisilthiane 601 to give sulfides such as methyl phenyl sulfide 1899 in 90%yield, sulfur, and HMDSO 7 [108–110]. Analogously, the S-oxide of diethylsulfide


Scheme 12.28

Scheme 12.29

[104] W. C. Still, J. Org. Chem. 1976, 41, 3063[105] T. Hiyama, M. Obayashi, I. Mori, H. Nozaki, J. Org. Chem. 1983, 48, 912[106] A. Mori, A. Fujita, K. Ikegashira, Y. Nishihara, T. Hiyama, SynLett 1997, 693[107] T. Tsuji, S. Kajita, S. Isobe, M. Funato, J. Org. Chem. 1993, 58, 3607[108] H.S. D. Soysa, W. P. Weber, Tetrahedron Lett. 1978, 235[109] M.R. Detty, M.D. Seidler, J. Org. Chem. 1982, 47, 1354[110] M.D. Mizhiritskii, V. O. Reikhsfel’d, Zh. Obshch. Khim. 1986, 56, 1547; Chem. Abstr.

1987, 106, 137656

1900 is reduced by 601 in CH2Cl2 at 60 �C to give 87% diethyl sulfide and HMDSO 7[110]. A solution in DMF of a peptide containing methionine-S-oxide 1901 is reducedat 24 �C by PhSSiMe3 584 and catalytic amounts of TMSOTf 20 to give 1902, in 90%yield, plus diphenyl disulfide and HMDSO 7 [111] (Scheme 12.31). Sulfoxides such asdimethyl sulfoxide can also be reduced by PhSeSiMe3 1903 in CHCl3, giving dimethylsulfide in 98% yield and PhSeSePh 1904 and HMDSO 7 [112].

Aliphatic or aromatic sulfinic acids are reduced by aliphatic or aromatic thiolsin the presence of Me3SiCl (TCS) 14 to give disulfides [113]. Thus, tolylsulfinic

12.3 Reductions with Hexamethyldisilane, Hexamethyldisilthiane and Phenylthiotrimethylsilane 279

Scheme 12.30

Scheme 12.31

[111] S. Kuno, K. Akaji, I. Ikemura, M. Moriga, M. Aono, K. Mizuta, A. Takagi, H. Yaji-

ma, Chem. Pharm. Bull. 1986, 34, 2462[112] M.R. Detty, J. Org. Chem. 1979, 44, 4528[113] S. Oae, H. Togo, T. Numata, K. Fujimori, Chem. Lett. 1980, 1193

acid 1905 is reduced by butanethiol in the presence of TCS 14 to give phenylbutyl-disulfide 1906 in 70% yield, and formation of dibutyldisulfide, HMDSO 7, andHCl [113]. Methyl methylthiosulfinate 1907 is converted by phenylthiotrimethyl-silane 584 into methyl phenyl disulfide 1908, in 90% yield, and HMDSO 7 [114].Phenyl phenylthiosulfinate 1909 reacts with hexamethylsilthiane 601 to give thediphenyltrisulfide 1910, in 95% yield, and trimethylsilyl sulfinate 1911 [115].Finally, diphenyl sulfoxide on treatment with TMSOTf 20 then PhMgCl gives 75%triphenylsulfonium triflate 1912 [116] (Scheme 12.32).

The anion of primary nitro compounds such as nitroethane reacts with hexa-methylsilthiane 601 to give acetothiohydroxamic acid 1913 in 81% yield [117],whereas reaction with phenylthiotrimethylsilane 584 affords phenyl acetothiohy-droximate 1914 in 62% yield [117] (Scheme 32.33). Secondary nitro compounds


Scheme 12.32

Scheme 12.33

[114] G. Capozzi, A. Caperuzzi, A. Degl’Innocente, R. del Duce, S. Menichetti, Tetrahe-dron Lett. 1989, 30, 2995

[115] G. Capozzi, A. Caperuzzi, A. Degl’Innocente, R. del Duce, S. Menichetti, Tetrahe-dron Lett. 1989, 30, 2991

[116] R. D. Miller, A.F. Renaldo, H. Ito, J. Org. Chem. 1968, 53, 5571[117] J. R. Hwu, S.-C. Tsay, Tetrahedron 1990, 46, 7413

such as nitrocyclohexane give rise to 83% cyclohexanone oxime [117]. Finally, at185 �C aromatic nitro compounds, such as nitrobenzene, are reduced by sodiumtrimethylsilanethiolate to amines, such as aniline, in 70–96% yield [118].

12.4Reductions of Esters with Metals in the Presence of Trimethylchlorosilane

In this section primarily reductions of aldehydes, ketones, and esters with so-dium, lithium, and potassium in the presence of TCS 14 are discussed; closely re-lated reductions with metals such as Zn, Mg, Mn, Sm, Ti, etc., in the presence ofTCS 14 are described in Section 13.2. Treatment of ethyl isobutyrate with sodiumin the presence of TCS 14 in toluene affords the O-silylated Rühlmann–acyloin-condensation product 1915, which can be readily desilylated to the free acyloin1916 [119]. Further reactions of methyl or ethyl 1,2- or 1,4-dicarboxylates are dis-cussed elsewhere [120–122]. The same reaction with trimethylsilyl isobutyrate af-fords the C,O-silylated alcohol 1917, in 72% yield, which is desilylated to 1918[123] (Scheme 12.34). Likewise, reduction of the diesters 1919 affords the cyclizedO-silylated acyloin products 1920 in high yields, which give on saponification theacyloins 1921 [119]. Whereas electroreduction on a Mg-electrode in the presenceof Me3SiCl 14 converts esters such as ethyl cyclohexane-carboxylate via 1922 andsubsequent saponification into acyloins such as 1923 [124], electroreduction of es-ters such as ethyl cyclohexylcarboxylate using a Mg-electrode without Me3SiCl 14yields 1,2-ketones such as 1924 [125] (Scheme 12.34).

The O-silylated acyloins such as 1920c and 1927 are useful synthons for prepa-ration of five-membered aromatic heterocycles such as the substituted imidazole1925, pyrrole 1926, and furan 1928 [119] (Scheme 12.35).

Whereas �-trimethylsilyloxy esters 1929 are reduced by Li/TCS 14 at 0 �C to givethe enoxysilanes 1930, which can be readily hydrolyzed to the acylsilanes 1931[126] (Scheme 12.36), O-silylated cyanohydrins such as 1932 with Li/TCS 14 inTHF at 0 �C afford 24% of the enamine 1933, 10% of the trimethylsilyloxysilane1934, and 25% of recovered starting material 1932 [126].

Because Me3SiCl 14 is almost inert to lithium organic compounds or Grignardreagents in non-polar solvents, formation of tertiary alcohols on addition of MeLior n-BuLi to free carboxylic acids [127] or their methyl or ethyl esters [128] in THF

12.4 Reductions of Esters with Metals in the Presence of Trimethylchlorosilane 281

[118] J. R. Hwu, F. F. Wong, M.-J. Shiao, J. Org. Chem. 1992, 57, 5254[119] K. Rühlmann, Synthesis 1971, 236[120] J. J. Bloomfield, Tetrahedron Lett. 1968, 587[121] J. J. Bloomfield, Tetrahedron Lett. 1968, 591[122] J. J. Bloomfield, J.R. S. Irelan, A. P. Marchand, Tetrahedron Lett. 1968, 5647[123] I. Kuwajima, T. Sato, N. Minami, T. Abe, Tetrahedron Lett. 1976, 1591[124] A. Sekiguchi, W. Ando, Tetrahedron Lett. 1979, 4077[125] S. Kashimura, Y. Murai, M. Ishifune, H. Masuda, H. Murase, T. Shono, Tetrahedron

Lett. 1995, 36, 4805[126] J.-P. Picard, A. Aziz-Elyusufi, R. Calas, J. Dunooguès, N. Duffaut, Organometallics

1984, 3, 1660


Scheme 12.34

Scheme 12.35

Scheme 12.36

can be minimized by sequential addition [127] or in the presence [128] of Me3SiCl14. Thus ethyl valerate reacts with n-BuLi and five equivalents of TCS 14 in THFat –100 �C to give 77% di-n-butylketone and 6% tri-n-butylcarbinol 1935. Applying25 equivalents of TCS 14 raises the yield of di-n-butyl ketone to 90% [128]. Appli-cation of this reaction to the �-thioester 1936 gives, on addition of MeLi/Me3SiCl14, the methyl ketone 1937 in 65% yield with 80% ee [129] (Scheme 12.37).

Enolization of methyl �-cyclogeranate 1938 with n-butyllithium, then addition ofallylmagnesium chloride, and, finally, quenching with Me3SiCl 14 affords nearlypure E-1939 in 76% yield [130] (Scheme 12.38). The amide 1940 reacts analo-gously with allylmagnesium chloride/LiN(i-Pr)2 (LDA) to give, after quenchingwith TCS 14, the O-trimethylsilylenolate 1941 in 70% yield [131]. Analogously, ad-dition of allylmagnesium chloride to free carboxylic acids such as benzoic acidthen quenching with TCS 14 affords the enol silyl ether 1942 and the free tertiaryalcohol 1943 [132].

12.4 Reductions of Esters with Metals in the Presence of Trimethylchlorosilane 283

Scheme 12.37

Scheme 12.38

[127] G. M. Rubottom, C.-W. Kim, J. Org. Chem. 1983, 48, 1550[128] M.P. Cooke, J. Org. Chem. 1986, 51, 951[129] A. M. Ponce, L.E. Overman, J. Am. Chem. Soc. 2000, 122, 8672[130] C. Fehr, J. Galindo, J. Org. Chem. 1988, 53, 1828[131] C. Fehr, J. Galindo, Helv. Chim. Acta 1986, 69, 228[132] T. Inaba, S. Watanabe, M. Sakamoto, T. Fujita, Chem. Ind. 1989, 763

In the presence of catalytic amounts of TiCl4 nitrogen (N2) is reduced bylithium/Me3SiCl 14 (or by Mg/Me3SiCl 14) in situ, by Ti1, to give N(SiMe3)3 1326;this reacts with benzoyl chloride in the presence of CsF to give benzamide andbenzimide [133] (Scheme 12.39). Carboxylic acids 28 are readily transformed byMe3SiCl 14/triethylamine in CH2Cl2 into their silyl esters, which are reduced insitu at –78 �C by DIBAL, in good yields, via intermediates such 1944, to their alde-hydes [134]. In the presence of a polymer-supported sulfonamide catalyst 1945 ke-tones such as acetophenone can be enantioselectively reduced by NaBH4/Me3SiCl14 in boiling THF to give alcohols in high chemical and enantiomeric yield [135](Scheme 12.39). Cyclohexyl isocyanate reacts with Me3C(Ph)2SiLi 1946 via 1947 togive the isonitrile 1948 and Me3C(Ph)2SiOLi [136].

12.5Oxidations with Bis(trimethylsilyl)peroxide

Although bis(trimethylsilyl)peroxide (BTSP) 1949 is considered in a review to bequite stable [137], some minor accidents with its use have been reported [138]. Itis usually prepared from 85% H2O2 and Me3SiCl (TCS) 14 in ether–pyridine


Scheme 12.39

[133] M. Mori, M. Kawaguchi, M. Hori, S.-I. Hamaoka, Heterocycles 1994, 39, 729[134] S. Chandrasekhar, M.S. Kumar, B. Muralidhar, Tetrahedron Lett. 1998, 39, 909[135] J.-B. Hu, G. Zhao, Z.-D. Ding, Angew. Chem. Int. Ed. 2001, 40, 1109[136] J. E. Baldwin, A. J. Derome, P.D. Riordan, Tetrahedron 1983, 39, 2989[137] D. Brandes, A. Blaschette, J. Organomet. Chem. 1974, 78, 1[138] H. Neumann, D. Seebach, Chem. Ber. 1978, 111, 2785

[138], from DABCO–H2O2 [139–141], from the H2O2–hexamethylenetetraminecomplex [142] on treatment with TCS 14 in CH2Cl2, and from the urea–H2O2

complex [143] on boiling for 12 h with bis(trimethylsilyl)urea 23 a in CH2Cl2.Primary alcohols such as benzyl alcohol or cinnamyl alcohol react rapidly with

BTSP 1949 in the presence of catalytic amounts of RuCl2·(PPh3)3 to give aldehydesin high yields whereas secondary alcohols are oxidized much more slowly to ketones[144] (Scheme 12.40). When carbanions are treated with BTSP 1949 the anions canattack BTSP at the oxygen or silicon atom leading thus to either the C-OSiMe3 or C-SiMe3 moieties. Thus phenyllithium reacts with BTSP 1949 in THF at –78 �C to give44% phenyltrimethylsilane 81 and 48% phenoxytrimethylsilane [138]. The same re-action in pentane–Et2O [140, 145] furnishes 86–93% phenoxytrimethylsilane. Vinyl-lithium compounds such as 1-cyclooctenyllithium 1950 afford 52% enol silyl ether1951, which reacts in methanol with 2,4-dinitrophenylhydrazine to give the DNP-hy-drazone of cyclooctanone 1952 [138]. Cyclohexyl magnesium bromide furnishes 78%cyclohexanol [145]. Heterocyclic lithium compounds such as 2-furyllithium 1953 re-act with BTSP 1949 to give, e.g., the 2-O-trimethylsilyl compound 826, in 90% yield,and 10% of the corresponding C-trimethylsilylfuran 1954 [140, 145]. Other hetero-cycles such as 2- or 3-lithiumthiophene react analogously [140, 145] (Scheme 12.40).


Scheme 12.40

[139] P.G. Cookson, A. G. Davies, N. Fasal, J. Organomet. Chem. 1975, 99, C31[140] M. Taddei, A. Ricci, Synthesis 1986, 633[141] P. Dembech, A. Ricci, G. Seconi, M. Taddei, Org. Synth. 1997, 74, 84[142] P. Babin, B. Bennetau, J. Dunoguès, Synth. Commun. 1992, 22, 2849[143] W. P. Jackson, SynLett 1990, 536[144] S. Kanemoto, K. Oshima, S. Matsubara, K. Takai, H. Nozaki, Tetrahedron Lett. 1983,

24, 2185[145] L. Camici, P. Dembech, A. Ricci, G. Seconi, M. Taddai, Tetrahedron 1988, 44, 4206

Conversion of sulfones such as 1955 into their �-sulfonyl anions by treatmentwith n-BuLi at –78 �C in THF then addition of bis(trimethylsilyl)peroxide (BTSP)1949 afford, via intermediates such as 1956, aldehydes or ketones such as cyclo-hexanone and HMDSO 7 [146]. This reaction has subsequently been applied tothe synthesis of aldehydes [147]. After lithiation with n-BuLi thioethers such asphenyl benzyl sulfide 1957 react with BTSP 1949 to give mixtures of the O-silyl1958 and C-silyl 1959 products [148]. On treatment with n-BuLi at –30 �C the�,�-bis-(trimethylsilyl)dimethylsulfide 1960 is, likewise, converted into its anion,which reacts with 1949 to give the �-trimethylsilyloxy sulfide 1961 and Me3SiOLi98 [149] (Scheme 12.41).

In THF at –20 �C the N-trimethylsilylated 2-pyrrolidinone 388 is converted byLDA into the �-anion which, on reaction with 1949 and subsequent acidificationwith AcOH, gives 43% 3-hydroxy-2-pyrrolidinone 1962 [150]. Lithium enolates ofketones such as camphor react with BTSP 1949 to give > 95% of a mixture of exo-and endo-2-hydroxycamphor [151]. Lithiated methyl heterocycles such as lithiated2-methylpyridine 1963 are converted into mixtures of the O-SiMe3 1964 and C-SiMe3 1965 compounds and C-methylated compounds such 1966 [152]. 2-Lithioto-luene 1967 is oxidized by 1949 into 1968 [140, 145] (Scheme 12.42).

In the reaction of lithiated 2-allylbenzothiazole 1969 with 1949 40% of the expected�-trimethylsilyloxy product 1970, 60% of the C-methylation product 1972 (via 1971),and Me3SiOLi 98 and (Me2SiO)3 54 are obtained [153, 154] (Scheme 12.42).


Scheme 12.41

[146] J. R. Hwu, J. Org. Chem. 1983, 48, 4432[147] F. Chemla, M. Julia, D. Uguen, Bull. Soc. Chim. Fr. 1993, 130, 547[148] P. Dembech, A. Guerrini, A. Ricci, G. Seconi, M. Taddei, Tetrahedron 1990, 46, 2999[149] A. Ricci, A. Degl’Innocenti, M. Ancillotti, G. Seconi, P. Dembech, Tetrahedron

Lett. 1986, 27, 5985[150] D.H. Hua, S.W. Miao, S.N. Bharathi, T. Katsuhira, A.A. Bravo, J. Org. Chem. 1990,

55, 2682[151] W. Adam, M.N. Korb, Tetrahedron, 1996, 52, 5487[152] E. Epifany, S. Florio, L. Troisi, Tetrahedron 1990, 46, 4031[153] S. Florio, L. Troisi, Tetrahedron Lett. 1989, 28, 3721[154] S. Florio, L. Troisi, Tetrahedron Lett. 1993, 34, 3141

Lithium enolates of carboxylic acids such as phenylacetic acid or of amides such asN-methyl-N-phenylvaleric acid amide 1974 are oxidized by BTSP 1949 to �-hydroxyacids, which are isolated after esterification, e.g., to 1973, or to �-hydroxyamides suchas 1975 [155] (Scheme 12.43) (cf. also the formation of 3-hydroxybutyrolactam 1962).

Terminal acetylenes such as phenylacetylene are transformed by ZnI2, CuCl,CuBr, or CuCN and BTSP 1949 into 1-iodo- 1976, 1-chloro- 1978, 1-bromo- 1979,or 1-cyano-4-phenylalkynes 1980 and to the diacetylene 1977 [156] (Scheme 12.44).

Combination of BTSP 1949 with TMSOTf 20 [157], with sulfur trioxide SO3

(which, with BTSP 1949, forms Me3SiO2SO2OSiMe3 1982 [158]), or with SnCl4


Scheme 12.42

Scheme 12.43

[155] M. Pohmakotr, C. Winotai, Synth. Commun. 1988, 42, 2141[156] A. Cesarini, P. Dembech, G. Reginato, A. Ricci, G. Saconi, Tetrahedron Lett. 1991,

32, 3141[157] M. Suzuki, H. Takeda, R. Noyori, J. Org. Chem. 1982, 47, 902[158] M. Camporeale, T. Fiorani, L. Troisi, W. Adam, R. Curci, J. O. Edwards, J. Org.

Chem. 1990, 55, 93

[159] effects smooth Baeyer–Villiger oxidations (Scheme 12.45). Thus, 4-tert-butyl-cyclohexanone, cyclohexanone, or 4-phenylcyclohexanone are readily transformedby 1949 or by 1982 [158] into the lactones 1981, caprolactone, and butyrolactone1983, and to 1984 in 76%, 94%, 6%, and 91% yield in the presence of TMSOTf20 [157], SnCl4 [159], or SnCl4 in combination with TCS 14 and trans-1,2-diamino-cyclohexane [159]. Asymmetric Bayer–Villiger oxidation of ketones such as 3-phe-nylcyclobutanone with BTSP 1949 can be achieved in the presence of Co–salencomplexes in CH2Cl2 [160]. Under special reaction conditions with TMSOTf 20 ascatalyst in MeCN at 0 �C aldehydes or ketones such as acetone or cyclohexanoneare transformed by BTSP 1949 into the 1,2,4,5-tetroxanes 1985 in high yields [161](Scheme 12.45).


Scheme 12.44

Scheme 12.45

[159] R. Göttlich, K. Yamakoshi, H. Sasai, M. Shibasaki, SynLett 1997, 971[160] A. Watanabe, T. Uchida, K. Ito, T. Katsuki, Tetrahedron Lett. 2002, 43, 4481[161] C.W. Jefford, A. J. J. Boukouvalas, Synthesis 1988, 391

Aromatic hydrocarbons such as p-xylene are oxidized by BTSP 1949 in the pres-ence of AlCl3, via ipso attack and subsequent rearrangement, to give, in 40%yield, a 7 : 3 mixture of 2,5-dimethylphenol 1986 and 2,4-dimethylphenol [162].Likewise, treatment of aromatic silyl compounds such as 1987 with BTSP 1949 inthe presence of Bu4NF·2–3H2O in THF results in ipso substitution to give 4-cya-nophenol [163]. In the presence of triflic acid and BTSP 1949 toluene is oxidizedin 88% yield to 63% o-cresol, 10% m-cresol and 27% p-cresol and HMDSO 7 [164]whereas naphthalene affords 67% �-naphthol and 33% �-naphthol [164]. Adaman-tane is oxidized by 1949 in CH2Cl2 to give 83% 4-oxa-homoadamantane 1989 and4% 1-hydroxyadamantane 1990 [165] (Scheme 12.46).

On using Barton-oxidation procedures cyclohexane is oxidized by 1949, in thepresence of FeCl3 and the FeIII–picolinate complex, to give cyclohexanone andcyclohexanol [166] whereas with FeCl2 1-chlorocyclohexane is the mayor product,with cyclohexanone and a small amount of cyclohexanol [167] (Scheme 12.47).

The combination of BSTP 1949 with SnCl4 converts olefins such as cyclopen-tene 1991a, cyclohexene 1991 b, or cycloheptene 1991 c into their trans-1,2-chloro-hydrins 1992a– c in 74, 85 and 92% yield, respectively [168]. Reaction of the cyclic


Scheme 12.46

[162] J. O. Apatu, D.C. Chapman, H. Heaney, J. Chem. Soc. Chem. Commun. 1981, 1079[163] S. Prouihac-Cros, P. Babin, B. Bennetau, J. Dunoguès, Bull. Soc. Chim. Fr. 1995,

132, 513[164] G. A. Olah, T.D. Ernst, J. Org. Chem. 1989, 54, 1204[165] G. A. Olah, T.D. Ernst, C.B. Rao, G.K.S. Prakashj, New J. Chem. 1989, 13, 791[166] D.H.R. Barton, B. M. Chabot, Tetrahedron 1997, 53, 487[167] D.H.R. Barton, B.M. Chabot, Tetrahedron 1997, 53, 511[168] I. Sakurada, S. Yamasaki, R. Göttlich, T. Iida, M. Kanai, M. Shibasaki, J. Am.

Chem. Soc. 2000, 122, 1245

olefins 1991 with BTSP 1949 in the presence of Me3SiN3 19 or Me3SiCN 18 givesrise to trans-2-hydroxyazides 1993 [169] or trans-2-hydroxycyanides 1994 [170]. Thechromene 1995 is enantioselectively epoxidized by BTSP 1949 in the presence ofan asymmetric Salen–Mn(III) catalyst [171] to give the chromen epoxide 1996[171]. Olefins such as vinylcyclohexane 1997 react with BTSP 1949 in the presenceof Re2O7 or MeReO3 (MTO), in CH2Cl2, to give epoxides such as 1998 [172].These epoxidations are catalyzed by small amounts of H2O or MeOH, which ap-parently serve to hydrolyze BTSP 1949 to HMDSO 7 and free H2O2, which seemsto be necessary for reaction with the Re compound to give the active ReO3 catalyst[172, 173] (Scheme 12.48).

Likewise, pyridines such as methyl isonicotinate 1999 or quinolines are readilyoxidized by BTSP 1949 in the presence of HOReO3 in CH2Cl2 to give, after 6 h at24 �C, 98% yield of, e.g., methyl isonicotinate N-oxide 2000 [174] (Scheme 12.49).The oxidation of diphenylsulfide with BTSP 1949 and triphenylphosphine dichlo-ride in acetonitrile results, after 60 h at room temperature, in only 12% diphenylsulfoxide 2001 and 88% recovered diphenyl sulfide [175] (Scheme 12.49), whereasthianthrene 5-oxide 2002 is oxidized by the peroxy-Mo complex 2003 to give 58%of a mixture of 2004 to 2007 in which the trans 5,10-thioxide 2005 predominates[176] (Scheme 12.50).

Kinetic studies of the oxidation of phosphites such as triisopropyl phosphitewith BTSP 1949 to give phosphates such as triisopropyl phosphate [177] led to thediscovery that oxidation of diphosphite nucleotide intermediates such as 2008with BTSP 1949 at –20 �C in the presence of TMSOTf 20 (instead of iodine in


Scheme 12.47

[169] I. Sakurada, S. Yamasaki, M. Kanai, M. Shibasaki, Tetrahedron Lett. 2000, 41, 2415[170] S. Yamasaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2001, 123, 1256[171] R. Irie, N. Hosoya, T. Katsuki, SynLett 1994, 255[172] A. K. Yudin, K.B. Sharpless, J. Am. Chem. Soc. 1997, 119, 11536[173] A. K. Yudin, J. K. Chiang, H. Adolfsson, C. Copéret, J. Org. Chem. 2001, 66, 4713[174] C. Copéret, H. Adolfsson, J.K. Chiang, A. K. Yudin, K. B. Sharpless, Tetrahedron

Lett. 1998, 39, 761[175] K. Shibata, Y. Itoh, N. Tokitoh, R. Okazaki, N. Imamoto, Bull. Chem. Soc. Jpn. 1991,

64, 3749[176] W. Adam, D. Golsch, J. Sundermeyer, G. Wahl, Chem. Ber. 1996, 129, 1177[177] V. V. Gorbatov, N.V. Yablokova, Yu. A. Aleksandrov, V. I. Ivanov, Zh. Obshch. Khim.

1983, 53, 1752; Chem. Abstr. 1984, 100, 6681


Scheme 12.48

Scheme 12.49

Scheme 12.50

H2O) in CH2Cl2 afforded the desired nucleotide diphosphates 2009 in nearlyquantitative yield [178–180] (Scheme 12.51).

The tetrahedral phosphorus complex 2010 is, likewise, readily oxidized by BTSP1949 to give the complex 2011, with two PO groups as complex ligands, andHMDSO 7 [181] (Scheme 12.52). A similar oxidation of tetraphosphocubane is de-scribed elsewhere [182].

The cyclic disilazane 2012, which is readily accessible by treatment of 45 withNH3, reacts with the urea–H2O2 adduct to give, in 68% yield, the liquid cyclic ana-logue 2013 of BTSP 1249; 2013 seems, to be more hindered and thus less reactivethan BTSP 1949 [183] (Scheme 12.53).


Scheme 12.51

Scheme 12.52

Scheme 12.53

[178] Y. Hayakawa, M. Uchiyama, R. Noyori, Tetrahedron Lett. 1986, 27, 4191[179] Y. Hayakawa, M. Uchiyama, R. Noyori, Tetrahedron Lett. 1986, 27, 4195[180] Y. Hayakawa, Bull. Chem. Soc. Jpn. 2001, 74, 1547[181] O.J. Scherer, J. Braun, P. Walther, G. Heckmann, G. Wolmershäuser, Angew.

