ORGANICREACTIONMECHANISMS 2012€¦ · Contributors K.K.BANERJI FacultyofScience,NationalLawUniversity,Mandore, Jodhpur342304,India C.T.BEDFORD DepartmentofChemistry,UniversityCollegeLondon,

ORGANIC REACTION MECHANISMS ⋅ 2012

ORGANIC REACTIONMECHANISMS ⋅ 2012An annual survey covering the literature

dated January to December 2012

Edited by

A. C. KnipeUniversity of Ulster

Northern Ireland

This edition first published 2015© 2015 John Wiley & Sons, Ltd

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Contributors

K. K. BANERJI Faculty of Science, National Law University, Mandore,Jodhpur 342304, India

C. T. BEDFORD Department of Chemistry, University College London,20 Gordon Street, London, WC1H 0AJ, UK

M. L. BIRSA Faculty of Chemistry, “Al. I. Cuza” University of Iasi,Bd. Carol I, 11, Iasi 700506, Romania

S. CHASSAING Centre National de la Recherche Scientifique, Universitéde Toulouse, Toulouse, France

Centre Pierre Potier, ITAV, Université de Toulouse,F-31106 Toulouse, France

INSA, F-31400 Toulouse, France

J. M. COXON Department of Chemistry, University of Canterbury,Christchurch, New Zealand

M. R. CRAMPTON Department of Chemistry, University of Durham, SouthRoad, Durham, DH1 3LE, UK

N. DENNIS 3 Camphor Laurel Court, Stretton, Brisbane, Queensland4116, Australia

E. GRAS Laboratoire de Chimie de Coordination, Centre Nationalde la Recherche Scientifique, Toulouse, France

A. C. KNIPE Faculty of Life and Health Sciences, University of Ulster,Coleraine, Northern Ireland

P. KOCOVSKY Department of Organic Chemistry, Arrhenius Laboratory,Stockholm University, Stockholm SE 10691, Sweden

Department of Organic Chemistry, Charles University,12843 Prague 2, Czech Republic

R. A. McCLELLAND Department of Chemistry, University of Toronto, Toronto,80 St George Street, Toronto, Ontario M5S 1A1, Canada

K. C. WESTAWAY Department of Chemistry and Biochemistry, LaurentianUniversity, Sudbury, Ontario P3E 2C6, Canada

v

Preface

The present volume, the 48th in the series, surveys research on organic reaction mech-anisms described in the available literature dated 2012. In order to limit the size of thevolume, it is necessary to exclude or restrict overlapwith other publicationswhich reviewspecialist areas (e.g., photochemical reactions, biosynthesis, enzymology, electrochem-istry, organometallic chemistry, surface chemistry, and heterogeneous catalysis). In orderto minimize duplication, while ensuring a comprehensive coverage, the editor conducts asurvey of all relevant literature and allocates publications to appropriate chapters. Whilea particular reference may be allocated to more than one chapter, it is assumed that read-ers will be aware of the alternative chapters to which a borderline topic of interest mayhave been preferentially assigned.In view of the considerable interest in application of stereoselective reactions to

organic synthesis, we now provide indication, in the margin, of reactions which occurwith significant diastereomeric or enantiomeric excess (de or ee).We are pleased to have retained for ORM2012 our current team of experienced authors

who have contributed to ORM volumes for periods of 7 to 34 years.However, it is unfortunate that intervention of the editor to avoid an anticipated delay

between title year and publication date for this volume was thwarted by unusually latearrival of a particularly long chapter. Nonetheless, we hope soon to regain our optimumproduction schedule.I wish to thank the staff of John Wiley & Sons and our expert contributors for their

efforts to ensure that the review standards of this series are sustained, particularly duringa period of substantial reorganisation of production procedures.

A. C. K.

vii

Contents

1. Reactions of Aldehydes and Ketones and their Derivativesby A. C. Knipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and theirDerivatives by C. T. Bedford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

3. Oxidation and Reduction by K. K. Banerji . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914. Carbenes and Nitrenes by E. Gras and S. Chassaing . . . . . . . . . . . . . . . . . . . . . 1715. Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2096. Carbocations by R. A. McClelland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2517. Nucleophilic Aliphatic Substitution by K. C. Westaway . . . . . . . . . . . . . . . . . . 2678. Carbanions and Electrophilic Aliphatic Substitution by M. L. Birsa . . . . . 3079. Elimination Reactions by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32510. Addition Reactions: Polar Addition by P. Kocovsky . . . . . . . . . . . . . . . . . . . . . 33311. Addition Reactions: Cycloaddition by N. Dennis . . . . . . . . . . . . . . . . . . . . . . . 43312. Molecular Rearrangements by J. M. Coxon . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579

ix

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

A.C. Knipe

Faculty of Life and Health Sciences, University of Ulster, Coleraine,Northern Ireland

Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . . . 2Reactions of Glucosides and Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . 3Reactions of Ketenes and Ketenimines . . . . . . . . . . . . . . . . . . . . . . . . . 4Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . . . 4

Imines: Synthesis, Tautomerism, and Catalysis . . . . . . . . . . . . . . . . . . 4The Mannich and Nitro-Mannich reactions . . . . . . . . . . . . . . . . . . . . 5Addition of organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Other alkenylations, allylations, and arylations of imines . . . . . . . . . . . . 8Oxidation and reduction of imines . . . . . . . . . . . . . . . . . . . . . . . . 9Iminium species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Imine cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Other reactions of imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Oximes, Hydrazones, and Related Species . . . . . . . . . . . . . . . . . . . . 13

C–C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . . . 15Reviews of Organocatalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Asymmetric Aldols Catalysed by Proline, Its Derivatives,and Related Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Other Asymmetric and Diastereoselective Aldols . . . . . . . . . . . . . . . . 16Mukaiyama and Vinylogous Aldols . . . . . . . . . . . . . . . . . . . . . . . . 19Other Aldol and Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . . 19The Henry (Nitroaldol) Reaction . . . . . . . . . . . . . . . . . . . . . . . . . 21The Baylis–Hillman Reaction and Its Morita Variant . . . . . . . . . . . . . . . 21Allylation and related reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 22Alkynylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Michael Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Miscellaneous Condensations . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Addition of Organozincs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Arylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Addition of Other Organometallics, Including Grignards . . . . . . . . . . . . 28The Wittig Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Hydrocyanation, Cyanosilylation, and Related Additions . . . . . . . . . . . . 31Hydrosilylation, hydrophosphonylation, and related reactions . . . . . . . . . . 31Miscellaneous additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 33Enolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33𝛼-Alkylation, 𝛼-Halogenation, and Other 𝛼-Substitutions . . . . . . . . . . . . 33

Organic Reaction Mechanisms 2012, First Edition. Edited by A. C. Knipe.© 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd.

