Synthesis of Amidines

5.19Amidines and N-SubstitutedAmidines

P. J. DUNN

Pfizer Global Research and Development, Sandwich, UK

5.19.1 AMIDINES 6565.19.1.1 Introduction and General Methods 6565.19.1.1.1 Introduction 6565.19.1.1.2 General methods 656

5.19.1.2 Formamidines (HC(NR1)NR22) 6585.19.1.2.1 Preparation from formamides and thioformamides 6585.19.1.2.2 Formamidines, prepared by reduction of carbodiimides and ureas 6595.19.1.2.3 Formamidines from orthoformates, acetals, and aminals 6595.19.1.2.4 Formamidines from 1,3,5-triazine 6605.19.1.2.5 Formamidines from isonitriles 6615.19.1.2.6 Formamidines, prepared by miscellaneous methods 661

5.19.1.3 Aliphatic Amidines, R1C(NR2)NR32 (R1=alkyl, allyl, propargyl, etc.) 662

5.19.1.3.1 Aliphatic amidines from nitriles 6625.19.1.3.2 Aliphatic amidines from amides 6655.19.1.3.3 Aliphatic amidines from thioamides and thioimidic esters 6665.19.1.3.4 Aliphatic amidines from orthoesters 6675.19.1.3.5 Aliphatic amidines from compounds with cumulated double bonds 6675.19.1.3.6 Aliphatic amidines, prepared by N-alkylation of simpler amidines 6675.19.1.3.7 Aliphatic amidines, prepared by miscellaneous methods 668

5.19.1.4 Aromatic Amidines, ArC(NR1)NR22 6685.19.1.4.1 Aromatic amidines from nitriles 6685.19.1.4.2 Aromatic amidines from amides 6715.19.1.4.3 Aromatic amidines from thioamides and thioimidic esters 6715.19.1.4.4 Aromatic amidines from compounds with cumulated double bonds 672

5.19.1.5 N-Acyl- and N-Heteroacylamidines 6735.19.1.5.1 N-Acylamidines, R1C(NR2)NR3COR4 6735.19.1.5.2 N-Thioacylamidines 6735.19.1.5.3 N-Selenoacylamidines 674

5.19.2 AMIDINE-DERIVED STRUCTURES WITH AN N-HETEROATOM BOND 6755.19.2.1 N-Haloamidines 6755.19.2.1.1 N-Fluoroamidines 6755.19.2.1.2 N-Chloroamidines 6755.19.2.1.3 N-Bromoamidines 6765.19.2.1.4 N-Iodoamidines 676

5.19.2.2 N-Imidoylhydroxylamines and Related Structures 6765.19.2.2.1 N-Imidoylhydroxylamines from hydroxylamine 6765.19.2.2.2 N-Imidoylhydroxylamines from amines and ammonia 6775.19.2.2.3 N-Imidoylhydroxylamines by miscellaneous methods 678

5.19.2.3 N-Imidoylsulfenamides, -sulfimides, -sulfinamides, and -sulfonamides 6785.19.2.3.1 N-Imidoylsulfenamides R1C(NR2)NR3SR4 6785.19.2.3.2 N-Imidoylsulfimides 6795.19.2.3.3 N-Imidoylsulfinamides 6805.19.2.3.4 N-Imidoylsulfonamides 6805.19.2.3.5 Amidine derivatives with an N-selenium or N-tellurium bond 682

655

5.19.2.4 Amidrazones and Related Structures 6835.19.2.4.1 Introduction and nomenclature 6835.19.2.4.2 Primary amidrazones, RC(NH)NHNH2 6835.19.2.4.3 N-Alkyl-, aryl-, or alkenyl-substituted amidrazones 6845.19.2.4.4 N-Acylamidrazones 685

5.19.2.5 Amidine Derivatives with an NP, NAs, or NSb Bond 6875.19.2.5.1 N-Phosphorylamidine derivatives 6875.19.2.5.2 N-Phosphorus amidines (excluding N-phosphorylamidines) 6885.19.2.5.3 Amidines with an N-arsenic bond 6885.19.2.5.4 Amidines with an N-antimony bond 688

5.19.2.6 Amidine Derivatives with an N-Metalloid Bond 6895.19.2.6.1 N-Silylamidines 6895.19.2.6.2 N-Borylamidines 690

5.19.2.7 Amidine Derivatives with an N-Metal Bond, R1C(NR2)NR3-M 6915.19.2.7.1 Amidines with an N-metal bond, where M is a group 13 metal 6915.19.2.7.2 Amidines with an N-metal bond where M is a group 14 metal 6915.19.2.7.3 Amidines with an N-metal bond where M is a transition metal 6925.19.2.7.4 Amidines with an N-metal bond, where M is a lanthanide or actinide metal 692

5.19.1 AMIDINES

5.19.1.1 Introduction and General Methods

5.19.1.1.1 Introduction

In this chapter the synthesis of amidines is reviewed. This review is restricted to compounds ofstructural formula 1 where R1 is hydrogen or a carbon substituent. Thus, guanidines (R1=NR2,etc.) and haloamidines are excluded along with cyclic amidines such as 2, which are covered inComprehensive Heterocylic Chemistry . Some cyclic amidines mayalso be included when the method of synthesis is likely to be applicable to acyclic compounds.

NR3R4NR2

NR2N

1 2

R1

There are several reviews of amidine synthesis published in the literature . The reviewby Boyd includes haloamidines. The most structured review is provided inCOFGT (1995) . Two small chapters in HoubenWeyl and related reviews on imidic ester chemistry also give useful information as does a review on additions to metal-activatedorganonitriles . This review covers the years 19942003 as some 1994 referenceswere not abstracted in time for COFGT (1995).

5.19.1.1.2 General methods

The most common methods of preparing amidines are from nitriles, amides, and thioamides. Allthese methods involve disconnection of the product to an iminium cation synthon and a nitrogennucleophile.Although discovered in 1877, the Pinner reaction remains the most common

way of making primary amidines. In the review period (19942003), one-third of all publications,in which amidines were synthesized from nitriles, used a Pinner reaction. The nitrile is treatedwith an alcohol under anhydrous conditions in the presence of hydrogen chloride or hydrogenbromide to form the imidic ester salt 3 (Scheme 1). Subsequent reaction with ammonia oramines gives the amidine. As materials (alcohol, HCl and NH3) are cheap, this method can beeconomical for large-scale synthesis. Recent examples of the Pinner reaction which contain

656 Amidines and N-Substituted Amidines

experimental details include the following . The Pinner reaction can also be used for synthesis of some substituted amidines. Amidine formation via base-catalyzed imidate formation is alsocommon and works well for certain substrates . Conversion of thenitrile into the amidoxime, by reaction with hydroxylamine, followed by reduction to give theamidine is a widely used synthetic method for making primary amidines . The amidoxime method has also been used for large-scale synthesis. Forming primary amidines, by the reaction of a nitrile withmethylchloroaluminum amide (ClMeAlNH2), is a method of growing importance. This is anexcellent general method which succeeds for hindered nitriles where the Pinner reaction fails or isless successful (see Sections 5.19.1.3.1 and 5.19.1.4.1) . The procedure is also reported to be more convenient in the laboratorythan the Pinner method . Methylchloroaluminum amide may also be used toconvert esters directly into amidines .

A modification of the Pinner synthesis involves the formation of the thioimidic ester 4(Scheme 1). Reaction of the isolable thioimidic ester with aromatic amines or the acetate saltsof aliphatic amines or ammonium acetate reliably forms amidines. The thioimidic ester methodcan be used for acid-sensitive substrates, such as those with an N-BOC group .A particularly useful variant of this reaction is the catalytic process with N-acetylcysteine.A method which has been widely used to prepare N-substituted or N,N-disubstituted amidines

is to heat the nitrile with a primary or secondary amine in the presence of aluminum chloride.By definition, reactions from nitriles do not form tertiary amidines. Tertiary amidines and other

substituted amidines are generally prepared from amides or thioamides. Activation of the mono-substitued amide to give the imidoyl chloride 5 is best achieved with phosphorus pentachloridethough a variety of chlorination agents can be used . The imidoyl chloride can then be reacted with a wide variety ofmono- or disubstituted amines to produce amidines. Alternatively, the amide can be activated byalkylation and the alkoxy group displaced from the resulting imidic ester salt 6 .The most common method of preparing formamidines is through the high yielding reaction

of a formamidine acetal, such as 7, with an amine or ammonia .Preparation from Vilsmeier reagents or equivalents is also very common .

R2NOR

OR

7

NR3R4NR2

SR

NH

OR

NH2

NHR2O

NR2Cl

NHR2

OEt

R1CN

+

R3R4NH

R3R4NH

(R2 = H)

(R2 = H)

R3R4NH

R3R4NH

3 5

64

+

R1

R1

R1

ROHHCl

RSHR1

R1

R1

PCl5

Et3O+BF4

Scheme 1

Amidines and N-Substituted Amidines 657

5.19.1.2 Formamidines (HC(NR1)NR22)

5.19.1.2.1 Preparation from formamides and thioformamides

(i) Formamidines from monosubstituted formamides

Di- or trisubstituted formamidines are readily prepared from monosubstituted formamides. Themonosubstituted formamide can be activated by a reagent such as phosphorus pentachloride ordimethyl sulfate (Scheme 2). This chemistry was summarized in chapter 5.19.1.2.1 of. A variant on this method is the reaction between a monosubstitutedformamide and a carbamoyl chloride (Scheme 2). Results from this chemistry were tabulatedand summarized in COFGT (1995) .

(ii) Formamidines from disubstituted formamides, Vilsmeier reagents, and disubstitutedthioformamides

Trisubstituted formamidines have been widely prepared from Vilsmeier reagents, most commonlyfrom DMF and phosphorus oxychloride. The Vilsmeier salt forms amidines with both aliphaticand aromatic amines, and typical results are tabulated in COFGT (1995) . Vilsmeier salts will also react with acylated amines to give formamidinehydrochlorides and carbon monoxide .In the preparation of trisubstituted formamidines via a Vilsmeier reagent, it is reported to be

more favorable to start from a disubstituted formamide and a primary amine as opposed to amonosubstituted formamide and a secondary amine .Activation of DMF has also been achieved with triflic anhydride (Equation (1))

and arylsulfonyl chlorides (Equation (2)) . The arylsulfonyl chloridecatalyzed reactions proceed in good yields (generally 8095%) and are extremely rapid taking just15 min at room temperature and this means that even hindered amines such as t-butylamine willform a formamidine (although in lower yield, 38%). Several arylsulfonyl chlorides were examinedas potential activating agents and pyridine-2-sulfonyl chloride was found to be optimal.