Chem. Int. Ed. 1991, 30, 852[182] X.-B. Ma. , M. Birkel, T. Wettling, M. Regitz, Heteroat. Chem. 1995, 6, 1[183] W. Adam, R. Albert, Tetrahedron Lett. 1992, 33, 8015

12.6Oxidations with Phenyliodoso Compounds

Hydroxy(tosyloxy)iodobenzene 2014 reacts with phenyltrimethylsilane 81 in boil-ing acetonitrile to give diphenyliodonium tosylate 2015 and trimethylsilanol 4 orHMDSO 7 [184, 185]. Likewise, treatment of 2,5-bis(trimethylsilyl)furan 2016 with2014 in boiling acetonitrile/methanol affords 78% iodonium tosylate 2017 and tri-methylsilanol 4 [185]. In the presence of BF3·OEt2 iodosobenzene oxidizes allyl-trimethylsilanes such as 2018 to unsaturated aldehydes such as 2019 in 63%yield, with formation of iodobenzene and trimethylsilanol 4 [186]. Analogously,vinyltrimethylsilanes such as (Z)-1-trimethylsilyl-2-phenylethylene 2020 afford, via2021, acetylenes such as phenylacetylene in 61% yield and iodobenzene and tri-methylsilanol 4 [187] (Scheme 12.54).

The iodosobenzene·HBF4 complex 2022 adds to the enol silyl ether 653 of acet-ophenone to give the labile iodonium salt 2023, which reacts with cyclohexene ortetramethylethylene to give the adducts 2024 and 2025 [188] (Scheme 12.55).

Iodosobenzene reacts with TMSOTf 20 (or with TMSONf 21) to give the ad-ducts 2026 or 2027, which are transformed by TMSCN 18 to the adduct 2028[189]. 2028 is also obtained from iodobenzene by treatment with pertrifluoroaceticacid then reaction with TMSOTf 20 and Me3SiCN 18 [190] (Scheme 12.56). The


Scheme 12.54

[184] G. F. Koser, R. H. Wettach, C.S. Smith, J. Org. Chem. 1980, 45, 1543[185] C.S. Carman, G.F. Koser, J. Org. Chem. 1983, 48, 2534[186] M. Ochiai, E. Fujita, M. Arimoto, H. Yamaguchi, Tetrahedron Lett. 1983, 24, 777[187] M. Ochiai, K. Sumi, Y. Nagao, E. Fujita, M. Arimoto, H. Yamaguchi, J. Chem. Soc.

Chem. Commun. 1985, 697[188] V. V. Zhdankin, R. Tykwinski, R. Caple, B. Berglund, A. S. Koz’min, N.S. Zefirov,

Tetrahedron Lett. 1988, 29, 3703[189] V. V. Zhdankin, C.M. Crittel, P. J. Stang, Tetrahedron Lett. 1990, 31, 4821[190] V. V. Zhdankin, M.C. Scheuller, P. J. Stang, Tetrahedron Lett. 1993, 34, 6853

adduct 2028 not only oxidizes the enolsilyl ether of acetophenone 653 to a mix-ture of 2029 and 2030 [189], it also reacts with the tributyltin derivatives 2031 and2033 to afford the iodonium triflates 2032 and 2034 with elimination of tributyltincyanide [190, 191] (Scheme 12.56).

The benzoiodoxol 2035 is converted by Me3SiN3 19 into 2036, which oxidizes cyclo-hexene to �-azidocyclohexanone 2037 [192], whereas 2035 reacts with bis(trimethyl-silyl)acetylene 2038 to give the iodonium salt 2039 [193] (Scheme 12.57).

Reaction of N,N-dimethylaniline with 1-cyanobenziodoxol 1783 to afford N-methyl-N-cyanomethylaniline 1784 in 97% yield has been discussed in Sec-tion 12.1 [31]. Analogously, oxidation of dimethylaniline with iodosobenzene andtrimethylsilyl azide 19 at 0 �C in CDCl3 gives the azido compound 2040 in 95%yield, iodobenzene, and HMDSO 7 [194, 195] (Scheme 12.56). Likewise, the nu-cleophilic catalyst 4-dimethylaminopyridine (DMAP) is oxidized, in 95% yield, tothe azide 2041, which is too sensitive toward hydrolysis to 4-N-methylaminopyri-dine to enable isolation [194, 195]. Amides such as 2042, in combination with tri-


Scheme 12.55

Scheme 12.56

[191] P. M. Gallop, M. A. Paz, R. Flückiger, P. J. Stang, V. V. Zhdankin, R. R. Tykwinski,J. Am. Chem. Soc. 1993, 115, 11702

[192] V. V. Zhdankin, C. J. Kuehl, A.P. Krasutsky, M.S. Formanek, J.T. Bolz, TetrahedronLett. 1994, 35, 9677

[193] V. V. Zhdankin, C. J. Kuehl, J.T. Bolz, M.S. Formanek, A. J. Simonsen, TetrahedronLett. 1994, 35, 7323

[194] P. Magnus, J. Lacour, W. Weber, J. Am. Chem. Soc. 1993, 115, 9347[195] P. Magnus, J. Lacour, W. Weber, Synthesis 1998, 547

methylsilyl azide 19 in boiling CH2Cl2, react with o-iodosylbenzoic acid 2043 toafford 64% of the azide 2044, HMDSO 7, and o-iodobenzoic acid 2045 [196]. Thetriisopropylsilyl (TIPS) enol ether of cyclohexanone 2046 is oxidized by the combi-nation of iodosobenzene with trimethylsilyl azide 19 in CH2Cl2 to give 95% of theazide 2047 and only traces of the bis(azide) 2048, whereas the same reaction inthe presence of Tempo (2,2,6,6-tetramethylpiperidine-N-oxide) affords 91% of thebis-azide 2048 [30, 197, 197a] (Scheme 12.58).

The 5,6-disubstituted dihydropyran 2049 is converted by iodosobenzene diace-tate and Me3SiBr 16 or Me3SiI 17 in pyridine to the 3-bromo (or 3-iodo) com-pounds 2050 in 79 or 84% yield, respectively [198] (Scheme 12.59). Reaction ofolefins such as cyclohexene (or enol ethers) with iodosobenzene diacetate, tetra-


Scheme 12.57

Scheme 12.58

[196] P. Magnus, C. Hulme, W. Weber, J. Am. Chem. Soc. 1994, 116, 4501[197] P. Magnus, J. Lacour, J. Am. Chem. Soc. 1992, 114, 767[197a] P. Magnus, M.B. Roe, C. Hulme, J. Chem. Soc. Chem. Commun. 1995, 263[198] P.A. Evans, J.D. Nelson, T. Manangan, SynLett 1997, 968

ethylammonium bromide, and Me3SiN3 19 in CH2Cl2 at –25 �C results, viaEt4N·I(N3)2, in 92% yield of a 20:1 mixture of the racemic 1,2-azidobromides2051 and 2052 [199] (cf. also the transformation of olefins with (Me3SiO)2 1949and Me3SiN3 19 into trans hydroxyazides such as 1993 [169]).

12.7Miscellaneous Oxidations

On conversion of N-trimethylsilyl compounds of primary amines such as of cyclo-hexylamine 2053 into their lithium salts, e.g. 2054, and subsequent rapid air oxi-dation with dry air, the intermediate salts, for example 2055, eliminate Me3SiOLi98 to give intermediate oximes, which are converted during flash chromatographyon SiO2 into ketones such as cyclohexanone [200] (Scheme 12.60). Aliphatic oraromatic thiols such as thiophenol are oxidized by DMSO in the presence of aslight excess of HMDS 2 at ambient temperatures, via intermediates such 2055,to the corresponding disulfides such as diphenyldisulfide in high yields [201](cf. also the subsequently described oxidation of 2070 to 2071 by DMSO)(Scheme 12.60). The enol silyl ethers of cyclopentanone or cyclohexanone (107a)are readily oxidized by dry air, in the presence of a catalytic amount of Pd onSiO2, in polar solvents such as DMF or N-methylpyrrolidone, to give the unsatu-rated ketones 2056a and 2056b in high yields [202]. Likewise, the enol silyl ether2057 is oxidized in DMSO to give 2058 [203] (Scheme 12.60).

Whereas silylated hydroquinone 2059 is readily oxidized by dry air in the pres-ence of catalytic amounts of NO2 to give a quantitative yield of the quinone 2060


Scheme 12.59

[199] A. Kirschning, M.A. Hashem, H. Monenschein, L. Rose, K.-U. Schöning, J. Org.Chem. 1999, 64, 6522

[200] H.G. Chen, P. Knochel, Tetrahedron Lett. 1988, 29, 6701[201] B. Karimi, D. Zareyee, SynLett 2002, 346[202] T. Bab, K. Nakano, S. Nishiyama, S. Tsuruya, M. Masai, J. Chem. Soc. Perkin II 1990,

1113[203] R. T. Larock, T.H. Hightower, G.A. Kraus, P. Hahn, D. Zheng, Tetrahedron Lett.

1995, 36, 2423

and HMDSO 7 [204], silylated primary or secondary alcohols such as silylated 1-octanol (or cyclohexanol or benzyl alcohol) are readily oxidized by the Swern re-agent to aldehydes such as 2061 (isolated as its 2,4-dinitrophenylhydrazone 2062)or ketones, in high yields [205] (Scheme 12.61).

The Collins reagent in CH2Cl2 oxidizes silylated primary alcohols in preferenceto the more hindered silylated secondary alcohols, as described for oxidation ofthe prostaglandin intermediate 2963 to the rather labile aldehyde 2964, which isimmediately subjected to a Horner–Wittig-reaction to introduce the lower sidechain [206] (Scheme 12.61).

In an alternative oxidation, addition of chromium trioxide to hexamethyldisilox-ane (HMDSO) 7 gives bis(trimethylsilyl)chromate 2065, which is stabilized by ad-dition of SiO2 and which oxidizes primary or secondary alcohols such as 2066 or2968, in CH2Cl2, to their corresponding carbonyl compounds 2067 or 2069, inhigh yields [207] (Scheme 12.62).

Trimethylsilyl esters of tris(thio)phosphonic acids 2070 are readily oxidized byDMSO in toluene at –30 �C to give the dimeric tetra(thia)diaphosphorinanes 2071and HMDSO 7 [208] (cf. also the oxidation of silylated thiophenol via 2055 to di-phenyl disulfide). The polymeric SeO2 is depolymerized and activated by reactionwith trimethylsilyl polyphosphate 195 to give the corresponding modified polymer

12.7 Miscellaneous Oxidations 297

Scheme 12.60

[204] R. Rathore, E. Bosch, J. K. Kochi, Tetrahedron Lett. 1994, 35, 1335[205] C.M. Afonso, M.T. Barros, C.D. Maycock, J. Chem. Soc. Perkin I 1987, 1221[206] R. Mahrwald, F. Theil, H. Schick, H.-J. Palme, H. Nowak, G. Weber, S. Schwarz,

Synthesis 1987, 1012[207] J. G. Lee, J.A. Lee, S.Y. Sohn, Synth. Commun. 1996, 26, 543[208] J. Hahn, T. Nataniel, Z. Naturforsch. 1987, 42b, 1263


Scheme 12.61

Scheme 12.62

Scheme 12.63

containing O-Se(O)-O-P(O)(OSiMe3)-O groups 2072 [209], which oxidizes unsatu-rated six-membered rings such as cyclohexene, via 2073–2075, to cyclohexadieneand, finally, to benzene in 95% yield [209] (Scheme 12.63).


A solution of 1 mmol Me2SiI2 1745 is added to a mixture of 3 mmol zinc dustand 1 mmol pinacolone in CH2Cl2, whereupon an exothermic reaction occurs im-mediately. After 10 min at room temperature analysis of the reaction mixture byGLC reveals the formation of 86% 1747, 60% of octamethylcyclosiloxane 55, and10% decamethylcyclopentasiloxane 56 (n= 5) [13] (Scheme 12.64).

Dry HCl is passed into 4 mL anhydrous CH2Cl2 for 12 min with stirring andcooling to 0 �C. Cooling and stirring are continued and a solution of a mixture of0.2057 g 1-methyl-1-cyclohexanol 1794a and 0.4188 g triethylsilane 84 b in 1 mL ofCH2Cl2, and 0.1206 g anhydrous AlCl3 are added. The mixture is kept at 0 �C for15 min and then at room temperature for 45 min. After addition of ice-cold waterand octane as internal standard, the aqueous layer is separated and extractedtwice with CH2Cl2 and the combined organic layer is dried with MgSO4. Analysisby GLC indicates 86% yield of methylcyclohexane 1796a [40] (Scheme 12.65).

Triethylsilane (1.2 mmol) 84b is added, at –30 �C, to a stirred mixture of1.2 mmol benzaldehyde, 1.2 mmol allyloxytrimethylsilane, and 0.1 mmol TMSOTf


[209] J. G. Lee, K.C. Kim, Tetrahedron Lett. 1992, 33, 6363

Scheme 12.64

Scheme 12.65

Scheme 12.66

20 in CH2Cl2. The reaction mixture is warmed to 0 �C and then, after 12 h, toroom temperature. The mixture is diluted with ether, washed with sat. NaHCO3,dried over MgSO4, the solvent is evaporated, and the product is chromatographedon silica gel to give the allyl ether 1820 in 99% yield [50] (Scheme 12.66).

Et3SiH 84 b (2–3 equiv.) is added at room temperature, under an argon atmo-sphere, to a stirred mixture of 2–5 mol% 10% Pd on carbon and a 0.5–1 M solu-tion of thiol ester 1849 in acetone. Stirring is continued at room temperature un-til reduction is complete (30–60 min). The catalyst is isolated by filtration throughCelite and washed with acetone. Evaporation, and separation on a silica gel col-umn, gives the desired aldehyde 1850 in 91% yield [76] (Scheme 12.67).

Pd-C (10%, 15 mg), polymethylhydrosiloxane (PMHS) 1856 (180 mg), and di-t-butyl dicarbonate, (BOC)2O (240 mg, 1.1 mmol) are added to a solution of 1 mmol1855 in 10 mL ethanol. After stirring for 4 h at room temperature the reactionmixture is filtered and the filtrate evaporated in vacuo. The residue is chromato-graphed on silica gel to give the N-Boc-derivative 1857 in 94% yield [81](Scheme 12.68).

A solution of 2 mmol 4-nitroacetophenone, 2.4 mmol dimethylchlorosilane 882,and 0.1 mmol In(OH)3 in 4 mL CHCl3 is stirred for 2 h at room temperature togive, after work-up, ca. 99% 1878 [90] (Scheme 12.69).


Scheme 12.67

Scheme 12.68

Scheme 12.69

A stirred solution of 1 mmol �-ketoamine 1879 and 1.2 mmol Ph(Me)2SiH in1–2 mL HMPA is treated at 0 �C with 2–5 mol% of a 0.5 M commercial solutionof Bu4NF·2–3H2O in THF and then kept at room temperature for 12 h to give,after work-up and GLC analysis, 83% 1880 [93] (Scheme 12.70).

Trans-4-Octene oxide 1885 (1.2 mmol), then hexamethyldisilane 857 (1.8 mmol)in 5 mL HMPA, are added, at 65 �C under argon, to 0.2 mmol potassium methox-ide in 10 mL anhydrous HMPA. After 3 h stirring at 65 �C and cooling to roomtemperature saturated aqueous NaCl solution is added to the reaction mixture,which is then extracted with pentane. The pentane extracts are combined anddried with Na2SO4 and analyzed by vapor phase chromatography (VPC) to revealthe formation of 99% cis 4-octene 1887 [103] (Scheme 12.71).

A mixture of 1 mmol allyl acetate 1893, 2 mmol hexamethyldisilane 857,0.5 mmol NaCl, and 0.040 mmol Pd(DBA)2 in 3.8 mL DMF is heated, with stir-ring, at 100 �C for 40 h to give, on work-up and chromatography, 62% allylsilane1894 [107] (Scheme 12.72).


Scheme 12.70

Scheme 12.71

Scheme 12.72

Scheme 12.73

Sodium metal (46 g, 2 mol) is added, under nitrogen, to 600 mL abs. toluene ina three-necked, 1.5-L round-bottomed flask with stirrer, reflux condenser, additionfunnel, and nitrogen inlet and the mixture is heated and the sodium lumpscrushed by rapid stirring. After cooling, the toluene is decanted, the sodium sandis washed with abs. ether (6�50 mL), then abs. ether (600–800 mL) and Me3SiCl14 (217.3 g, 2 mol) are added. Diester 1919 (0.5 mol) is added dropwise to this stir-red mixture at a rate such that the ether boils gently. If boiling stops the reactionflask should be heated in an oil bath. After complete reaction of the sodium-metalthe reaction mixture is filtered and the NaCl washed repeatedly with a total of300 mL ether. After removal of the ether by distillation, the residue is distilled invacuo to give 81% 1920a, b.p. 75–76 �C/10–11 Torr, 93% 1920b, b.p. 93–94 �C/10–12 Torr, or 89% 1920c, b.p. 102–105 �C/10–12 Torr [119] (Scheme 12.73).

In a three-necked 1.5 L round-bottomed flask with stirrer, reflux condenser, andnitrogen inlet, 1,2-bis(trimethylsilyloxy)alkene 1920 a– c (0.5 mol) is stirred with18.6 g 1 M HCl, which is rinsed into the flask with 300 mL ether and 100 mLTHF. The reaction mixture is heated on a steam bath for 1–2.5 h to vigorous re-flux, then cooled and the aqueous HCl layer is separated. The ether layer is stir-red for 3 h with 12 g freshly precipitated CaCO3, filtered, and distilled in vacuo togive 58% 1921a, b.p. 95–97 �C/15 Torr, 78% 1921b, b.p. 78–80 �C/10–12 Torr, or72% 1921c, b.p. 76–83 �C/10–12 Torr, m.p. 113–115 �C [119] (Scheme 12.73).

A solution of bromocyclohexane (1 g, 6.14 mmol) in 2.5 ml THF is added, undernitrogen, to magnesium (200 mg, 8.23 mmol) in 1 mL diethyl ether. The mixture isheated under reflux for 1.5 h, then cooled to 0 �C, and bis(trimethylsilyl)peroxide1949 (1.09 g, 6.14 mmol) is added. The mixture is warmed to room temperatureand 2 mL methanol and a catalytic amount of 10 M aqueous HCl is added. The sol-vent is evaporated under vacuum and the residue purified by distillation to give0.480 g (78%) cyclohexanol, b.p. 159–160 �C [145] (Scheme 12.74).

(Me3SiO)2 1949 (2 equiv.) in CH2Cl2 is added to a stirred mixture of 1 equiv. 4-phenylcyclohexanone, 25 mol% of both SnCl4 and trans-1,2-diaminocyclohexane,and some 4- molecular sieve in CH2Cl2 at 25 �C to give, after 4.5 h, 91% caprolac-tone 1984 [159] (Scheme 12.75).


Scheme 12.74

Scheme 12.75

A mixture of methyl isonicotinate 1999 (2.74 g, 20 mmol) and perrhenic acid(HOReO3; 25 mg, 0.1 mmol) in 3 mL CH2Cl2 is treated with 1949 (6 mL,30 mmol). The mixture is stirred for 6 h at 24 �C in a water bath then diluted with6 mL hexane, cooled to 0 �C, and filtered. The resulting solid is washed with coldhexane (2�4 mL) and dried in vacuo to give 3.00 g (98%) of the N-oxide 2000 [174](Scheme 12.76).

Ph=I=O (2.4 equiv.) is added at –20 �C to a solution of 4-dimethylaminopyridine(DMAP; 1 equiv.) and Me3SiN3 19 (2.5 equiv.) in CDCl3. Analysis of the reactionmixture at 0 �C by 1H NMR indicates 95% yield of the azide 2041, which is toosensitive to hydrolysis to enable its isolation [194, 195] (Scheme 12.77).


Scheme 12.76

Scheme 12.77

13.1Dehydration–Activation of Inorganic and Organic Salts

Several anhydrous inorganic halides are very interesting Lewis acids or Friedel–Crafts catalysts but are often only commercially available as their hydrates. Somehydrates of inorganic salts such as CeCl3·7H2O can, apparently, be only partiallydehydrated by heating in vacuo [1, 2], whereas treatment with SOCl2 gives anhy-drous CeCl3 [3]. SnCl2·2H2O gives only impure anhydrous SnCl2 on heating [4],but affords anhydrous SnCl2 on treatment with COCl2, whereas SOCl2 leads toSnCl4, SO2, and sulfur [5]. Despite this, apparently all these hydrates react readilywith excess trimethylsilyl halides such as trimethylchlorosilane (TCS) 14 or tri-methylbromosilane (TBS) 16 to give pure anhydrous halides; for each equivalentof hydrate–water one equivalent of HMDSO 7 (b.p. 100 �C) and two equivalents ofhydrogen halide are formed [6–8] (Scheme 13.1).

Thus reaction of BaCl2 · 2H2O, CoCl2 · 6H2O, CuCl2 · 2H2O, CrCl3 · 6H2O,FeCl3·6H2O, SnCl2·2H2O [8], or ZnCl2·2H2O with excess TCS 14 affords the anhy-drous chlorides in high yields and volatile HMDSO 7 and HCl, which are removed oncompletion of the reaction in vacuo [6–8]. Analogously, CeCl3·7H2O can be expectedto react with 14 equivalents of TCS 14 to give anhydrous CeCl3.

Hydrates of acids such as TsOH·H2O can probably also be dehydrated by treat-ment with silyl esters such as TsOSiMe3 (Scheme 13.1). Likewise, TsOH·H2O isdehydrated in situ during aminations of hydroxy-N-heterocycles such as purines242 (Scheme 4.24) or (1H,3H)-quinazoline-2,4-dione 250 (Scheme 4.27) by HMDS2, in the presence of higher-boiling primary or secondary amines, to give the ami-

305

13

Dehydration–Halogenation–Activation and Silylationof Inorganic and Organic Salts and Metallorganic Compounds


[1] T. Ooi, T. Miura, Y. Kondo, K. Maruoka, Tetrahedron Lett. 1997, 38, 3947[2] N. Takeda, N. Imamoto, Org. Synth. 1998, 76, 228[3] P. Eckenberg, U. Groth, T. Köhler, Liebigs Ann. Chem. 1994, 673[4] Gmelin Handbuch Zinn Teil C 1, 193[5] H. Hecht, Z. Anorg. Allg. Chem. 1947, 254, 37[6] P. Boudjouk, J.-H. So, Inorg. Synth. 1992, 29, 108[7] J.-H. So, P. Boudjouk, Inorg. Chem. 1990, 29, 1592[8] H. Nakahira, I. Ryu, A. Ogawa, N. Kambe, N. Sonoda, Organometallics 1990, 9, 277

nated purines 244 or the quinazoline 252, which are both partially transformedinto their tosylates with liberation of volatile NH3 and HMDSO 7.

Instead of heating the hydrates with TCS 14 or TBS 16, with evolution ofHMDSO 7 and HX, some hydrates for example SnCl2.2H2O might also react atambient temperature with HMDS 2 and TCS 14 in absolute acetonitrile to gener-ate the anhydrous salt, e.g. SnCl2, HMDSO 7 and NH4Cl (cf. Section 2.1). Be-cause NH4Cl precipitates from acetonitrile, and because electrophilic anhydroussalts such as SnCl2 will probably form soluble �-complexes with acetonitrile, theacetonitrile solution should give, after removal of the NH4Cl by filtration, a solu-tion of anhydrous SnCl2. Concentration or evaporation of the acetonitrile will pro-vide the free anhydrous SnCl2 (Scheme 13.2).

Ammonium molybdate 2076 reacts with TCS 14 in 1,2-dimethoxyethane atroom temperature to give hexachloromolybdenium, which reacts in situ withamines such as aniline, ammonia or tert-butylamine in the presence of triethyla-mine to give chloroimino molybdates such as 2077, HMDSO 7, and triethylaminehydrochloride [9] (Scheme 13.3).

The dehydration and activation of commercial tetrabutylammonium fluoride di-or trihydrate to obtain anhydrous Bu4NF [10, 11] is complicated because thehighly active anhydrous Bu4NF decomposes already at T > 14–17 �C to give tri-butylamine, tributylamine hydrofluoride, 1-butylfluoride, and 1-butene [12]. Thus

13 Dehydration–Halogenation–Activation and Silylation of Inorganic and Organic Salts306

Scheme 13.1

Scheme 13.2

[9] H.H. Fox, K. B. Yap, J. Robbins, S. Cai, R.R. Schrock, Inorg. Chem. 1992, 31, 2287[10] R. K. Sharma, J. L. Fry, J. Org. Chem. 1983, 48, 2112[10a] D.P. Cox, J. Terpinski, W. Lawrynowicz, J. Org. Chem. 1984, 49, 3216[11] K. Seppelt, Angew. Chem. Int. Ed. 1992, 31, 292[12] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1983, 24, 5337

all the thermal methods described will give rise to mixtures of fluorides contain-ing Bu3N·(HF)n [12, 13].

On very slow addition of a solution of hexamethyldisilane 857 at 0–10 �C to arapidly stirred commercial solution of Bu4NF·2–3H2O in THF a solution of veryreactive anhydrous Bu4NF in THF is obtained, also containing the volatile Me3SiF71 (b.p. 17 �C), Me3SiH 84 a, and HMDSO 7, which do not normally interfere withthe reactions of the Bu4NF [12]. Only methyl o-nitrobenzoate, apparently, is re-duced, to o-nitrobenzyl alcohol, by the in-situ generated Me3SiH 84 a [12]. Otherreagents such as allyltrimethylsilane 82 or benzyltrimethylsilane 83 will also dehy-drate Bu4NF·2–3H2O to generate, in situ, anhydrous Bu4NF and propene ortoluene [13]. Alternatively, and apparently much more simple and economical forlarger scale preparations of anhydrous Bu4NF, is dehydration with HMDS 2,whereupon HMDSO 7 is formed and ammonia is evolved although the reactiontemperature of < 15 �C was not controlled [14] (Scheme 13.4).