1

2 Organic Reaction Mechanisms 2012

Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . . . 35Regio-, Enantio-, and Diastereo-selective Reduction Reactions . . . . . . . . . 35Other Reduction Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Formation and Reactions of Acetals and Related Species

Mechanisms and energetics for Brønsted-acid-catalysed glucose condensations, dehy-dration, and isomerization reactions have been reviewed.1 Recent developments in theasymmetric synthesis of spiroketals have been reviewed and the potential for furtherapplication of transition metal catalysis and organocatalysis has been highlighted.2 ee©

Hemiacetal formation from formaldehyde and methanol has been studied by intrin-sic reactivity analysis at the B3LYP/6-311++G(d,p) level and the beneficial combinedassistance of watermolecules and Brønsted acids has been quantified.3 Theoretical studyof hemiacetal formation from methanol with derivatives of CH3CHO (X=H, F, Cl, Br,and I) has shown that the energy barrier can be reduced by a catalytic molecule (MeOHor hemiacetal product).4

A combined experimental and density functional theory (DFT) study of the thermaldecomposition of 2-methyl-1,3-dioxolane, 2,2-dimethyl-1,3-dioxolane, and cyclopen-tanone ethylene ketal, in the gas phase, has established that acetaldehyde and thecorresponding ketone are formed by a unimolecular stepwise mechanism; concertednonsynchronous formation of a four-centred cyclic transition state is rate determiningand leads to unstable intermediates that then decompose rapidly through a concertedcyclic six-centred transition state.5

Real-time ultrafast 2D NMR observations of an acetal hydrolysis at 13C natural abun-dance have enabled observation of the reactive hemiacetal intermediate.6 Mutual kineticenantioselection (MKE) and enantioselective kinetic resolution (KR) have been exploredfor aldol coupling reactions of ketal- and dithioketal-protected 𝛽-ketoaldehydes expected ee©to have high Felkin diastereoface selectivity with a chiral ketone enolate.7 de©

The quantitative transacetalization of 2-formylpyrrole found in RONa/ROH mayinvolve highly reactive azafulvene intermediates.8

Baldwin’s rules can account for the unprecedented ring expansion, whereby poly-oxygenated eight- and nine-membered rings are formed regioselectively by rhodium-catalysed reaction of cyclic acetals with 𝛼-diazo 𝛽-ketoesters and diketones under mildconditions.9

It has been found that if an acetal OR group is first displaced to form a pyridinium-typesalt, then the resulting electrophile can be reacted with various nucleophiles under mild(non-acidic) conditions.10

An intermediate 1-methoxyfulvene is believed to form through a cyclization–cycloaddition cascade on reaction of allenyl acetals with nitrones catalysed by a goldcomplex and a silver salt (Scheme 1).11

A kinetic study of intermolecular hydroamination of allylic amines by N-alkylhydroxylamines has revealed a first-order dependence on aldehyde catalyst.

1 Reactions of Aldehydes and Ketones and their Derivatives 3

•

OMe

R2 NR1

++ −MeOH

NO

R1

H

R2

H

OMe

Au+

OMe

O−

Scheme 1

R1

HN

R2

+ R3

NH

OHR4 H

O

(Catalyst)N

N

R2

R4 R3

OH

R1

HN

R1

R2

NR3 OH

Scheme 2

This is a consequence of advantageous formation of a mixed aminal intermediate,which is able to undergo intramolecular Cope-type hydroamination, thereby leading tohigh yield of the required hydroamination product (Scheme 2).12

Coupling of alkenyl ethers (Ene–OR) with ketene silyl acetals R1R2C=C(OR3)OSiMe3, catalysed by GaBr3, forms 𝛼-alkenylated esters Ene–C (R1R2)CO2R3.13

Reactions of Glucosides and Nucleosides

Recent advances in transition-metal-catalysed glycosylations have been reviewed.14,15

Plausible transition states for such reactions have been discussed16 and primary 13Cisotope effects have been determined as a guide to the mechanism of formation of𝛼-manno- and gluco-pyranosides.17 The influence of protecting groups on the reac-tivity and selectivity of glycosylation chemistry of 4,6-O-benzylidene-protectedmannopyranosyl donors and related species has been reviewed.18

A commentary on diastereoselectivity in chemical glycosylation reactions has dis-missed molecular orbital explanations that invoke stereoelectronic effects analogous tothe anomeric effect in kinetically controlled reactions.19

de©A reversal of the usual anomeric selectivity for glycosidation methods with thiols

as acceptors has been observed for O-glycosyl trichloroacetimidates as donors andPhBF2 as catalyst; the reaction proceeds without anchimeric assistance to form mainly𝛽-thioglycosides, apparently through direct displacement by a PhBF2–HSR adduct.20

𝛼-Glycosylation of protected galactals to form 2-deoxygalactosides, promoted by athiourea organocatalyst, occurs by syn-addition.21 Cyclopropenium-cation-promoted de©𝛼-selective dehydrative glycosylations have been initiated using 3,3-dibromo-1,2-diphenylcyclopropene to generate 2-deoxy sugar donors from stable hemiacetals.22 Theyield obtained on 𝛼-glycosidation of 𝛼-thioglycosides in the presence of bromine is


undermined by partial anomerization of the intermediate 𝛽-bromide to the unreactive𝛼-isomer.23