NH2Ph Ph NH

N

H

+ DMFCH2Cl2, 0 C

59%

+

Tf2O

Tf1

X

R

NH2X

R

N

H NMe2

+ DMF

R = H, X = CHR = H, X = NR = Br, X = NR = OH, X = CHR = OH, X = N

ArSO2Cl

95%87%95%88%79%

2

Other methods of activating DMF leading directly to dimethylformamidines are the use ofMeerweins reagent (Et3OBF4), phosgene or dimethyl sulfate . Phosphorustrichloride has also been used for DMF activation giving formamidines . Anotherrecent method is the use of PyBroP (a common coupling agent in peptide synthesis), which gaveformamidines in moderate yield .

NHR1

NR1

NR2R3R2R3NH

R2R3NCOCl

NHR1

O PCl5 O

Scheme 2


Formamidines have been prepared by the reaction of amines and thioamides e.g.,. In the review period, it has been reported that this reaction may be catalyzedby mercury(II) oxide. Thus, thioamide 8 reacts with primary or secondary amines at roomtemperature to give moderate yields of formamidines (Equation (3)) .

OSAcOCH2

AcO

AcO

OAc

NHO NR1R2

AcO

OAc

AcOCH2

AcO

NR1R2NH

HgO, CH2Cl2rt

R1 and R2 = (CH2)5 33%

R1 = iPr, R2 = H 40%

8 3

5.19.1.2.2 Formamidines, prepared by reduction of carbodiimides and ureas

Formamidines can be prepared by reduction of ureas or carbodiimides and these methods aresummarized in Scheme 3 and were covered in chapter 5.19.1.2.2 of COFGT (1995). Also covered in COFGT (1995) was the preparation of formamidinesfrom thioureas. The overall reaction from the thiourea is a reduction, though the reagent ishydrogen peroxide, and the reaction proceeds via the S,S-dioxide 9 followed by expulsion ofsulfur dioxide. In the review period the reduction of N,N0-dialkyl thioureas (10, R1, R2= n-Bu,cyclohexyl, n-Pr) with nickel borohydride (prepared in situ from nickel(II) chloride andsodium borohydride) was reported to give N,N0-dialkylformamidines .Reduction of N,N0-diarylthioureas with nickel borohydride does not give N,N0-formamidines,instead further reduction to the arylamine and the N-methylarylamine was observed.

5.19.1.2.3 Formamidines from orthoformates, acetals, and aminals

An excellent and widely used method of preparing formamidines is the reaction of an amine witha formamide acetal such as 11 (Equation (4)). The method gives high yields under mild conditionsand even works well for weakly basic amines such as 12 , 13 , and14 .

NR2R3

R1HN NR2R3

O

NR2R3S

NR2R3S

OO

NR2R3S

NaBH4or H2

R3 = H

NiCl2, NaBH4 MeOH, rt

R3 = H

9 10

R1N=C=NR2

R1N

LiAlH4

R1HNR1HN

SO2

H2O2

R1HNMeOH

Scheme 3


Me2NOMe

OMeH

NR

NMe2+

11

RNH2 DMF 4

N

N

NC

H2N O2N NH2

N

N

NC

H2N

Ph

1412 13

To make a wide range of formamidines starting from DMF-dimethyl acetal, two strategies arepossible. The first strategy is to react the DMF-dimethyl acetal first with an amine, such asdibenzylamine to give another acetal 15 which is subsequently reacted with a second amine, suchas 16, to give the N,N0-dibenzylformamidine 17 (Scheme 4) . This also illustratesthat the formamidine acetal method works well for very hindered amines such as 16. Dibenzyl-formamidines are very useful protecting groups for amines which can be removed by hydroge-nolysis .

The second strategy is to react DMF-dimethyl acetal first with an amine to give the formami-dine 18. Subsequent amine exchange of the formamidine 19 with indoline 20 gave the chiralformamidine 21 with concomitant loss of dimethylamine (Scheme 5) . The preparation of formamidines from aminals (HC(OR)(NMe2)2) is covered inchapter 5.19.1.2.3 in .

5.19.1.2.4 Formamidines from 1,3,5-triazine

A high-yielding method of preparing N,N0-disubstituted formamidines is to heat 6 equiv. of anamine with 1 equiv. of 1,3,5-triazine (Equation (5)). This reaction is particularly effective using aprimary aliphatic amine under neat conditions. This chemistry is summarized in chapter 5.19.1.2.4of . In the review period most formamidine syntheses from 1,3,5-triazineformed polyformamidines.

NHCH2Ph

CH2PhMe2N

OMe

OMe

HN

NPhCH2

CH2Ph

NOMe

PhCH2

PhCH2

NH2

+

94%

15

16

17

DMF

OMe

Scheme 4


N N

N

RHN

H

NR+RNH2 5

5.19.1.2.5 Formamidines from isonitriles

Arylisonitriles (22, Ar=Ph, o-, m-, p-ClC6H4; and o-, p-NO2C6H4) can undergo reaction with1 equiv. of secondary amine at 15 C in the presence of a catalytic amount of silver(I) chloride togive the (Z)-formamidine 23. This product, characterized by infra-red and NMR spectroscopy,can be converted into the more stable (E)-isomer 24 by heating in boiling chloroform for 6 h or bytreatment with acid at room temperature (Scheme 6) . Further exam-ples of formamidines prepared from isonitriles are summarized in chapter 5.19.1.2.5 of COFGT(1995) . The reaction of isonitriles with amines may also be catalyzed bycopper(II), zinc(II), and cadmium(II) salts.

5.19.1.2.6 Formamidines, prepared by miscellaneous methods

A new method for preparing formamidines is the reaction of an amine with a carbene equivalent,the C-phosphanyl-C-chloroiminium salt 25. The reaction takes place under mild conditions(dichloromethane, 78 C to rt) (Equation (6)) .

NPr2P

Cl Me

Me

NPr2

NMe2+

Pr2NH

60% +

25

TfTfi i

i6

N Ar HN

ArN

Ar+ R1R2N R1R2N

23 24(Z )-Formamidine (E )-Formamidine

R1, R2 = Me, Et

or (CH2)n, n = 2 to 5

CHCl3,

22

CR1

R2

AgClN

+

Scheme 6

Me2NOMe

OMe

H2N

HO

But

NH

N

HO

ButMe2N

N ButMe2N

MeO

N

N But

MeO

+

18

19

20

21

95 %

Scheme 5


5.19.1.3 Aliphatic Amidines, R1C(NR2)NR32 (R1=alkyl, allyl, propargyl, etc.)

Nearly all of the methods described in this section are equally applicable to aromatic amidines,and only when there are important differences will the synthesis of aromatic amidines bediscussed separately in Section 5.19.1.4.

5.19.1.3.1 Aliphatic amidines from nitriles

In 1877, Pinner described the synthesis of amidines from nitriles via the imidic ester (Equation (7)). As mentioned in the general methods, the Pinner method is still the mostcommon method of preparing amidines (especially primary amidines) and during the reviewperiod (19942003) around one-third of all publications covering the preparation of amidinesfrom nitriles used the Pinner method.

NH

OR NR2R3NH

R1CNROH/HCl R2R3NH

R1 R17

The nitrile is usually dissolved in anhydrous alcohol, typically ethanol or methanol , cooled and treated with excess ofHCl gas to form the imidic ester hydrochloride. Subsequent reaction with an ammonium salt,alcoholic ammonia , or liquid ammonia gives the primary amidine (Equation (7), R2, R3=H). In the review periodthere were few reports of N-substituted or N,N0-disubstituted amidines being prepared from theimidate salt, but examples of such reactions were tabulated in HoubenWeyl .The Pinner reaction can be performed with reduced amount of ethanol (13 equiv.) in an inert

solvent such as dioxan, ether, benzene, or chloroform and sometimes this is advantageous; forexample, the extent of a side reaction to form orthoesters is reduced. Other side reactions includeformation of N,N0-disubstituted amidines and hydrolysis of the nitrile to the amide (despite thesupposedly anhydrous conditions).The Pinner reaction was used to complete a total synthesis of Distamycin A (Scheme 7).

Formation of the imidate takes place with concomitant deprotection of the t-BOC group.Following the formation of the amidine, the amine, liberated by the BOC removal, was formy-lated to give Distamycin A in 45% overall yield from 26 .

For nitriles having an electron-withdrawing group in the -position, the basicity of the nitrilenitrogen is decreased and the Pinner synthesis does not work well . How-ever, in these cases the base-catalyzed addition of alcohols to the nitrile works well. A recentexample is shown in Equation (8) .

O

HN

NMe

O

HNN

Me

O

HNN

Me

t-BOCHN

CN

O

HN

NMe

O

HNN

Me

O

HNN

Me

H2N

NH2NH

H N N

O

O

HN

NMe

O

HN

NMe

O

HN

NMe

NH2NH

HN

OH

26

HCl/EtOH

NH3/EtOH

Distamycin A

Scheme 7


OOAc

OAc

OAcNH

O

ONC

CO2Me

O

OAc

OAc

OAcNH

O

O

CO2Me

NH

H2N

MeONa, MeOH

57%2 h, 50

C

NH4Cl8

A nitrile 27 with an electron-withdrawing group in the -position was converted into theamidinium salt by Eschenmoser and co-workers. The reaction could be carried out without acatalyst but was significantly accelerated by using L-cysteine as catalyst (Equation (9)). The same reaction can also be carried out using N-acetylcysteine as catalyst. The N-acetylcysteine is particularly good for electron-poor aromatic nitriles (seeSection 5.19.1.4.1).

HN

O

CN HN

ONH2

NH2NH3/MeOH, L-cysteine (cat.)+

27

RT, 2 days, then TsOH89%

OTst-BOCHN t-BOCHN 9

Highly electrophilic nitriles such as trichloroacetonitrile will react directly with amines to giveamidines in very high yields .Aliphatic and aromatic nitriles react with primary and secondary amines in the presence of

aluminum chloride to give amidines. Examples with yields and references are tabulated inHoubenWeyl and chapter 5.19.1.3.1 of . The reactionmay also be catalyzed by tin(IV) chloride (see Equation (10), Table 1) , copper(I) chloride , or trimethylaluminum. An environmentally friendly variant of the reaction is to use a Zeolite catalyst(Equation (10), Table 1) .