This very reactive “anhydrous” Bu4NF activates hexamethyldisilane 857 and allyl-trimethylsilane 82 or benzyltrimethylsilane 83 by generating the tetrabutylammo-nium salts of the trimethylsilyl anion [12], the allyl-anion [13] 2078, or the benzyl[13] anion and volatile Me3SiF 71 (b.p. 17 �C) [12–14]. Relative large amounts ofanhydrous Bu4NF are needed, however, to generate two equivalents of the tetrabu-tylammonium salts of the allyl-anion 2078 (or the benzyl anion) which react insitu, e.g. with 1,6-dibromohexane to form, in the presence of Hünig’s baseiPr2NEt (DIPEA), �1,11-dodecadien 859 in 61.2% yield, 9% of the mono-substi-tuted product 2079a, and 4–5% of the fluoride 2079 b, which is formed by dis-

13.1 Dehydration–Activation of Inorganic and Organic Salts 307

Scheme 13.3

Scheme 13.4

[13] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett. 1984, 25, 1259[14] A. Kirschning, F. Narjes, E. Schaumann, Liebigs Ann. Chem. 1991, 933

placement of the bromine in 2079a by fluorine [15, 16] (Section 13.5). In these re-actions the larger scale dehydration of Bu4NF·2–3H2O with HMDS 2 [14] at tem-peratures < 10 �C should be considered (Scheme 13.5).

As described in Section 7.4, hexamethyldisilane 857 reduces, analogously, pyri-dine, quinoline and isoquinoline N-oxides to the free bases [17] and converts aro-matic nitro groups to azo compounds [12]. Likewise, as already discussed allyltri-methylsilane 82 and benzyltrimethylsilane 83 will gradually dehydrate and activateBu4NF·2–3H2O in situ to catalyze the addition of 82 and 83 to pyridine, quino-line, and isoquinoline N-oxides [13] (cf. Section 7.2).

13.2Conversion of Inorganic Oxides into the Corresponding Halides and Triflates

Trimethylchlorosilane TCS 14 readily transforms metal oxides such as ZnO, MgO,MnO, BeO, Al2O3, or TiO2 and oxides of transition metals such as SmO or In2O3

into the corresponding reactive anhydrous chlorides and volatile HMDSO 7(b.p. 100 �C) (Scheme 13.6).

Metals such as zinc, magnesium, or aluminum have smooth and elastic oxide sur-faces and are therefore resistant to oxygen and corrosion. As a consequence of trans-forming the oxygen atoms on the surface of these metals into their metal chlorides,the resulting metal powders gain a very reactive surface and will therefore reducereactive groups rapidly as suspensions in solvents such as acetonitrile or THF inthe presence of TCS 14. Other reagents such as Me3SiX or SiX4, where X= Br, I


Scheme 13.5

[15] M. Marschner, Ph. D. Dissertation, Technical University, Berlin 1984[16] H. Vorbrüggen, Acc. Chem. Res. 1995, 28, 509

Scheme 13.6

[37, 56, 57], F, OSO2CF3 [62, 65], Me2SiCl2 48 [22], Me2Si(Cl)(CH2)3CN [23, 51, 52,64], Me2Si(Cl)(CH2)2Si(Cl)Me2 45 [24, 26, 64], or (Me3Si)2SO4 can transform, analo-gously, any metal oxide surface into reactive chlorides, bromides, iodides, fluorides,triflates, or sulfates. Thus, e.g., SiF4 is used to dope the surface of SiO2 2080 in chipproduction to produce compounds such as polymeric OSiF2 2081 [18] (Scheme 13.7).

All these silicon reagents which activate metal surfaces are also Lewis acids,which can also contribute as such to the acceleration of any of the subsequentlydiscussed reactions, because of their inherent Lewis acid properties.

Because of the many examples of such activation of metal powders by TCS 14only a limited and arbitrary number will be discussed here. The Clemmensen-type reduction of ketones such as cyclohexanone with Zn powder in the presenceof TCS 14 affords, via 2082, 2084, and 2085, cyclohexene and, via 2082, O-silylatedpinacol 2083 [19, 20]. Ketones such as 5�-cholestan-3-one 2086 are reduced by Zndust–TCS 14 in THF, in ca 65–70% yield, to give 5�-cholest-2-ene 2087 and ca 5%5�-cholest-3-ene [21] (Scheme 13.8).

Cyclohexanone reacts with Zn/Cu couple/Me2SiCl2 48 to generate cyclohexylcarbene, which inserts to cyclohexanone to afford 2088 in unspecified yield withformation of 56 [22] (Scheme 13.9).

Unsaturated ketones such as 2089 are dimerized by Zn/TCS 14 to give McMur-ry products such as 2090 in 85% yield [20]. In a new and very efficient modifica-tion of the McMurry reaction dicarbonyl compounds such as 2-benzoylaminoace-tophenone 2091 are cyclized in high yields, e.g. to the indole 2092, either by Zn/Me2Si(Cl)(CH2)3CN in the presence of catalytic amounts of TiCl3 in acetonitrile[23, 51, 53, 64] or by Ti dust/Me3SiCl 14 in boiling DME [23, 51, 53, 64]. Aromaticaldehydes, for example benzaldehyde, and �/�-unsaturated cyclic ketones are di-merized by Zn powder and 1,2-bis(chlorodimethylsilyl)ethane 45 in high yields togive dimers such as stilbene with formation of the oxide 47 [24]. Ketones such as

13.2 Conversion of Inorganic Oxides into the Corresponding Halides and Triflates 309

[17] H. Vorbrüggen, K. Krolikiewicz, Tetrahedron Lett 1983, 24, 5337[18] M. McCoy, Chem. Eng. News 2000, Nov. 20, 17[19] W. B. Motherwell, J. Chem. Soc. Chem. Commun. 1973, 935[20] A. K. Banerjee, M.C. Sulbaran de Carrasco, C.S.V. Frydrich-Houge, W.B. Mother-

well J. Chem. Soc. Chem. Commun. 1986, 1803[21] P. Hodge, M.N. Khan, J. Chem. Soc. Perkin I 1975, 809[22] C.L. Smith, J. Arnett, J. Ezike, J. Chem. Soc. Chem. Commun. 1980, 653[23] A. Fürstner, Pure Appl. Chem. 1998, 70, 1071[24] C.A. M. Afonso, W.B. Motherwell, D.M. O’Shea, L. R. Roberts, Tetrahedron Lett. 1992,

33, 3899

Scheme 13.7

2093 with an �-olefinic bond are cyclized by Zn/TCS 14, via 2094, to give prod-ucts such as 2095 in high yields [25] (Scheme 13.10).

Treatment of aromatic aldehydes such as p-anisaldehyde with Zn-powder and1,2-bis(chlorodimethylsilyl)ethane 45 give Zn–carbene adducts such as 2096 whichadd readily to olefins such as cyclohexene [22, 26] or styrene [26] to give highyields of cyclopropanes such as 2097 and the oxide 47 [26]. Acetals such as 2098react analogously with cyclohexene to afford the endo and exo cyclopropanes 2099and 2100 [22, 27] (Scheme 13.11).

The McMurry pinacol coupling of aldehydes and ketones such as benzaldehydewith Zn powder/TCS 14 and ultrasonic irradiation [28] or in the presence of TCS14 and TiCl3·(THF)3 as catalyst in 1,3-diethyl-1,3-diphenylurea (DEPU) gives 90%of, mainly, the O-silylated d,l-pinacol 2101 [29] whereas reaction of benzaldehydewith Zn/TiCl4 in the absence of Me3SiCl 14 in CH2Cl2 gives only 57% of mainlyd,l-pinacol 1891 [29 a]. Likewise, coupling with Zn/Cp2TiCl2 [30], with Zn/MgBr2/


Scheme 13.8

Scheme 13.9

[25] E. J. Corey, S.G. Payne, Tetrahedron Lett. 1983, 24, 2821[26] W. B. Motherwell, L.R. Roberts, J. Chem. Soc. Chem. Commun. 1992, 1582[27] W. B. Motherwell, D. J. R. O’Mahony, M.E. Popkin, Tetrahedron Lett. 1998, 39, 5285[28] J.-H. So, M.-K. Park, P. Boudjouk, J. Org. Chem. 1988, 53, 5871[29] T.A. Lipski, M.A. Hilfiker, S. G. Nelson, J. Org. Chem. 1997, 62, 4566[29a] T. Li, W. Cui, J. Liu, J. Zhao, Z. Wang, J. Chem. Soc. Chem. Commun. 2000, 139[30] Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717

Me3SiCl 14/Cp2TiCl2/THF, or with Zn/Me3SiCl 14/Cp2Ti(Ph)Cl/THF [32, 33] alsoaffords mainly d,l-pinacol 1891. Reductive coupling of benzaldehyde with ZnEt2 inthe presence of TCS 14 and catalytic amounts of Ce(OCHMe2)3, however, givesrise to high yields of nearly exclusively meso 1891 [34], whereas benzaldehydewith Mg/Me3SiCl 14 in the presence of InCl3 furnishes a 1 : 1 mixture of d,l- andmeso-pinacol 1891 [34a]. Reaction of aliphatic aldehydes such as n-hexanal withZn/Me3SiCl 14 in the presence of catalytic amounts of CpV(CO)4 affords up to


Scheme 13.10

Scheme 13.11

[31] A. Gansäuer, J. Chem. Soc. Chem. Commun. 1997, 457[32] Y. Yamamoto, R. Hattori, K. Itoh, J. Chem. Soc. Chem. Commun. 1999, 825[33] Y. Yamamoto, R. Hattori, T. Miwa, Y. Nakagei, T. Kubota, C. Yamamoto, Y. Okamoto,

K. Itoh, J. Org. Chem. 2001, 66, 3865[34] U. Groth, M. Jeske, Angew. Chem. Int. Ed. 2000, 39, 574

91% of stereoisomers of 1,3-dioxolanes such as 2,4,5-tri-n-pentyl-1,3-dioxolanes2102 [35]. Pinacol coupling of aliphatic aldehydes with aliphatic vinyl ketones inthe presence of excess CrCl2 and Me3SiCl 14 at 0 �C in DMF, then fluoride-cata-lyzed transsilylation, gives very high yields of mainly anti pinacols, whereas at75 �C the syn pinacols predominate [35 a] (Scheme 13.12).

Addition of TCS 14 to CH2I2/Zn, which contains up to 0.04 mol% of lead im-purity, improves the Simmons–Smith reaction of olefins such as cyclooctene togive up to 96% of the cyclopropane 2103 [36] (Scheme 13.12).

The reduction of pyridine-N-oxides such as 867 a with Zn/Me3SiCl/NaI in aceto-nitrile, whereupon not only is Me3SiI 17 generated but, apparently, also the Znmetal is activated, leads to high yields of pyridines such as �-picoline [37] (cf.Scheme 12.8, and the reduction of pyridine-N-oxides with hexamethyldisilane 857in Scheme 7.31). Schiff bases such as 2104 are dimerized by Zn powder in thepresence of TCS 14 in acetonitrile to give, in 97% yield, a 1 : 1 mixture of 2105and 2106 [38]. Reformatsky reactions between ethyl bromoacetate and aldehydesor ketones such as cyclopentanone give higher yields in the presence of TCS 14[39]. Organozinc reagents are readily prepared from Zn powder with primary orsecondary aliphatic iodides such as 1-iodo-n-butane in the presence of TCS 14 and1,2-dibromoethane in THF to give, with CuCN, the reagent BuCu(CN)ZnI 2107;this reacts with acid chlorides such as benzoyl chloride to give ketones such as2108 or readily undergoes 1,4-additions to give unsaturated ketones such as cyclo-hexenone in high overall yield [40]. Benzylidene malonitrile 2109 is dimerized byZn/Me3SiCl 14 in the presence of Cp2VCl2 in DMF to give 79% the trans dimer2110, whereas Al/Me3SiCl 14 gives rise to 81% of a mixture of the trans 2110 andcis 2111 dimers, demonstrating that the oxide layer of aluminum is likewise acti-vated by TCS 14 [41] (Scheme 13.13).


Scheme 13.12

[35] T. Hirao, T. Hasegawa, Y. Muroguma, I. Ikeda, J. Org. Chem. 1996, 61, 366[35a] K. Takai, R. Morita, C. Toratsu, Angew. Chem. Int. Ed. 2001, 40, 1116[36] K. Takai, T. Kakiushi, K. Utimoto, J. Org. Chem. 1994, 59, 2671[37] T. Morita, K. Kuroda, Y. Okamoto, H. Sakurai, Chem. Lett. 1981, 921[38] A. Alexakis, I. Aujard, P. Mangeney, SynLett 1998, 873[39] G. Picotin, P. Miginiac, J. Org. Chem. 1987, 52, 4796[40] P. Knochel, M.C .P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem. 1988, 53, 2390

Addition of TCS 14 to Cu-catalyzed 1,4-additions of Grignard reagents of Lialkyls to �/�-unsaturated carbonyl compounds has recently been repeatedly re-viewed [42–44a] and is thus not treated here.

Silylated benzyl alcohol 2112a or benzhydrol 2112b are reduced by Mg/TCS 14in HMPA to give benzyl-2113 a (= 83) or benzhydryltrimethylsilanes 2113b [45],whereas the O-silylated pinacol 2101 affords the dimeric benzyltrimethylsilane2114 in 93% yield [45]. Allyl alcohol gives rise to allyltrimethylsilane 82 in 63%yield and, on continued reaction with TCS 14/Mg, the 1,3-bis-(trimethylsilyl)pro-pene 2115 is formed in 58% yield [45]. Ketones such as acetophenone are con-verted by Mg/TCS 14 in DMF, in 66% yield, to adducts such as 2116 [46], fromwhich trimethylsilanol 4 is eliminated on heating with KHSO4 at 150 �C to affordthe olefin 2117 in 51% yield [46]. Phenyltrifluoromethylketone 2118 is convertedby Mg/TCS 14 in 91% yield into the difluoro enol silyl ether 2119 [47]. Iminessuch as 2120 are reduced by Mg/TCS 14 in DMF, in 72% yield, to N-silylatedenamines such as 2121 [48].


Scheme 13.13

[41] L. Zhou, T. Hirao, Tetrahedron Lett. 2000, 41, 8517[42] N. Krause, A. Gerold, Angew. Chem. Int. Ed. 1997, 36, 186,[43] S.H. Bertz, A. Chopra, M. Eriksson, C.A. Ogle, P. Seagle, Chem. Eur. J. 1999, 5, 2680[44] E. Nakamura, S. Mori, Angew. Chem. Int. Ed. 2000, 39, 3751[44a] B. H. Lipshutz, S. Sengupta, Org. React. 1992, 41, 135[45] C. Biran, N. Duffaut, J. Dunogues, R. Calas, J. Organomet. Chem. 1975, 91, 279[46] Y. Ishino, H. Maekawa, H. Takeuchi, K. Sukata, I. Nishigushi, Chem. Lett. 1995,

829[47] H. Amii, T. Kobayashi, Y. Hatamoto, K. Uneyama, J. Chem. Soc. Chem. Commun.

1999, 1323[48] M. Mae, H. Amii, K. Uneyama, Tetrahedron Lett. 2000, 41, 7893

Mg powder can probably be activated for any subsequent Grignard reaction bytreating the metal with Me3SiCl 14 in either ether or THF, or entirely without sol-vent, followed by removal of unreacted Me3SiCl 14 and HMDSO 7 and any etheror THF in vacuo before adding the halogen compound dissolved in ether or THF(Scheme 13.14).

On stirring with Me3SiCl 14 and PbCl2 in THF manganese powder affords ac-tive Mn powder, which reacts with cyclododecanone 2122 and allylbromide orethyl bromoacetate in the presence of PbCl2 to give the adducts 2123 a and 2123bin 99% and 88% yields, respectively [49]. Likewise, benzaldehyde adds allylbro-mide in the presence of Mn powder and catalytic amounts of In powder and ex-cess TCS 14 in THF to give 86% 2124 [50]. In the first catalytic Nozaki–Hiyamareaction of octanal with iodobenzene in the presence of CrCl2/Mn/Me3SiCl 1467% yield of 2125 was obtained [51, 52]. In a catalytic and enantioselective versionof this reaction benzaldehyde is reacted with allyl bromide in the presence of cata-lytic amounts of the commercially available [Cr(salen 1)] complex and triethyl-amine in acetonitrile to give the adduct 2124 in 65% yield with 65% ee [53]. Thesame reaction with a new salen-complex containing (S,S)-endo,endo-2,5-diamino-


Scheme 13.14

[49] K. Takai, T. Ueda, T. Hayashi, T. Moriwake, Tetrahedron Lett. 1996, 37, 7048[50] J. Augé, N. Lubin-Germain, A. Thiaw-Woaye, Tetrahedron Lett. 1999, 40, 9245[51] A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 2533[52] A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 12349[53] M. Bandini, P.G. Cozzi, P. Melchiorre, A. Romani-Ronchi, Angew. Chem. Int. Ed.

1999, 38, 3357

norbornane as the central link affords 2125 in 72% yield and 90% ee [53a]. Treat-ment of iodoform with Mn powder and excess TCS 14 in DME gives Me3SiCHI2

2126 in 59% yield; this reacts with �-phenylacetaldehyde the presence of CrCl2 togive 90% 2127 [54]. Direct reaction of �-phenylpropionaldehyde with iodoform inthe presence of Mn/TCS 14/CrCl2/THF affords 74% 2127 [54] (Scheme 13.15).

Benzyl bromide adds to acrylonitrile in the presence of CrCl3/Mn and 4-tert-bu-tylpyridine in THF/H2O, via in situ formation of CrCl2, to afford 85% 4-phenylbu-tyronitrile 2128 and traces of dibenzyl [55]. If only catalytic amounts of CrCl3 areused, TCS 14 and isopropanol must be added [55] (Scheme 13.15).

On treatment of �-halocarbonyl compounds such as 2-chlorocyclohexanone 2129or �-bromolactones with Sm powder/TCS 14/NaI in acetonitrile the intermediateMe3SiI 17 apparently oxidizes the Sm metal to SmI2 while forming HMDSO 7 orMe3SiSiMe3 857, whereupon the SmI2 reduces 2-chlorcyclohexanone 2129 at–40 �C to cyclohexanone [56, 57]. At room temperature cyclohexanone is readilydimerized under these reaction conditions to give the pinacol 2130 [57]. Likewise,in the presence of Sm powder and TCS 14 in THF acetophenone forms the pina-col 2131 in 73% yield [56, 57]. Related pinacol couplings of carbonyl compounds


Scheme 13.15

[53a] A. Berkessel, D. Menche, C.A. Sklorz, M. Schröder, I. Paterson, Angew. Chem. Int.Ed. 2003, 42, 1032

[54] K. Takai, S. Hikasa, T. Ishiguchi, N. Sumino, SynLett 1999, 1769[55] J. Augé, R. Gil, S. Kalsey, Tetrahedron Lett. 1999, 40, 67[56] N. Akane, Y. Kanagawa, Y. Nishiyama, Y. Ishii, Chem. Lett. 1992, 2431[57] N. Akane, T. Hatano, H. Kusui, Y. Nishiyama, Y. Ishii, J. Org. Chem. 1994, 59, 7902

with SmI2/Mg [58] or Sm/Me3SiCl 14 [59–61] have also recently been described.Reaction of cyclohexanone with ethyl bromoacetate affords, in a Reformatsky reac-tion, the adduct 2132 in 75% yield whereas addition of methyl acrylate gives 57%of the spirolactone 2133 [57]. Spirolactones such as 2134 can also be prepared ingood yields by using Hg-activated Zn metal, catalytic amounts of SmI2, andTMSOTf 20 in THF [62] (Scheme 13.16).

In a new version of the Simmons–Smith reaction allyl or allenic alcohols suchas cyclohexenol are converted by Sm/CH2I2/Me3SiCl 14 in THF at –78 �C into syncyclopropanols such as 2135 [63] (Scheme 13.17).

As already discussed, low-valent titanium can be generated in situ from catalyticamounts of TiCl3, by use of excess Zn powder and TCS 14 in acetonitrile, to cy-clize reductively 2-benzoylaminoacetophenone 2091 to the indole 2092, in 80%yield, in an elegant version of the McMurry reaction [23, 64]. Replacement of theZn metal powder by Ti powder and TCS 14 is very effective – 2092 is obtained in97% yield [64]. In these reactions the intermediate Ti(O)Cl is apparently recycledby Me3SiCl 14 into TiCl3 [64]. In these Fürstner versions of the McMurry reaction


Scheme 13.16

[58] R. Nomura, T. Matsuno, T. Endo, J. Am. Chem. Soc. 1996, 118, 11666[59] A. Ogawa, H. Takeuchi, T. Hirao, Tetrahedron Lett. 1999, 40, 7113[60] T. Honda, M. Katoh, J. Chem. Soc. Chem. Commun. 1997, 369[61] M. Yu, Y. Zhang, Org. Prep. Proc. Int. 2001, 33, 187[62] E.J. Corey, G.Z. Zheng, Tetrahedron Lett. 1997, 38, 2045[63] M. Lautens, Y. Ren, J. Org. Chem. 1996, 61, 2210[64] A. Fürstner, A. Hupperts, J. Am. Chem. Soc. 1995, 117, 4468

replacement of the catalytic amounts of TiCl3 by finely powdered TiO2 in combi-nation with Zn powder and TCS 14 has, apparently, not yet been tried.

In an analogous reaction the catechol titanate 2136 is converted by TMSOTf 20,via 2137, to give the bis-(trimethylsilyl)ester 2138, which eliminates HMDSO 7 toregenerate 2136 [65] (Scheme 13.18). The intermediate compound 2137 apparentlyserves as catalyst for the reaction of 1-O-trimethylsilyl-2,3,5-tri-O-benzyl-d-arabino-furanose with O-silylated alcohols to afford mainly the 1-�-arabinofuranosides.

Reaction of MnO2 with TCS 14 generates MnCl4 which chlorinates ketonessuch as propiophenone 2139 or cycloheptanone 2141 to give the chloro com-pounds 2140 and 2142 [66] (Scheme 13.19).

Iodosobenzene is converted by TMSOTf 20 to 2143 and HMDSO 7 [67]. Addi-tion of water to 2121 gives the Zefirov reagent 2027, which can be reconverted by20 into 2143 and HMDSO 7. Iodosobenzene reacts analogously with two equiva-lents of Me3SiCN 18 to give the air-sensitive dicyano compound 2144 andHMDSO 7 [68], whereas reaction of iodosobenzene with Me3SiN3 19 affords, at–40 �C, HMDSO 7 and the diazido compound 1781, which decomposes at 0 �C togive iodobenzene and nitrogen [67]. On reaction of the propargylsilane 2145 withPhI(OAc)2 [69] or [PhI(OTf)]2 2027 [70] in the presence of F3B·OEt2 at –20 �C a[3,3] sigmatropic iodonio–Claisen rearrangement of the presumed intermediate


Scheme 13.17

Scheme 13.18

[65] T. Mukaiyama, M. Yamada, S. Suda, Y. Yokomizo, S. Kobayashi, Chem. Lett. 1992, 1401[66] F. Bellisia, F. Ghelfi, U.M. Pagnoni, A. Pinetti, J. Chem. Res. (S) 1990, 188[67] N.S. Zefirov, S.O. Safronov, A.A. Kaznacheev, V. V. Zhdankin, Zh. Org. Khimii 1989,

25, 1807; Chem. Abstr. 1989, 112, 118338[68] V. V. Zhdankin, R. Tykwinski, B. L. Williamson, P. J. Stang, N. J. Zefiron, Tetrahedron

Lett. 1991, 32, 733[69] M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, J. Am. Chem. Soc. 1991, 113, 1319[70] D.A. Gately, T. A. Luther, J. R. Norton, M.M. Miller, O.P. Anderson, J. Org. Chem.

1992, 57, 6496

2146 leads to 2147. Dibutyltin oxide 2148 is converted by a large excess of TCS 14into dibutyltin dichloride 2149 and HMDSO 7 [71] (Scheme 13.20).

SeO2 reacts with TCS 14 to give selenium(IV)oxychloride Se(O)Cl2 2150, whichconverts primary and secondary alcohols such as cyclohexanol into chlorocyclohex-ane in 93% yield [72]. Likewise, CrO3 is converted by TCS 14 into Cr(O2)Cl2 2151and HMDSO 7 [72]. Sodium perrhenate 2152 reacts with TCS 14 to give thetrimethylsilylperrhenate 2153, which eliminates HMDSO 7 to form dirhenium-heptoxide 2154. Reaction of dirheniumheptoxide 2154 with TCS affords HMDSO7 and chlorotrioxorhenium 2155, which reacts with SnMe4 to generate the veryinteresting new oxidation catalyst methyltrioxorhenium 2156 [73] (Scheme 13.21).Reaction of Re2O7 2154 with triphenylsilanol 104 leads to Ph3SiOReO3 2157 [74],


Scheme 13.19

Scheme 13.20

[71] S. Kohama, J. Organomet. Chem. 1975, 99, C44[72] J. G. Lee, K.K. Kang, J. Org. Chem. 1988, 53, 3634[73] W. A. Herrmann, R.M. Kratzer, R.W. Fischer, Angew. Chem. Int. Ed. 1997, 36, 2652[74] T. Schoop, H.W. Roesky, M. Noltemeyer, H.-G. Schmidt, Organometallics 1993, 12, 571

which serves as a catalyst for isomerizations of allylic alcohols [75] such as of2158 to galanthamine 2159 [76] (Scheme 13.21).

Dirheniumheptoxide 2154 is converted by TCS 14, in the presence of 2,2�-dipyri-dine, into the dipyridine complex 2160 [77]. Free ReCl5, NbCl5, and WCl5 reactwith HMDSO 7 and 2,2�-bipyridine to form bipyridine oxochloride complexes2161 and TCS 14, with reversal of the hitherto described reactions of metal oxideswith TCS 14. The analogous Mo complex 2162 undergoes silylation–amination byN-trimethylsilyl-tert-butylamine 2163 to give the bis-imine complex 2164 andHMDSO 7 [77] (Scheme 13.22).

Whereas cyclotrimerization of phenylacetylene with uncomplexed PdCl2 pro-vides only low yields of the unsymmetrical trimer, and polymers, on treatment of3-hexyne with Pd/C and Me3SiCl 14 hexaethylbenzene 2165 is obtained in quanti-tative yield [78] (Scheme 13.23).

13.3Supplement

Treatment of the tetralone oxime 2166 with iron powder in DMF in the presenceof Me3SiCl 14 and a mixture of acetic anhydride and formic acid gives the N-for-myl amine 2167 in high yield [79]. �-Unsaturated alkoxyalkylazides such as 2168

13.3 Supplement 319

Scheme 13.21

[75] S. Bellemin-Laponnaz, H. Gisie, J.P. Le Ny, J.A. Osborn, Angew. Chem. Int. Ed. 1997,36, 976

[76] B. M. Trost, F. D. Toste, J. Am. Chem. Chem. 2000, 122, 11262[77] W. A. Herrmann, W.R. Thiel, E. Herdtweck, Chem. Ber. 1990, 123, 271[78] A. K. Jhingan, W. F. Maier, J. Org. Chem. 1987, 52, 1161[79] M. Yoshida, T. Watanabe, T. Ishikawa, Heterocycles 2001, 54, 433

decompose on treatment with catalytic amounts of FeCl2 in the presence ofMe3SiCl 14 in EtOH to give the oxazolidin-2-ones 2169 and 2170 and N2 [80]. Re-action of indole with the N,O-acetal 2171 in the presence of 0.2 equiv. Cu(OTf)2

and excess Me3SiCl 14 (or BF3·OEt2/Me3SiCl 14) in CH2Cl2 affords the 3-substi-tuted indole 2172 in 90% yield [81] (Scheme 13.24).