High diastereoselectivity, giving 𝛼- and 𝛽-C-glycosides, respectively, has beenreported for reaction of C-nucleophiles with 2-O-benzyl-4,6-O-benzylidene-protected3-deoxy gluco- and manno-pyranoside donors. This does not parallel the preferentialformation of 𝛽-O-glycosides on reaction with alcohols, for which nucleophilic attackby Osp3 on oxocarbenium ions should be less sterically hindered than for Csp2 attack bya typical carbon nucleophile.24

de©A 2,4-O-di-t-butylsilylene group induces strict 𝛽-controlled glycuronylations, without

classical neighbouring group participation, by hindering approach of ROH to interme-diate oxocarbenium ion.25

A kinetic study of acid hydrolysis of methyl 𝛼- and 𝛽-d-glucopyranosides has revealeddirect participation by the counterion (Br− or Cl−), which becomes more pronounced asthe proportion of 1,4-dioxane is increased.26

Cyclodextrins carboxymethylated at the secondary rim have been evaluated aschemzymes for glycoside hydrolysis.27

A DFT investigation of the mechanism of alkaline hydrolysis of nitrocellulose dimerand trimer in the gas phase and in bulk water has indicated that, following a C(3) toC(6) to C(2) denitration route, peeling-off will be preferred to ring cleavage of the ringC–O bond.28 A DFT study of the kinetics and thermodynamics of N-glycosidic bondcleavage in 5-substituted-2′-deoxycitidines has provided insight into the role of thymineDNA glycolase in active cytosine demethylation.29 A real-time 1H NMR study of theacidic hydrolysis of various carbohydrates has revealed that for insulin the activationenergy decreases with chain length.30 Concentrated aqueous ZnCl2 is found to convertcarbohydrates into 5-hydroxymethylfurfural.31

Reactions of Ketenes and Ketenimines

The thriving chemistry of ketenimines has been reviewed32 and an overview of the devel-opment of silyl ketene imines and their recent applications in catalytic, enantioselectivereactions has also been summarized.33 ee©

Asymmetric synthesis of trans-𝛽-lactams from disubstituted ketenes and N-tosyl arylimines has been catalysed by (R)-BINAPHANE with up to 98% ee and ee©dr≥ 90 : 10.34 However, the Staudinger cycloaddition method can be unsuitable if de©the reactants (ketones + imines) bear electron-withdrawing substituents as 𝛽-lactamsundergo base-induced isomerization to the azacyclobutene followed by electrocyclicring opening to the corresponding 𝛼,𝛽-unsaturated alkenamide.35

Formation and Reactions of Nitrogen Derivatives

Imines: Synthesis, Tautomerism, and Catalysis

A restricted Hartree–Fock study of formation of Schiff base (N-[(Z)-furan-2-ylmethylidene]-4-methoxyaniline) from aromatic amine and furaldehyde has revealedthat an auxiliary water molecule enables proton transfer in the carbinolamine-forming


step.36 The temperature-dependent kinetics of second-order formation of N-salicylideneaniline in ethanol has been interpreted.37 Mechanistic analysis with the aid of DFTcalculations has enabled easy formation of triarylmethanimines from Ph2CO andPhNH2 under mild conditions catalysed by a Lewis acid–base pair (AlCl3–Et3N).38

An unprecedented highly enantioselective catalytic isomerism of trifluoromethylim-ines (2) has been promoted by a chiral organic catalyst (1) and thereby provided a newapproach to optically active alkyl and aryl trifluoromethylated amines (3).39

ee©

N

H N

Cl

OMe

OH

Z CF3

N

Ar

Z = RCH2 or RC6H4

10 mol% (1)

PhMe, 0.1 M

Ar = 4-NO2Phee ≤ 94%

(2)(1) (3)

Z CF3

N

Ar

Infrared spectra and structures have been reported for nitrile imines generated pho-tochemically and thermally in Ar matrices at cryogenic temperature. The results areconsistent with theoretical predictions, and the isomerization of both propargylic andallenic forms to the corresponding carbodiimides could be reversed by flash vacuumthermolysis.40

The kinetics and thermodynamics of the formation of E and Z enamines between alde-hydes with 𝛼-stereocentres and pyrrolidine-based catalysts that lack an acidic protonhave been studied as a guide to the probable diastereo- and enantio-selection towards ee©electrophiles when introduced.41

de©Fifty years of established views of the Ugi reaction have been challenged by results of a

theoretical study which suggests, for example, that the intermediate imine is not in equi-librium with its isocyanide adduct.42 An asymmetric three-component Ugi reaction hasapplied chiral cyclic imines in synthesis of morpholino- or piperazine-keto-carboxamidederivatives.43 ee©

The Mannich and Nitro-Mannich reactions

The Bignelli reaction of aldehydes, 𝛽-ketoester, and urea catalysed by (2R,3R)-tartaricacid has been confirmed, by DFT calculations, to proceed by attack of the C-nucleophileon a protonated imine intermediate.44

ee©Three-component Mannich reactions of cyclohexanone and anilines with aro-

matic aldehydes, in the presence of H2O, have been promoted by amphiphilicisosteviol–proline organocatalysts with excellent de and ee.45 DFT calculations indicate

ee©de©

that the proline-catalysed single and double Mannich reactions between acetaldehydeand N-Boc imines, to give (S) and (S,S)-conformation products, respectively, are ee©stereochemically controlled by hydrogen bonding.46 High enantioselectivity has been ee©reported for l-proline-catalysed addition of aldehydes to 2-aryl-3H-indol-3-ones,47


and chinchona alkaloid-directed Mannich reaction of malononitrile with imines to give𝛽-amino malonoitriles,48 and azlactones with aliphatic imines to give 𝛼,𝛽-diamino ee©acid derivatives.49 The aza-Mannich reaction of azlactones with imines has also been ee©catalysed by a powerful synergistic ion pair combination of a chiral phosphate ionand Ag+, resulting in excellent diastereo- (up to 25:1 dr) and enantio-selectivity ee©(ee≤ 99%).50

de©Bifunctional thiourea catalysts containing an activating intramolecular hydrogen bond

have been redesigned to effect highly enantioselective Mannich reactions between mal-onates and aliphatic and aromatic imines.51

ee©𝛽-Amino 𝛼-cyanosulfones are formed with high stereoselectivity on reaction of 𝛼-

cyano 𝛼-sulfonyl carbanions with N-Boc imines catalysed by chiral 1,2,3-triazolium ionsthat have anion-recognition ability.52

de©Reactions of sulfonylimidates (4) with Boc-protected imines (5) have been found to

exhibit an induction period, and proceed with high anti selectivity, in the presence of anorganosuperbase (7) that works as an initiator (Scheme 3).53

de©

R1 H

N

R1 = aryl, alkyl

(4)