NS

NNH2

R2N

S

NH2 R2CN, SnCl4

or

R2CN, HYZeolite, 60 C

R1R1 10

In some cases, the nitrile can be converted into the amidine by first forming the amidoximefollowed by reduction of the NO bond to give the amidine. A recent high-yielding example isshown in Equation (11) . Further examples of the preparation of aromaticamidines via this method can be found in Section 5.19.1.4.1.

Table 1 The reaction of nitriles and amines catalyzed by SnCl4and zeolites

Substrate

R1 R2 Method Yield (%) References

Me Me SnCl4 80 Me Me Zeolite 87 H Me SnCl4 80 H Me Zeolite 85 Me CH2Cl SnCl4 63 Me CH2Cl Zeolite 92 H CH2Cl SnCl4 96 H CH2Cl Zeolite 90


SOH

MeO

CN SOH

MeO

NH2

NHi. NH2OH, H2O, EtOH

ii. Pd, H2, EtOH 89%

11

Conversion of nitriles into amidines by reaction with methylchloroaluminum amide is areaction that has been widely used since it was first reported by Garigipati (Equation (12)). In a separate paper, a series of sterically hindered nitriles (2830) wassubjected to amidine formation via the classical Pinner reaction and reaction with methylchloroaluminum amide. The results, in Table 2, show that the Garigipati method was superiorboth in terms of yield and much shorter reaction time, down from days to hours.

CNNH

NR1R2MeAl(Cl)NR1R2

R1 = R2 = H, 95%R1 = H, R2 = Me, 94%R1 = R2 = Me, 60%

H2O12

CN

28 29 30

Me3CCH2CN Me(Ph)2CCN

Another very impressive application of this methodology was the conversion of the porphyrinderivative 31 into the amidine 32 (Equation (13)). In spite of the high molecular weight andcomplexity of the starting nitrile, the product was isolated in very high yield . Theequivalent reaction via the Pinner method was limited by the relative insolubility of porphyrinnitriles in alcohol. The Garigipati method has also been widely used for difficult aromaticsubstrates and will be covered in Section 5.19.1.4.1.

NN

N N

Et

Et

Et

EtEt

Et

Et

Et

CN

NN

N N

Et

Et

Et

EtEt

Et

Et

Et

NH2

NHMeAl(Cl)NH2, PhCH3

31 32

90%

NiNaOH Ni 13

Table 2 Comparison of reaction times and yields for the Pinner andGarigipati methods

Pinner method Garigipati method

Starting nitrile Time (days) Yield (%) Time (h) Yield (%)

28 21 40 18 6429 14 38 15 7030 15

In COFGT (1995), the reaction of nitriles with strong bases such as sodium or potassium amidewas reported to give primary amidines (e.g., Equation (14)). In the review period, the anion ofhexamethyldisilazide was shown to react with nitriles to give primary amidines, but as thesubstrates are mostly aromatic nitriles this chemistry is discussed in Section 5.19.1.4.1.

EtCN

Et

NH2

NH(1.1 equiv.)

R1 = Et, R2 = Bun, 80%R1 = Bun, R2 = n - C6H13, 75%R1 = Pri, R2 = n- C6H13, 40%R1 = Bun, R2 = s- octyl, 32%

R1

R2R1

R2

NaNH2

PhH

14

5.19.1.3.2 Aliphatic amidines from amides

Scheme 8 shows a method which is generally poor for making primary amidines but is an excellent and general way of making di- and tri-substituted amidines. The secondary ortertiary amide can be activated by a number of methods but most commonly as the imidoyl chloride,subsequent reaction with primary or secondary amines yielding the corresponding amidine.

A classical procedure is to heat the amide and the amine with PCl5 or POCl3 in an inert solventsuch as benzene or chloroform, and examples with conditions, yields, and references are tabulatedin chapter 5.19.3.2 in . Surprisingly, in spite of the toxicity of benzene,PCl5 in benzene has still been widely used in the review period (,), and interestingly quite hindered amidines can be made via this method ingood yield (Equation (15)) .

NH2iPr Pri

NHAciPr Pri iPr

HN NPri Pri

iPr

+

PCl5, benzene

75%

15

However, in the review period there have been more examples of the use of more laboratoryfriendly solvents, e.g., POCl3/CH3CN (see also ), POCl3 neatand then amine in DME , and SOCl2/CH2Cl2 (see Section 5.19.1.4.2).A more recent mild procedure for the activation of amides is to use triflic anhydride. Charette

and Grenon reported 19 examples of which a selection is given in Equation (16) (see also ). Another recent procedure is to use an arylsulphonyl chloride as theactivating agent (Equation (17)) .

NR1R2

O

NR1R2OTf

NR1R2

NEtTf2O, Py

40 C to 0 C

+

40 C to rt

R1 = Me R2 = H, 77%R1 = Bu R2 = H, 83%R1 = Me R2 = Me, 75%R1 = iPr R2 = iPr, 55%

CH2Cl2

EtNH2

CH2Cl2

16

RNHR1

OR

Cl

NR1R

NR1

NR2R3R2R3NHPCl5

Scheme 8


NH2Br

N

O

Me

MeBr

N

N MeMe

rt, 20 min+

Ar = 2-pyridyl

ArSO2Cl

71%

17

Another way of activating the amide is to use alkylation and this has the advantage thatthe method can be used to prepare primary as well as more highly substituted amidines(Equation (18)) .

RNH2

OR

NH2

OEtR

NH2

NH+

(Et3O)BF4 NH3 18

5.19.1.3.3 Aliphatic amidines from thioamides and thioimidic esters

The condensation of ammonia or an amine with a thioamide gives an amidine (sometimes as itsH2S salt). The reaction is improved by the addition of a mercury salt as a sulfide scavenger, e.g.,HgCl2 or HgO (Equation (19)) .

OSAcOCH2

AcO

AcO

OAc

NH

O NR1R2AcO

OAc

AcOCH2

AcO

NR1R2NH

HgO, CH2Cl2rt

R1 = Et R2 = Et, 61%R1 = H R2 = Bn, 59%

19

Alkylation of thioamides with alkyl halides or triethyloxonium tetrafluoroborate gives thio-imidic esters which react more readily with amines or ammonia to give amidines (see Chapter5.19.1.3.3 of and ). In thisreview period, advances include the alkylation of thioamides with 2-naphthyl chloride to give athioimidate, which on subsequent reaction forms the amidine and a relatively nonodorous thiolby-product . Another advance has been to perform the reaction as partof a solid-phase synthesis. Hence, thioamides undergo reaction with the resin-bound reagent 33 togive resin-bound thioimidates 34. Subsequent reaction with an amine gave the free amidine(Equation (20)) . A benefit is that a nonodorous thiol by-product is generated, inthis case a polymer-bound thiol.

S NH2

Cl S NH.HCl

H2NNHBoc

NH

NHBOCNH

+THF or 1,4-dioxane

70 C, 15 h

Argopore - Cl resin

Et3N, THF, , 3 h70% 33

34

20


5.19.1.3.4 Aliphatic amidines from orthoesters

The preparation of symmetrical N,N0-substituted amidines from orthoesters is covered in chapter5.19.1.3.4 in and other recent references include . In addition, it is also possible to prepare unsymmetrical amidines,e.g., when an amine is heated with excess triethyl orthoacetate in acetic acid to give the imidicester 35 which can then undergo reaction with a second amine to give the unsymmetrical amidine36 (Equation (21)) .

RN OEt RN NH2N

35 36AcOH

R = adamantyl, cyclohexyl or norbornyl

27% for R = adamantyl

RNH2CH3C(OEt)3

AcOH 21

5.19.1.3.5 Aliphatic amidines from compounds with cumulated double bonds

The addition of organometallic compounds to carbodiimides is a relatively rare example of anamidine synthesis via CC bond formation. Hence, methyllithium can be added to a carbodi-imide followed by water quench to give the amidine 37. If the water quench is replaced by amethyl iodide quench, a more substituted amidine 38 can be obtained (Equation (22)). Other organometallic nucleophiles may also add to carbodiimides includingGrignard reagents and organozinc reagents. Further examples are given inchapter 5.19.1.3.5 of . Stabilized carbanions may also add to carbodi-imides, e.g., the lithium anion of acetonitrile will add to a carbodiimide to give an amidine.

NPh

HN

SiMe3

SiMe3N

SiMe3

SiMe3NMe

PhMe3Si

Me3Si

37

MeLi in etherTHF, 0 C, 30 min

H2O quench

3885%

N=C=NPh 22

The preparation of amidines from isocyanates and ketenimines is covered in chapter 5.19.1.3.5of . In the review period, the mechanism for the addition of amines toketenimines has been studied by NMR spectroscopy and ab-initio calculation .In a series of papers, Wentrup and co-workers have prepared amidines from iminopropadienones(Equation (23)) .

RN

O

NMe2

NMe2

CDCl3/40 CR = t-BuCH2, mesityl, 2,6-difluorophenyl 2-t-butylphenyl

Reaction ona cold finger

Me2NH

RN=C=C=C=O

or23

5.19.1.3.6 Aliphatic amidines, prepared by N-alkylation of simpler amidines

This method is most effective for the alkylation of symmetrical N,N0-disubstituted amidines, alkylation of N,N-disubstituted amidines, or monoalkylation ofprimary amidines (see chapter 5.19.1.3.6 of ).


Attempts to monoalkylate monosubstituted amidines have attracted little synthetic interest assuch reactions generally have poor regioselectivity . The most useful results havebeen observed in the alkylation of N-aryl amidines which are alkylated predominantly on thenitrogen bearing the aryl groups (Equation (24)) (see also and).

SMe

NH

NH

N

OMeBr OMe

SMe

N

NH

N

+

THF, rt, 17 h 40%

NaN(SiMe3)224

In the absence of strong base, N-benzoylacetamidine 39 is alkylated on the more nucleophilicnitrogen to give the alkylated amidine 40 (Equation (25)) .

NH2

NCOPh

NHMe

NCOPh

rt, 15 h 89%39 40

Me2SO425

Acylated amidines may be alkylated on a nitrogen bearing an acyl group using Mitsunobuconditions .