Reaction of organozinc compounds 2173 or 2175 with benzaldehyde in the pres-ence of NiCl2·(PPh3)2 gives, via addition products such a 2174, with loss ofMe3SiOH 4, good yields of stilbene or the ester 2176 [82]. 2-Cyclohexen-1-onereacts with in-situ-formed organoberyllium compounds, in the presence of excessMe3SiCl 14 (cf. Refs. [42–44a] for the analogous reactions of organocopper re-agents) to give, nearly exclusively, the 1,4-addition product 2177 and traces of the1,2-addition product 2178 [83] (Scheme 13.25).


Scheme 13.22

Scheme 13.23

[80] T. Bach, B. Schlummer, K. Harms, Chem. Eur. J. 2001, 7, 2581[81] N. Sakai, T. Hamajima, T. Konakahara, Tetrahedron Lett. 2002, 43, 4821[82] J.-X. Wang, Y. Fu, Y. Hu, Angew. Chem. Int. Ed. 2002, 41, 2757[83] A. Krief, M.J. de Vos, S. de Lombart, J. Bosret, F. Couty, Tetrahedron Lett. 1977, 38,

6295

In the presence of In powder 2-cyclohexen-1-one is converted by allyl iodide andMe3SiCl 14, in 63% yield, into the 1,4-addition product 2179 [84], which is also obtainedin 73% yield by Sakurai 1,4-addition of allyltrimethylsilane 82 to 2-cyclohexene-1-one inthe presence of excess Me3SiCl 14 and catalytic amounts of InCl3 [85] (Scheme 13.25).Ytterbium(III) triflate-catalyzed imino-ene reactions of N-tosylaldimines with �-methylstyrene are dramatically accelerated on addition of Me3SiCl 14 [85a].

13.3 Supplement 321

Scheme 13.24

Scheme 13.25

[84] P.H. Lee, H. Ahn, K. Lee, S.-Y. Sung, S. Kim, Tetrahedron Lett. 2001, 42, 37[85] P.H. Lee, K. Lee, S.-J. Sung, S. Chang, J. Org. Chem. 2001, 66, 8646[85a] M. Yamanaka, A. Nishida, M. Nakagawa, Org. Lett. 2000, 2, 159

Mukaiyama-aldol additions with TiCl4/NBu3 as catalyst are accelerated by0.05equiv. Me3SiCl 14. Thus diisopropyl ketone reacts with isobutyraldehyde inCH2Cl2 to give the aldol 2180 in 87% yield. Likewise, phenacylchloride condenseswith benzaldehyde in 81% yield to give a mixture of the syn 2181 and anti 2182aldol products in a 89:11 ratio [86]. Finally, the �-unsaturated �-ketoester 2183cyclizes in the presence of catalytic amounts of PdCl2(MeCN)2 and excess Me3SiCl14, via 2184, to give methyl cyclohexanone-2-carboxylate in 91% yield [87](Scheme 13.26).


Chromium(III) chloride hexahydrate (2.66 g, 10 mmol) is magnetically stirred in20 mL THF in a 100-mL three-necked round-bottomed flask equipped with a con-denser fitted with a drying tube. Me3SiCl 14 (32 mL, 253 mmol) is added to theslurry, dropwise at room temperature with stirring, causing evolution of heat. Thecolor of the reaction mixture changes from dark green to deep purple. The purplesolid that precipitates is washed with hexane and residual solvent is evaporated atreduced pressure to give 3.34 g (8.9 mmol; 89%) CrCl3·3 THF [6] (Scheme 13.27).The preparation of anhydrous Cu(THF)0.8Cl2, Zn(THF)2Cl2, ZnCl2, and FeCl3 pro-ceeds analogously [6].


Scheme 13.26

[86] Y. Yoshida, N. Matsumoto, R. Hamasaki, Y. Tanabe, Tetrahedron Lett. 1999, 40, 4227[87] T. Pei, R. A. Widenhoefer, J. Chem. Soc. Chem. Commun. 2002, 650

Scheme 13.27

In a carefully dried three-necked round-bottomed flask equipped with a thermo-meter, addition funnel, and argon inlet, a solution of Bu4NF·2–3H2O (Aldrich) inTHF (1 M, 20 mL, 20 mmol) is cooled to 0–5 �C and stirred magnetically whilehexamethyldisilane 857 (14.638 g, 100 mmol) is added very slowly dropwise suchthat formation of H2 gas (formation of foam) has subsided before the next dropsare added. Whereas dehydration of 20 mmol Bu4NF·2–3H2O to anhydrous Bu4NFtakes about 8–10 h, larger scale dehydrations of 40–50 mmol Bu4NF.2–3H2O willtake up to 30–40 h, so addition of hexamethyldisilane 857 should be interruptedduring the night, when the reaction flask should be stored in the freezer at 24 �C.Toward the end of the activation to anhydrous Bu4NF the development of H2 be-comes more vigorous, so hexamethyldisilane 857 must be added even moreslowly, until the solution of anhydrous Bu4NF in THF turns deep red (Scheme13.28). This “activated” Bu4NF can be stored at –24 �C for weeks but decomposeson storage at 5–7 �C in a refrigerator [15] (Scheme 13.28).

Bu4NF·2–3H2O (1.89 g, 6 mmol) in 20 mL abs. THF is cooled to 0 �C and hexa-methyldisilazane 2 (HMDS; 4.3 g, 27 mmol) is added with stirring and exclusionof humidity. After stirring for 12 h at room temperature the volatile components,including the hexamethyldisiloxane (HMDSO) 7 (b.p. 100 �C), are removed in va-cuo. After 3 h the semi-crystalline, colorless residue is dissolved, under argon, in10 mL abs. THF [14] (Scheme 13.29).

Because of the thermal instability of anhydrous Bu4NF (cf. the preceding proce-dure) it is recommended, however, to keep the reaction temperature below 10 �Cat all times during the dehydration of Bu4NF·2–3H2O with HMDS 2 and to storethe anhydrous Bu4NF in a freezer at –24 �C to prevent its decomposition to 1-bu-tene, Bu3N·HF and other products [12, 13, 15–17].


Scheme 13.28

Scheme 13.29

Scheme 13.30

1,6-Dibromohexane (1.5 mL, 10 mmol), allyltrimethylsilane 82 (4 mL, 22.2 mmol),and Hünig’s base, i-Pr2NEt (1.75 mL, 10 mmol, in 2 mL abs. THF) are added drop-wise, within 2 h, at 0 �C, with stirring, to solution of activated “anhydrous” Bu4NF(0.7 M, 46.0 mL, 32 mmol) in abs. THF (cf. the preceding activation of Bu4NF·2–3H2O with hexamethyldisilane 857) and the reaction mixture is kept at 0 �C for18 h. On warming to room temperature within 1 h Bu4NBr starts to precipitate. Fil-tration, washing of the Bu4NBr crystals with THF, and evaporation of the filtrategives 2.37 g colorless oil which is chromatographed with hexane on a column of35 g Al2O3 (A I, basic) then with hexane on a column of 65 g silica gel, to give1.02 g (61.2%) �1,11-dodecadiene 2079. GC–MS can be used to reveal the presenceof 9% 2080a and 4–5% 2080b in the more polar eluate fractions [15] (Scheme 13.30).

Titanium powder (0.626 g, 13.07 mmol) is suspended in 10 mL DME. Me3SiCl14 (1.59 mL, 13.07 mmol) and (iPrO)3TiCl (9 mol%) are added and the mixtureheated under reflux for 68 h under argon. 2-Acetylbenzanilide 2091 (ca. 4 mmol)is added to this preactivated titanium reagent and the mixture is heated under re-flux for 2.5 h. After filtration and evaporation of the filtrate the residue is chroma-tographed with hexane–ethylacetate (20:1) on silica gel to give 3-methyl-2-phenyl-indole 2092 as colorless crystals, m.p. 91–93 �C, in 97% yield [64] (Scheme 13.31).

A solution (0.2 M, 1 equiv.) of the �-acetylenic ketone 2093 in THF, Zn powder(20 equiv.), Me3SiCl 14 (6 equiv.), and 2,6-lutidine (2–4 equiv.) are heated underreflux under an atmosphere of argon or nitrogen for 12–18 h to give, via inter-mediate 2094, after aqueous work-up with NaHCO3 and subsequent chromatogra-phy, 77% of the cyclized product 2095 [25] (Scheme 13.32).


Scheme 13.31

Scheme 13.32

Me3SiCl 14 (2.3 mL, 18 mmol) is added, under an argon atmosphere, to a sus-pension of CrCl2 (39 mg, 0.32 mmol) and manganese powder (0.99 g, 18 mmol)in 12 mL THF. After stirring the mixture at 25 �C for 30 min a solution of iodo-form (2.4 g, 6 mmol) in 8 mL THF is added to the mixture at 25 �C over a periodof 5 min and the mixture stirred for 5 min. A solution of 3-phenylpropanal(0.27 g, 2 mmol) in 8 mL THF is added to the mixture over a period of 5 min andthe mixture stirred at 25 �C for another 24 h, whereupon the color of the mixtureturns gradually from dark red to brown. The mixture is poured into 50 mL waterand the mixture obtained is extracted with hexane (3�40 mL). The organic ex-tracts are washed with aqueous Na2S2O3 and brine, dried over anhydrous MgSO4,and concentrated. Purification by column chromatography with hexane on silicagel gives 0.3 g (74%) trimethyl-[(E)-4-phenyl-1-butenyl]silane 2127 (E/Z = > 99:1), asa colorless oil, along with 0.029 g (11%) 4–phenyl-1-butene [54] (Scheme 13.33).

Me3SiCl 14 (37 g, 0.34 mol) is added dropwise, with stirring, at room tempera-ture, to SeO2 (15 g, 1.136 mol) in a 100-mL round-bottomed flask. After stirringfor 2 h all the SeO2 dissolves. On standing the mixture separates in two layers.When CCl4 is used as solvent an homogeneous solution is obtained. After an ini-tial hexamethylsiloxane 7 (b.p. 100 �C) fraction, 16.2 g (74%) SeOCl2 (b.p. 170–171 �C/760 mmHg) is obtained by fractional distillation [72] (Scheme 13.34).

A 50-mL round-bottomed flask equipped with a reflux condenser is chargedwith a solution of 3-hexyne (4.5 mL, 35.5 mmol) and Me3SiCl 14 (4.5 mL,34.5 mmol) in 15 mL abs. THF and with 1 g Pd/C (10%). The reaction mixture isheated under reflux for 3 h with exclusion of humidity. Filtration and evaporationin vacuo give 3.3 g (100%) hexaethylbenzene 2165 as a colorless liquid (b.p. 50 �C/20 mm) which subsequently solidifies. Recrystallization from heptane affords col-orless needles, m.p. 130 �C [78] (Scheme 13.35).


Scheme 13.33

Scheme 13.34

Scheme 13.35

14.1Introduction

Persilylated organic or inorganic monomers can polymerize on heating withliberation of HMDSO 7, TCS 14, Me3SiF 71, (OSi(Me)2O)n 56, or ROSiMe3 13, asdescribed in recent reviews [1–7]. Because these reviews cover the literature onorganic and inorganic polymers, only a few examples from the reviews arepresented, and supplemented by examples from the most recent literature.

14.2Formation of Organic Polymers

On heating the silylated bisamine 2185 with diphenyl isophthalate 2186 the polya-mide 2187 and phenoxytrimethylsilane 13d are formed [2, 8]. On reacting 2185with 4-chloroformylphthalic anhydride 2188 at 50 �C Me3SiCl 14 is eliminated togive 2189, which cyclizes with elimination of trimethylsilanol 4 or hexamethyldi-siloxane (HMDSO) 7 at 200 �C to give the polyamide 2190 [1, 2, 9] (Scheme 14.1).

Terephthaldicarboxaldehyde 2191 condenses with persilylated m-phenylenedia-mine 2192 at 30 �C to give 2193 which, at 100 �C, eliminates HMDSO 7(b.p. 100 �C) to give the polymeric azomethine 2194 [1, 10] (Scheme 14.2).

327

14

Formation of Organic and Inorganic Polymers


[1] A. L. Rusanov, Russ. Chem. Rev. 1990, 59, 1990[2] R. D. Katsarawa, Ya.G. S. Vygodskii, Russ. Chem. Rev. 1992, 61, 629[3] D.A. Loy, K. J. Shea, Chem. Rev. 1995, 95, 1431[4] M. Birot, J.-P. Pillot, J. Dunoguès, Chem. Rev. 1995, 95, 1443[5] R.N. Neilson, P. Wisian-Neilson, Chem. Rev. 1988, 88, 541[6] I. Manners, Angew. Chem. Int. Ed. 1996, 35, 1602[7] R. Richter, G. Roewer, U. Böhme, K. Bush, F. Bobonneau, H.P. Martin, E. Müller,

Appl. Organomet. Chem. 1997, 11, 71[8] Y. Imai, “Polymer Science Contemporary Themes”, Tata McGraw Hill, New Delhi, 1991, 3,

3[9] Y. Oishi, K. Kakimoto, Y. Imai, Polym. Prep. Jpn. 1987, 36, 315

[10] K. Miyazawa, T. Munetoh, T. Matsumoto, T. Kurosaki, Polym. Prep. Jpn. 1987, 36, 324

Silylated diphenols such as persilylated hydroquinone 2195 react with difluorocompounds such as 2,6-difluoropyridine 2196 in the presence of CsF at 140–300 �C to give aromatic polyethers such as 2197 and the volatile Me3SiF 71(b.p. 17 �C) [11] (Scheme 14.3).

In the presence of the reactive “initiator” phenyl p-nitrobenzoate 2198 phenoxy-trimethylsilane 13d is eliminated in the CsF/18-crown-6 catalyzed polymerizationof silylated phenyl p-N-(n-octyl)aminobenzoate 2199 in THF to form the polymer2200 [12] (Scheme 14.4).

Bis(4-formylphenyl) succinate 2201 and octamethylene N,N �-bis(trimethylsilyl)carbamate 2202 condense with allyltrimethylsilane 82 in the presence of 10 mol%trityl perchlorate or TMSOTf 20 to give, after 24 h at 0 �C in CH2Cl2, the poly-

14 Formation of Organic and Inorganic Polymers328

Scheme 14.1

Scheme 14.2

[11] H.R. Kricheldorf, G. Schwarz, J. Erxleben, Makromol. Chem. 1988, 189, 2255[12] T. Yokozawa, T. Asai, R. Sugi, S. Ishigooka, S. Hiraoka, J. Am. Chem. Soc. 2000, 122,

8313

urethane 2203, number averaged molecular weight 12 000 [13, 14]. The allyl sidechains in 2204 or analogous polymers can be expected to undergo ring-closingmetathesis with adjacent or extra strand allyl groups (Scheme 14.5).

N,O-Bissilylated glycine 2204 polymerizes on heating in DMF to give the poly-mer 2205, in nearly quantitative yield, and HMDSO 7, which can be removed bydistillation [15, 16] (Scheme 14.5). As discussed in Section 9.2, glycylglycine 1454acan also cyclize via 1455a to the diketopiperazine 1456a and HMDSO 7. In view

14.2 Formation of Organic Polymers 329

Scheme 14.3

Scheme 14.4

Scheme 14.5

[13] L. Niimi, K.-I. Serita, S. Hiraoka„ T. Yokozawa, Tetrahedron Lett. 2000, 41, 7075[14] L. Niimi, K. Shiino, S. Hiraoka, T. Yokozawa, Tetrahedron Lett. 2001, 42, 1721[15] V. P. Kozyukov, N. V. Mironova, V. F. Mironov, J. Obshch. Khim. 1978, 48, 1184; Chem.

Abstr. 1978, 89, 180401a[16] V. P. Kozyukov, N. V. Mironova, V. F. Mironov, J. Obshch. Khim. 1978, 48, 2541; Chem.

Abstr. 1979, 90, 87565

of the technical importance of poly(aspartic acid), persilylation–polymerization ofd,l-aspartic acid, derived from maleic acid and ammonia, might be an interestingalternative means of obtaining a mixture of �- or �-bonded poly(aspartic acids) andHMDSO 7 [17, 18], which can be reconverted to TCS 14 by treatment with phos-gene (cf. Section 2.6).

In contrast with the ready polymerization of persilylated glycine 2204, N,O-bis-silylated 4-aminobenzoic acid 2206a polymerizes only at 150 �C in DMF in thepresence of Lewis acids such as ZnCl2 to give the polyamide 2207a and HMDSO7 [15, 16] The polyamide 2207a can also be obtained in quantitative yield by boil-ing free 4-aminobenzoic acid in pyridine in the presence of SiCl4 57; SiO2 andHCl are formed as primary side products [19]. Likewise, aromatic diamines suchas p-phenylenediamine and terephthalic acid condense on heating with SnCl4 togive the polyamide 2208 [19] (Scheme 14.6).

The polymeric intermediate 2209 a, derived, e.g., from substituted N,O-bissilyl-ated 4-aminobenzoic acids 2206b or 2206c and free or silylated terephthalic acid,affords, on heating to 180–200 �C, the fire resistant polybenzoxazole (PBO) 2210and H2O [20, 21] (Scheme 14.7). O-Silylated 2209b should, likewise, cyclize onheating to give the polymer PBO 2210 with formation of the volatile trimethylsila-


Scheme 14.6

[17] M. Schwamborn, Nachr. Chem. Tech. Lab. 1996, 44, 1167[18] M.S. Reisch, Chem Eng. News 2002, February 25, 23[19] P. Strohriegl, W. Heitz, Makromol. Chem. Rapid Publ. 1985, 6, 111[20] E.K. Wilson, Chem Eng. News 1999, April 16, 24[21] E.M. Pearce, Chem Eng. News 1999, May 17, 6

nol 4 and HMDSO 7 and their azeotrope, which can all be removed by distillation(cf. Chapter 9)

Insoluble chitin 2211 is readily silylated by HMDS 2 and Me3SiCl 14 to formthe soluble, much more lipophilic 2212, whose 6-silyloxy groups can either be tri-tylated with Ph3CCl or glycosylated with the peracetylated oxazolidine 2213, de-rived from d-glucosamine, in Cl(CH2)2Cl in the presence of camphorsulfonic acid(CSA) to give, on work-up with methanol, the branched chitin 2214 in high yields[22] (Scheme 14.8).

14.3Formation of Inorganic Polymers

The thermal polymerization of N-trimethylsilylphosphoranimines 2215 to 2216 withelimination of CF3CH2OSiMe3 2217 is the prototype for formation of inorganic poly-mers [5, 23, 24]. Polyphosphazene 2216 is also prepared from bromodimethyl(tri-

14.3 Formation of Inorganic Polymers 331

Scheme 14.7

Scheme 14.8

[22] K. Kurita, M. Hirakawa, Y. Nishiyama, Chem. Lett. 1999, 771[23] P. Wisian-Neilson, R.H. Neilson, J. Am. Chem. Soc. 1980, 102, 1848[24] P. Wisian-Neilson, R.H. Neilson, Inorg. Chem. 1980, 19, 1875

methylsilyl)phosphoranimine 2217 with Me3SiBr 16 as the leaving group [23](Scheme 14.9). This type of reaction could, in principle, be used to prepare polymer-ic very strong Schwesinger bases [26]. Polymerization of, e.g., 2219 where X = NR2,which is probably readily available on heating P(NR2)3 with Me3SiN3 17, should af-ford the strongly basic polymer 2220 whereas N-trimethylsilylsulfonimidates 2221polymerize on heating, with elimination of CF3CH2OSiMe3 2217, to give the poly-mers 2222 [25, 27–29]. Finally, one example is presented of the many modes of po-lymerization of dimethyldichlorosilane 48 to silicon oil 56, which proceeds in a fewminutes at room temperature in the presence of tert-butanol and catalytic amountsof BiCl3 and TCS 14, with Me3CCl as the leaving group [30] (Scheme 14.9).


O-Silylated hydroquinone 2195 (80 mmol), 2,6-difluoropyridine 2196 (82 mmol)and CsF (100 mg) are weighed into a 250-mL two-necked round-bottomed flask


Scheme 14.9

[25] A. K. Roy, J. Am. Chem. Soc. 1993, 115, 2598[26] R. Schwesinger, C. Hasenfratz, H. Schlemper, L. Walz, E.-M. Peters, K. Peters, H.G.

v. Schnering, Angew. Chem. Int. Ed. 1993, 32, 1361[27] A. K. Roy, G. T. Burns, G. C. Lie, S. Grigoras, J. Am. Chem. Soc. 1993, 115, 2604[28] V. Chunechom, T. E. Vidal, H. Adams, M.L. Turner, Angew. Chem. Int. Ed. 1998, 37,

1928[29] C.H. Honeyman, I. Manners, C.T. Morrisey, H.R. Alcock, J. Am. Chem. Soc. 1995,

117, 7035[30] M. Labrouillère, C. Le Roux, A. Oussaid, H. Gaspard-Iloughmane, J. Dubac, Bull.

Soc. Chim. Fr. 1995, 132, 522

equipped with a reflux condenser and gas inlet tube. The mixture is heated in ametal bath under a slow stream of nitrogen to a temperature of 140 ± 10 �C, atwhich the condensation starts. This temperature is maintained until evolution ofMe3SiF 71 (b.p. 17 �C) has almost ceased (60–120 min) and then increased insteps of ca 30–40 � until 300 �C has been reached. Finally, vacuum is applied for15 min. All condensations of O-silylated bis-phenols are complete within 3.5 h.The reaction product is dissolved in 4 : 1 CH2Cl2–CF3CO2H, precipitated withmethanol and dried at 60 �C in vacuo to give 91% polyether 2197 [11] (Scheme14.10).

A mixture of 27.5 g N,O-bis(trimethylsilyl)glycine 2204 and 1 mL DMF is heatedat 130–150 �C for 5 h in a flask connected to a rectification column with continu-ous distillation of hexamethyldisiloxane 7 (b.p. 101 �C, 93.5%) to give, after dryingin vacuo, almost quantitative yield of polyglycine 2205 as a brown powder [16](Scheme 14.11).


Scheme 14.10

Scheme 14.11

Some Sources of Silicon Chemicals for Large or Bulk Scale Synthesis

ABCR GmbH & Co, KG, Pf 210135, 76151 Karlsruhe, GermanyMe3SiNHSiMe3 (HMDS), $ 25.00/kg; (Me2SiNH)3, $192.00/0.1 kg; Me3SiSiMe3,$156.00/0.1 kg

Bayer AG, 51368 Leverkusen, Germany, www.bayerchemicals.com

K. Bucher GmbH, An der Günz 1, 89367 Waldstetten, Germany,[email protected] (HMDS), $6.00/kg; Me3SiCl, $4.00/kg; hexamethylcyclotrisilazane(Me2SiNH)3, $40.00/kg; Me3SiSiMe3 . . .

Dow-Corning, USA, www.dowcorning.comMe3SiCl, Me2Cl2 . . .

Gelest Inc., 612 William Leigh Drive, Tullytown, PA 19007-6308, USA,www.gelest.comMe3SiCl, Me3SiNHSiMe3 (HMDS), . . .

Wacker-Chemie GmbH, Sparte S, 8000 München 22, Germany,[email protected], www.wacker.comMe3SiCl, Me2Cl2, Me3SiNHSiMe3 (HMDS), Me3SiSiMe3, . . .