Boc

(5)

OPri

N

R2

H

O2S

Ar

+ 0.5–5 mol%

DMF

NH NO2S

R2

R1 OPri

Boc

Ar

(6)

anti/syn up tp 99 : 1

N

NPN

Pri

N

Pri

Pri

(7)

Scheme 3

Highly efficient asymmetric anti selectivity has also been reported for reactionsof carbonyl compounds with N-carbamoyl imines catalysed by a series of amino-thiourea organocatalysts.54 Mannich reaction of glycinate Schiff bases (Ar2C= de©NCH2CO2Bu-t) with aliphatic imines (RCH=NTs) generated in situ from 𝛼-amidosulfones(RCH(Ts)NHTs) is highly diastereo- and enantio-controlled byCu(I)-Fesulfos catalyst; typically syn/anti >90:<10, ee> 90%.55 Syn-adducts were

ee©de©

also obtained in up to 99% ee from reaction of imino esters Ph2C=NCH2CO2R′ withsulfonyl imines catalysed by N,N,N-tridentate bis(imidazolidine) pyridine–Cu(OTf)2

ee©complex.56 Direct asymmetric (ee≤ 95% and 13 : 1 dr) vinylogous Mannich reaction de©of 3,4-dihalofuran-2(5H)-one with aldimines (ArCH=NTs) catalysed by quinineprovides a route to 𝛾-substituted amino butyrolactones.57 Up to 93 : 7 dr has been

ee©de©

achieved for the formation of 𝛽-aryl-𝛽-trifluoromethyl-𝛽-aminoarones through reactionof ketone enolates with chiral aryl CF3-substituted N-t-butanesulfinyl ketiminesR′(CF3)C=NSO2Bu-t.58

de©Imidazoline-anchored phosphine ligand–Zn(II) complexes promote asymmetric

Mannich-type reaction of F2C=C(R3)OTMS with hydrazones (R1CH=NNHCOR2)under mild conditions.59 ee©


The spontaneous emergence of limited enantioselectivity in an uncatalysed Mannichreaction has been discussed60 and a rare example of a Brønsted base-catalysed Mannich ee©reaction of unactivated esters has been reported.61

In contrast to its intermolecular counterpart, an intramolecular Borono–Mannichreaction (Petasis condensation) has been found to proceed with exclusive antistereoselectivity.62 The aza-Cope/Mannich reaction has been reviewed.63

de©Unprecedented nucleophilic tribromomethylation of N-t-butanesulfinylimines by bro-

moform enables the synthesis of enantiomerically pure 𝛼-tribromomethyl amines and2,2-dibromoaziridines.64 ee©

Addition of organometallics

Addition of lithiated alkoxy ethynyl anion with chiral N-sulfinyl imines proceeds withdr> 95 : 5, which can be reversed in the presence of BF3.65 Excellent diastereoselec- de©tivity has been reported for zinc-mediated addition of methyl and terminal alkynes tochiral N-t-butanesulfinyl ketimines (to form 3-amino oxindoles).66 Zinc–BINOL com- de©plexes have been used to achieve enantioselective addition of terminal alkynes to N-(diphenylphosphinoyl)imines (up to 96% ee)67 and terminal 1,3-diynes to N-arylimines ee©to trifluoropyruvates (up to 97% yield and 97% ee).68

A complete reversal of 𝛼- to 𝛾-regioselectivity in the allylzincation of imines has beenachieved by fine-tuning of the N-side-chain.69

ee©Enantioselective synthesis of homopropargyl amines can be effected through copper-

catalysed reaction of an allenyl boron reagent with aldimines.70 The first nucleophilic ee©allylation of 𝜋-electrophiles by allylboron reagents has been achieved enantioselectivelyusing a chiral rhodium catalyst (Scheme 4);71 an allylrhodium intermediate has been ee©implicated. Similar additions of R1CH=CR2BF3K have also been reported.72

N

R1

SX

OO

+R3

R2 BF3K

Ph

Me

Ph Me

Rh (cat.)

MeOH (5 equiv)THF, 55 °C

NHS

X

OO

R1R3

R2

99 % ee19 : 1 dr

Scheme 4

A metal complex has also been used to promote enantioselective arylation of 𝛼-iminoesters by Ar2B(OH)2 and provide direct access to chiral arylglycine derivatives(Scheme 5).73 ee©

Allylation of imines R1CH=NR2 by CH2=CHCH2SnBu3 in tetrahydrofuran(THF) has been achieved enantioselectively (ee≤ 98%) using a newly developed


+NAr1 OEt

O

Ar2B(OH)2

catalyst (10 mol%)CH3NO2, 50 °C, 15–48 h

NHAr1 OEt

O

Ar2

up to 95% yieldup to 99% ee

NPd

N

OO

OAcAcO

(S, S)-catalyst

Scheme 5

𝜋-allylpalladium catalyst that incorporates (−)-𝛽-pinene bearing an isobutyl side-chain;74 a menthane-based complex was less effective.75

ee©A rhenium-catalysed regio- and stereo-selective reaction of terminal alkynes with

imines forms N-alkylideneallylamines rather than the expected propargylamines. The𝛽-carbon of the alkynyl rhenium is believed to attack the imine carbon to give avinylidene rhenium intermediate (Scheme 6).76

R′ H

N

R′′R′′

H+RHcat. Re(I)