5.19.1.3.7 Aliphatic amidines, prepared by miscellaneous methods

The preparation of amidines by reactions of carbanions with chloroformamidines is covered inchapter 5.19.1.3.7 of . The preparation of amidines from imines, hydra-zones, aldoximes, ammonolysis, and by addition reactions to yneamines is covered in previousreviews .

5.19.1.4 Aromatic Amidines, ArC(NR1)NR22

5.19.1.4.1 Aromatic amidines from nitriles

Nearly all of the synthetic methods described in Section 5.19.1.3.1 also apply to aromaticamidines. An important exception is the synthesis of aryl amidines from ortho-substituted arylcyanides (41, R=Me, Cl, SO2NH2) (42, R=NO2, NH2) and 1-naphthonitrile which exhibit aproximity effect and do not form imidic esters when treated with ethanol and anhydrousHCl. Positional isomers where the positions ortho- to the nitrile are unoccupied behavenormally and hence 4-methylbenzonitrile and 2-naphthonitrile form imidic esters, which are then converted into amidines. The proximityeffect has some synthetic utility in differentiating between vicinal dinitriles; hence, symmetricaldinitriles such as 43 form salts of monoimidic esters which have been converted into amidines.Further examples of differentiating between vicinal dinitriles can be found in chapter5.19.1.4.1 in .

CNR

CNR

41 42


NH

NX

CN

CN43

X = N or CH

If the desired product is the amidine, one way of solving the problem of the proximity effectis to use the Garigipati method . Interestingly, two competing male erectiledysfunction drugs, sildenafil (the active ingredient in ViagraTM) and 44, a key intermediate in thesynthesis of vardenafil (the active ingredient in LevitraTM), both use the Garigipati method asa method of synthesis. For sildenafil, the nitrile 45 is converted into the amidine 46 in 58%yield by reaction with methylchloroaluminum amide (Scheme 9) . Forvardenafil, 2-ethoxybenzonitrile is converted into 2-ethoxybenzamidine 47 with methylchloro-aluminum amide in 76% yield. The amidine was subsequently converted into the intermediate44 via the amidrazone (Scheme 10) .

Interestingly, the nitrile 45 (Scheme 9) will undergo a Pinner reaction butin this case it was the conversion of the imidic ester into the amidine, which was problematic, thereverse of the general trend where formation of the imidate causes most problems. Workers atPfizer were also able to convert the nitrile 45 into the amidine 46 by reaction with hydroxylamineto give the amidoxime 48 which was cyclized to give the oxadiazole 49 followed by hydrogenolysis. This work was based upon literature reports by Horwell and co-workers and Kohrt and co-workers .Workers at Bayer were also able to prepare the vardenafil intermediate, 2-ethoxybenzamidine

via the amidoxime (Scheme 10). 2-Ethoxybenzonitrile was treated with hydroxylamine hydro-chloride in the presence of triethylamine to give the amidoxime 50, which was subjected tohydrogenolysis to give 2-ethoxybenzamidine 47 on a 136Kg scale (Scheme 10). Hence these methods proceeding via the amidoxime represent other waysof circumventing the proximity effect. Other multi-kg amidine syntheses via hydrogenolysis of anamidoxime have been reported and .Sometimes the NO bond can be difficult to reduce and in these cases in situ activation of the NO

bond by forming the acetate or trifluoroacetate ester followed by hydrogenolysis gives the desired

CN

SN

NO

O

Me

SN

NO

O

NH2

NH

Me

NN

SN

NO

O

N

HN

Pr

MeO

Me

SN

NO

O

NHOH

NHO

Me

SN

NO

O

O

Me

NO

NCF3

Sildenafil

45 46

48 49

NH2OHmethanol, Et3N20 C78%

TFA, TFAA, 20 C

85%

H2, Raney NiMeOH/H2O 20 C63%

Toluene80 C58%

EtOEtO EtO

Et Et

MeClAlNH2

Scheme 9


amidine under mild conditions. A detailed study was reported by workers at Glaxo Wellcome and aselection of results is summarized in Scheme 11 and Table 3 . Formation of theamidoxime works well for a variety of electron-donating and withdrawing substituents and for systemscontaining an ortho-substituent, e.g., 51e. The yield from 2,6-dimethylbenzonitrile is significantlylower but it is worth noting that 2,6-dimethylbenzamidine had not been previously reported.Hydrogenolysis of 52d and 52c proceeded slowly (16h) in the absence of an acylating agent butfor 52a, hydrogenolysis without an acylating agent was so slow as to be impractical. However,hydrogenolysis after in situ activation to form the acetate gave excellent results for (52a52f). Forsubstrate 52g, more powerful activation as the trifluoroacetate was required to get a reasonableyield of the desired amidine. There are other reported examples of in-situ activation by formingthe acetate and the trifluoroacetate . In-situactivation of the NO bond is also possible using (t-BOC)2O .

A very promising new method of preparing amidines from nitriles is to use an N-acetylcysteine-catalyzed reaction. The method works best for electron-deficient nitriles (Equation (26))

CNNH2

NH

NHNH2

NH

N NN

HN

O

Pr

NN

N

HN

O

Pr

SN

NO

O

Et

NH2

NOH

80 Ctoluene, 17 h 44

H2 Pd/C

PriOH

Vardenafil

50

47

68% 91%

76%

EtO EtOMeAl(Cl)NH2

EtOEtO

EtO

EtO EtOAcH2NOH.HCl

Et3N

NH2NH2

Scheme 10

N

NHH

51a51g 52a52g

H2 Pd/C

Ac2O, AcOHR4NHOHCN

R1

R2

R3

N

NHOH

R1

R2

R3R4

R1

R2

R3R4

Scheme 11

Table 3 Synthesis of amidines by reduction of amidoximes

SubstrateYield for amidoxime

Yield for amidine formation (%)

R1 R2 R3 R4 reaction (%) Ac2O method (CF3CO2)O method

a F H H H 90 84 No better than Ac2Ob MeO2C H H H 60 94c Me2N H H H 81 90d CF3 H H H 91 99e H Me H H 77 45f H Me Me H 16 56g F H H Me 87

and also works well for some hindered nitriles, although reaction times areincreased and yields reduced . Ammonium acetate may be substituted for gaseousammonia to give a more convenient laboratory procedure.

N CN NNH

NH2NH4OAc, N-acetylcysteine

MeOH, 50 C

1 equiv. N-acetylcysteine, 94%0.1 equiv. N-acetylcysteine, 68%

26

Reaction of the nitrile 53 with lithium hexamethyldisilazide followed by acid hydrolysis gavethe desired amidine in 83% yield (Equation (27)) . Other examples of amidinesprepared by the reaction of nitriles with lithium hexamethyldisilazide have been reported.

OO

S CN

OO

SNH2

NH

i. LiN(SiMe3)2THF, 25 C

ii. Aq. HCl85%

53

27

5.19.1.4.2 Aromatic amidines from amides

Aromatic amides are converted into amidines via the imidoyl chloride (normally by reaction withPCl5 or POCl3). The classical procedure is to heat an aryl amide, amine, and phosphorus chloridetogether in an inert solvent such as chloroform or benzene. A second classical method which canbe used for arylamides or other amides which do not possess a -hydrogen atom is to isolate theimidoyl chloride and then subsequently react with the amine. This procedure is tolerant of amineswhich react with phosphorus chlorides (e.g., aminophenols). Slightly more modern laboratory-friendly conditions are demonstrated by the conversion of the triamide 54 into the triamidine 55(Equation (28)) . Other examples include .

CONHEt

CONHEt

EtHNOCCl

NEtCl

EtN

NEtCl

NHEt

NEtEtHN

EtN

NEtNHEt

SOCl2 (excess),

Remove excessSOCl2

3 h

20 C to rt65% 56%

54

55

EtNH2

CH2Cl2

28

Aryl amides may be alkylated with Meerweins reagent (Et3OBF4) and converted into primaryor substituted amidines .

5.19.1.4.3 Aromatic amidines from thioamides and thioimidic esters

The reaction of aromatic thioimidates with aromatic amines gives amidines in very good yield;hence, the reaction of thioimidic ester 56 with aniline leads to amidine formation in 88% yield(recrystalized) (Scheme 12). However with more basic aliphatic amines, elimination occurs toreturn the nitrile (Scheme 12).


The problem can be overcome by using a buffered system. Hence, the reaction of 56 withdiisopropylamine in sodium acetate/acetic acid buffer gives the desired amidine .This principle also works for primary amidines; hence, the reaction of thiomidate 57 withammonium acetate gives the desired amidine (Equation (29)) , whereas unbuf-fered conditions (alcoholic ammonia) can give elimination with aromatic thioimidates (see chapter5.19.1.4.3 in ).

MeS

NH

(CH2)4O

HN

NH

O

Ph

O

OBut

OButO

H2N

NH

(CH2)4O

HN

NH

O

Ph

O

OBut

OButO

MeOH 100%57

NH4OAc 29

The thioimidic ester method can be used to overcome the proximity effect. For example, 4-sub-stituted-1-naphthamidines 58 can be prepared via the thioimidic esters 59, whereas preparationfrom the nitriles 60 via the imidic ester (the Pinner reaction) failed (Scheme 13) .

Other recent syntheses of aromatic amidines from thioimidates include .

5.19.1.4.4 Aromatic amidines from compounds with cumulated double bonds

In the review period there have been a number of amidines prepared by adding an aryl anion to acarbodiimide. For example, both ortho-lithiation (Equation (30)) , and morefrequently metalhalogen exchange have been used to generate the aryl anion.

OO

NPriHNNHPriiPr

TMEDA, BuLihexane

iPrN

61% PriN=C=NPri

30

CN

N(C16H33)2 N(C16H33)2

NHEtS

N(C16H33)2

NHPhNH

Pr2NH 88%

56

PhNH2EtSH

i

Scheme 12

R

CN NHMeS

R

NHH2N

R

Pyr, Et3N acetone6094% 8395%

NH4OAc, EtOH

3780%

60 59 58R = Me, COPh, CH2COPh, CH2CH2COPh

H2S MeI

Scheme 13


5.19.1.5 N-Acyl- and N-Heteroacylamidines

5.19.1.5.1 N-Acylamidines, R1C(NR2)NR3COR4

Not surprisingly, the most common way of preparing acylamidines is via direct acylation. Directacylation with acid chlorides, chloroformates, or phenolic esters is covered in chapter 5.19.1.5.1 of, and more recent references include and (where the preparations of 24 acylated amidines are described). Severalt-BOC-protected amidines were prepared by the reaction of an aryl amidine with (t-BOC)2O.Amidines bearing an N-aryl substituent such as 61 are reported to undergo acylation with acid

chlorides on the nitrogen bearing the aryl substituent as outlined in Scheme 14. A wide varietyof benzamidines and naphthamidines have been prepared by this method .However, N-phenylbenzamidine 62 is reported to acylate on the other nitrogen when treated withthe ester 63 (Equation (31)) .