335

Appendix


aacylamidine 49acyloin condensation 129–130, 218, 281acyluridine, 4-O-trimethylsilylated-2�,3�5�-O-

acyluridine 541,2-addition 107, 121, 3201,4-addition 30, 87, 107, 113, 121, 312, 313,

320–321– of allyltrimethylsilane 321adenosine 55–56, 58– N 6-aminoethyladenosine 57– N 6-benzyl-1�-adenosine 58– N-substituted 56alanine– �-alanine 44, 45– – persilylated 118, 227– 2-allyl-N-formylalanine 89–90– N-BOC-alanine 43N-alkylimidazole-4-acetate 126N-alkylimidazole-5-acetate 126allene, aminoallene 111allylamine, persilylated (N,N-

bis(trimethylsilyl)allylamine) 13allylmagnesium chloride 283allyltrimethylsilane 10, 21, 23, 67, 73, 86,

89, 107, 111–133, 138–139, 144, 146,160–161, 163, 164, 184, 185, 307–308,313, 323, 328

– 1,4-addition of 321amidine 14, 39, 45–48, 72, 74, 126– acylamidine 49– benzamidine 46– N,N�-diarylformamidine 46– N,N�-dimethylamidine 47– N,N�-dimethylformamide dimethylace-

tal 47– formamidine acetate 126– hydrochloride 228amidine 126

– isobutyramidine 1262-aminoadenosine 57aminoallene 111N 6-aminoethyladenosine 57N 4-(5-amino-3-oxapentyl)cytidine 53N 4-(3-amino-propyl)cytidine 54ammonium trimethylsilanolate 29, 40,

422,2�-anhydrouridine 34aryl-Grignard reagents 93L-aspartic acid 13, 266-azacytidine 556-azauracil 55azide, trimethylsilyl s. trimethylsilylazide 87azoxybenzene 166

bBayer-Villinger oxidations 288Beckmann– fragmentation 67– reaction 181– rearrangement 264benzaldehyde dimethyl acetal 33, 114benzamide– N-silylated 99– N,O-bis(trimethylsilyl)benzamide 12, 47,

66, 99benzamidine 46benzhydryltrimethylsilane 313benzoate, trimethylsilyl 41, 71, 1452-benzoylamino-3-chloropyridine 231N-benzoylglycine 70N 6-benzyl-1�-�-adenosine 58benzylamide, L-phenylalanine-N-benzyl-

amide 79benzylpyridine– 2-benzylpyridine 159–160, 184– 3-benzylpyridine 1202-benzylquinoline 161

337

Subject Index


benzyltrimethylsilane 21, 23, 160–161, 183,249, 307–308, 313

bipyridine oxochloride complex 3191,2-bis(chlorodimethylsilyl)ethane 309–310N,N-bis(trimethylsilyl)allylamine (persilylated

allylamine) 16N,O-bis(trimethylsilyl)benzamide 12, 47, 66,

99N,O-bis(trimethylsilyl)carbamate 12, 68N,N�-bis(trimethylsilyl)carbodiimide 20, 69,

95, 103N,N-bis(trimethylsilyl) form 74N,O-bis(trimethylsilyl) form 74N,N-bis(trimethylsilyl)formamide 17, 74–75,

89, 94, 237N,O-bis(trimethylsilyl)glycine 329, 333N,O-bis(trimethylsilyl)hydroxyl-

amine 179, 180, 181bis(trimethylsilyl)methylamine 88N,O-bis(trimethylsilyl)methylhydroxylamine

162, 179N,N-bis-trimethylsilyloxyenamine 1772,5-bis(trimethylsilyloxy)pyrroles 48, 76bis(trimethylsilyl)peroxide (Me3SiO2) 284–

292, 296, 302N,O-bis(trimethylsilyl)trifluoracetamide 11,

171bromide, trimethylsilylbromide (Me3SiBr) 9,

46, 107, 135, 142, 172, 202–203, 295, 305Brook rearrangement 20, 189, 197BSA (N,O-bis(trimethylsilyl)acetamide) 3,

11–12, 17, 44, 47, 66, 74, 89, 112, 123,155, 156, 171–173, 176, 180, 186, 187,198, 237, 270

BSTFA 11, 171BTSP (bis(trimethylsilyl)peroxide) 284–292,

302tert-butyldimethylsilanol 24, 28–29, 73– chloride 24tert-butyldimethylsilyl– enol ether 115– triflate 163, 191, 198tert-butyldiphenylsilanol 24, 28– chloride 244-tert-butylpyridine 315tert-butyl-N�-trimethylsilylcarbodiimide 207

cn-C4F9SO2OSiMe3 (TMSONf/trimethylsilyl

nonaflate) 10–11, 16, 27, 293C4F9SO3K (potassium nonaflate) 10, 133carbamate, N,O-

bis(trimethylsilyl)carbamate 12, 68

carbodiimide– N,N�-bis(trimethylsilyl)carbodiimide 20,

69, 95, 103– tert-butyl-N�-trimethylsilylcarbodiimide 207carbon dioxide, free and derivatized, reactions

of 39–82carbon suboxide 71carbon-phosphorus double bonds 253–259carboxylic acids, free and derivatized, reac-

tions of 39–82catechol 7, 22, 26, 86CF3CH2OSiMe3 (trifluoroethoxytrimethylsi-

lane) 331–332CF3SO3H (triflic acid) 85, 94, 115, 139, 227,

232–233, 239, 247, 271, 289Cl3SiOSiCl3 (hexachlorodisiloxane) 33, 36,

226Claisen rearrangement 317ClSi[N3]3 (triazidochlorosilane) 121, 152C-C coupling, Suzuki-type 22cyanide, trimethylsilyl 9, 11, 21, 73, 113,

147–148, 150, 155, 157, 159, 162, 182, 1994-cyano-6-fluoroquinoline-oxide 1682-cyano-3-methylpyridine 1482-cyano-4-methylpyridine 1482-cyano-5-methylpyridine 1482-cyanoimidazole 1565-cyanoimidazole 1562-cyanopyridine 1474-cyanopyridine 1472-cyanopyrimidine 1521-cyanoisoquinoline 147, 1512-cyanoquinoline 147–148, 151cyclizations and ring enlargements 217–239– Diels-Alder cyclization 220– Pummerer-type cyclization 224– sila-Pummerer cyclization 98, 191, 194, 217cycloaddition, 1,3-dipolar 90, 174–175, 190–

191, 225–226, 228, 257–258cyclohexane, 1-trimethylsilyloxycyclo-

hexane 1332-cyano-3-hydroxypyridine 148, 182cytidine 2–3, 50–55– N 4-(3-amino-propyl)cytidine 53– aracytidine 53– 6-azacytidine 55– dimer 58– 5-methyl-2�-deoxycytidine 53– sodium-cytidine-5�-phosphate 54– N 4-substituted 50cytosine 55

Subject Index338

dDanishefsky– triene 249– (trimethylsilyloxy)dienes 164, 220DBU 16, 29–30, 42, 95, 125, 142, 150–151,

154–156, 158, 168–170, 227, 234dehydration-halogenation-activation and sily-

lation of salts and metalorganic com-pounds 305–325

2�-deoxyinosine 57desilylation 4N,N�-diarylformamidine 462,3-dicyanopyridine 1492,5-dicyanopyridine 1492�,3�-dideoxyuridine 53Diels-Alder– adduct 220– – bicyclic 132– – hetero 178– cyclization 220– reaction/-products 98, 108–109, 112, 193,

220, 247, 2492,4-diethoxypyrimidine 51diethylamino trimethylsilane 41, 88, 195,

2212-(2,3-dihydroquinoxaline) acetate 127diisopropylethylamine (DIPEA) 10, 175,

191, 195, 198, 263dimethoxyamine (HN(OMe)2) 181–182, 188dimethylamine– N,N�-dimethylamidine 47– N-trimethylsilyldimethylamine 92, 101–

102, 1294-dimethylaminopyridine (DMAP) 247, 294,

303dimethylaminotrimethylsilane 102, 118dimethylchlorosilane (Me2HSiCl) 151, 276,

300dimethyldichlorosilane (Me2SiCl2) 18, 25,

66, 201, 204, 276, 332dimethyldisilanol 18N,N�-dimethylformamide dimethylacetal 47N,N-dimethyliminium perchlorate 1182,5-dimethylpyrrole 228, 239dimethylsilanediol 18, 31DIPEA (diisopropylethylamine) 10, 175,

191, 193, 195, 198, 263, 324diphenylurea– N-trimethylsilyl-diphenylurea 74– N-trimethylsilyl-N,N�-diphenylurea 23, 1701,3-dipolar– cycloaddition 90, 174–175, 190–191, 225–

226, 228, 257–258

dipyridine complex 319DMAP (4-dimethylaminopyridine) 247, 294,

303

eenamine 101–102, 104, 128, 226, 234,

313– N,N-bis(silyloxy)enamine 177– N,N-bis(trimethylsilyloxy)enamine 102,

177enol-silyl ether 30, 31, 33, 102, 117, 123,

129, 163, 178, 198, 283, 293–296, 313– aminoenol silyl ether 129– tert-butyldimethylsilylenol ether 115– triisopropylsilyl (TIPS) enol ether 295– 1-trimethylsilyloxycyclohexane 31, 32, 133Et2NSiMe3 41, 88, 195, 221Et3SiF 268Et3SiH (triethylsilane) 23, 73, 113, 122–123,

134, 267–275, 299Et3SiOSiEt3 (hexaethyldisiloxane) 19, 25, 28,

272, 274–275

ffluoride, trimethylsilyl 21, 27, 144, 159,

206–207, 241, 253, 277, 307, 327–328, 3335-fluorouracil 219formamide– N,N�-diarylformamidine 46– N,N�-dimethylformamide

dimethylacetal 47– N,O-bis(trimethylsilyl)acetamide s. BSA– N,N-bis(trimethylsilyl)formamide 11, 12,

17, 74–75, 89, 94, 237formamidine acetate 126formate, trimethylsilyl 41, 43

gglycine– N-benzoylglycine 70– N,O-bis(trimethylsilyl)glycine 329, 333Grignard reagents/reactions 93, 96, 213,

243, 265, 280–281, 283, 313–314guanosine 55–58

hHeck-Suzuki-type reaction 29hexachlorodisiloxane (Cl3SiOSiCl3) 33, 36,

226hexaethyldisiloxane (Et3SiOSiEt3) 19, 25, 28,

272, 274–275hexamethylcyclotrisilazane 17, 24, 31, 66hexamethylcyclotrisiloxane 24, 213

Subject Index 339

hexamethyldisilane (Me3SiSiMe3) 142, 144,165–167, 185, 257, 261, 277–278, 301,307–308, 312, 315, 323–324

hexamethyldisilthiane 61, 108, 109, 278,280

hexamethylphosphoric triamide(HMPA) 276–278, 300–301

HMDS– Li-HMDS (lithium-HMDS) 16, 96, 98,

104, 132, 206– Na-HMDS (sodium-HMDS) 16, 73, 99HMPA (hexamethylphosphoric tri-

amide) 166, 276–278, 300–301HN(OMe)2 (dimethoxyamine) 181–182, 188Horner-Wittig reaction 297hydrogenation, ionic 267N-hydroxyindole 1683-hydroxypyridine-N-oxide 148, 182–1833-hydroxyquinoline N-oxide 152

iimidazole 98, 126, 129, 156, 194–195, 230– N-alkylimidazole-4- und 5-acetates 126– 2-cyanoimidazole 156– 5-cyanoimidazole 156– mercaptoimidazole 230– N-methylthiomethylimidazole 194– 2-phenylbenzimidazole 230– N-(trimethylsilyl)imidazole 194–195– 2,4,5-triphenylimidazole 99, 230iminium– N,N-dimethyliminium perchlorate 118– salts 93–96, 102–103, 111, 116,

118indole 203–204, 320, 324– addition of 203– 3-chloroindole 203–204– N-hydroxyindole 168– 2-phenylindole 251– 2-substiuted 228inosine 55–56, 79– 2-deoxyinosine 57– 1�-�-inosine 58inosine-5�-phosphate 57iodide, trimethylsilyl 10, 91, 117, 135, 141–

142, 144, 191, 201, 261–265, 271, 2752-iodopyridine 265iodotrimethylsilane s. iodide, trimethylsilylionic hydrogenation 267isobutyraminidine 126isocyanate, trimethylsilyloxy 68, 1812-isopropyl-6-chloromethyl-pyrimidine 126

isoquinoline 147, 150, 152, 165–166, 185,277

– N-oxide 147, 150, 152, 166, 185, 277isothiocyanate, Me3SiNCS 20, 158

kketenimine, tris(trimethylsilyl) 67

l�-lactam 96–97, 101, 111, 117, 195Lawesson’s reagent 45L-leucine 44lithium– Li-HMDS (lithium-HMDS) 16, 96, 98,

104, 132, 206– Me3SiOLi/LiOSiMe3 (lithiumtrimethylsila-

nolate) 29, 162–163, 181, 205–206, 241–243, 286, 296

– reagents 93

mMcMurry reaction 309–310, 316Me2HSiCl (dimethylchlorosilane) 151, 276Me2SiCl2 (dimethyldichlorosilane) 17, 18,

103, 201, 204Me2Si(Cl)(CH2)2Si(Cl)Me2 15, 292, 309Me2SiI2 262, 299Me3C(Ph)2SiLi 284Me3CSi(Me2)OH 73Me3CSi(Me2)OTf 191, 198Me3SiBr (trimethylsilylbromide) 9, 46, 107,

135, 142, 159, 177, 202–203, 295Me3SiCN (trimethylsilylcyanide) 9, 11, 21,

23, 73, 113, 147–148, 150, 155, 157, 158,160, 162, 164, 182, 199, 246, 265, 293, 317

Me3SiCNS 158–159Me3SiF (trimethylsilylfluoride) 21, 27, 144,

159, 206–207, 246, 277, 307, 327–328, 333Me3SiH (trimethylsilane) 23, 122, 269, 271,

274, 307Me3SiI 94, 107, 111, 142, 261, 263, 265,

268, 271, 275, 277, 295, 315Me3SiLi 166, 278Me3SiN3 (trimethylsilylazide) 9, 87, 119,

136, 158, 184, 233, 265, 290, 293–296,303, 317, 332

Me3SiNCS (trimethylsilylisothiocyanate) 20,158–159

Me3SiNH2 (trimethylsilylamine) 9, 58(Me3SiO)2 (bis(trimethylsilyl)peroxide) 284–

292, 296, 302Me3SiOK 29, 71–72, 82, 181, 277– lipophilic 72

Subject Index340

Me3SiOLi/LiOSiMe3 (lithiumtrimethylsilano-late) 29, 162–163, 181, 205–206, 241–243, 286, 296

Me3SiONa (sodium trimethylsilanolate) 89Me3SiSiMe3 (hexamethyldisilane) 142, 144,

164–167, 185, 257, 261, 277–278, 301,307–308, 312, 315, 323–324

Me3SiSO2C4F9 (trimethylsilyl nonaflate) 151Me3SiSSiMe3 (hexamethyldisilathiane) 61,

138, 189, 213Me3SiXSiMe3, X= S, Se 108mercaptoimidazole 230methanesulfenyl chloride 203methyl– isonicotinate 303– 5-methyl-2�-deoxycytidine 52– orthosilicate of Si(OMe)4 34, 36methylamine– bis(trimethylsilyl)methylamine 88, 89,

129N-methyl-N,O-bis(trimethylsilyl)hydroxyl-

amine 162, 184N-methylhydroxylamine, persilylated 1622-methylpyridine 2864-methylpyridine-N-oxide 149, 265N-methylthiomethylimidazole 194mobility 20– of silyl groups 19–22– of the trimethylsilyl group 20, 172Moffat-Pfitzner oxidation 204monosilylated methylamine 89morpholine, N-trimethylsilylmorpholine 66,

92, 102, 129, 208

nN(SiMe3)3 284Na-HMDS (sodium-HMDS) 16, 73, 99, 2425-nitroquinoline 169N-O systems, reactions of 147–187nonaflate, Me3SiSO2C4F9 (trimethylsilyl

nonaflate) 10, 151nonaflic acid (perfluorobutanesulfonic

acid) 10, 60Nozaki-Hiyama reaction 244, 314

oolefin-formation, Peterson’s 163OMCTS (octamethylcyclotetrasilazane) 17,

24, 31, 39, 60–61, 66, 80, 125– 2-pyridone with OMCTS 31, 60organic and inorganic polymer, formation

of 327–3336-oxauracil 55

oxidations– and reductions 261–303– Moffar-Pfitzner oxidation 204– Swern oxidation 204oxochloride complex, bipyridine 319oxyfuran, 2-trimethylsilyloxyfuran 140, 163,

181, 184

pP(SiMe3)3 (tris(trimethylsilyl)-

phosphine) 254–255, 257–258perfluorobutanesulfonic acid (nonaflic

acid) 10, 60peroxide, bis(trimethylsilyl)peroxide

(Me3SiO)2 284–292, 296, 302N,O-persilylated L-proline 90Peterson– olefin-formation 163– reaction 241, 243–244– reagent 244, 245Peterson-type reagent 163, 245phenylacetylene 287, 293L-phenylalanine 44–45, 79L-phenylalanine-N-benzylamide 792-phenylbenzimidazole 2302-phenylindole 251phenylthiotrimethylsilane (PhSSiMe3) 107,

279–280phenyltrimethoxysilane 22, 23phenyltrimethylsilane 22–23, 285, 293PhMgBr 280phosphine, tris(trimethylsilyl)phosphine

(P(SiMe3)3) 254–255, 257–258PhSSiMe3 (phenylthiotrimethylsilane) 107,

279–280pivaldehyde 86–88, 90PMHS (polymethylhydrosiloxane) 274, 300polymer, organic and inorganic, formation

of 327–333polymethylhydrosiloxane (PMHS) 267, 274,

300polyphosphoric acid trimethylsilyl ester

(PPSE) 47, 71, 193, 231, 297potassium– nonaflate (C4F9SO3K) 10, 133– trimethylsilanolate 29, 71–72, 82, 181,

277– trimethylsilyl 277PPSE (polyphosphoric acid trimethylsilyl

ester) 47, 71, 193, 231, 297L-proline 131– N,O-bis(trimethylsilyl)-L-proline 90, 131,

221

Subject Index 341

Pummerer– product vinylsulfides 263– reaction 189, 191, 210– sila-Pummerer– – cyclization 217, 224– – products/reaction/rearrangements 189,

191–201, 210–211Pummerer-type cyclization 224pyridine 8, 11, 17, 101, 120, 124–126, 147–

149, 165–166, 183, 226, 230–231, 234–235,274, 277, 290, 302, 312, 319

– 2-benzoylamino-3-chloropyridine 231– 2-benzylpyridine 159–160, 184– 3-benzylpyridine 120– bipyridine oxochloride complex 319– 4-tert-butylpyridine 315– 2-cyano-3-hydroxypyridine 148, 182– 2-cyano-3-methylpyridine 148– 2-cyano-4-methylpyridine 148– 2-cyano-5-methylpyridine 148– 2-cyanopyridine 147– 4-cyanopyridine 147– 3-cyanopyridine-N-oxide 149– 2,3-dicyanopyridine 149– 2,5-dicyanopyridine 149– dipyridine complex 319– 2-iodopyridine 265– methyl isonicotinate 303– 2-methylpyridine 286– 4-methylpyridine-N-oxide 149, 265– 2,5-substituted 150– 2,4,6-trimethyl-3-acetylpyridine 124pyridine-2-aldehyde 92pyridine-4-aldehyde 93pyridine-2-one 31, 59pyridine-N-oxide 147, 157, 161, 165–166,

274, 312– 3-hydroxypyridine-N-oxide 148, 182–183pyridinoquinolines 1692-pyridone with OMCTS 31, 60pyrimidine 3, 11, 55, 150–152, 235– 2-cyanopyrimidine 152– 2,4-diethoxypyrimidine 50– 2-isopropyl-6-chloromethyl-pyrimidine 126pyrimidine-N-oxide 152pyrrole 8, 17– 2,5-dimethylpyrrole 228, 239– 2-phenylpyrrole 228– 2,5-bis(trimethylsilyloxy)pyrroles 48, 762-pyrrolidinone 89, 286

qquinazoline-2,4-dione 305– 2,4-(1H,3H) 60quinazoline-N-oxide 155quinoline 147–148, 150, 152, 166–169, 274,

277, 290– 2-benzylquinoline 161– 4-cyano-6-fluoroquinoline 168– 1-cyanoisoquinoline 147, 151– 2-cyanoquinoline 147–148, 151– 3-hydroxyquinoline N-oxide 152– isoquinoline 147, 150, 152, 165–166, 185,

277– 5-nitroquinoline 169– pyridinoquinolines 169quinoline-N-oxide 147, 150, 161, 274

4(1H)-quinolinone 61p-quinone 95, 103, 104quinoxaline 127, 154– 2-(2,3-dihydroquinoxaline) acetate 127– lactone 128

rreductions and oxidations 261–303Reformatsky reaction 312, 316Reissert-Henze reaction 147ring– contraction 267– enlargement 191, 217–239, 267Ritter reaction 196Rühlmann-acyloin condensation 129–130,

218, 281

ssarcosine 45– silylated (N,O-

bis(trimethylsilyl)sarcosine) 90Schiff base 96–99, 111, 117–118, 162– N-silylated 96Schwesinger bases 332Se-O systems 189–216SiBr4 159SiCl4 (silicium tetrachloride) 18, 32–33, 44,

87, 106, 121, 142, 159, 204, 223, 226, 239,330

– tetrachlorosilane s. SiCl4 36sigma(�)-complex 261sigmatropic– shift 211– [2,3]sigmatropic rearrangement 210sila-Pummerer products/reaction/rearrange-

ments 189, 191, 194, 197–199, 201, 210–211

Subject Index342

silicium tetrachloride (s. SiCl4) 18, 32–33,36, 44, 87, 106, 121, 142, 159, 204, 223,226, 238, 330

silicon– hypervalence of 22– hypervalent properties of 22silicontetrabromide 18, 34, 159silyl– ether– – deprotection of 18– – enol-silyl ether (see there) 30, 31, 33, 102,

117, 123, 129, 163, 178, 198, 283, 293–296, 313

– groups, mobility of 19–22, 24silylation/silylated– activation 1–4– and dehydration-halogenation-activation

of salts and metalorganic com-pounds 305–325

– sarcosine, silylated sarcosine (N,O-bis(trimethylsilyl)sarcosine) 90

silylenol ether 115, 234silyloxy– enamine, N,N-bis(silyloxy)enamine 177– leaving groups 27–37Simmons-Smith reaction 312, 316Si(NMe2)4 (tetra(dimethylamino)silane) 32,

36Si(OAc)4 (tetra(acetoxy)silane) 32, 34, 36, 41Si(OEt)4 (tetra(ethoxy)silane) 18, 32–34, 36Si(OMe)4 (tetra(methoxy)silane) 18, 32–34,

36–37, 83, 111– methyl orthosilicate of s. Si(OMe)4

S-O systems 189–216sodium– Me3SiONa s. sodium trimethylsilanolate– Na-HMDS (sodium-HMDS) 16, 73, 99,

242– trimethylsilanolate 28, 35, 71–72, 89– uridine-5�-phosphate 54sodium-cytidine-5�-phosphate 54sulfate, bis(trimethylsilyl)sulfate 207sulfoxide, sila-Pummerer rearrangements

of 189Suzuki-type C-C coupling 22Swern oxidation 204, 297

tTBS s. Me3SiBrtetra(acetoxy)silane (Si(OAc)4) 32, 34, 36, 41tetra(dimethylamino)silane (Si(NMe2)4) 32,

36

tetra(ethoxy)silane (Si(OEt)4) 18, 32–33–34,36

tetra(methoxy)silane (s. Si(OMe)4) 18, 32–34, 36–37, 83, 111, 132

tetra(methyl)silane s. Si(OMe)4

tetrachlorosilane SiCl4 s. SiCl4 36tetrakis(trimethylsilyloxy)silane 35tetramethoxsilane 132TfOH s. triflic acidthiane– bis(trimethylsilyl)thiane s. Me3Si-S-SiMe3

– Me3SiSSiMe3 (hexamethyldisilathiane) 61,108–109, 138, 189, 213

thymidine 52TIPS (triisopropylsilyl) enol ether 295TIS (trimethyliodosilane) s. trimethylsilylio-

dideTMSBr s. bromide trimethylsilylbromideTMSCN 293TMSONf (n-C4F9SO2OSiMe3/trimethylsilyl-

nonaflate) 10–11, 16, 27, 293transamination 58–59transesterification 71transient protection 3, 18transition state 21transsilylation 3, 18–19, 21, 42, 52–62, 91,

117, 148, 173, 177, 249, 312– and deprotection of silyl ether 18triazidochlorosilane (ClSi[N3]3) 121, 152triethylammonium trimethylsilanolate 42triethylsilane (Et3SiH) 23, 73, 113, 122–123,

134, 267–275, 299triethylsilanol 28triethylsilyl– chloride 19– imino ether 273triflic acid (CF3SO3H) 85, 94, 115, 139, 227,

232–233, 239, 247, 271, 289trifluoroethoxytrimethylsilane

(CF3CH2OSiMe3) 331–332triisopropylsilanol 28, 30triisopropylsilyl (TIPS) enol ether 295trimethoxysilyl– of enol-silyl ether 33, 1152,4,6-trimethyl-3-acetylpyridine 124trimethylfluorosilane s. fluoride trimethylsi-

lyl 27trimethyliodosilane (TIS) s. trimethylsilylio-

didetrimethylsilane (Me3SiH) 23, 122, 269, 271,

274, 307

Subject Index 343

trimethylsilanolate– ammonium 29, 42– lithium 29– potassium 29, 71–72, 82, 277– sodium (see there) 28, 35, 71–72, 89– triethylammonium 42trimethylsilyl– acetamide– – bis(trimethylsilylacetamide) 132– – N-trimethylsilylacetamide 12, 27– – N,O-bis(trimethylsilyl)acetamide

(BSA) 3, 11–12, 17, 44, 47, 66, 74, 89,112, 123, 155, 171–173, 176, 180, 186,237, 270

– azide 9, 87, 119, 136, 158, 184, 233, 290,293–296, 303, 317, 332

– group– – acetate 40–41– – benzoate 41, 71, 145– – cyanide 9, 11, 21, 23, 73, 113, 147–148,

150, 155, 157, 160, 162, 164, 182, 199,246, 265, 293, 317

– – enol ethers (enol-silyl ether) 11, 30– – fluoride 21, 27, 144, 159, 206–207, 241,

277, 307, 317–318, 328, 333– – formate 41, 43– – iodide 10, 91, 117, 135, 141–142, 144,

191, 201, 261–265, 271, 275, 315– – mobility of 20, 172– – L-proline 131– – sarcosine 90– – sulfate 207– – thiane 108–109– nonaflate (Me3SiSO2C4F9) 151– polyphosphate 47, 71, 193, 231, 297– potassium 277– 4-O-trimethylsilylated-2�,3�,5�-O-acyl-

uridine 54N-trimethylsilylallylamine 13trimethylsilylamine (Me3SiNH2) 9, 58trimethylsilylazide (Me3SiN3) 9, 87, 136,

158, 184, 233, 265, 290, 293–296, 303,317, 332

trimethylsilylbromide (Me3SiBr) 9, 46, 107,135, 142, 159, 177, 202–203, 295

trimethylsilylcyanide (Me3SiCN) 9, 11, 21,23, 73, 113, 147–148, 150, 155, 157, 160,162, 182, 199, 246, 265, 293, 317

N-trimethylsilyldiethylamine 41, 88, 195,208, 221

N-trimethylsilyldimethylamine 92, 101–102,129

trimethylsilylfluoride s. fluoride, trimethylsilyl2-trimethylsilylfuran and (2-O-trimethylsilyl

compound) 285N-(trimethylsilyl)imidazole 194–195trimethylsilylisothiocyanate

(Me3SiNCS) 158–159N-(trimethylsilyl)methylamine 129N-trimethylsilylmorpholine 66, 92,102, 129,

208trimethylsilylnonaflate (TMSONf/

n-C4F9SO2OSiMe3) 10–11, 16, 27, 293trimethylsilyloxy– 2,5-bis(trimethylsilyloxy)pyrole 48– isocyanate 68, 1811-trimethylsilyloxycyclohexane 133(trimethylsilyloxy)dienes, Danishefsky 164,

2202-trimethylsilyloxyfuran 140, 164, 181,

184, 2852,4,5-triphenylimidazole 99tris(trimethylsilyl) ketenimine 67tris(trimethylsilyl)phosphine

(P(SiMe3)3) 254–255, 257–258

uuracil 55– 6-azauracil 55– 5-fluorouracil 219– 6-oxauracil 55uridine 2–3, 5, 34, 48, 50–53, 55–56,

91– ara-uridine 53– 2�,3�-dideoxyuridine 53– 4-O-trimethylsilylated-2�,3�,5�-O-acyl-

uridine 54uridine-5�-phosphate 57– sodium 54

vvicarious nucleophilic substitution

(VNS) 167, 169vinylsulfide, sila-Pummerer reactions to 191,

263

wWittig reaction/reagent 255, 297

xxanthosine 56–57

Subject Index344

aAbdulla, R. F. 47Abe, M. 86, 171Abe, T. 281Abel, E.W. 107Abel, U. 114Abeysekera, B. 217Achiwa, K. 101, 190, 225Adair, N. K. 138Adam, W. 286, 287, 290,