R

H

R′

N

R′′

R′′

H

RRe

N−

·

R′

R

Re+

R′′H

R′′

•

Scheme 6

Asymmetric arylation of aldimines has been performed using organoboron reagents asthe aryl transfer reagents in the presence of ruthenium catalysts along with known chiralphosphane ligands and an NHC-type chiral ligand.77 Aryl transfer from arylboroxines ee©(ArBO)3 to cyclic N-sulfonyl ketimines has been promoted in the presence of a rhodiumcatalyst bearing a chiral diene ligand, to create a triaryl-substituted carbon centre with93–99% ee.78 ee©

Other alkenylations, allylations, and arylations of imines

Vinylogous niitronate nucleophiles generated from 𝛽,𝛽-disubstituted nitroolefins havebeen used for highly stereoselective aza-Henry reactions base catalysed by chiral


ammonium betaines; high 𝛼-selectivity with 95–99% ee has been reported for thenitroallyl addition.79

ee©The first example of olefinic C–H addition to N-sulfonylaldimines and aryl aldehydes

has been achieved through olefinic C–H bond activation by a rhodium complex.80 C–Hbond functionalization by Rh(III) catalysts has also been used to achieve arylation of N-protected aryl aldimines by 2-arylpyridine81 and benzamide;82 mechanistic studies haveprovided insight for further development of this means of creating 𝛼-branched aminefunctionality. A cobalt-N-heterocyclic carbene (NHC) catalyst has also directed aryla-tion of aromatic aldimines through C–H bond functionalization of 2-arylpyridines.83

Oxidation and reduction of imines

A DFT study of Rh(II)-catalysed asymmetric transfer hydrogenation of acetophenoneN-benzylimine has indicated why (S,S)-TsDPEN ligand promotes the formation of (S)-amine, whereas (R)-amine is normally obtained from endocyclic imines.84 DFT stud- ee©ies of the role of a base in such hydrogenations have revealed a correlation betweenbasicity and diastereoselectivity.85 A further study of chiral cationic Ru(diamine) com- de©plexes in hydrogenation has explored the counterion and solvent effects and substratescope for N-alkyl and N-aryl ketimines.86 Catalysis based on Ru(II) having an achiralaminoalcohol ligand has been used for hydrogenation of chiral N-(t-butylsulfonylimine);DFT calculations have rationalized the diastereoelectivity of the amines obtained (ondesulfination).87

de©Hydrogenation of seven-membered cyclic imines of benzodiazepinones and benzodi-

azepines has been promoted by an Ir–diphosphine complex with up to 96% ee.88ee©

Bifunctional rhenium complexes [Re(H)(NO)(PR3)(C5H4OH)] (R=Cy, i-Pr) haveeffected the transfer hydrogenation of ketones and imines; DFT calculations suggest asecondary-coordination-sphere mechanism for the former.89

A mechanistic study has enabled enantioselective (up to 87% ee) hydrosilylation ofvarious imines for the first time using a novel frustrated Lewis pair (FLP) metal-freecatalyst (Scheme 7).90

ee©

R1

NR2

−B(C6F5)2

H

But3PH

+

PhMe2SiH R1

HNR2

*

ee ≤ 87%

Scheme 7

A selectivity determining hydride transfer identical to that for a related B(C6H5)3-catalysed carbonyl reaction has been proposed for hydrosilylation of imines by a silanereactant catalysed by an axially chiral borane (Scheme 8).91

ee©


Ph Me

NArSi

R

+

C6F5B

H −

Scheme 8

An N-pivaloyl-l-prolineanilide promotes high-yield imine hydrosilylation by HSiCl3with up to 93% ee.92 𝛼-Deuterated amines have been formed with up to 99% ee by chi- ee©ral phosphoric-acid-catalysed enantioselective transfer of deuterium from 2-deuteratedbenzothiazoline to ketimines; the isotope effect suggests that C–D bond cleavage is ratedetermining.93

ee©Enantioselective epoxidations (ee≤ 98%) of N-alkenyl sulfonamides and N-tosyl

imines have been catalysed by chiral Hf(IV)-bishydroxamic acid complexes.94ee©

Iminium species

The mechanism of geometric and structural isomerization of enammonium and iminiumcations derived from captodative trifluoromethylated enamines has been studied byMP2/6-311+G(dp) calculations.95

de©Nucleophile-specific parameters N and sN of enamides have allowed their rates of

reaction with various electrophiles to be predicted and thereby reveal the stepwise natureof iminium-activated reactions of electrophilic 𝛼,𝛽-unsaturated aldehydes with enamidesand the inadvisability of using strong acid co-catalysts.96

As a consequence of direct observation of enamine intermediates, it has been con-cluded that the failure to achieve organocatalytic aza-Michael additions of imidazolesto enals is due to unfavourable proton transfer within the adduct from the imidazoliumfragment to the enamine unit.97

𝛼-Amination of ketone-derived nitrones by an imidoyl chloride has been found tooccur via [3, 3]-rearrangement (Scheme 9).98

Imine cycloadditions

Imines derived from (R)-𝛼-methyl benzyl amine have been aziridinated by reactionwith ethyldiazoacetate and secondary diazoacetamides promoted by both (R)- and

R

R′′

NOR′−

+Z

N

YCl−H+ N

N

O Y

R′′

R

R′

Z

[3,3] N

N

O Y

R′′

R

R′

Z

+

Scheme 9


N

Ph

R CONHPh

N2

NHPh

O

(S) or (R)-VBC

R

N

Ph

N2

OEt

O

(S)-VBCN

Ph

R CO2EtR = Ar, 1er, 2er, 3er, alkyl

Scheme 10

(S)-VANOL boroxinate catalysts (VBCs); the high diastereoselectivity achieved issummarized in Scheme 10.99 de©

Organocatalysts derived from cinchona alkaloids promote [2+ 2] asymmetric cycliza-tion reactions of allenoates with electron-deficient imines; the range of products obtainedfrom alkenes has also been discussed.100 ee©

A DFT study of 1,3-dipolar cycloadditions of azomethine imines with electron-deficient dipolarophiles CH2=CH–CN, CH2=CHCO2Me, and dimethyl maleate hassuccessfully predicted the regioselectivity and reactivity and found little evidence ofcharge transfer in the transition states.101