NPh

NH2Ph

O HAr

EtO2CCN O

NPhPh

NHO

ArH

CN+

Toluene, , 4 h

55% recryst. yield62 63

31

Activated carbonates may also be used to acylate amidines in quantitative yield as shown inEquation (32) .

NH

NHH2N

CO2Et NH

NH

CbzHN

CO2Et

N

O

O

Cbz-O

Et3N, DMF, rt, 17 h

100%

32

5.19.1.5.2 N-Thioacylamidines

Amidines can be thioacylated by reaction with thiochloroformates under phase-transfer conditions orby rt reaction with isothiocyanates (Scheme 15). Both methods were described in chapter 5.19.1.5.2 in. More recent literature reports of synthesis from isothiocyanates include (where reaction takes place at 0 C).

N

NH

ON

NHN

NH

O

Cl

Cl

ClO

benzene70 C, 6 h 6895%

R1 = phenyl, subst. phenyl, 2-naphthylR2 = H, Cl, Me, CF3

61

R2R1 R2R1MeCOClR2R1

H

Scheme 14


Thiobenzamide undergoes reaction with protonated acetonitrile to give thiobenzoylacetamidine64. The reaction of thiobenzamide with dimethylformamide dimethyl acetal forms the thioben-zoylformamide 65 in excellent yield and under mild conditions (Scheme 16) .Further references covering the preparation of thioacylamidines from formamide acetals can befound in .

N-Thioacylamidines can also be prepared from the reaction of an N-acylamidine with phos-phorus(V) sulfide (Equation (33)) . Another method involves sequential reaction ofan amine with N,N0-thiocarbonyldiimidazole followed by displacement of the second imidazolewith the amidine 66 (Scheme 17) .

Ar NH

NMe2

O

Ar NH

NMe2

S

pyridine6293%

P4S1033

5.19.1.5.3 N-Selenoacylamidines

In the preparation of selenoacylamidines by the reaction of isoselenocya-nates such as 67 with benzylamine was described. In the review period, the reaction has beenextended to aliphatic amines such as morpholine, as shown in Scheme 18 and.

NH

NR1Ph Ph NMe2

N

S

NHPh

Ph

N

S

O

NH2

Cl OR2S

R1 = MeR1 = H

R2 PhNCS

2

Scheme 15

S

NH2PhMe NH2

N

S

PhN

S

NMe2

Ph

Me2NOMe

OMe

20 C, 1 h 97%

dry HCl24 h, 20 C

6465

reagent and solvent MeCN

Scheme 16

NHMe

NC

S

N NNN

NC

N NMe

N

S

ArH2N

NH

Ar

NC

NMe

S

HN

NH

+

38%

Ar = 2,6-dichlorophenyl66

THF

DMF63%

Scheme 17


Two other methods of preparing selenoacylamidines are shown in Scheme 19 .

5.19.2 AMIDINE-DERIVED STRUCTURES WITH AN N-HETEROATOM BOND

5.19.2.1 N-Haloamidines

CAUTION: Nitrogen-halide compounds are potentially explosive; please read the primary litera-ture carefully and take appropriate precautions.

5.19.2.1.1 N-Fluoroamidines

N-Fluoroamidines are formed in high yield by the action of ammonia or dimethylamine on theimidoyl fluoride 68 (Equation (34)) . In addition, 69a may further be fluorinatedby elemental fluorine to give the trifluoroamidine .

F

NF NF

NR2 NF2

NF(R2)2NH

78 C, Me2O, CFCl3 (R2 = H)R2 = H 95% yieldR2 = Me 90% yield

6869a (R2 = H)69b (R2 = Me)

RfF2

RfRf2 34

5.19.2.1.2 N-Chloroamidines

Baird and Bruce have shown that temperature control is important in influencing whether2-amidinothiophene 70 is chlorinated with sodium hypochlorite to give the N-chloroamidine 71or the chlorodiazirine 72. At temperatures below 25 C, the N-chloroamidine is the only isolatedproduct, However, if the sodium hypochlorite is added rapidly and the temperature allowed to

Ar NH2

Se

Ar

Se

N

R

NMe2

ROMeMeO

Me2N

Ar N

Cl R

NMe250 C, 30 min

+

R = H Ar = 4-Me2NC6H4

CH2Cl2, 1.5 h

R = H 30% (0 C) R = Me 90% (25 C)

Ar = Ph

37%

NaSeH

DMF ClO4

Scheme 19

R

N

N

NO2

Se

OHN

R

N

NO2

NH

N

Se

O

R = H, Br, F, Me, MeO, CN4999.5%

acetone

rt, 1530 min67

Scheme 18


rise to 35 C, 72 is formed in 65% yield (Scheme 20) (seealso ). Several examples of high-yielding methods to prepare N-chloroamidineswere tabulated in chapter 5.19.2.1.2 of .

5.19.2.1.3 N-Bromoamidines

N-Bromoamidines are prepared from the parent amidine with sodium hypobromite as describedin chapter 5.19.2.1.3 in . No further advances have occurred since thepublication of this chapter.

5.19.2.1.4 N-Iodoamidines

N-Iodobenzamidine may be prepared from benzamidine and potassium triiodide .No further advances have occurred since the publication of .

5.19.2.2 N-Imidoylhydroxylamines and Related Structures

N-Imidoylhydroxylamines are also known as amide oximes, hydroxamidines, and most commonlyas amidoximes. The syntheses of N-imidoylhydroxylamines have previously been reviewed in and , as well as a small section in a reviewby Abele and Lukevics .

5.19.2.2.1 N-Imidoylhydroxylamines from hydroxylamine

Hydroxylamine is sufficiently nucleophilic to undergo an addition reaction to a nitrile without thepreformation of an imidic ester. This is the most common method of making N-imidoylhydroxyl-amines with over 100 publications reporting this reaction in the review period. Some recentexamples are shown in Equation (35) . Further examples can be found in Sections 5.19.1.3.1 and 5.19.1.4.1.

CNNH2

NOH

R = 4-F 90%R = 4-Me 92% R = 3-Cl 85%R = 4-CF3 91% R = 3-CF3 96%

NH2OHR R

35

Hydroxylamine is also sufficiently nucleophilic to react directly with thioamides without the needfor thioimidic ester formation. The reaction of 73 with hydroxylamine gave the imidoylhydroxyl-amine in 50% yield over two steps from the starting amide (Equation (36)) .

O

NH

NPh NHN

S

Ph NH

N

NOH

Ph73

P2S5 H2NOH

EtOH36

SNH2.HCl

NHS

NH2

NClS

NNCl

NaOCl(aq.), LiCl, NaClDMSO, CH2Cl2

1025 C70 71

NaOCl(aq.), LiCl, NaCl

DMSO, CH2Cl21035 C72

65%

Scheme 20


N-Imidoylhydroxylamines may be prepared from the imidoyl chloride and hydroxylamine(Equation (37)) . In the review period, a modified reaction between the imidoylchloride and O-trimethylsilylhydroxylamine was reported. A series of 12 amidoximes was pre-pared, a selection of which is shown in Equation (38). The trimethylsilyl group is removed underthe reaction conditions . The reaction of N-(2-methylphenyl)hydroxylamine withan imidoyl chloride also yields an amidoxime .

NHO

PhN

Ph

ClN

Ph

HOHN

NH2OH.HClNaOEtEtOH/Et2O

R1, R2 = H 92% R1, R2 = Me 98% R1 = H, R2 = Me 90%R1 = NO2, R2 = H 95%R1 = MeO, R2 = H 92%

yields from NH 2OH.HCl

R1

R2

R1

R2

PCl5

R1

R2

37

R F

O

NH

N

R F

NH

NNOH

R F

N

NCl

CH2Cl2, 5 h 20 C, 20 h

R = H, F, CF3, OMe (5279% over 2 steps)

PCl5 H2NOTMS

THF 38

A further method for preparing N-imidoylhydroxylamines is the treatment of an amidine withhydroxylamine. This reaction is a common way of preparing formamidoximes (Equation (39)) (see also chapter 5.19.2.2.1 of ).

O

NN

N

R

NMe2

O

NN

N

R

NHOHdioxane/MeOH

R = H 38%, reaction time 3 h at 20 CR = Me 86%, reaction time 24 h at reflux

H2NOH.HCl

39

5.19.2.2.2 N-Imidoylhydroxylamines from amines and ammonia

Chlorination of aldoximes gives oxyimidic chlorides which readily react with amines or ammonia togiveN-imidoylhydroxylamines (see chapter 5.19.2.2.2 in). The oxyimidic chlor-ide 74 reacts with 2,2-dimethylaziridine to give the (Z)-imidoylhydroxylamine 75 (Equation (40)). The reaction is thought to proceed via the stereospecific addition of the aziridineto the arylnitrile oxide . For other recent examples of N-imidoylhydroxylaminesprepared from oxyimidic chlorides (see ).

NOH

R'

R

ClN

OH

R1

R

N

R'

R

NOHNH

2535 C74 75

Et3N, Et2O0 C, 1 h

R = H, R1 = H 64% R = Cl, R1 = H 65% R = Me, R1 = HR = H, R1 = Cl 90%

NCS

DMF

57%

40


N-Trimethylsilyldiethylamine 76 undergoes facile addition to acetonitrile N-oxide to give thekinetically favored O-silylated (Z)-imidoylhydroxylamine. Over several days at room temperature,the (Z)-isomer rearranges to the thermodynamically more stable (E)-isomer (Equation (41)).

N OEt2N NEt2N -TMS

NEt2N

O-TMS+

+

Et2O, 25 C

80%

Et2O, 25 C

100 %76

several daysTMS

O41

3-Alkyl-5-aminopyrazoles 77 undergo reaction with oxyimidic chlorides at the pyrazole nitro-gen rather than at the amino group to give 78 as the (Z)-isomer (Equation (42)) .This reaction also proceeds via the nitrile oxide.