292Adams, H. 114, 332Adashi, T. 34Adlington, M.G. 268Adolfsson, H. 290Adrianov, K.A. 8Afonso, C.A. M. 309Afonso, C.M. 297Ager, D. J. 190Ager, W. 243Ahern, C. 271Ahmed, G. 103Ahn, H. 321Ahn, K. H. 34Ahn, Y. 78Aida, T. 94, 108Aikawa, T. 139Aiube, Z.H. 31Aizpura, J.M. 245, 266,

268Akaji, K. 279Akane, N. 315Akazawa, M. 152Akester, J. 129Akita, M. 1, 241Akiyama, T. 198Albanov, A. I. 120, 142, 144Albert, R. 292Alcaide, B. 99

Alcázar, J. 156Alcock, H.R. 332Aleksandrov, Yu.A. 290Alexakis, A. 312Algee, S. E. 149Ali, S.M. 99Alleston, D.A. 29Allinger, N.L. 28Allred, L. 28Allspach, T. 257Altobelli, M. 65Amelot, A. 50Amer, F. A. 121Amii, H. 313Amort, J. 24Amouroux, R. 142Ancillotti, M. 212, 286Andavan, G. T.S. 22Andavan, S. 22Andersen, R.A. 277Andersen, S.H. 171Anderson, D.A. 84, 161Anderson, D.G. 189Anderson, G. 126Anderson, H.N. 32Anderson, O.P. 317Ando, K. 190Ando, S. 139Ando, W. 191, 243, 249,

262, 281Andreoli, P. 95Andrew, R. G. 62Andrews, S. L. 200Andrianov, K. A. 46Angermann, J. 178, 179Ansari, S.A. 203Anton, T. 45Antonini, I. 126Antonov, A. A. 44

Aono, M. 190, 279Aoyama, T. 224, 233,

235Apasov, A.V. 92Apasov, E.T. 92Apatu, J. O. 289Appel, R. 206, 253Arai, H. 67Archer, D. A. 84Arend, M. 10, 118, 135,

261Arendsen, D.L. 246Arimoto, M. 293Armstrong, A. 103Armstrong, R.W. 223Arnett, J. 309Arnold, M.B. 157Arnold, T. 178Asai, T. 328Asakawa, K. 33Asanuma, M. 109Asaoka, M. 171Aspinall, S. R. 50Astakhin, V. V. 8Astapov, B. A. 43Atsuumi, S. 235Aube, P. 92Auerbach, J. 275Augé, J. 314, 315Aujard, I. 312Aumann, R. 247Aumüller, A. 104Auricchio, S. 124Avery, M.A. 87Awajima, K. 152Ayer, W.A. 261Aziz-Elyusufi, A. 281Azumaya, I. 223

345

Author Index


bBaati, R. 93Bab, T. 296Baba, A. 276Babcock, R. 69Babin, P. 285, 289Bacelo, M.J. 105Bach, T. 10, 189, 320Bacon, F. 30Bacquet, C. 241Bailey, M. 114Bailly, F. 230Baine, N.H. 92Bajwa, J. S. 123Bakassian, G. 66Baktibaev, O.M. 149Bal, B.S. 9, 201Balaram, B. G. 277Balashova, L.D. 254Baldwin, J.C. 29Baldwin, J.E. 284Ballister, M. 10Balmer, M.K. 261Balzarini, J. 12Bamfield, P. 226Bandini, E. 97Bandini, M. 314Banerjee, A.K. 309Baney, R.H. 2, 27Barbirad, S. A. 30Bardos, T. J. 13Barili, P.L. 63Barnette, M.S. 234Barrio, J. R. 144Barros, M.T. 297Barta, N.S. 1Bartlett, P.A. 91, 107Barton, D.H.R. 209, 289Barton, T. J. 31, 249Barua, J. N. 263Barua, N.C. 263Baruah, J. N. 161Basenko, S. 31Basha, F. Z. 15, 246Bassindale, A.R. 11, 207Bastani, B. 172Bastian, V. 206Basu, M.K. 68Batistini, L. 141Bauer, A. 77Baukov, Yu.I. 92, 105Bayard, J. 50Bayard, P. 98

Bayston, D. J. 114Bazavova, I.M. 75Bazouin, A. 66, 270, 273Beaudegnies, R. 98Beaver, K. A. 91Beavers,. E.M. 147Beck, A. K. 88, 172, 179Becker, G. 253, 255, 256,

257Beezer, A.E. 29Beggiolin, G. 64Begtrup, M. 156, 159Begum, K. 84Belavin, I. Yu. 92Bellassoued, M. 244Bellemin-Laponnaz, S. 319Bellesia, F. 202, 203, 317Belletire, J.L. 223Bellosta, V. 84Below, P. 217Belyankin, A. V. 172Belysheva, G. V. 277Bender, P.E. 234Bendich, A. 50Benkeser, R.A. 261Benn, M.H. 172Bennetau, B. 285, 289Bennua, B. 10Bennua-Skalmowski, B. 8,

91, 127, 217, 223, 228Benoit, B. 232Benson, S. 267Berens, U. 84, 85, 219Bergeron, R. J. 149, 152Berggräßer, U. 257Berglund, B. 293Bergsträßer, U. 254Berk, S.C. 312Berkessel, A. 315Berkowitz, P.T. 55Bernal, F. 84Bernardi, P. 181Bernardi, R. 124Bernardinelli, G. 84Bernier, J.-L. 230Bernier, S.E. 57Berry, M.B. 48, 105Berthault, A. 271Bertz, S. H. 226, 313Bestmann, H. J. 242, 255Beutner, G. L. 33Beyl, V. 206Bhagwat, S. S. 71

Bhakuni, D.S. 57Bharathi, S.N. 286Bhat, B. 52Bhat, K. L. 171, 221Bhrathi, S. N. 78Biagi, G. 63Bianco, E. J. 50Biermacher, U. 50Bigan, M. 149Bigge, C.F. 152Biggers, C.K. 221Billet, M. 111Binnewies, M. 33Biran, C. 313Birkel, M. 292Birkofer, L. 1, 7, 8, 11, 12,

15, 27, 68, 69, 71, 72, 96,103, 194, 221

Birot, M. 327Bisagni, E. 157Bither, T. A. 20Blacklock, T. J. 104, 123Blagg, J. 48, 105Blaschette, A. 284Bloch, R. 71Blohowiak, K. Y. 22Blondeau, D. 149Bloomfield, J. J. 281Boa, A.N. 90Bobonneau, F. 327Bochnowicz, S. 234Böhme, M. 157Böhme, U. 327Boivan, J. 9Bolestova, G. I. 267Bolourtchian, M. 96Bols, M. 17Bolz, J. T. 266, 294Bomhard, A. 255Borbaruah, M. 30Bordwell, F. G. 30Börner, A. 85Bos, H.J. T. 242Bosch, E. 297Bose, G. 227Bosnich, B. 112Bosret, J. 320Boudin, A. 22Boudjouk, P. 179, 305, 310Boukouvalas, A. J. J. 288Bourgeois, P. 207Bourguignon, J.-J. 230Boyer, B.D. 157

Author Index346

Boyer, J. 276Brady, K. T. 138Brandes, D. 284Brandsma, L. 242Branzoli, U. 195Brashenkov, G. G. 208Braun, J. 292Braun, M. 139Bravo, A.A. 78, 286Bredereck, H. 74, 129, 237Breederveld, H. 34Brevnova, T.N. 277Brewer, S.T. 17Brewster, A.G. 209Briehl, H. 255Brindle, M.A. 78Brinkmeyer, R. S. 47Brokmeier, D. 15Bromidge, S.M. 84Brook, A.G. 20, 189Brook, M.A. 70, 86, 90,

126, 227Brossi, A. 142Brown, G. B. 50, 230Brown, R. S. 226Brownbridge, P. 227Brownfain, D.S. 204Broxterman, Q.B. 45Brückner, C. 271Brückner, R. 94Bruker, A. B. 254Brummerhop, H. 10, 189Brunel, J. M. 142Bruynes, C.A. 8Bruzzzese, T. 53Bühler, W. 127Buono, G. 142Bur, S.K. 141Burchenal, J. H. 62Burgtorf, J. R. 201Burman, M. 234Burnell, D. J. 218Burnell-Curty, C. 104Burns, G.T. 249, 332Bush, K. 327Bussenius, J. 152Buston, J.E. H. 34

cCabras, M.A. 157Cai, L. 47Cai, S. 306Cainelli, G. 95, 96, 97, 120

Calabrese, J. C. 172Calas, R. 66, 207, 270, 271,

273, 281, 313Caldwell, C.G. 17Calheiros, T. 105Cameron, D.W. 126Camici, L. 285Camiletti, C: 161Camporeale, M. 287Caperuzzi, A. 280Caple, R. 293Capozzi, G. 280Capperucci, A. 108, 109Caputo, R. 265Cardenas, G. I. 78Cardillo, G. 181Carganico, G. 195Carman, C. S. 293Carpenter, J.C. 18, 31Cartwright, D. 62Casiraghi, G. 141Castaño, A.M. 13Castellvi, J. C. 201Catteau, J.-P. 230Cauliez, P. 77, 232Cava, M.P. 45, 212Cecarelli, S. 65Cee, V. J. 271Celeda, M. 156Celerier, J.-P. 77Cella, J. A. 18, 31Cerny, M. 28Cerreta, F. 109Cerveau, G. 22Cesarini, A. 287Cha, J. K. 272Chabala, J. C. 96Chabot, B. M. 289Chaly, T. 86Chambers, D.W. S. 33Chan, T.H. 44, 70, 84, 86,

94, 95, 108, 126, 227Chandraiah, L. 274Chandrasekhar, S. 274, 84Chandrasekhar, V. 22, 32Chaney, J.E. 221Chang, S. 321Chang, Y. H. 180Chapman, D.C. 289Chastrette, M. 142Chaykovsky, M. 45Chelucci, G. 157Chelucci, G. 157

Chemla, F. 286Chen, S.-Y. 28Chen, B.-L. 138Chen, E. 161Chen, H.G. 228, 296Chen, H.-J. 141Chen, J. 172Chen, S.-F. 43Chenard, B.L. 71Cheng, M.-C. 87Cheong, L. 50Chernishev, E.A. 68Chernyshev, A. I. 46Cherskaya, N. O. 171Chiang, J. K. 290Chiang, Y.-C.P. 96Chiaroni, A. 198Chiasson, M. 84Chiba, T. 97Chiu, A. 273Chiu, F.-T. 180Cho, N. 154Cho, P. S. 271Chojnowski, J. 31Chopra, A. 313Chotard, J. C. 23Chou, M.C. 43Chou, T. S. 201Chou, W.-C. 43Christalli, G. 126Christensen, S. B. 234Christot, I. 92Chu, D.T. W. 123Chu, G.-Nam 247Chudeova, L.M. 19Chuit, C. 22Chunechom, V. 332Chung, C.-S. 73Chvalovsky, V. 27, 28Cieslinski, L.B. 234Ciommer, B. 180Ciszewski, L. 104Claes, P.G. 201Clardy, J. 107Clark, C.G. 23Clark, R. N. 123Clarke, L. F. 74Clayton, T.L. 170Clommer, B. 28Coindet, C. 78Coldham, I. 34Coll, A.P. 201Collas, M. 178

Author Index 347

Colman-Saizarbitoria,T. 201

Colvin, E. 20Colvin, E. D. 172Colvin, E. W. 96, 97, 172,

179Combret, J.-C. 92, 129Comel, A. 78Comi, R. 102Confalone, P. N. 91Connell, S. 8, 106Constantieux, T. 245Contento, M. 95, 97, 120Cook, F.L. 277Cook, N.C. 274Cooke, M.P. 283Cookson, P.G. 285Cookson, R.C. 190Cooper, B. E. 1, 8Copenhafer, W. C. 11Copéret, C. 290Corbett, R. M. 88Corey, E. J. 10, 17, 19, 107,

310, 316Corriu, R. J. P. 22, 34, 101,

228, 276Corson, B. B. 129Cossey, J. 84Cossrow, J. 111Cossy, J. 1, 8, 220Cothron, D.A. 261Coutourier, D. 77Coutts, I. G.C. 261Couture, A. 105Couturier, D. 227, 232, 233Couty, F. 320Cox, D. P. 306Cozzi, P. 195Cozzi, P.G. 314Craig, D. 48, 113, 197Cram, D. J. 277Crane, S.N. 218Crittel, C.M. 293Crouch, R. D. 18Csábár, A. 62Cui, J. 129Cui, W. 310Cui, Z. 3Cunico, R. F. 231Cuong, N.K. 180Curci, R. 287Curphey, T. J. 110, 212Currie, J. 84

Curtis, M.D. 23Cutler, A.R. 272Cutting, I. 190Cypric, M. 42Czernecki, S. 57

dD’Allessandro, A. 65Dahinden, R. 172Dalko, P. I. 220Damour, D. 220Damrauer, R. 28Daniels, K. 197Danilenko, V. M. 171Danishefsky, S. 20Dannhardt, G. 77Darcy, R. 271Dardaine, M. 198Das, J. 107Das, N.B. 171Daudt, W.H. 29Dauffaut, N. 99Davidovich, Yu.A. 94Davies, A.G. 285Davies, J. 112Davies, J.S. 44Davis, A.P. 85Davis, P. 3de Benneville, P. 49De Clercq, E. 12de Koning, J. 201de la Hoz, A. 156de la Moya Cereo, S. 157de Lima, B.R. 46de Lombart, S. 320de Luca, G. 9de Lucchi, O. 189de Meglio, G. 53de Shong, P. 22de Souza, A.R. 46de Vos, M.J. 320Dea, P. 55DeBernardis, J. F. 15, 246Declercq, J.-P. 114, 158Decoster, G. 201Defretin, S. 232Degl’Innocenti, A. 102,

108, 212, 280, 286DeGoy, D.A. 141Dehaen, W. 171del Duce, R. 280Del Nin, J.W. 22Delbecq, P. 77

Dembech, O.P. 181Dembech, P. 285, 286, 287Demuth, M. 10, 244Deniau, E. 105Denis, J. M. 71Denis, J. N. 265Denmark, S.E. 33Dennis, W. E. 66Derkach, N.Y. 208Derome, A. J. 284Dervan, P. B. 277Désaubry, L. 230Desmoni, G. 74Detty, M.R. 278, 279Deudon, S. 23DeWolf, W.E. 234Dhavale, D. D. 161Diaz, M. J. 30Dickopp, H. 27, 72Digenis, G. A. 221Dikic, B. 195Dilley, G. J. 115Dilman, A.D. 172, 176Dimitrieva, A. B. 68Ding, Z.-D. 284Dirnens, W. 28Dittman, W.R. 268Djuric, S. 15Dmitricheva, N.A. 43Doerr, I. L. 50Dolan, S. 114Dölle, A. 111Domsch, D. 10, 74Donati, F. 161Donelly, S. J. 267, 268Dorfmeister, G. 254, 255Dormoy, J.-R. 66Dostalek, R. 242, 255Dötz, K. H. 247Doughty, V.A. 72Doyle, M.P. 267, 268Drabowicz, J. 264Dräger, G. 263Drechsler, K. 135Drummond, J.T. 152Drusiani, A. 120Du, H. 248Dua, P.R. 203Dubac, J. 135, 332DuBeshter, B. 11Dubinskaya, E. I. 35, 120,

121, 135, 142, 144, 275Dubs, P. 74

Author Index348

Duffaut, N. 207, 281, 313Duffy, J. L. 172Dumont, W. 114Duncia, J.V. 234Dung, J.-S. 223Dunigan, D.A. 50Dunkerton, L.V. 138Dunoguès, J. 207, 245, 281,

285, 289, 313, 327Dupin, J.-P. 99Dutta, D. K. 161Duval, R. 114

eEaborn, C. 31Early, J. V. 45Echivarren, A.M. 13Eckenberg, P. 305Edinoff, M.L. 50Edstrom, E. D. 199Edwards, J.O. 287Eggleston, D.S. 234Egorochkin, A. N. 277Eguchi, S. 172El Giani, M. 111El Gihan, M.T. 11El-Aziz, A.-A.E. 121El-Ghammarti, S. 139El-Khawaga, A. M. 11Elliott, B. 42Ellis, A.L. 201Elman, B. 158Elmorsey, S.S. 226Elmorsy, S. S. 121Elvidge, J. A. 76Elzey, T. 157Emde, H. 10, 74Enders, D. 84Endo, M. 139Endo, T. 316Engelhardt, G. 28Entmayr, P. 241Epifany, E. 286Epstein, P. S. 23Eriksson, M. 313Ernst, T. D. 289Erxleben, J. 328Eschenmoser, A. 74, 77Esclamadon, C. 270Estermann, H. 70Euske, J.M. 138Evans, D.A. 106, 121, 271,

273

Evans, P.A. 265, 295Ewing, W.R. 171Ezike, J. 309

fFabbri, G. 181Fahrni, C. 48Falco, E.A. 50Fan, H.-F. 270Fan, Y. 33Fang, X.-P. 201Farnoux, C.C. 45Fasal, N. 285Fasseur, D. 77, 232Fedrick, J. L. 59Feely, W.E. 147Feger, H. 10, 74, 172Fehr, C. 283Felker, D. 9, 261Fen, Y. 33Feneau-Dupont, J. 114Fengl, R. W. 71Fensterbank, L. 17Ferguson, J. R. 62Feringa, B.L. 97Feutrill, G. I. 126Fewig, J. M. 225Fiascher, P. 74Field, G. F. 45Field, L. D. 264Fife, W.K. 157Finkbeiner, H. 11Fiorani, T. 287Fiorenza, M. 241Firouzabadi, H. 262Fischer, P. 237Fischer, R.W. 318Fitch, D. M. 271Fitt, J. S. 76Flammang, R. 255Fleming, I. 193, 244, 246Fleming, R.F. 29Florence, G. J. 244Florian, W. 47Florio, S. 286Flosi, W. J. 141Flouzat, C. 231Floyd, C.D. 246Flückiger, R. 294Fobare, W. F. 117Fölling, P. 253Formanek, M.S. 294Forster, C. J. 234

Forsyth, C. J. 271Fortgens, H.P. 114Fox, H.H. 306Fox, J. J. 50, 62Fraenkel, G. 129Frainnet, E. 66, 270, 271,

273Fraizier, K. A. 271Franchetti, P. 126Franck, R. W. 102Freeborn, E. 129Freemantle, M. 22Frey, H. 95Frick, U. 10, 74Frickel, F. 242Friederich, E.C. 9Friedman, O. 171Frierson, M.T. 28Frisque-Hesbain, A.-M. 98Fritz, G. 257Fry, J. L. 268, 306Frydrich-Houge,

C.S. V. 309Fryer, R. I. 45Fu, G. C. 268Fu, Y. 320Fuchigami, T. 234Fuchikami, T. 8Fujimori, C. 196, 199Fujimori, K. 279Fujimori, S. 33Fujioka, H. 67, 87Fujisawa, T. 139Fujita, A. 278Fujita, E. 293Fujita, M. 8, 276Fujita, S. 196, 199Fujita, T. 283Fujiwara, T. 190Fujiwara, Y. 220Fukuda, T. 270Fukumoto, K. 84, 220Fukumoto, T. 70Fukunaga, T. 167Fukushima, A. 233Fukuyama, T. 273Funato, M. 278Fung, A. P. 264Funicello, M. 110Fürstner, A. 309, 314, 316Furth, P.A. 138Furuhashi, K. 138Furusawa, K. 17

Author Index 349

Furuya, S. 154

gGabler, B. 57Gaffney, B.L. 244Gaffney, B.L. 3Gaiba, A. 97Galindo, J. 283Galletti, P. 97Gallop, P.M. 294Gamba, A. 74Gammarti, S.E. 233Gan, Y. 54Gandolfi, C.A. 64Gansäuer, A. 311Gardiner, W. 42Garnett, I. 103Gaspard-Iloughmane,

H. 135, 332Gately, D.A. 317Gaudemar, M. 244Gauthier, D. R. 17Gautier, J.-A. 45Gautret, P. 139, 233Gautschi, M. 88Gentilucci, L. 161, 181Geogieva, A. 46George, J. 54Gerlach, K. 244Gerlach, R. 242Gerold, A. 313Gerster, J. F. 56Gesellchen, P.D. 157Gevorgyan, V. 267Ghelfi, F. 202, 203, 205,

317Ghosez, L. 98Ghosh, S.K. 33Giacomini, D. 95, 96, 97Giannopoulos, T. 62Gianotti, M. 161, 181Giere, H.H. 10Giessler, W. 11Gihani, M.E. 84, 270Gil, G. 87, 315Gilman, H. 123Gingold, K. 105, 152Giorgi, I. 63Girolami, G. S. 277Gisie, H. 319Glaudemans, C.P. J. 91Gleason, J. G. 234Glerup, J. 157

Glusgkov, R. G. 77Goacolou, K. 103Gokel, G. W. 277Golankiewicz, B. 230Goldhill, j. 193Golding, B. 77Goldmann, S. 242Golsch, D. 290Golshani, B. 16González, I.C. 271Goodson, P. A. 157Gorbatov, V.V. 290Gordon, P.F. 226Görlach, Y. 246Gorsuch, S. 78Göschi, E. 74Gosh, A. K. 272Gossauer, A. 8, 228Göttlich, R. 288, 289Götz, A. 10, 74Gouni, I. 233Gouverneur, V. 98Grampovnik, D. J. 141Grandclaudon, P. 105Grandi, R. 202, 205Granik, V.G. 77Graubaum, H.-J. 7Gravestock, D. 243Greber, G. 27Green, L.Q. 35Greenspan, P. D. 30Greer, S. B. 53Gregg, B.T. 272Greif, N. 249Gresser, G. 253, 257Greth, E. 126Grieco, P. A. 117Grifantini, M. 126Grigoras, S. 332Grillot, A.-L. 91Grimm, K. G. 106Griswold, D. E. 234Groth, U. 305, 311Grous, M. 234Groutas, W.C. 9, 261Grubb, M. 9Grubb, W. T. 2, 27, 28, 31Grundschober, F. 49Grynkiewicz, G. 272Gu, Z. 201Guerrini, A. 286Guest, A.W. 94Guider, A. 234

Guillaumet, G. 231Gunterman, H.P. 269Günther, E. 104Guo, L. 32Gupta, B.G.B. 10, 71, 135,

172, 261, 263, 277Gupta, P.K. 57Gupta, S.P. 28

hHa, D.-C. 97Haber, C.P. 17Hadri, A. L. 149Hagen, V. 15Hagio, H. 117Hahn, J. 297Hahn, P. 296Haig, D. 105Hain, U. 178Haines, D. R. 233Hakimelahi, G. H. 73,

223Haltiwanger, R. C. 234Ham, G.E. 33Hamaguchi, F. 49Hamajima, T. 320Hamann, H. 18Hamann, P. R. 71Hamaoka, S.-I. 284Hamasaki, R. 322Hamblett, C.L. 72Hamblett, G. 34Hamdouchi, C. 224Hamelin, J. 228Hamilton, K. M. 195Hamilton, R. J. 22Hamzink, M.R. J. 97Han, B. H. 28Han, J. S. 107Han, Y. 47Handa, Y. 310Handy, C. J. 22Haneda, T. 235Harada, H. 224Harada, T. 85, 115Harms, K. 247, 320Harpp, D.N. 94, 108Harring, S. R. 235Harrington, F. P. 94Harris, B.D. 171, 221Harris, H.P. 277Hart, D. J. 96, 97, 193Hartz, N. 271

Author Index350

Hartz, R. A. 271Harwood, L.M. 34Hasegawa, T. 312Hasenfratz, C. 332Hashem, M.A. 296Hashimoto, H. 85Hashimoto, K. 157Hashimoto, Y. 46Hassall, C.H. 44Hässig, R. 8, 192, 193Hasske, F. 57Hassner, A. 171Hatada, K. 196Hatakeyama, S. 123, 270Hatamoto, Y. 313Hatano, T. 315Hatfield, G. L. 135Hatke, K. 124Hattori, R. 311Hauptmann, E. 23Hausen, J. 32Hayakawa, Y. 292Hayashi, J. 33, 111Hayashi, M. 113Hayashi, N. 277Hayashi, T. 314Hayashi, Y. 102Hazarkhani, H. 262Hazell, A. C. 171Hazell, R. G. 171Heaney, H. 11, 84, 103,

111, 270, 289Heathcock, C.H. 107, 241Hebd, C.R. 66Hecht, H. 305Heck, J. V. 96Heckmann, G. 292Hees, U. 257Hegarty, A. F. 74Hehre, W. 12Heilmann, S.M. 10, 30,

148Heilporn, S. 158Heinen, H. 247Heirtzler, F.R. 157Heitz, W. 330Helferich, B. 32Hellberg, L.H. 102Hellenius, M. 157Heller, D. 85Hemmilä, I. 157Henmi, S. 77Henze, M. 147

Herdtweck, E. 319Hergott, H.H. 10, 11, 13,

74Hermes, A.R. 277Herrmann, W. A. 318, 319Herzog, G. 28Heydt, H. 258Heymes, A. 66Hiemstra, H. 90, 114Higashino, T. 154Hightower, T. H. 296Hikasa, S. 315Hilfiker, M.A. 310Hillegas, M.L. 234Hills, J. 7Hillwer, F. 178Hilpert, H. 149Hils, J. 15Hino, T. 269Hinrichs, J. 84Hippeli, C. 178Hirabayashi, K. 30Hirabayashi, R. 117Hirai, Y. 152Hiraiwa, Y. 115Hirakawa, M. 331Hirao, T. 312, 313, 316Hiraoka, S. 115, 117, 328,

329Hiroi, K. 193Hirokawa, N. 158Hirota, K. 53Hiruma, K. 85Hiyama, T. 30, 276, 278Ho, T.-L. 15Hoashi, Y. 161Hodge, P. 309Hodgson, D. J. 157Hoechstetter, C. 228Hoffmann, H.M.R. 11Hoffmann, M.A. 254Hoffmann, R. 94Hoffmann, R.W. 242Höfle, G. 11Hofmann, K. 10, 74Hofmann, M.A. 258Hölderich, W. 257Holker, J. S.E. 210Holler, T. P. 230Hollis, T.K. 112Holmes, B. N. 230Holtwick, J. B. 230Holz, J. 85

Holzmann, G. 28Homann, K. 179Homma, K. 73Honda, T. 316Honerl, D. 144Honeyman, C.H. 332Hopkins, K. H. 44Hopkins, P. B. 17, 230Hoppe, M.L. 22Hori, M. 191, 284Horikawa, H. 219Horikawa, M. 157Horito, S. 85Horn, H.-G. 10, 27Horn, K.H. 23Hornberger, K. R. 72Horng, D.-N. 166Hoshino, K. 193Hosomi, A. 31, 33, 111,