Asymmetric 1,3-dipolar cycloadditions of azomethine imines with terminal alkyneshave been catalysed by 11 chiral ligand (8) coordinated metal amides to form N,N-bicyclic pyrazolidinone derivatives. Mechanistic studies have established the factorsthat determine the regioselectivity of the stepwise reaction.102 Novel phosphoramidite ee©ligands (9) coordinated with palladium have been used to effect enantioselectivesynthesis of pyrrolidines by 3+ 2-cycloaddition of trimethylenemethane (from2-trimethylsilylmethyl allyl acetate) to a wide range of imine acceptors (Scheme 11).103

ee©

R1 R2

NR3

TMS

AcO R4

Pd,

PhCH3

NR3

R2R1

R4

orN

R3

R2R1 R4

(8): Ar =

PAr2

PAr2

Pri

Pri

O

P

O

N

Ar

Ar

( )n

(9a): n = 1, Ar = 2-Naph(9b): n = 0, Ar = Ph

Scheme 11


Dinitrogen-fused heterocycles have been formed in high yield by thermal3+ 2-cycloadditions of two types of azomethine imines with allenoates.104 Rhodium-catalysed formal 3+ 2-cycloadditions of racemic butadiene monoxide with iminesin the presence of a chiral sulfur–alkene hybrid ligand have furnished spirooxindoleoxazolidines and 1,3-oxazolidines stereoselectively.105 Formation of 1,2-disubstituted ee©benzimidazoles on reaction of o-phenylenediamine with aldehydes is promoted byfluorous alcohols that enable initial bisimine formation through electrophilic activationof the aldehyde.106

Other reactions of imines

Synthesis of 1,2-aminoalcohols via cross-coupling of imines with ketones or aldehydescan be achieved using Ti(OPr-i)4/c-C5H9MgCl in Et2O, although some ketones formcis-2,3-dialkyl aziridines predominantly.107

NHCs have been used to promote reactions of enals with N-substituted isatini-mines108,109 and oxindole-derived 𝛼,𝛽-unsaturated imines110 to form spirocyclic𝛾-lactam oxindoles. Asymmetric cross-aza-benzoin reactions of aliphatic aldehydeswith N-Boc-protected aryl imines to form RCOCH(Ar)NHBoc have also been NHCcatalysed.111

ee©The ambivalent role of metal chlorides, which may act as Lewis acids or electron

donors, in ring-opening reactions of 2H-aziridines by imines, enaminones, and enam-inoesters to form imidazoles, pyrroles, and pyrrolinones has been discussed.112

Experimental and theoretical mechanistic studies of the Davis–Beirut reaction,whereby 2H-indazolenes are obtained from o-nitrosobenzaldehydes and primaryamines, implicate o-nitrosobenzylidine imine as a pivotal intermediate in the N,N-bondformation.113

The mechanism of Schiff base hydrolysis continues to receive attention.114–117 Directspectroscopic observation of the decay of two protonated imines, N-methylisobutylideneand N-isopropylethylidene, has enabled kinetic monitoring of the carbinolamine as anon-steady-state intermediate.114 The kinetics and activation parameters for hydrolysisof the N-salicylidenes of m-methylaniline115 and p-chloroaniline116 have been monitoredin the pH range 2.86–12.30 and 293–308 K; a mechanism has been suggested to accountfor the rate minimum in the pH range 5.21–10.22 and subsequent plateau (found at pH>10.73 and >11.15, respectively).

The mechanism of action of a type I dehydroquinate dehydratase has been exploredtheoretically by MD and DFT methods.117

Enantioselective addition of primary amides to aromatic aldimines (Ar1CH=NCO2CH2Ar2) has been catalysed by chiral 1,1′-binaphthyl-2,2′-disulfonate salts andfound to occur in high yield (75–99%) with 71–92% ee.118

ee©Synthesis of 2,3-dihydroquinazolinones has been achieved with 80–98% ee through

intramolecular amidation of imines catalysed by Sc(II)-inda-pybox (Scheme 12).119ee©

The bisaziridination reaction of symmetric (E-s-trans-E)-𝛼-diimines (10) with ethylnosyloxycarbamate as aminating agent occurs diastereospecifically as the aza-anionattacks opposite faces of the conjugated system to form (11) (Scheme 13).120

de©


R1

NH2

NH

O

R2

+ R3 H

O

Sc(III)-inda-pybox

CH2Cl2

R1

NH

N

O

R2

R3H

80–98% ee

Scheme 12

HN

H N

R*

R*

NsONHCO2Et

(10)

N

NR*

EtO2C

H

ONs

N

NNsO CO2Et

CaO −NsO−

very fast

N

NR* H

N

CO2Et

HN

R*

EtO2C

(11)

−

H

−R*

Scheme 13

Highly reactive o-quinone methides are proposed intermediates of reaction of2-hydroxymethylphenols with Lawesson’s reagent.121

Enantioselective hydrocyanation of a range of N-benzyloxycarbonyl aldimines byHCN has been promoted with 92–99% ee by Ru[(S)-phgly]2[(S)-binap] systems; theimine-to-catalyst molar ratio required was 500–5000.122

ee©Strecker reactions of ethyl cyanoformate with cyclic (Z)-aldimines (indoles and thi-

azines) catalysed by chinchona alkaloid derivatives,123 and with various aromatic andaliphatic N-benzhydrylimines catalysed by a chiral polyamide (12),124 proceed with ee©excellent ee values.

NH HN

HN

Ph

O

PhPh

O

Ph

NH

S

p-TolS

p-Tol

O

OO

O

(12)

Oximes, Hydrazones, and Related Species

A statistical study for prediction of pKa values of substituted benzaldoximes has beenbased on quantum chemical methods.125


The kinetics of oxidative deoximation (in AcOH) of N-methyl-2,6-diphenyl piperidin-4-one oximes by acid dichromate126 and of 3,5-dimethyl-2,6-diaryl piperidin-4-oneoximes by pyridinium chlorochromate127 have been determined and are found to beconsistent with polar mechanisms, first order in each reactant and subject to acidcatalysis.