NH

N NH2R

Cl

NOHN

N NH2

NR OH

+

Et3N, dioxan

25 C, 3 h

R = CH2CH2Ph 57 %R = C6H4NO2 48 % (yields up to 84% for best examples)

7778

42

5.19.2.2.3 N-Imidoylhydroxylamines by miscellaneous methods

O-Alkylation and O-acylation of amidoximes are well known (see chapter 5.19.2.2.1 of). However during the review period, N-arylations of O-methylamidoximeshave been reported by a palladium-catalyzed reaction of the O-methylamidoxime with an arylbromide, iodide, or an activated aryl chloride. Twelve examples are reported, a selection of whichis shown in Equation (43) .

NH2

NOMe Br NOMe

NPd2(DBA)3Xantphos, CsCO3dioxane, , 18 h

(R1 = Cl, H or Me; R2 = H, Me, CF3, CHO, CO2Me, CN, NO2)6987%

R1R2

R1R2

H 43

The synthesis of O-vinylamidoximes has been reported using KOH/DMSO as base (Equation(44)) (Note: O-vinylamidoximes can explode on heating).

NH2N

R

OH

NH2N

R

O

Acetylene (1535 atm)KOH, DMSO

~75 C, 7 minR = Me, 46% R = Ph, 80%

44

5.19.2.3 N-Imidoylsulfenamides, -sulfimides, -sulfinamides, and -sulfonamides

5.19.2.3.1 N-Imidoylsulfenamides R1C(NR2)NR3SR4

N-Imidoylsulfenamides, also known as sulfenylamidines, are stable materials which are oftenisolated as crystalline, sharp melting solids; are slowly hydrolyzed by aqueous alcohol.N-Imidoylsulfenamides are prepared by the reaction of an amidine with a sulfenyl chloride


or other sulfenating agent. Examples are tabulated in chapter 5.19.2.3.1 of .Recent examples include the high-yielding sulfenation of benzamidine with N-(phenylthio)phthal-imide (Equation (45)) . Very hindered sulfenating agents such as tritylsulfenylchloride also give good yields of the desired N-imidoylsulfenamide (Equation (46)).

NH2

NHPh

O

O

N SPh

NH2

N-SPhPh

CH2Cl2, rt, 2.5 h99%

45

NH

CO2Et

NH

H2N

NH

CO2Et

NH

NH

TrSTrSCl

Pr2NEt, DMF, rt, 1 h86 %

Fmoc Fmoci

46

5.19.2.3.2 N-Imidoylsulfimides

N-Imidoylsulfimides are prepared by three general methods, from either N-chloroamidines,amidines, or imidoyl chlorides. These are shown in Scheme 21. References for these pre-parations can be found in chapter 5.19.2.3.2 of or in a review byGilchrist and Moody . Since the publication of the chapter there has beenlittle research activity into the preparation of N-imidoylsulfimides. One exception is thediscovery that sulfimide (Ph2SNH) will undergo a platinum-mediated coupling reactionwith a nitrile to give a platinum amidine complex (Equation (47)) (see also).

PtRCNCl

ClClNCR

ClPtN

Cl

ClClN

Cl

R

N SPh

PhN

R

SPh

Ph+

R = Me, Et, PhCH2

rtPh2S=NH

CH2Cl247

N NArR2S Cl NAr

R1 R1

R1

R1

NHArNCl

NArH2N N

O

O

SR2+

R = Ph

Ph2S=NH

R2S

Scheme 21


5.19.2.3.3 N-Imidoylsulfinamides

N-Imidoylsulfinamides can be prepared by the reaction of a sulfinamide 79 with trimethylorthoformate to give the imidate 80, which subsequently undergoes reaction with the lithiumsalt of N-methylaniline to give the desired N-imidoylsulfinamide 81 (Scheme 22) .The imidate 80 also undergoes reaction with dimethylamine in THF to give an imidoylsulfinamide. The stereochemistry of the sulfinamide is maintained through the reactionsequence and this is important as these reactions are used to build up chiral ligands for catalysis.Racemic sulfinamides can be prepared by reaction of a silylated amidine with 4-toluenesulfinylchloride .

5.19.2.3.4 N-Imidoylsulfonamides

Two of the most common ways of making N-imidoylsulfonamides 82 are by direct sulfonation ofthe amidine (Scheme 23) or by converting an N-sulfonylcarboxamide into its imidoyl chloridefollowed by reaction with an amine or ammonia to give the imidoylsulfonamide 82 (Scheme 23).Both of these approaches were covered in chapter 5.19.2.3.4 of .

The preparation of N-imidoylsulfonamides from sulfonamides and imidates was also covered inchapter 5.19.2.3.4 of . In the review period, sulfonamides have alsobeen shown to react under Vilsmeier conditions to give N-imidoylsulfonamides (Scheme 24) (see also ), and to react with DMF-dimethyl acetal to giveN-imidoylsulfonamides in very high or quantitive yields (Scheme 24) . The reaction works for both aryl and alkyl sulfonamides but isonly successful for primary sulfonamides (e.g., RSO2NH2). The reaction of secondary sulfona-mides with DMF-dimethyl acetal does not form the N-imidoylsulfonamide, instead N-methyla-tion of the sulfonamide nitrogen takes place .

A particularly useful variant of the DMF-dimethyl acetal chemistry was reported by workers atHoechst Roussel. 2-Bromobenzenesulfonamide was treated with DMF-dimethyl acetal at roomtemperature to give the N-imidoylsulfonamide 83 in 98% yield. Performing a Suzuki reactionon 83 gave 84 in 93% yield. Hence, this methodology could then give access to a wide variety ofN-imidoylsulfonamides by using different boronic acids (Scheme 25) .

But S NH2

O

But SO

N OMe ButSO

N NMe

Php -TsOH (cat.)

100 C, 3 h THF, rt, 1 h

92% 72% 79 80 81

HC(OMe)3 Ph(NMe)Li

Scheme 22

N

NR3R4

SO2R2NH

OSO2R2

NH

NR3R4

82R3R4NH

R2SO2Cl

R2 = aryl, alkyl, vinylR1

R1

PCl5

R1

Scheme 23

RSO2N CHNMe2

Me2NOMe

OMeRSO2Ntoluene, 70 C

0.5 h95%

DMF/POCl3rt, 15 h82%

R = HOCH2C(CH3)2CH2R = ArOCH2C(CH3)2CH2

RSO2NH2CHNMe2

Scheme 24


In the review period a number of new methods have been reported for making N-imidoyl-sulfonamides. These include the reaction of a ketone, an amine, and a fluoroalkanesulfonyl azide(Equation (48)) , the reaction an N-sulfonylamine 85 with a dimethylaminoazirine 86(Equation (49)) and through an insertion reaction of cyclohexene which wasdiscovered by Evans and co-workers (Scheme 26) . Evans proposed that theinitially formed metal catalyst 87 undergoes a [2+2]-reaction with the solvent acetonitrile togive 88 which rearranges to 89 prior to allylic insertion (Scheme 26) .

OHN N

NSO2C4F9

+ +rt, 5

h

53% when morpholine is the amine

83%

C4F9SO2N3Et2O

48

NO

OR

N

NMe2Ph

Et

NSO2

NMe2Ph

ONH

PhR = cinnamoyl (E )

+78 Crt

45% 85 86

CH2Cl2S 49

A number of recent papers report the preparation of N-imidoylsulfonamides from sulfamide 90and are shown in Scheme 27. The imidic esters 91 and 92 are prepared via a Pinner reaction, andsubsequent reaction with sulfamide gives the N-imidoylsulfonamide . Sulfamide will also react with the methylation product of 93 to give theN-imidoylsulfonamide 94 (Scheme 27) .

BrSO2NH2

Br

N

NMe2

O SOMe2N

OMe

OMeBMeOH

OH N

NMe2

O SOMe

DMF, rt, 2 h 98%

Pd(OAc)2, PPh3Na2CO3 toluene, , 4 h

93% 83 84

Scheme 25

NH

Me

NTs

N

NMn Me

Me

NTs

Ph=NTs, MeCN

63%

+MeCN

[ 2 + 2 ]

87

88

89

Mn(TPP)ClO4

X(TPP)Mn=NTs

X(TPP)

X(TPP)Mn=N

C6H10

Ts

Scheme 26


5.19.2.3.5 Amidine derivatives with an N-selenium or N-tellurium bond

(i) Amidine derivatives with an N-selenium bond

The number of amidine derivatives with anN-selenium bond has increased in recent years mainly dueto the research efforts of the Chivers group. Treatment of the lithium salt of the disilylamidine 95withphenylselenium chloride gave the selenium derivative 96 as an off-white solid in 25% isolated yield.The derivative 96 could be treated with 1 equiv. of methanol in THF, with gentle heating to give thedesilylated compound as dark purple crystals (Equation (50)) .

TolNTMS2

NSePh

NH2

NSePhTol Tol

78 C to rt25%

MeOH, THF

40%

95 96

NTMS

NTMS

PhSeClCH2Cl2 Et2OLi 50

Tris(trimethylsilyl)formamidine was treated with phenylselenium chloride to give the seleniumderivative with concomitant desilylation (Equation (51)) . A single crystal X-raystructure was reported for the product.

NH2

NSePh

NTMS2

NTMS

78 C to rt48%

PhSeClCH2Cl2 51

Treatment of the tris(trimethylsilyl)amidine 97 with 3 equiv. of phenylselenium chloride pro-duces an intensely colored purple solution upon warming to room temperature. The reaction isthought to proceed via the tris(seleno)amidine followed by dimerization with elimination ofdiphenyl diselenide to give the purple diazene 98 (Equation (52)) (see also). In a close analog, the diazene nitrogenselenium bond distance is reported to

NAr

NH2

NSO2NH2

OS NH2H2NO

NArNH

OMe

ArCH2S NH2

NSO2NH2

ArCH2SNH

OMe

O

NSO2NH2H2N

O2N

O

NCONH2H2N

O2N

91

70 C, 2 h27%

9092MeOH, rt, 60 h

30%

+ MeI

94

93

MeOCH2CH2OH

NaH, THF, , 2.5 h48%

Scheme 27


be around 2.65 A (cf. 3.5 A for the sum of the van der Waals radii for selenium and nitrogen) and the authors suggest there is some nitrogenselenium bonding interaction(shown by the broken lines) for the diazene 98.