139, 142, 270, 277Hosoya, N. 290Hossain, M.M. 248Howard, G. A. 2, 51Hoye, T. A. 88Hoye, T. R. 17Hsu, C.H. 73Hu, C.M. 172Hu, D.H. 78Hu, H. 221Hu, J.-B. 284Hu, J. R. 73Hu, Y. 276, 320Hua, D. H. 286Huang, J.-T. 62Huang, S.-L. 204, 205Huber, G. 14, 32Huckin, S.N. 123Huel, C. 157Huet, F. 179Hughes, P.F. 221Hulme, C. 265, 295Humblet, C. 152Hung, S.-C. 270Hünig, S. 75, 104Hunter, R. 195Hunter, R. 198Huo, M. 201Hupperts, A. 316Hurst, K.M. 121Hurwitz, M.J. 49Husain, A. 10Husmann, G. 31Hussmann, G. P. 31

Author Index 351

Huwiler, A. 127Huynh, V. 101, 228Hwang, C.-K. 271Hwu, H.R. 84Hwu, J. R. 28, 84, 138, 161,

166, 280, 281, 285Hyde, J.F. 29Hyodo, C. 190

iIbatullin, U.G. 267Ibuka, T. 247Ichi, D. 275Igarashi, Y. 191Ignatov, S.M. 181Ihara, M. 84, 220Iida, T. 289Iijima, C. 154Iimori, T. 87Ikano, M. 262Ikeda, I. 312Ikeda, S. 149Ikegami, S. 87, 217, 270Ikegashira, K. 278Ikemizu, D. 195Ikemura, I. 279Il’in, M.M. 46Iley, J. 105Imai, T. 139Imai, Y. 47, 191, 193, 327Imamoto, N. 290, 305Imamoto, T. 47Imbach, J.-L. 58Imoto, S. 77Imoto, T. 277Imwinkelried, R. 88, 111Inaba, T. 283Inada, Y. 154Inanaga, J. 310Innocenti, A. Degl. 109,

110Inomata, K. 70Inoue, A. 85Inoue, I. 34, 219Inubushi, A. 113Invernezzi, A.G. 74Ioffe, S.L. 92, , 171, 172,

176Ipaktschi, J. 103, 118Iqbal, J. 101, 228Iranpoor, N. 262Irelan, J. R.S. 281Irie, R. 290

Irie, Y. 53Isager, P. 171Ishida, Y. 265Ishifune, M. 281Ishigooka, S. 328Ishiguchi, T. 315Ishihara, K. 115Ishii, A. 111Ishii, Y. 230, 263, 315Ishiina, I. 70Ishikawa, T. 139, 319Ishino, Y. 313Ishiwata, A. 114Ishiyama, H. 271Isobe, S. 278Issleib, K. 254Itala, A. 44Ito, H. 280Ito, K. 288Ito, N. 30Ito, T. 84, 317Itoh, F. 194, 199Itoh, K. 67, 311Itoh, Y. 290Ivanov, V. I. 290Iwasaki, T. 161, 219Iwasawa, N. 123, 269Iwata, C. 203Iyer, P.S. 270Izumi, J. 71Izumi, Y. 67

jJackson, B.G. 200Jackson, W. P. 285Jahn, U. 103Jana, U. 19Jancke, H. 28Jandeleit, B. 84Janousek, Z. 114Jansen, J.F.G. A. 97Janzen, A. F. 194Jarwie, A. W. 14Jatzak, M. 142Jeanguenat, A. 191Jefford, C.W. 84, 288Jeffrey, S. C. 115Jerry, D.E. 144Jeske, M. 311Jhingan, A.K. 319Jiang, X. 123Jimenez-Diaz, A. I. 34Jimeno, M.L. 12

Jin, S.-J. 84Joachim, K. 230Joachim, V.D. 126Joergenson, R. D. 171Johannson, O.K. 29Johnson, A. P. 90Johnson, F. 64Johnson, G. 152Jones, J. W. 56Jones, P.R. 211Jones, R. A. 3Joullie, M.M. 171, 221Juarez, A. 102Julia, M. 286Julien, J. 227Jung, J.-K. 113Jung, M.E. 121, 135, 261Jung, Y.-W. 161Jurriens, T. K. 8Just, G. 223

kKabeya, M. 233Kaboudin, B. 122Kagamihara, Y. 85Kagechika, H. 223Kageyama, H. 33Kahlen, N. 20Kajita, S. 278Kakimoto, K. 327Kakimoto, M. 47, 193Kakiushi, T. 312Kal’nitskii, M.N. 64Kalinin, A. V. 92Kalman, T. L. 53Kalsey, S. 315Kambe, N. 305Kamiyama, Y. 277Kämpchen, T. 124Kampf, J. 22Kamphuis, J. 90, 114Kanagawa, Y. 263, 315Kanai, K.-I. 96Kanai, M. 289, 290Kaneda, S. 149, 152Kaneko, M. 50Kaneko, T. 195, 196Kanemasa, S. 120, 249Kanemoto, S. 139, 285Kang, G. J. 227Kang, K. K. 135, 318Kang, M.-C. 208Kankare, J. 157

Author Index352

Kanoh, N. 271Kantlehner, W. 74, 237Kantor, E.A. 120Kantor, S.W. 17, 18, 31Kaptein, B. 90, 114Karaghiosoff, K. 253Karanewsky, D.S. 149Kardon, F. 102Karel’skii, V.N. 44Karimi, B. 16, 296Karo, W. 45Karpenko, N.F. 171Karpinski, J.P. 234Kashima, C. 124Kashimura, N. 62Kashimura, S. 281Kashutina, M.V. 171Katagiri, N. 235Katampe, I. 207Kataoka, T. 191Katchala, V.V. 172Kato, J.-I. 269Kato, K. 8Kato, T. 123, 235Katoh, M. 316Katsarawa, R. D. 327Katsuhira, T. 78, 286Katsuki, T. 288, 290Katsura, T. 17Katsurayama, T. 77Kaur, G. 139Kaushik, M. 139Kautsky, H. 267Kawada, H. 53Kawaguchi, M. 284Kawahama, R. 272Kawahara, N. 95Kawano, N. 196Kawashima, M. 139Kawashima, T. 154Kazakova, V.V. 46Kazimierczuk, Z. 57Kaznacheev, A.A. 317Keck, H. 267Keese, R. 77Keinan, E. 275Keiner, P. 94Keller, T. H. 172Kempf, D. J. 141Kennedy-Smith, J. J. 269Kenney, M.E. 28Kenrick, L.M. 42Kerkman, D. J. 246

Kerremans, L.A. 201Keyser, G. E. 144Khalaji, H.R. 96, 118Khan, M.N. 309Khananshvili, L.M. 68Khorshidi, H.S. 54Khoudary, K.P. 161Kielbasinski, P. 264Kihara, T. 53Kim, B. H. 172Kim, C.-W. 283Kim, D.W. 93Kim, H.-S. 84Kim, K. 172Kim, K. C. 46, 299Kim, S. 321Kim, S.-H. 113Kimura, H. 234King, D.B. 138King, F. D. 180Kingston, J. V. 22Kinoshita, H. 70Kinrade, S. D. 22Kinrade, S. T. 22Kira, M. 269Kirilin, A. D. 12, 68, 181Kirsanov, A.V. 253Kirsch, G. 78Kirschning, A. 263, 296,

307Kishi, Y. 272Kisin, A. V. 68, 181Kita, T. 46Kita, Y. 67, 87, 194, 196,

197, 199Kitagaki, S. 87Kitagawa, H. 87Kitahara, Y. 152Kitano, K. 123, 232, 270Kitteringham, J. 161Kjeldsen, G. 171Klebe, J. F. 1, 3, 11, 12, 66,

74, 170Klein, B. 228Klein, J.-L. 92, 129Klein, L.L. 141Kless, A. 85Kliegman, J.M. 23Kliment, M. 28, 249Klotz, P. 111Knapp, S. 221Knausz, D. 102Knight, C.T.G. 22

Knoch, F. 253Knochel, P. 228, 296, 312Knoll, F. 253Knoll, J. E. 50Knoth, W. H. 20Knudsen, J. S. 171Kobayashi, H. 27Kobayashi, K. 104Kobayashi, S. 117, 317Kobayashi, T. 313Kober, W. 10, 74Köbrich, G. 241Kochi, J. K. 297Kocienski, P. J. 190Kocovsky, P. 135Koehler, K. F. 161Koetsch, J. 24Koga, G. 114Kohama, S. 318Kohara, Y. 154Kohda, K. 247Kohl, A. 124Köhler, T. 305Kojima, S. 46Kolodiazhnji, J. L. 255Kolyadina, N. M. 149Komarov, V. 142Komarov, V. G. 120, 121,

142, 144Komatsu, M. 157, 228Konakahara, T. 245, 320Kondo, K. 34Kondo, M. 87Kondo, S. 44Kondo, Y. 305Konn, A. 149Kooistra, D.A. 267Kooreman, H.J. 201Korb, M.N. 286Korenevskii, V. A. 171Kornev, A.N. 277Korotaeva, I.M. 120, 142Koseki, Y. 275Koser, G. F. 293Koshino, H. 46Kositsina, E. I. 144Kostyanvsky, R. G. 181Kosugi, H. 193Kotake, H. 70Kotera, G. 111Kotian, K. D. 271Kotrikadze, E.L. 68Kotter, W. 139

Author Index 353

Koz’min, A. S. 293Kozintsev, A. V. 172Kozyukov, V.P. 12, 88, 92,

103, 105, 117, 221, 329Krägeloh, K. 10, 17, 74Krasutsky, A. P. 266,Kratzer, R. M. 318Kraus, G. A. 271, 272, 296Krause, N. 313Kreiser, W. 217Kremp, M. 28Krepski, L.R. 30Kresze, G. 207Kricheldorf, H. J. 231Kricheldorf, H.R. 7, 66,

221, 328Krief, A. 114, 265, 320Krieger, L. 253Krolikiewicz, K. 2, 4, 9, 19,

46, 51, 52, 56, 57, 91,133, 147, 158, 159, 161,165, 166, 230, 277, 306,307, 309

Krow, G.R. 74Krüger, C. 66, 95, 99Krysin, E. P. 44Ku, B. 106Ku, H. 43Ku, J. 161Kuan, C.P. 231Kubo, A. 152Kubo, K. 154Kubota, T. 311Kuczma, A.S. 30Kuehl, C. J. 266, 294Kugel, W. 74, 237Kühlmann, K. 281Kukhar, V.P. 75Kukolja, S.P. 201Kumada, M. 277Kumar, M.S. 284Kumazawa, Z. 62Kummert, K. 192Kunha, S. 46Kuno, S. 279Kunze, H. 267Kupce, E. 28Kuramshina, E.A. 267Kurihara, M. 86Kurita, K. 331Kuroda, K. 166, 265, 312Kurokowa, H. 115Kurosaki, M. 152

Kurosaki, T. 327Kursanov, D.N. 267Kurth, M.J. 172Kusano, S. 275Kusche, A. 94Kusui, H. 315Kuwajima, I. 281Kuznetsova, M.G. 68Kvita, V. 8, 125Kvita, Y. 234Kwast, A. 168Kwiatkowski, M. 157Kyncl, J. J. 246

lLabroullière, M. 135, 332Lacour, J. 265, 294,

295Laine, R.M. 22, 69Lajis, N.H. 9Lake, K. L. 27Lam, P. Y. S. 23Lammerink, B.H.-M. 205Lammert, S.R. 201Lampe, J. W. 221Lane, S. 191Langanis, E. D. 71Langer, P. 227Langer, S.H. 106Langer, S.L. 8Langlois, N. 198Lappert, M.F. 29Larock, R. T. 296Laroussine, C. 50Larsen, S. D. 117Lattes, A. 99Laubach, B. 253Laudenslager, H.B. 29Lautens, M. 316Lavagnino, E. R. 200Lawesson, S. O. 212Lawrynowicz, W. 306Lazukina, L.A. 75Le Ny, J. P. 319Le Roux, C. 135, 332Leander, J. D. 157Lebedev, A.V. 181Lebedeva, A.B. 181Lecka, B. 266Leclerc, G. 149Leduc, C. 77Lee, J. A. 297Lee, J.-C. 270

Lee, J. G. 135, 297, 299,318

Lee, J. Y. 172Lee, K. 321Lee, P. H. 321Lee, S. J. 28, 34Leffler, A. J. 254Lefort, M. 66Legido, M. 245Legrand, A. 139Legrand, O. 142Leighton, J.L. 72Leissring, E. 254Leonard, N. J. 52, 230, 233Leroy, F. 149Lespagnol, C. 66Leth, T. D. 50Leu, L.-C. 84Leutenegger, U. 48Lever, J.R. 72Levin, A.A. 171Levin, V.A. 171Levinson, M.I. 45, 212Levorse, A.T. 221Levsen, K. 180Lewis, D. 14Lewis, M.D. 272Lewis, N. 161Lewis, P. K. 121Ley, S. V. 209Lhommet, G. 77Li, B. F.L. 50Li, C. 172Li, T. 104, 273, 310Liak, T.-J. 223Liaw, B. R. 166Libby, A. H. 212Lickiss, P.D. 24Lie, G.C. 332Lieb, F. 255Liebeskind, L. S. 71Liepinss, E. 28Lillie, B. M. 87Limbach, H.H. 144Lin, L.C. 138, 166Lin, S. 20Lin, S.-C. 273Lindsey Jr, R. V. 20Lindsey, R. U. 254Link, R. 144Linstead, R.P. 76Liotta, C.L. 277Lippsmeyer, B. 10, 17

Author Index354

Lipshutz, B. H. 313Lipski, T. A. 310Lipták, A. 85Liskamp, R. J. J. 45Lissel, M. 135Liu, C.Z. 149Liu, J. 310Liu, J.-X. 267Livantsov, M.V. 223Livi, O. 63Livinghouse, T. 199Lodge, D. 157Loewenthal, H. J. E. 85Loin, N.M. 267Löliger, P. 77Lombardo, M. 161Long, R. A. 55Lopatin, G.V. 277Lopez, M.C. 90Loretto, M.A. 181Lorey, H. 271Louca, J. B. 86Louer, C. T. 91Love, B.E. 34Loy, D.A. 327Lozinskii, M.O. 75Lu, L.-D. 270Lu, S.-P. 88Lu, Y.-Y. 43Lubin-Germain, N. 314Lucacchini, A. 63Ludwig, H. 15Ludwik, L. 49Luke, R. W. A. 90Lukess, I. 30Lukevics, E. 28Lunn, W. H.W. 206Luo, F.-T. 68Luo, S.-Y. 270Lüss, H. 45Luther, T.A. 317Lyapkalo, I.M. 171, 172,

176Lyapkalo, L.M. 172Lyons, J. E. 274Lypka, G.N. 194Lythgoe, B. 2, 51Lytwyn, E. 180

mMa., X.-B. 292Maak, N. 242Maaroufi, A. 180

Mack, A. 257MacKenzie, A.R. 197Mae, M. 313Maekawa, H. 313Maesano, M.G. 207Maeshima, T. 232Maetzke, T. 191Magnane, R. 265Magnus, P. 15, 265, 294,

295Magnus, P. D. 199Mahrwald, R. 297Mai, K. 10Maier, W. F. 319Majee, A. 19Majlis, S. K. 72Maki, S. 62Makosza, M. 167, 168Mal’chikowa, L.S. 221Malacria, M. 17Malhotra, 172Malhotra, R. 10, 135, 261,

263, 277Malkita, K. 220Malkov, A.V. 135Malone, T. C. 152Mamedov, M.G. 29Manangan, T. 295Mancuso, A. J. 204Manera, C. 63Mangeney, P. 312Mangini, L. 265Mann, A. 111Manners, I. 327, 332Manning, C.D. 234Mansui, D. 23Mantus, E. K. 107Mao, Z. 272Maquestiau, A. 255Marchand, A.P. 281Marcor, J.E. 152Marcotte, E. J.-P. 226Märkl, G. 254, 255Markó, I.E. 111, 114Markovskii, L.N. 253Marquez, V. E. 49Marschner, M. 144, 308Marsmann, H.C. 10, 27,

28Martelli, G. 95, 96, 97Martelli, S. 126Martin, H.P. 327Martin, S. F. 141

Martin, Y. C. 246Martini, C. 63Maruoka, K. 265, 305Marx, M.A. 91Masai, M. 296Masaki, Y. 317Mase, T. 217Masuayama, A. 84Masuda, H. 281Masuyama, A. 84Mathews, T.R. 55Mathey, F. 253Matoba, K. 77Matsubara, S. 285Matsubara, Y. 232Matsuda, I. 67. 230Matsuda, K. 161Matsuda, T. 114Matsuda, Y. 99Matsumoto, H. 23, 24Matsumoto, K. 196Matsumoto, M. 67Matsumoto, N. 322Matsumoto, T. 327Matsunaga, M. 87Matsuno, T. 316Matsuura, T. 158Matsuyama, A. 195Matyaskova, M. 49Mäusle, F. 144Maycock, C.D. 297Mayr, H. 103, 176McCoy, M. 309McCullough, K. 84McCullough, K. J. 84McGarry, D. 96McGarry, D.G. 97McKean, D. R. 191, 263McLaughlin, J. J. 201McLeod, M.D. 72McManis, J. S. 149, 152McOsker, C.C. 268Meah, Md.Y. 85Mecca, T. 109Medvedev, O.S. 221Meerwein, H. 47Meguro, H. 86Mehrotra, A. K. 108Meichsner, G. 246Mekhalfia, A. 111, 114Melchiorre, P. 314Mellingar, M. 92Menche, D. 315

Author Index 355

Mendes, E. 105Menichetti, S. 280Menta, E. 64Merz, A. 255Messinger, J. 263Mester, Z. 140Metlesics, W. 45Meul, T. 127Meyers, A. I. 275Miao, S.W. 286Miao, S.W. 78Midgley, J. M. 1, 241Miginiac, L. 220Miginiac, P. 312Mikami, K. 111Mikhail, G. 10Miki, T. 196, 197, 199Mikolajczik, M. 264Miljkovic, D. 77Miller, J.D. 88Miller, M.M. 317Miller, N. 50Miller, R.D. 191, 192, 193,

263, 280Millership, J. S. 1, 241Milner, P. 94Minakata, S. 157Minami, N. 281Minamikawa, J. 142Miocque, M. 45Mioshi, N. 111Miotti, U. 189Mironov, V.F. 12, 68, 88,

103, 105, 117, 329Mironova, N.V. 12, 221,

329Mishra, N.C. 54Mismash, B. 266Misra, R.N. 149Mistryukov, E. A. 99Mitchel, M.B. 161Mitchel, M.R. 161Mitrowski, A. 46Mitsunobu, O. 195Mitsuzuka, H. 270Miuara, K. 31Miura, K. 270Miura, T. 305Miwa, N. 158Miwa, T. 311Miyamoto, H. 270Miyashita, A. 154Miyashita, K. 203

Miyashita, M. 70, 71Miyata, H. 228Miyata, K. 261, 263Miyata, N. 86Miyazaki, M. 67Miyazawa, K. 327Miyoshi, S. 70Mizhiritskii, M.D. 279Mizuno, H. 203Mizuta, K. 279Mloston, G. 156Moberg, C. 158Mochizuki, A. 47Modena, G. 189Moffatt, J.A. 204Möhring, E. 74, 237Moisan, L. 220Moiseenkov, A. M. 172Mojtahedi, M. 96Mojtahedi, M.M. 103Molander, G.A. 115Molina, M.T. 272Monenschein, H. 296Mooiweer, H.H. 114Mordas, D.M. 170Mordini, A. 102, 108, 109More, K. M. 189Moreau, J. J. E. 101, 228Moreira, R. 105Mori, A. 30, 278Mori, H. 123, 270Mori, I. 104, 107, 278Mori, M. 284Mori, S. 224, 313Moriga, M. 279Morimoto, T. 94, 100,

117Morin, R.A. 200Morita, R. 312Morita, T. 166, 265, 312Moriwake, T. 314Morizawa, Y. 139Moromoto, T. 101Morrisey, C. T. 332Mortimer, C.T. 29Mörtl, M. 102Motherwell, W. B. 309,

310Mousalouhouddine, M. 129Movsum-zade, E.M. 29Mowery, M.E. 22Mozdzen, E.C. 261Mueller, R.A. 200

Mukaiyama, T. 70, 71, 73,107, 111, 113, 123, 198,269, 317

Mukerji, S. K. 171Mukhopadhyay, T. 179Mukkala, V.-M. 157Mukuta, T. 171Mulholland, K. R. 34Mullakhmetova, Z.F. 120Müller, E. 327Müller, G. 247Müller, K. 77Mullins, M. 189Münch, A. 256Münch, W. 91Mundt, M. 253Munetoh, T. 327Murai, S. 108, 109Murai, Y. 281Murakami, M. 111Muralidhar, B. 284Murase, H. 281Murata, S. 10, 11, 115, 137Muroguma, Y. 312Murphy, F. 114Murugavel, R. 32Musachio, J.L. 72Musavirov, R. S. 120Mushkalo, I.L. 75Muslukhov, R.R. 225Muth, C.L. 261

nNagai, Y. 23Nagao, Y. 293Nagaoka, H. 111Nagasaka, T. 49, 275Nagasawa, K. 46Nagashima, S. 23Nagatsuma, M. 97Nagendran, S. 22Naimi-Jamal, M.R. 103Naka, T. 154Nakagawa, M. 321Nakagawa, T. 31Nakagawa, Y. 234Nakagei, Y. 311Nakahara, S. 152Nakahashi, K. 8Nakahira, H. 305Nakai, H. 171Nakai, T. 97, 152Nakai, Y. 24

Author Index356

Nakajima, T. 108, 109Nakamura, A. 1, 241Nakamura, E. 313Nakano, K. 296Nakano, T. 24Nakao, R. 70Nakaoka, K. 95Nakata, T. 46Nakatsuka, Y. 33Namme, R. 270Nang-Chi, G. 247Narang, S. C. 9, 10, 71,

108, 135, 172, 261, 263,264, 277

Nardi, P. 22Naritomi, T. 120Narjes, F. 307Nashed, E.M. 91Nasielski, J. 158Nasielski-Hinkens, R. 158Nataniel, T. 297Natsune, H. 138Nedogrei, E.P. 120Negron, A. 28Neilson, R. H. 331Neilson, R. N. 327Nelson, J.D. 295Nelson, S.G. 310Nelson, T. D. 18Neplyuev, V. M. 75Neri, O. 265Nesbitt, S.L. 106Neuenschwander, K. 271Neuhausen, P. 8, 221Neumann, H. 284Neumann, W. P. 167Nezu, Y. 101Nicolaou, K. C. 84, 93, 271Nieballa, U. 2Niedballa, U. 4, 51Niederprüm, H. 206Nieger, M. 157Niimi, L. 115, 117, 329Niinomi, J. 245Niitsuma, S. 152Nikiforov, B. P. 8Nikishina, I.S. 181Nishi, S. 53Nishida, A. 95, 321Nishida, M. 95Nishida, Y. 86Nishigushi, I. 313Nishihara, J. 28

Nishihara, Y. 30, 278Nishikawa, K. 154Nishikawa, N. 102Nishikawa, S. 62Nishikimi, Y. 62Nishikori, H. 270Nishimura, S. 149, 152Nishitani, T. 219Nishiyama, H. 67Nishiyama, K. 93Nishiyama, S. 296Nishiyama, Y. 263, 315,

331Nishizawa, M. 123, 270Nittoli, T. 32Noack, R. 247Noda, H. 149Nojima, M. 84Nolin, K. A. 269Noltemeyer, M. 318Nomura, R. 316Nonaka, T. 234Nonami, Y. 84Normant, J. F. 241Norton, J. R. 317Nowak, H. 297Noyori, N. 111Noyori, R. 10, 11, 83, 115,

122, 137, 201, 270, 287,292

Nozaki, H. 104, 139, 278,285

Nshimyumukiza, P. 98Nugent, M. J. 96Nugiel, D.A. 271Numata, T. 279Nydegger, F. 8, 228Nyulaszi, L. 254

oOae, S. 279Oba, M. 93Obayashi, M. 278O’Brian, E. 210Ochiai, M. 293, 317Ochoa, C. 12Oda, K. 275Oda, M. 246Oehme, H. 47, 246Oesterle, T. 74Oesterle, Z 10Ofial, A.R. 103Ogata, S.-I. 47

Ogawa, A. 108, 305,316

Ogawa, D. 276Ogle, C.A. 313Oguni, N. 97Ogura, K. 211Ogura, N. 84Oh, D. Y. 106Ohashi, M. 230Ohkawa, K. 24Ohkawa, Y. 97Ohki, S. D. 49Ohkura, Y. 270Ohno, M. 172, 228Ohno, T. 224Ohrui, H. 86Ohshiro, Y. 157Ohtake, H. 87Ohwaki, Y. 152Oishi, Y. 327Ojima, I. 8, 267Ojima, M. 154Oka, K. 70Okada, H. 67Okamoto, T. 99, 147Okamoto, Y. 166, 196, 265,

311, 312Okano, K. 117Okano, M. 139Okazaki, R. 164, 290Oki, A. R. 157Okino, T. 161Oku, A. 85, 115Okumura, K. 149Olah, G.A. 9, 10, 71, 108,

135, 156, 172, 261, 263,264, 270, 271, 277, 289

O’Leary Bartus, J. 234Oliveros-Desherces, E. 99Ollevier, T. 114O’Mahony, D. J.R. 310Omura, K. 205O’Murchu, C. 126O’Neil, I. 195O’Neill, P. M. 112Onishi, Y. 276Ono, S. 95Ooi, T. 305Ootsuka, K. 270Oranovskaja, E.W. 221Ordanini, G. 53Orfanopoulos, M. 268Orito, K. 152

Author Index 357

Oriyama, T. 114Oriyama, T. 114Orlov, G. I. 105Orlova, N. A. 92, 105Ornaf, R. M. 221Ornstein, P.L. 135, 157,

261Orschel, B. 178Ortwine, D.F. 152Osaka, N. 67Osborn, J. A. 319Osborn, R. R. 234O’Shea, D.M. 309Oshima, K. 104, 139, 285Oshima, M. 111Oshiro, Y. 228Osthoff, R.C. 17, 27Oussaid, A. 135, 332Overman, L.E. 283Owens, J. 56Ozawa, N. 49

pPadwa, A. 161, 235Pagnoni, U. 204Pagnoni, U.M. 202, 203,

205, 317Pai, C.-L. 270Pale, P. 1, 8Palme, H.-J. 297Palomo, A. L. 10Palomo, C. 245, 266, 268Palumbo, G. 265Palumbo, M. 64Pang, J. 226Pannel, K.H. 23Panuncio, M. 95, 96, 97,