Biodegradable imidazolium-based ionic liquid solvents have been applied effectivelyto cyanuric-chloride-catalysed Beckmann rearrangement of ketoximes.128 Conflictingviews of the mechanism of aldoxime to amide rearrangements catalysed by metals havebeen reviewed and whether or not a universal mechanism applies has been discussed inthe light of new evidence.129

Double (umpolung) nucleophilic N-alkylation of 𝛼-oxime-esters by Grignard reagents,as a route to N,N-dialkyl 𝛼-amino acids, is dependent on an (E)-configuration for theoxime that may bear electron-donating or -withdrawing groups on nitrogen.130

The cyclization step, whereby Pt(IV)-mediated nitrile–amidoxime coupling leads to1,2,4-oxadiazoles (14), is promoted by strong acceptor substituents R′ and unaffectedby the metal centre (Scheme 14).131

N

O HN

HNM H

R

R′

−M

N

O HN

HN H

R

R′

M–N R

H2N R′

NHO

N

ON

R

R′

−NH3

(13) (14)

Scheme 14

A detailed DFT study has been made of the mechanisms involved in a multiple-stepcascade synthesis of substituted 4-amino-1,2,4-triazol-3-one from Huisgen zwitte-rion and aldehyde hydrazone.132 Metal–carbene migratory insertion is proposed toaccount for N-tosylhydrazone reactions involving the formation of a Csp2–Csp3 bondin Pd-catalysed oxidative coupling with allyl alcohols.133 and a Csp–Csp3 bond inCu-catalysed coupling with trialkylsilylethynes.134

The mechanism of addition of oxime derivatives to alkynyl Fischer carbene complexeshas been studied experimentally and by DFT methods.135

Conjugate addition of donor–acceptor hydrazones (EDG-NH–N=CH-EWG) to 𝛼,𝛽-unsaturated aldehydes, catalysed by a proline derivative through a formal diaza–enereaction, gives access to 1,4-dicarbonyl compounds with up to 99% ee.136

ee©


C–C Bond Formation and Fission: Aldol and Related Reactions

Reviews of Organocatalysts

Reviews have featured recent applications of organocatalysts to asymmetric aldolreactions,137 including particular focus on catalysis by small molecules.138 The ee©effects of introduction of a diaryl (oxy)methyl group into chiral auxiliaries, catalysts,and dopants have been discussed139 and applications of amidine-, isothiourea-, andguanidine-based nucleophilic catalysts for a range of reactions of carbonyl compoundshave been highlighted.140

Asymmetric Aldols Catalysed by Proline, Its Derivatives, and Related Catalysts

Extensive molecular dynamic simulations of proline-catalysed asymmetric aldol con-densation of propionaldehyde in water have revealed that the stereoselectivity can beattributed to differences in transition-state solvation patterns.141 The hydrogen bond con-cept has been applied to design new proline-based organocatalysts.142 4-Hydroxyprolinederivatives bearing hydrophobic groups in well-defined orientations have been exploredas catalysts in water; an advantage of aromatic substituents syn to the carboxylic acidmoiety has been attributed to a stabilizing transition-state hydrophobic interaction andthis is supported by quantum mechanics (QM) calculations.143 Catalysts and solventswere screened for reaction between cyclohexanone and p-nitrobenzaldehyde.

A series of l-proline amides with 2-aminoamidazoles have promoted inter- and intra-molecular aldol reactions in high yields, ee≤ 98% and de 98/2, in the presence of tetraflu-oroacetic acid (TFA) catalyst.144

ee©de©

Aldol reactions between cyclic ketones and aldehydes have been used to evaluate theexcellent diastereo- and enantio-selectivities found using a multifunctional catalyst (15)featuring a prolinamide moiety, a gem-diamine unit, and a urea group.145 This model

ee©de©

has also demonstrated that the choice of the anion of an achiral triazabicyclo[4.4.0]dec-5-ene-derived guanidinium salt, used as a cocatalyst for proline, allows preparation ofeither anti- or syn-aldol with a very high ee value.146

ee©

NHN

H

O

NH

OPh

NH

CF3

CF3

(15)

NH

COR

−O3SO

N+N

R = OCH3, NH2

(16)

BO

O Ph

Ph

(17)

NH


Chiral imidazolium salts (16) derived from trans-l-hydroxyproline have catalysedaldol reaction in [Bmim]NTf2 as solvent with near quantitative yield, dr 99 : 1 andee≤ 89%; the origins of the selectivity have been discussed with reference to saltshaving different H-bonding potentials.147

ee©de©

Di[3,5-(trifluoromethyl)phenyl]prolinol has been used to effect enantioselective for-mation of 𝛾-oxo-𝛽-hydroxy-𝛼-substituted aldehydes with anti selectivity.148 Homoboro- ee©proline bifunctional catalysts have been fine-tuned for asymmetric aldol reactions inDMF by adjusting the Lewis acidity of boron through in situ esterification with mildlysigma-electron-withdrawing diols. NMR study of the more stable five-ring boronateesters has shed light on their mode of action; (17) was particularly effective.149

ee©The counterion of Zn–prolinamide complexes in aldol condensation has also been

found to exert modulation of the Lewis acidity of zinc cation and thereby affect thereactivity and stereoselectivity of these complexes.150

A desymmetrizing aldol reaction of 3-substituted cyclobutanones with aryl aldehydesin CH2Cl2 has been promoted with dr up to 99 : 1 and ee≤ 99% stereodirected by N-phenylsulfonyl (S)-proline.151 Proline-based di-152 and tri-amides153 have also been used

ee©de©

effectively to catalyse asymmetric aldol condensation and the importance of each chiralcentre of the catalyst has been discussed.

The efficacies of prolinamide bearing a carbohydrate group on nitrogen,154 six 𝛽-cyclodextrin conjugates with proline,155 and two with the enantiomers of proline-derived2-aminomethylpyrrolidine156 have been reported for aldol reactions in water. The per- ee©formance of new pyrrolidine-based organocatalysts derived from tartaric and glycericacids proved to be disappointing.157

A computational study using DFT methods has rationalized selectivity, reportedpreviously,158 for proline-catalysed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds.159 Steric effects are relatively unimportant and the several

ee©de©

contributing controlling factors are quite different to those for 6-enolexo aldolizationsknown to be much less sensitive to experimental conditions.