N(SePh)2

NSePhTol2Tol

NTMS2

NTMS

TolNSe

NTol

N Se Ph

Ph97

3TMSCl

98

22PhSeSePh6PhSeCl

N 52

(ii) Amidines with an N-tellurium bond

Preparations of these derivatives were covered in chapter 5.19.2.3.5 of (seealso ). No major advances have been made since the publication of thischapter.

5.19.2.4 Amidrazones and Related Structures

5.19.2.4.1 Introduction and nomenclature

Amidrazones are also known as hydrazidines, amide hydrazines, or N-imidoylhydrazines. In thisreview the name hydrazidines will be used for structures such as 99. There have been two previousreviews on amidrazones by Neilson and co-workers as well as thereview in (see also ). This review in conformancewith previous reviews will number the nitrogen atoms as shown for compound 100 and istherefore named N1-phenyl-N1,N3,N3-trimethylpropanamidrazone.

RNHNH2

NNH2Et

N NMePh

NMe2

99 100

2 1

3

5.19.2.4.2 Primary amidrazones, RC(NH)NHNH2

The preparation of primary amidrazones from the reaction of hydrazine with a nitrile is coveredin chapter 5.19.2.4.2 of . More recent examples include as shown in Equation (53) and .

NNHN

CH2CNH2NO2S

PhPh

NNHN

H2NO2S

PhPh

NH

NHNH2

EtOH, , 2 h Piperazine (cat.)

70%

N2H4.H2O 53

The most common method of preparing primary amidrazones is through a substitution reac-tion of imidic esters (101, X=O) with hydrazine (Scheme 28) . Care has to be taken with the hydrazine stoichiometry and the reaction tem-perature to avoid formation of the hydrazidine 102.The preparation of primary amidrazones from thioimidic esters (101, X=S) and from thioa-

mides is covered in chapter 5.19.2.4.2 of .


5.19.2.4.3 N-Alkyl-, aryl-, or alkenyl-substituted amidrazones

(i) N-Substituted amidrazones from hydrazines

Imidic esters react with hydrazine, mono-, di-, and trisubstituted hydrazines to give substitutedamidrazones. The reaction of imidic esters with monosubstituted and especially N,N-disubstitutedhydrazines gives amidrazones with fewer side products than the equivalent reaction with hydra-zine. A convenient method for preparing formamidrazones is to heat an amine such as 102, withtriethyl orthoformate to give the imidate, which can then undergo reaction with hydrazine, or asubstituted hydrazine to give the formamidrazone 103 (Equation (54)) . Forsimilar examples, see .

N NH2

PhCN

NN O

Ph

N

PhCN

NN O

Ph

N CHOEt N

PhCN

NN O

Ph

NNHNH2

102

HC(OEt)3, 5 h dioxane

rt, 30 min

103

85% 60%

N2H4.H2O

54

Another option is to convert the amine such as 104 into the formamide. The formamide isreactive enough to form the formamidrazone directly with hydrazine (Equation (55)).

N

NN

NH2ArHC N

NN

NHCHOArHC N

NN

ArHC NNHNH2104

Ac2O/HCO2H

reflux, 2 h

N2H4.H20

EtOHreflux50% 75%

55

Imidoyl chlorides are a very good source of amidrazones though the high reactivity of theimidoyl chloride can lead to some loss of selectivity. Hence, N-phenylbenzimidoyl chloride cleanlyforms the trisubstituted amidrazone 105 with a large excess of 1,1-dimethylhydrazine, but with2 equiv. of 1,1-dimethylhydrazine a mixture of 105 and 106 is obtained (Scheme 29). For more recent examples of amidrazones prepared from imidoyl chlorides,see .

The preparation of N-substituted amidrazones from the reaction of hydrazine with thioamides,triazine, formamide acetals, and ketenamines is covered in chapter 5.19.2.4.3 of.

RXalkyl

NHR

NH

NHNH2R

NNH2

NHNH2101

X = O or S 102

NH2NH2

Scheme 28

NPh

ClPh

NNMe2Ph

NHPhNPh

PhN

NPhPh

NMe2

105

Me2NNH2 (excess)

106

Scheme 29


(ii) N-Substitued amidrazones from amines and ammonia

Amidrazones can be prepared by reaction of a primary or secondary amine with an -nitrohydra-zone 107 (Scheme 30) (see also ). -Nitrohydrazones can also behydrogenated over Raney nickel to give amidrazones and .

(iii) N-Substituted amidrazones by N-alkylation of simpler amidrazones

The alkylation of amidrazones has been studied by Smith and co-workers . Depending upon the substitution pattern, alkylation can occur on anyof the three nitrogen atoms, but in most cases alkylation occurs atN2 orN3 so that an amidinium likedelocalized cation is formed. Scheme 31 gives an example of N2 alkylation via a delocalized cation,whereas in Scheme 32 amidrazones 108 and 109 are also alkylated to give a delocalized cation but viaalkylation at the N3 atom. Further examples are given in chapter 5.19.2.4.3 of ,and there have been no significant advances since the publication of that chapter.

5.19.2.4.4 N-Acylamidrazones

(i) N1-Acylamidrazones

Primary amidrazones are generally acylated directly at N1 in good yield .N3-Phenylbenzamidrazone is also acylated at N1 . Another way of makingN1-acylamidrazones is by the reaction of acylhydrazines with imidic esters. Not surprisingly,

NMe

NMeRPh

NMe2N NMe2

NRPh

Me

+

108, R = Ph109, R = Me

Warm gently

MeI

Scheme 32

NMe

NHMePh

NMe

NHMePh

N NMeR

NHMePh +

R = Ph or Me R = Ph 88% R = Me 79%

MeI HONMeR NMeR

Scheme 31

N

NO2

NHAr

Ph

CO2Et

NNHAr

Ph

CO2Et

NR1R2

107

R1R2NH,

13 h

R1, R2 = Et, 100% R1, R2 = Pri, 100% R1 = H, R2 = PhCH2, 63% (reaction in toluene at 80 C)

Scheme 30


the reaction is slower and much cleaner than the reaction of imidic esters with hydrazine.Some care must be taken to avoid cyclization to the triazole e.g., 110 (see Scheme 33).

A new method of preparing N1-acylamidrazones from acyl hydrazines is to use an engineeredpapain nitrile hydratase (Scheme 34) . The authors report that this method can avoid anumber of the side products which can be formed from the reaction of nitriles with hydrazides.

Further examples of making N1-acylamidrazones and N1-acylformidrazones can be found inchapter 5.19.2.4.4 of .

(ii) N3-Acylamidrazones

N1,N1-Disubstituted amidrazones are acylated on the N3-atom (Equation (56)) The N1-aryl-substituted amidrazone 111 was also reported to acylate on N3 to give 112 (Equation(57)) .

NNMe2

NH2Ph

NNMe2

NHCOTolPh

TolCOCl, Et3N

CH2Cl2 , rt, 12 h93%

56

N

NH2EtO2C

NHAr N

NHCOCO2EtEtO2C

NHAr

toluene, reflux111 112

ClCOCO2Et

57

NH

OMe

EtO

OMe

NH2NNHCOAr N

HN N

OMe

Ar

110

87%

Ar = 2-ethylphenyl

ArCONHNH2

Scheme 33

NH

Me

CNMeOCO NH

Me

NH

SEnzMeOCO

O

NHNH2

OH

MeOCOHN

NH

Me

NH

HN

O OH

EnzS

Conditions: 22 C, pH 5.0 buffer, 68 h

Phe Phe

Phe

Scheme 34


5.19.2.5 Amidine Derivatives with an NP, NAs, or NSb Bond

5.19.2.5.1 N-Phosphorylamidine derivatives

Several methods of preparing N-phosphorylamidine derivatives were outlined in chapter5.19.2.5.1 of . Three of the most common methods are shown in Scheme 35.N-Phosphorylamidines can be prepared from N-chloroamidines 113 via an Arbusov-type reactionwith tribenzyl phosphite. N-Phosphorylamidines may also be prepared from imidoyl esters(114, X=OR) or imidoyl chlorides (114, X=Cl) and amines, and from thiophosphorylationof amidines 115 (Scheme 35).

A new method of making N-phosphorylamidines involves the reaction of -lithioalkyl phos-phonates with cyanamides. Following initial addition to the nitrile, there is a migration of thephophoryl group to give the anion of the N-phosphorylacetamidine 116. This anion can bequenched with water to give 117 or benzaldehyde to give 118. Quenching with other electrophilessuch as methyl iodide, allyl bromide, or TMSCl is also possible . The N-phosphor-ylacetamidine 117 can also be deprotonated and quenched with an electrophile (Scheme 36),hence giving access to a wide range of phosphorylamidines.

RN

N POO

RX

N POO

RN

NCl

RNH2

NH.HClCl P OO

SZ

R2R3

Z

R2R3

(R1 = Bn)(Z = O)

115

(Z = S)(R1 = Ph)(R2R3 = H)R

2R3NH(R1 = alkyl )

(Z = O)

114

113 R1R1

R1R1

P(OBn)3 R1R1

Scheme 35

PO

EtOEtO

N

CH2

PO

EtOEtO

NMe2

NPO

EtOEtO

NMe2Me

NP

OEtOEtO

NMe2PhCH(OH)CH2

BuLi, THF78 C, 1 h

78 C, 10 min

i. LDA, THF, 78 C, 1 h

ii. PhCHO, 78 C to rt

116

118

117

Me2NCN

H2O

PhCHO

Me

Scheme 36


5.19.2.5.2 N-Phosphorus amidines (excluding N-phosphorylamidines)

Chapter 5.19.2.5.2 of gives several methods of making these compounds; forexample, the ylide 119 can be prepared from the corresponding N-chlorobenzamidine derivative bythe high-yielding reaction with phosphorus trichloride. The phosphinoamidine 120 can be preparedby the reaction of diisopropylphosphorus chloride with the trimethylsilylamidine 121.

NAr

N PCl3Ph

N

NMe

MeP

Pr i

Pr iPhN

NMe

Me

Ph

119 120 121

TMS

An alternative way of preparing NP ylides that has been reported in the review period is via thereaction of an amidewith triphenylphosphine in the presence of iodine (Equation (58)).