101, 120Papageorgiou, G. 103Paredes, C.G. 224Parello, J. 99Parikh, JJ.R. 204Park, B. K. 112, 210Park, M.J. 28Park, M.K. 28, 310Parnes, Z.N. 267Parshall, G. W. 254Parsons, P. J. 190Pashcal, J. W. 157Pataud-Sat, M. 101Patel, H.V. 161, 166Patel, P. 207Paterson, I. 72, 244, 315

Patil, G. 10Paulini, K. 16Paulvannan, K. 1Pauly, M. 66Pavlidis, V. H. 261Pavlov, S.F. 35, 142Pavlova, L.A. 94Pawlenko, S. 17Payne, S.G. 310Paz, M.A. 294Pearce, A. 244Pearce, E.M. 330Pearson, W. H. 87Pechine, J.M. 227Pedersen, B.S. 212Pedley, J. P. 29Peelegata, R. 221Pei, T. 322Pellacani, L. 181Pellagata, R. 44Pelter, A. 226Perbost, M. 50Perciaccante, R. 181Perez, D. 275Perez, M. 227Perry, D. A. 193Perry, P. J. 261Perz, R. 34, 276Petasis, N.A. 88Peters, E.-M. 246, 332Peters, K. 104, 246, 332Peterson, B. H. 88Petrosyan, V. S. 223Pfaltz, A. 48Pfitzner, K. E. 204Pflaum, S. 254Phan, S. M. 33Piade, J. J. 227Picard, J.P. 245, 281Pichl, R. 255Picotin, G. 312Pidvarko, T. I. 253Pierce, M.E. 234Piers, E. 217Piessi, L. 120Pietropaolo, D. 241Pietrusza, E. W. 27Pifferi, G. 221Pihko, P. M. 84Pike, R. M. 41Pike, S. 180Pillot, J.-P. 327Pinetti, A. 203, 204, 317

Pinnick, H.W. 9, 201Pinter, G. W. 152Pinza, M. 221Pinzani, D. 102Pisarnitskii, D.A. 223Plater, M.J. 226Pohmakotr, M. 287Pola, J. 27, 28Poletti, L. 161Ponaras, A.A. 85Ponce, A. M. 283Ponsford, R. J. 94Popkin, M.E. 310Porco, J. A. 276Pornet, J. 220Porskamp, P.A. T.W. 205,

206Post, R. 152Pothier, J. 9Prajapati, D. 161Prakash, G. K. S. 270, 271,

289Prasad, K. 123Prekash, G. K. S. 156Prishchenko, A.A. 223Promo, M.A. 17Prostakov, N.S. 149Prouihac-Cros, S. 289Provencio, R. 12Psarras, T. 53Pugh, M. 112Pump, J. 66Pusset, J. 23Pyman, F. L. 126Pyne, S.G. 195

qQian, W. 84Quadrelli, P. 74Quaedflieg, P.J.L.M. 45Quan, M.L. 225Quast, H. 246Quellhorst, H. 33Quian, L. 46Quick, S. J. 191Quin, L.D. 30

rRaibmann, B. 22RajanBabu, T. V. 167Rajapakse, H.A. 273Rakmankulov, D.L. 120Ramos, L. 9

Author Index358

Ranaivosata, J.-L. 84Rane, A.M. 30Ranu, B.C. 19Rao, C.B. 289Rao, M. 274Rao, M.N.S. 22Rao, R. J. 274Raphael, R. A. 62Rasmmussen, J. 10Rasmussen, J. K. 30, 148Rassu, G. 141Rathke, B. 46Rathore, R. 297Rautureau, M. 157Rayner, B. 58Razumaev, G. A. 277Read, R. W. 126Reader, J.C. 113Reddy, M.V. 274Reddy, P.Y. 44Reese, C.B. 50Reese, E. 27Reetz, M.T. 28, 180, 249Reginato, G. 102, 108, 109,

287Regitz, M. 253, 254, 257,

258, 292Rehwinkel, H. 126, 230Reich, H. J. 208, 211Reid, J.D. 32Reikhsfel’d, V.O. 279Reiner, J. 268Reinhoudt, D. N. 97Reisch, J. 140Reisch, M.S. 330Reiß, G. J. 254, 257Reissig, H.-U. 16, 178, 179,

247, 271Reitano, M. 102Ren, J. 34Ren, Y. 316Renaldo, A. F. 280Repic, O. 104, 123Retzko, I. 91Reusch, W. 245Reuter, K. 167Reye, C. 22, 276Reymand, S. 142Rhigetti, P.P. 74Ricca, A. 124Ricci, A. 108, 109, 181,

212, 241, 285, 286, 287Richardson, G.D. 84

Riche, C. 198Richter, P. 1, 69, 103, 194Richter, R. 327Rieder, H. 104Riemer, R. 255Rigaudy, J. 180Rigo, B. 8, 66, 77, 227,

232, 233Riordan, P.D. 284Ripka, W. C. 91Risch, N. 118Ritter, A. 1, 7, 8, 11, 27, 69,

103, 194, 221Ritter, G.W. 28Rivera, I. 28Rivera, M. 98Riviere, M. 99Robbins, J. 306Roberts, L.R. 309, 310Robertson, A.D. 172Robins, M.J. 57Robins, R. K. 55, 56Robinson, P.D. 138Robinson, T.R. 22Robl, J. A. 84, 161Roche, M.P. 29Rochow, E. E. 105Rochow, E. G. 28, 66, 95,

99, 152Roden, B. A. 261Rodionov, E.S. 68Rodriguez-Lópes, J. 99Rodriques, K. E. 221Roe, M.B. 265, 295Roesky, H.R. 32Roesky, H.W. 10, 318Roewer, G. 327Rogozhin, S. V. 94Romanenko, V. D. 253Romani-Ronchi, A. 314Romo, D. 78Roos, E.C. 90, 114Rösch, W. 257Rose, L. 296Rosenfeld, M.N. 209Rosenheim, A. 22Roskamp, E. J. 104Rossier, J.-C. 84Rostovskaya, G. E. 44Roth, B. D. 271Roth, M. 74, 178Rotter, H. 144Roush, W. R. 115

Rousseau, B. 8, 228Roy, A.K. 332Rozhkova, Z.Z. 206Ruano, J. L.G. 224Rubin, M. 267Rubottom, G.M. 283Rücker, C. 30Rudchenko, V. F. 181Rudchenko, V. O. 179Ruden, R. A. 244Rühlmann, K. 7, 15, 28,

40, 95, 99, 129, 218, 267Ruh-Pohlenz, C. 55Ruppert, I. 206, 253Rusanov, A.L. 327Russ, M. 261Ryan, K. 152Ryan, M.D. 234Rychnowsky, S.D. 111Ryu, I. 108, 305

sSaba, A. 157Sachdev, H.S. 210Sachdev, K. 210Saconi, G. 287Saeki, T. 111Safanov, I.G. 88Safarov, I. M. 225Safarov, M.G. 225Safronov, S.O. 317Sagi, M. 152Saidi, M.R. 96, 103, 118Sainte, F. 98Saito, H. 149Saito, S. 139Sakai, N. 320Sakai, T. 247, 261, 263Sakamoto, K. 85Sakamoto, M. 283Sakamoto, T. 149, 152Sakasaki, K. 277Sako, M. 53Sakurada, I. 289, 290Sakurai, H. 33, 111, 139,

142, 166, 265, 269, 277,312

Sakuta, K. 67Salem, G. F. 10, 71, 264Salonius, A. 84Salzmann, T.N. 193Sambeth, J. 49Sammes, P. G. 84

Author Index 359

Sampath, U. 53Sandhu, J. S. 161Sandler, S.R. 45Sanghvi, Y.S. 50Sano, T. 114Santella, J. P. 234Sardarian, A.R. 122Sarma, J. C. 263Sartori, P. 10, 17Sasai, H. 288Sasaki, K. 33, 111, 142Sasaki, R. 110Sasatani, S. 265Sassaman, M.B. 271Sato, M. 93Sato, N. 152, 158Sato, T. 281Sato, Y. 245Sauer, R. O. 3, 9, 51Savina, T. I. 206Scafato, P. 109, 110Scanlon, W. P. 200Scartoni, V. 63Schach, A.S. 22Scharf, H.D. 84, 219Schaumann, E. 192, 307Scheffer, J. R. 217Scheiblich, S. 192Scherer, O. J. 292Scheuller, M.C. 293Schick, H. 297Schiemann, K. 111Schier, A. 32Schill, G. 211Schilling, H. 95Schinzer, D. 241Schirawski, G. 9, 11, 237Schlemper, H. 332Schlummer, B. 320Schmeisser, M. 10, 17Schmidbaur, H. 14, 27, 32,

207, 208Schmidpeter, A. 253Schmidt, A. 261Schmidt, H. 254Schmidt, H.-G. 318Schmidt, J. 191Schmidt, M. 207, 208, 242Schmitt, A. 271Schmitt, W. 15Schoemaker, H.E. 114Schoemaker, H.S. 90Schoenfelder, A. 111

Schoepp, D.D. 157Schön, N. 47Schön, U. 263Schöning, K.-U. 296Schoop, T. 318Schorr, M. 15Schraml, J. 28Schramm, J. 96Schreiber, S.L. 86Schrock, R.R. 306Schröder, M. 315Schroth, W. 103Schultze, L.M. 3Schulz, D. 247Schulz, G. 118, 227f.Schunack, W. 126Schuyten, H.A. 32Schwamborn, M. 330Schwarz, G. 328Schwarz, H. 28, 180Schwarz, J. P. 1Schwarz, N. 126Schwarz, S. 297Schweiker, K. 17Schwerdtfeger, A.E. 84Schwesinger, R. 144, 332Schwindeman, J. A. 199Schwöbel, A. 207Scolastico, C. 101Scott, J. P. 244Scriven, E. F.V. 157Seagle, P. 313Seckar, J. A. 20Seconi, G. 181, 285, 286Seebach, D. 8, 70, 88, 111,

172, 179, 191, 284Seela, F. 57Seethaler, T. 247Segi, M. 108, 109Seidler, M.D. 278Seitz, G. 66Sekiguchi, A. 249, 281Sekiya, M. 94, 100, 101,

117, 225Selin, T. G. 102Semenov, A. A. 126Semenov, V. V. 277Semones, M.A. 235Senatore, G. 63Sengupta, S. 313Seppelt, K. 306Sergeev, V.N. 92Serita, K.-I. 117

Serita, K.-I. 329Seward, C. 226Seyferth, D. 20, 29Shabarova, Z. I. 9Shadle, J.K. 206Shafiullah, P.R. 203Shah, S. K. 208Sharkey, W.H. 20Sharma, H.K. 23Sharma, R.K. 306Sharma, R.P. 263Sharma, S.C. 171Sharpless, K. B. 290Shau, J.-H. 245Shcherbinin, V. V. 68Shea, K. J. 327Shea, K. L. 17Sheldon, B.G. 208Sheldrake, P.W. 92Sheludyakov, V.D. 12, 68,

181Shepherd, R. G. 59Shi, N. 314Shiao, M.-J. 281Shiba, S. A. 158Shibasaki, M. 217, 288,

289, 290Shibata, K. 290Shibata, N. 196, 197, 199Shih, N.-Y. 98Shiina, I. 70, 71Shiino, K. 115, 329Shikiev, I.A. 29Shimada, K. 109, 110Shimizu, B. 50Shimizu, H. 191Shimizu, M. 152, 198Shimomura, Y. 152Shin, C. 149Shin, D.-Y. 113Shintani, T. 85, 115Shioiri, T. 224, 233, 235Shiotani, S. 152, 154Shipov, A.G. 92, 105Shippey, M.A. 277Shiragami, H. 53Shirahama, H. 157Shirahata, A. 277Shitkin, V. M. 171Shono, T. 281Short, J.H. 50Shudo, K. 223Shum, C.C. 138

Author Index360

Shuman, R. T. 157Sieburth, S.M. 17, 32Siegel, H. 8Sigalov, M.V. 275Silverman, S. B. 268Simchen, G. 10, 11, 13, 17,

74, 172, 247Simon, C.D. 195, 198Simon, R. 28Simonsen, A. J. 266, 294Singer, P. P. 261Singh, G. 90Sinha, N.D. 3Siray, M. 253Sisko, J. 92Sissi, C. 64Sita, L.R. 69Sklorz, C.A. 315Skoboleva, S.E. 221Skrydstrup, T. 17Slade, J. 123Sloan, T. A. 22Smale, T. C. 94Smith, A. B. 88, 243, 271Smith, C. L. 309Smith, C. S. 293Smith, K. 226Smith, K. A. 27Smith, S. H. 221Smith, T. E. 271Smoot, J. 53Smrekar, O. 179Smrt, J. 50Snyder, B. B. 225Snyder, D. C. 137So, J.-H. 305, 310Soborwskii, L.Z. 254Söderholm, S. 104Soderquist, J. A. 28, 30Soga, T. 107Söger, N. 33Sohn, S. Y. 297Soldatenkov, A.T. 149Soliman, H. 121Solodenko, W. 263Sommer, L.H. 27Sommer, L.O. 35Sommer, P. 12, 68, 71Sone, K. 161Song, D. 49, 76, 91Sonoda, N. 108, 109, 305Sorm, F. 50Soysa, H.S. D. 278

Spagnolo, P. 110Spaltenstein, A. 230Speckamp, W.N. 90, 114Speier, J. L. 15Spinelli, S. 64Spoor, P. 135Spunta, G. 96, 97Srimal, R.C. 203Srinivasan, P. R. 28Stachulski, A.V. 94, 112Stañczyk, W. A. 31Stang, P. J. 293, 294, 317Stavenger, R. A. 33Steele, R. W. 90Steffens, R. 126Steglich, W. 227f.Steimann, H. 18Steinbach, G. 242Steiner, B. 180Stenkamp, D. 273Stepanova, E. E. 46Steppan, W. 10, 74Sternbach, L.H. 45Sternson, S. M. 86Stilke, R. 231Still, I.W. J. 197Still, W. C. 71, 278Stille, J. R. 1Stone, F. G.A. 28Stoner, E. J. 261Stopp, G. 47Stout, T. 11Strautmanis, J. R. 197Strelenko, Y.A. 171, 172,

176Ströhl, S. 103Strohriegl, P. 330Strunz, G. M. 84Stubbs, K. M. 24Stucky, G. 88Stump, E.C. 53Su, T.-L. 62Suda, S. 270, 317Suga, S. 108, 109Sugi, R. 328Sugiara, M. 117Sugiura, Y. 154Suh, J.-G. 113Sukata, K. 313Sulbaran de Carrasco,

M.C. 309Sumi, K. 293Sumino, N. 315

Sumrell, G. 33Sundberg, R. J. 62Sundermeyer, J. 290Sung, S.-J. 321Sung, S.-Y. 321Sung, W. L. 50Süss-Fink, G. 268Susuki, M. 270Suzuki, H. 230Suzuki, I. 98Suzuki, M. 10, 11, 83, 84,

111, 115, 122, 287Swann, P. E. 50Sweatlock, J. A. 53Swern, D. 204, 205Szabô, K. J. 62Szabó, L. 85Szweda, P. 54

tTabei, N. 235Tacchi, P. 63Taddai, M. 285Taddei, M. 241, 285, 286Taisne, S. 8, 227Takacs, J. M. 121Takagi, A. 279Takagi, Y. 245Takahashi, H. 270Takahashi, K. 104Takahashi, M. 109, 114Takahashi, T. 94, 230Takai, K. 285, 312, 314, 315Takalo, H. 157Takaoka, K. 235Takaoka, Y. 317Takayama, H. 95Takeda, A. 247, 261Takeda, H. 287Takeda, N. 305Takeda, T. 190Takemoto, Y. 161Takemura, K. 195Takemura, Y. 196Takenoshita, H. 73, 107Takeuchi, H. 313, 316Takeuchi, R. 152Takikawa, Y. 109, 110Talanov, V. N. 46Talbert, J. 312Talipov, R.F. 225Tamaki, K. 31Tamura, J.-I. 28, 85

Author Index 361

Tamura, O. 194, 196, 197,199

Tamura, Y. 194, 197, 199Tan, C.-W. 43Tan, H.S. 201Tanabe, Y. 322Tanaka, A. 203Tanaka, J. 120Tanaka, M. 203Tanaka, S. 85Tani, H. 147Tanigichi, K. 152Tanigushi, N. 70Tanimoto, S. 99Tao, B. 268Tapiero, C. 58Tardella, P. A. 181Tartakovskii, V.A. 92, 171,

172, 179Tartakovskii, Y. A. 172, 176Taschner, M.J. 271Taylor, P.G. 207Taylor, R. J. K. 191Teach, E. G. 254Tenud, L. 127Terao, Y. 190Terpinski, J. 306Texier-Boullet, F. 228Thayer, J.S. 20The, H.-S. 66Theil, F. 297Theilig, G. 129Theys, R.D. 248Thiaw-Woaye, A. 314Thiel, W. R. 269, 319Thiele, G. 144Thieme, E. 28Thomas, A. W. 84Thomas, D. G. 96Thomas, E. 179Thompson, K.L. 96Thomsen, L. 171Ti, G. S. 3Tietze, L.F. 111Tinant, B. 114, 158Tishkov, A. A. 171, 172Tius, M.A. 107Toce, J.A. 53Todd, A.R. 2, 51Togo, H. 279Tohjo, T. 196Tokitoh, M. 164Tokitoh, N. 164, 191, 290

Tokunago, Y. 220Tokuyama, S. 102Tolkunov, S.V. 64Tölle, J. 27Tolomelli, A. 181Tono, T. 197Toome, V. 45Toratsu, C. 312Torphy, T. J. 234Torssell, K. 171Torssell, K. B.G. 171, 172Toru, T. 44Toste, F.D. 269, 319Trehan, S. 139Treverton, J.A. 29Trieselmann, T. 72Troisi, L. 286, 287Trombini, C. 161Tronche, P. 50Trossell, K. B.G. 171Trost, B. M. 17, 30, 193,

319Trub, E. P. 221Truesdale, L.K. 106, 121Tsai, S.-C. 161Tsai, Y.-M. 193Tsay, S.-C. 138, 161, 280Tschernko, G. 18Tseng, W.N. 166Tsuboi, S. 247, 263Tsuchida, T. 190Tsuchihashi, G.-I. 211Tsuge, O. 120, 161, 249Tsui, F.-P. 166, 180Tsuji, T. 278Tsumaki, H. 243Tsunoda, K. 27Tsunoda, T. 83, 111, 122,

270Tsuruya, S. 296Tsutsumi, A. 232Tuchtenhagen, G. 99Tucker, J. A. 170Turner, M.L. 332Twerashima, M. 77Tykwinski, R. 293, 294, 317

uUchida, T. 288Uchimura, J.-j. 85Uchiyama, M. 292Uda, H. 193Ueda, S. 85

Ueda, T. 314Uemura, M. 102Ueno, K. 17Ueno, Y. 44Uesaka, N. 84Ugolini, A. 223Uguen, D. 286Uhl, G. 255Uhl, W. 253, 257Uhlenbrock, W. 9Uhlig, W. 17Umbricht, G. 48Umemura, K. 149Underwood, D.C. 234Uneyama, K. 313Unger, N. D. 202Ungur, N. D. 218Upadhya, K. 3Urano, S. 161Utaka, M. 247, 261, 263Utimoto, K. 312Uwano, A. 109Uyehara, T. 98

vVahlensieck, H. J. 24Valligny, D. 8, 227van der Leij, M. 205, 206van Eenoo, M. 265van Leeuwen, S.H. 45van Look, G. 1, 11van Praag, D. 50van Staden, L.F. 243Vanderhaeghe, H. 201Vanherck, J.-C. 114Vaquier, J. 30Varvounis, G. 62Vedejs, E. 189Vedsø, P. 159Velo, S. 63Venit, J. 15Venkatesvaran, P.S. 13Venkatesvarlu, A. 19Verboom, W. 97Vereshchagin, A.L. 126Vernhet, C. 101, 228Verweij, J. 201Veselovskii, V.V. 172Vidal, T. E. 332Villa, M. 44Villieras, J. 241Vinader, V. 135Vinson, J. R.T. 152

Author Index362

Visnick, M. 243Visser, R. 97Visser, R. G. 242Viswanadham, G. 57Vitkovskii, V.Yu. 275Vlad, P.F. 202, 218Vogel, T. M. 166, 180Vogelbacher, U. 257Vögtle, F. 157von E. Doering, W. 204von Matt, P. 48von Schnering, H.G. 104,

246, 332von Schütz, J.-U. 104Vorbrüggen, H. 2, 4, 8, 9,

10, 11, 19, 46, 49, 50, 51,52, 55, 56, 57, 76, 91,126, 127, 128, 133, 144,147, 158, 159, 161, 165,166, 217, 223, 228, 230,277, 306, 307, 308, 309

Voronkov, M.G. 9, 19, 31,35, 42, 120, 121, 135,142, 142, 144, 275

Voss, P. 206Vostikov, I.A. 221Vostokov, I.A. 221Vvedenskii, V.Yu. 42Vygodskii, Ya. S. 327

wwa Mutahi, M. 32Wada, E. 249Wada, I. 85Wadamoto, M. 33Wagner, S. 28Wahl, G. 290Wakefield, B. J. 62Wallach, P. 180Walley, D.R. 223Walling, J.A. 272Walther, P. 292Walton, D.R. M. 180Walz, A. J. 62Walz, L. 332Wang, C.C. 270Wang, C.-L. J. 91, 172Wang, J.-X. 320Wang, N. 28, 161Wang, S. 226Wang, Z. 310Wannagat, U. 9, 11, 95, 99,

179, 237

Ward, S.A. 112Wasylishen, R. E. 194Watabe, T. 246Watanabe, A. 288Watanabe, H. 109, 110Watanabe, K.A. 62Watanabe, S. 283Watanabe, T. 319Wataya, Y. 84Watkin, D. J. 34Weaver, J. W. 32Weber, G. 297Weber, W. 294, 295Weber, W.P. 189, 278Webster, J. 15Wegmann, H. 118Wehrli, P. 77Weiberth, F. J. 44Weimar, W. R. 152Weinreb, S. M. 102, 275Wells, D.A. 221Wempen, I. 50Wemple, J. 189Wender, I. 8, 106Wentrup, C. 255Wermuth, C.G. 230Werner, H.-P. 104Wesdemiotis, C. 28Wessely, H.-J. 255, 256West, C.T. 267, 268West, R. 2, 27, 123, 179West, W. 10, 74Wettach, R. H. 293Wettling, T. 292Wetzel, J.M. 84, 166Whalley, W. B. 1, 241Whang, D. 172Whatley, L.S. 27White, D.M. 11White, J. D. 208Whitmore, F.C. 27, 35Wiberg, N. 9Widenhoefer, R. A. 322Wiegand, J. 149, 152Wiemer, D.F. 233Wienand, A. 247Wikins, C. J. 33Wilke, G. 88Wilkening, A. 33Wilkins, R. F. 103Williams, R. M. 223Williamson, B. L. 317Willis, M.C. 48, 105

Wilson, E.K. 330Wilson, K.L. 22Wink, D. 272Winn, M. 246Winotai, C. 287Winter-Extra, S. 192Wisian-Neilson, P. 327, 331Wojciechowski, K. 167Wölcke, U. 230Wolf, H.C. 104Wolff, W. D. 31Wolmershäuser, G. 292Wong, F.F. 73, 166, 281Wong, H.N.C. 190Wong, J.C. 86Wong, K.-T. 33Wong, L.T. L. 44Woodward, J. K. 266Wrobel, Z. 168, 170Wu, J.-J. 10Wustrack, R. 47, 246Wuts, P.G. M. 161Wynants, C. 98Wynn, T. 33

xXi, R. 69Xia, M.X.B. 149Xu, D. 104Xu, Y.-Z. 50

yYablokova, N.V. 290Yagupol’skii, Y. L. 206Yajima, H. 279Yalpanu, M. 88Yamada, H. 123, 270Yamada, M. 107, 317Yamada, Y. 77Yamaguchi, H. 293Yamaguchi, K. 223Yamaguchi, S. 152Yamakoshi, K. 288Yamamoto, A. 246Yamamoto, C. 311Yamamoto, H. 33, 67, 115,

265Yamamoto, Y. 46, 98, 124,

234, 267, 311Yamanaka, H. 149, 152Yamanaka, M. 321Yamanaka, T. 67Yamantaev, F. A. 225

Author Index 363

Yamasaki, S. 289, 290Yamazaki, T. 77Yamoto, T. 270Yanagisawa, A. 33Yang, F. 248Yang, J. 78Yang, S.S. 96Yang, T.-K. 96, 97Yang, W.-C. 270Yankelevich, A.Z. 171Yao, G. W. 152Yap, K. B. 306Yashiro, A. 172Yasuda, H. 1, 194, 199, 241Yasuda, M. 276Yasuda, N. 53Yasuma, T. 154Ye, X.-S. 190Yeh, M.C.P. 312Yelland, L. J. 172Yep, G.L. 138Yeung, C.M. 141Yim, E. S. 28Yoder, C.H. 11Yokomizo, Y. 317Yokoyama, H. 47, 152,Yokoyama, M. 47

Yokozawa, T. 115, 117, 138,328, 329

Yonazawa, Y. 149Yoneda, F. 247Yonemitsu, O. 95Yoshida, K. 275Yoshida, M. 319Yoshida, N. 196Yoshida, T. 85Yoshida, Y. 322Yoshihara, M. 232Yoshihiro, K. 23Yoshimura, J. 85, 149Young, J. C. 22Yu, H. 42Yu, M. 316Yu, M.S. 71Yu, S. F. 138Yuan, C. 172Yudin, A.K. 290

zZally, W. 45Zamboni, R. 223Zamore, M. 275Zanardi, F. 141Zanarella, S. 65Zandi, K.S. 17

Zarantonello, P. 101Zareyee, D. 296Zefirov, N.S. 293, 317Zemlicka, J. 50, 56Zemskaya, E.A. 64Zeng, L. 201Zeuthen, O. 171Zhang, B. 3Zhang, L. 3Zhang, S. 30Zhang, Y. 316Zhao, G. 284Zhao, J. 310Zhdankin, V. V. 266, 293,

294, 317Zhdanov, A. A. 43Zheng, D. 296Zheng, G. Z. 316Zhou, L. 313Zicmane, I. 28Zimmer, R. 178, 179Zimmermann, R. 15, 242,

255Zoeckler, A.T. 69Zoete, V. 230Zon, G. 166, 180Zwanenburg, B. 205, 206

Author Index364

Documents

Silicon-Mediated Transformations of Functional Groups