Stereoselectivities of aldol additions catalysed by histidine have been shown to con-trast with those for proline.160 Quantum mechanical calculations suggest that the imida-

ee©de©

zolium and CO2H functionalities of histidine stabilize the cyclic aldolization transitionstate through hydrogen bonding and that stereoselectivity is a consequence of minimiza-tion of gauche interactions around the forming C–C bond. Extensive computations havebeen used to support rules that enable prediction of the outcome for asymmetric cross-aldol additions between enolizable aldehydes catalysed by histidine.161

ee©

Other Asymmetric and Diastereoselective Aldols

Cinchona-based primary amine catalysis in the asymmetric functionalization ofcarbonyl compounds has been reviewed162 and their modularly designed thioamide ee©derivatives have been applied successfully to direct cross-aldol reactions betweenaldehydes and ketones,163 reactions of activated carbonyl compounds (isatins) withacetylphosphonate as the enol precursor,164 and C(1) functionalization of 1,3-dicarbonylcompounds by aldehydes and ketones.165 Cross-aldol addition to C(3) of isatins by themethyl group of 4-aryl-trans-𝛼,𝛽-unsaturated methyl ketones has also been promoted


by a cinchona-based bifunctional Brønsted acid–Brønsted base catalyst with moderateenantioselectivity.166

ee©A fluorous chiral organocatalyst (18) promotes the formation of the anti-aldol product

(with up to 96% ee) on reaction between aromatic aldehydes with ketones in brine.167ee©

The enantioselectivity achieved on promotion of aldol and Mannich reactions by anothercis-diamine-based catalyst (19) can be reversed by the addition of an achiral acid and isto be the subject of further mechanistic investigation.168

ee©F17C8(CH2)3O

TfHN

(18)

H2N

(19)

TfHN CO2Et

NH2

DFT calculations, focusing on the C–C bond forming steps, have been used to ratio-nalize the high regio- and stereo-selectivities found for direct aldol reactions of aliphaticketones (propanone, butanone, and cyclohexanone) with a chiral primary–tertiarydiamine catalyst (trans-N,N-dimethyl diaminocyclohexane).169

A chiral bifunctional pyrrolidinylsilanol catalyst is able to direct enantioselective (88%ee) reaction of ethanal with isatin by silanol activation of the electrophile and enantio-control through hydrogen bonding.170

ee©Cross aldehyde reaction between simple ketones has been promoted enantioselectively

by chiral 1,1′-binaphthyl 2,2′-(POPh2) (BINAPO), with SiCl3OTf/i-Pr2NEt.171ee©

A reversal of diastereoselectivity from syn to anti is found on reducing the tem-perature from room temperature to −78 ∘C for enolboration–aldolization reaction ofmethylphenylacetate with RCHO promoted by Chx2BOTf/i-Pr2NEt in CH2Cl2; theconverse temperature dependence applies in nonpolar solvents.172

de©Biomimetic decarboxylative aldol reaction of 𝛽-ketoacids with RCOF3 has been pro-

moted enantioselectively by a chiral tertiary amine (Scheme 15).173ee©

The creation of chiral oxazolidones with a tetrasubstituted chiral centre has beenattributed to memory of chirality by an axially chiral enolate intermediate of the aldolreaction involved (Scheme 16).174 ee©

Ar O

O OH

+

CF3 R1

O

chiral t-amine Ar

O

O

O HNR*3

R1

SiH3HO

+

CO2

O

Ar R1

HO CF3

up to 98% yieldup to 90% ee

−

Scheme 15


N

R CO2Et

BocMOM+ Ar-CHO

KHMDS

toluene:t-BuOMe(2 : 1)

N

OO

Ar

CO2EtR

MOM

78–94% ee

Scheme 16

G

R

O

O

R′

R′′

R

O

R′

R′′

Nu*Nu* G

O

− +

Nu* R G

O O

R′ R′′

N Nu

*

+ −

R1CHOR

O

R′

R′′

O

R1

Nu G

O

N

*

+−

N Nu

*

+ −

Newprocess

R O

O R1

R′ R′′

O

G* *

*

Scheme 17

Vinylic esters are able to act simultaneously as the enol precursor and acylating agentin stereoselective aldol reaction when catalysed by nucleophilic ammonium betaines, asillustrated in Scheme 17.175

ee©de©

The highly chemoselective Lewis acid/hard Brønsted base cooperative chiral catalystused to promote anti-selective direct asymmetric aldol reaction of N-protected thiolac-tams permits the use of enolizable aldehydes as the aldol acceptor.176

ee©Preference for the formation of the anti aldol diastereomer, with increasing

steric constraints of the reactants, is a feature of such couplings of 3-aryl-1-alkyldihydrothiouracils.177 In contrast, the origin of syn preference found on coupling zin- de©cated 3-chloro-3-methyl-1-azaallylic anions with aromatic aldehydes, in the presence ofLiCl and THF, has been attributed by DFT to a highly ordered bimetallic six-memberedtwist-boat-like transition state.178 A syn preference has also been found for asymmetricreaction of 𝛼-sulfanyl lactones with aldehydes, catalysed by an AgPF6/(R)-biphep-typeligand/DPU complex.179

de©A DFT study of the origins of stereoselectivity in the aldol reaction of bicyclic amino

ketones (20) with aromatic aldehydes has been reported (Scheme 18).180

Base-catalysed direct aldolization of 𝛼-alkyl-𝛼-hydroxy trialkyl phosphonoacetateswith aldehydes proceeds via a fully substituted glycolate enolate intermediate formedby a [1,2]-phosphonate–phosphate rearrangement.181 High enantioselectivity can be ee©achieved by the application of chiral iminophosphorane catalysts.

Documents

ORGANICREACTIONMECHANISMS 2012€¦ · Contributors K.K.BANERJI FacultyofScience,NationalLawUniversity,Mandore, Jodhpur342304,India C.T.BEDFORD DepartmentofChemistry,UniversityCollegeLondon,