N

Me NH2

N

R Ph

N

Me N=PPh3

N

R PhPh3P, I2, Et3N

CH2Cl2, rt, 24 h5285%

58

Reaction of a bromodiazirine with trimethyl or triphenylphosphine gave the bisphosphorusadducts in high yield (Equation (59)) . The -electrons in the bisphos-phorus adducts are fully delocalized over the nitrogen and phosphorus atoms and the amidinecarbon.

N NPR3

Ph

R3PNN

BrPh

+CH2Cl2 78 C

R = Me, 85% R = Ph, 83%

BrR3P

=59

5.19.2.5.3 Amidines with an N-arsenic bond

Arsoranylbenzamidine derivatives 122 and 123 are prepared from the reaction of N-chloro-N,N0-dimethylbenzamidine with triphenylarsane or arsenic trichloride, respectively, as describedin chapter 5.19.2.5.3 of . No major advances have occurred since thepublication of this chapter.

5.19.2.5.4 Amidines with an N-antimony bond

The antimonybenzamidine complexes 124 and 125 are prepared from N-chloro-N,N0-dimethyl-benzamidine and triphenylantimony and antimony trichloride, respectively. Unlike the arsenicderivative 122, antimony prefers the chelated structure 124 . No major advanceshave occurred since the publication of .

NN

AsClCl

Cl

ClPh

Me

Me

NN

SbClCl

Cl

ClPh

Me

Me

NN

SbCl

Ph

Me

Me

PhPhPhNMe

N AsPh3Me

Ph

+

124 125123122

Cl


5.19.2.6 Amidine Derivatives with an N-Metalloid Bond

5.19.2.6.1 N-Silylamidines

(i) Monosilylamidines

Examples of the preparation of monosilylamidines from the lithium salt of a silylated amineand an imidoyl chloride or by direct silylation of amidines with trimethylsilyl chloride are givenin chapter 5.19.2.6.1 of . The diamidine is silylated with an excess ofbis(trimethylsilyl)amide to give 126 (Equation (60)) .

NH

NN

HN

N

NN

N

H2SO4 (cat.)

126

TMS

TMS(TMS)2NH

60

The bis-silylated diamine 127 undergoes deprotonation and reaction with 2 equiv. of benzoni-trile in diethyl ether to give the bis(monosilyl)amidine 128 which can be isolated as the dilithiumsalt (Scheme 37) (see also ). With 1 equiv. of benzonitrile, themonoamidine salt 129 is formed and a crystal structure of this compound is available.

When 1,4-dibromobenzene is treated with 2 equiv. of butyllithium, a double metal halogenexchange reaction occurs, and subsequent reaction with two molecules of dicyclohexylcarbodi-imide followed by silylation produced the silylated amidine (Equation (61)) .

Br

Br

N

TMSN

N

NTMS

BuLi, hexaneDCC, THF

52% TMSCl

61

NH

HN

NTMS

NTMS

N

N

NTMS

NHTMS

N2

2 equiv. BuLi in C6H14

2 equiv.PhCN

020 C

020 C1 equiv. BuLi in C6H14

020 C

1 equiv.PhCN

020 C+

-

127

129128

2Li+

TMS

TMS

Et2OC6H14Li

Scheme 37


(ii) Disilylamidines

The preparation of disilylamidines was covered in chapter 5.19.2.6.1. of .The main methods are the addition of the lithium or calcium salt of bis(trimethylsilyl)amide to anitrile, or the addition of a lithium carbanion to N1,N3-bis(trimethylsilyl)carbodiimide. Bothapproaches are shown in Scheme 38.

(iii) Trisilylamidines

The preparations of N,N,N0-tris(trimethylsilyl)benzamidine and its derivatives are described inchapter 5.19.2.6.1 of (see also ).

5.19.2.6.2 N-Borylamidines

A large number of borylamidines have been reported. These borylamidines may be mono-coordinate such as those prepared in Equation (62) , a reference thatgives the preparation of over 30 borylamidines, or di-coordinate such as those prepared by themethod outlined in Equation (63) (Note: R2B-S-alkyl can also be used as the reagent). Many other methods of making borylamidines are given in chapter5.19.2.6.2 of .

NAr

NAr2X

NAr

NAr+

8090%

R1 = H or CF3, R2 = Ph, Me, NMe2; X = Cl or Br TMS

R1R2

R2R1

R2B

B

262

N

NPh

R

RPh

NR1

NR2 7697% B

R1

R2

R3B 63

In the review period, the borylamidine 130 was prepared by a hydroboration reaction of acarbodiimide with 9-BBN. This compound undergoes a boron exchange reaction with borontrifluoride to give the difluoroborylamidine in 75% yield (Equation (64)) .

NN

NNF2B

130

hexane75%

B BF3.Et2O

64

NTMS

Ph

NTMS

Li N

N

PhCNLiN(SiMe3)2

TMS

TMS

PhLi

Scheme 38


5.19.2.7 Amidine Derivatives with an N-Metal Bond, R1C(NR2)NR3-M

Amidines form salts with alkali and alkaline earth metals and complexes with most other metals.The amidinato ligand can be either 1 or 2 with -type or NM -bonding. A comprehensive 78page review by Eldemann gives details of N-silylated benzamidine complexeswith main group elements, transition metals, and actinide elements.

5.19.2.7.1 Amidines with an N-metal bond, where M is a group 13 metal

Amidine complexes with aluminum, gallium, indium, and thallium were reported in chapter5.19.2.7.1 of . Since the publication of the chapter there has been a largenumber of publications which include amidine complexes of group 13 metals. One general methodof preparing aluminum or gallium complexes is shown in Scheme 39. Treatment of carbodiimideswith trimethylaluminum gives the dimethylaluminum acetamidine complex 131 (alkyl= iPr, tBu,cyclohexyl). Alternatively, the carbodiimide can be treated with an alkyl- or aryllithium to give thelithium salt of the amidine which can be further treated with gallium trichloride to give 132 oraluminum trichloride to give 133. Treatment of either 132 or 133 with a Grignard reagent gave 134and 135 respectively, in good yield , for examples starting from acarbodiimide and an aryllithium see and .

N,N0-Bis(trimethylsilyl)benzamidine forms a 2:1 complex 136 with aluminum trichloride in highyield as shown in Equation (65). The chloroaluminum complex 136 can be converted into thehydroaluminum complex 137 by treatment with potassium triethylborohydride (Equation (65)). For examples of indium and thallium complexes, see .

NTMS

NTMS

Li

2PhN

NPh Al

X

NTMS

TMS

PhN

+ AlCl3

136 X = Cl

137 X = H

Toluene81%

40 C to rt

44%

TMS

TMS

KBEt3H

65

5.19.2.7.2 Amidines with an N-metal bond where M is a group 14 metal

In chapter 5.19.2.7.2 of , the preparation of the germanium, tin, or leadcomplexes (138, M=Ge, Sn, Pb) was reported. The germanium complexes (139, R=Me, But)are prepared from 2 equiv. of the lithium amidinate and a metal source . For other examples of tin and germanium complexes of amidines, see.

N

N N

NMe

Me

MeN

N X NLi

alkyl

alkylalkyl

alkyl

alkyl

alkyl

tBu

alkyl

alkyl

tButBuLi

M = Ga X = Cl 132 M = Al X = Cl 133 M = Ga X = Me, Et, Bn 134 M = Al X = Bn, ButCH2 135

131

AlMe3AlM

NX

Scheme 39


NNPh M Me

Me

Me

N

N

Cy

R

Cy

NGe R

NCy

Cy

138 139 R = Me or But

TMS

TMS

5.19.2.7.3 Amidines with an N-metal bond where M is a transition metal

Amidines form complexes with most transition metals and with all first row transition metals.These complexes were reviewed in chapter 5.19.2.7.3 of and in more detailby Barker and Kilner . Since the publication of these two reviews there have beenmany further complexes reported. Common structural motifs for first row transition metals are140142 . A series of hindered amidine complexes were prepared from thecorresponding lithium salts (Equation (66)) .

R'N

NR

R

R'N

NR

R

R'N

NR

R'

R'

N NL

ML

RR

R'

NNR R

R'N

N

R

R

R'N

NR

R R'NR

HNR

X

M = Cr, Mn, Fe, Ni140

141M = Cr, Mn, FeL = none, Cl, OH

142M = Ni, CuX = Cl, Br

M MM

N

N

Ar

Ar

Ar

Ar

Ar

Ar

N

NMeMe

MeMe

N

N

Li N

N

78 C M = Cr, Mn, Fe, Co, Ni1966%

MMCl2

THFLiCl

66

Lead references for amidine complexes of some common transition metals including all of thefirst row transition metals are given in Table 4.

5.19.2.7.4 Amidines with an N-metal bond, where M is a lanthanide or actinide metal

The preparation of lanthanide complexes with silylated amidines Ln[4-RC6H4C(N-TMS)2]3 wasdescribed in chapter 5.19.2.7.4 of . In the review period the preparation oflanthanide complexes of N,N0-dicyclohexylacetamidine and N,N0-dicyclohexylbenzamidine havealso been reported . Carbodiimides can be inserted into the LnC bond oforganolanthanide complexes as shown in Equation (67) . For other examples ofamidinate lanthanide complexes see and .

N

N

Cp

CpLn

But

But

BunCp2LnClnBuLi ButN=C=NBut

Cp2LnBun(THF)

Ln = Er 82%Ln = Y 76%Ln = Gd 54%

LiCl67


The preparation of amidinato complexes with the actinide elements, uranium and thorium wascovered in chapter 5.19.2.7.4 of . With less sterically demanding amidinatoligands, complexes such as, [4-CF3C6H4C(N-TMS)2MCl (M=U, Th)] are formed with the metalin the +4 oxidation state. With sterically more demanding ligands complexes such as, 143 and144 are formed . During the review period the preparation of furtheruranium complexes for example, 145 has also been reported.

N

NAr M

Cl

Cl NAr

N

N

NPh

NN

Ph143 M = U144 X = Th

U

145

TMS

TMS TMS

TMS TMS;

TMS

BH4BH4

TMS

TMS

ACKNOWLEDGEMENTS

The author would like to thank Mr. D. F. Wood and Dr. S. Narayanaswami for conducting thecomputer literature searches for this review.

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Table 4 Amidine complexes of some common transition metals

Metal References

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Synthesis of Amidines