C h a ~ t e r Two

Dithiocarboxylic esters and Thioamides:

Synthesis and Reactivity

2.1 Introduction

Dithio Carboxylic acids and their esters are synthetic intermediates known for a

long time. Simple thioamides were also available to organic chemists for several decades.

Their chemistry have been extensively studied. There are a number of methods available

for their synthesis and most of the methods make use of very cheap starting materials. In

this chapter a review of the synthesis and reactivity of simple dithiocarboxylic acids, esters

and thioamides is presented, as a background to the chemistry of hnctionalised

dithiocarboxylic esters and thioamides that would be discussed in the coming chapters.

2.2 Dithiocarboxylic Acids and Esters

Dithiocarboxylic acids and esters are widely used in organic synthesis2'. ' despite

their offensive odour and relative instability The common methods leading to the

formation of dithiocarboxylic acids and their esters would be briefly described here. There

are several reviews available in the literature on the chemistry of these compounds.

2.2.1 Synthesis of dithiocarboxylic acids and esters

Dithiocarboxylic acids and their esters are valuable intermediates in organic

synthesis.' They can be obtained by a variety of synthetic procedures.2 Several methods

for the synthesis of simple and functionalized dithioesters are presented here.

2.2.1.1. Thioacylation

Dithiocarboxylates can be prepared from respective thioacyl halides, thioacyl anhydride

and thio ketenes by thioacylation Thioacyl halides undergo facile reaction with thiols in

the presence of base to afford alkyl or aryl dithiocarboxylates in high yields (Scheme 1).

1 2

Scheme 1

Similarly bis-thioacyl thioanhydride react with thiols to give correspondiqg

dithiocarboxylates4 (Scheme 2).

Scheme 2

The reaction of metal salts of dithiocarboxylic acids with phenyl thiochloroformate

leads to the formation of the mixed thiocarboxylic thiocarbonic acids 6, which

spontaneously undergo intramolecular thioacylation to hrnish corresponding phenyl

carbodithioates' (Scheme 3).

S

I< SM P hS C1 SPh

Thioacyl diphenyl thiophosphinyl sulphides are also valuable thioacylating agents."

Dithiocarboxylates can be obtained from them under mild conditions (Scheme 4). Addition

of thiols to thioketenes also afford respective dithioesters7 (Scheme 5).

S ;,~h dSAh + R-SM 00 -

H3C H3C

Scheme 4

9 10

Scheme 5

2.2.1.2 Reactioris of Organon~etallic Reagents with Carbondisulfide

A convenient method for the synthesis of dithiocarboxylic acids involve addition of

organometallic reagents, such as Grignard reagents, organolithium reagents or

organocuprates to carbon disulphide. Subsequent alkylation with alkyl halides afford

corresponding dithioesters. Among the various organometallic reagents. Grignard

reagents were used widely in the earlier years for the synthesis of dithiocarboxylic acids

and their esters8 Grignard reagents prepared from various alkyl and aryl halides undergo

smooth addition to carbon disulphide while the subsequent alkylation could be carried out

with alkyl halides including ally1 and propargyl bromides.

R-MgX + CS2 - a R SMgX R

11 12 13

Scheme 6

In an attempted preparation of a,P-unsaturated dithioesters employing this

protocol, the addition of Grignard reagent prepared from I-bromo propene to carbon

disulphide and subsequent alkylation with methyl iodide gave the expected methyl

dithiocarboxylate 15 which underwent dimerization involving a 4+2 cycloaddition to

afford the substituted thiopyran derivative 16' (Scheme 7).

SMe

16

Scheme 7

a,D-Unsaturated iminodithioates are known to undergo conjugate addition with

organometallic reagents. Subsequent sulfhydrolysis of the intermediate ketene-N,S-acetal

obtained with hydrogen sulphide furnish dithiocarboxylates with branched alkyl chains.''

18

Scheme 8

The dithioesters could be obtained in better yields by the addition of organo

copper reagents to carbondisulphide followed by subsequent alkylation with methyl

iodide."

Terminal alkynes are also used in the synthesis of dithioesters. The substituted

acetylene is first treated with butyl lithium and then with elemental sulfur to furnish the

corresponding lithium alkyne thiolates which on subsequent addition of two equivalents of

thiol affords the dithioesters. An example starting with inethyl acetylene is shown in

Scheme 9.

20 21 22

Scheme 9

The addition of organo cuprates across the triple bond affords vinyl substituted

cuprates. Addition of these intermediates to carbon disulphide followed by alkylation

provide a convenient method for the preparation of a,P-unsaturated dithioesters 26 ' I h

(Scheme 10).

R ' = A ~ ~ I , ~ r y l . R~=H, Alkyl, Aryl. R2v"e S

26

Scheme 10

Recently Hoppe and co-workers have shown that chiral organolithiurn reagents

prepared from the N,N-diisopropyl carbamate of (S)-1-phenyl ethanol react with

electrophiles with retention or inversion of stereochemistry depending on the nature of the

electrophile. Electrophiles which would have a strong interaction with the lithium cation,

such as those having alkoxy or carbonyl group, react with retention of configuration, while

electrophiles having an energetically low LUMO, such as acid chlorides.

heterocoumulenes and soft electrophiles react with inversion of configuration.

Dithiocarboxylation proceeds with inversion of configuration, since carbon disulphide is a

soft e l e ~ t r o ~ h i l e . ~ ' This method provide assess to chiral dithioesters (Scheme 11).

28

Schenie 11

Organolithiurn reagents derived from suitable aromatic substrates undergo facile

addition to carbon disulphide leading to the formation of substituted aromatic

dithiocarboxylic acids. a-Hydroxynaphthyl lithium 30 , for instance on addition to carbon

disulphide gave the dithiocarboxylic acid 31 (Scheme 12). 32 Several aromatic substrates

are known to undergo similar addition to carbon d i s u ~ ~ h i d e . ~ ~

Scheme 12

Several functional groups can be transformed in to dithiocarboxylic acids or

dithioesters by sulfurization. For instance the conversion of aldehydes to corresponding

dithiocarboxylic acids can be accomplished by hydrogen polysulphide or by ammonium l l b . 1 3 polysulphide

Addition of thiols to nitriles afford thioiminoesters . Treatment of thioiminoesters

in ether or pyridine with dry hydrogen sulphide furnish corresponding dithioesters in good

yields'4(~cheme 13).

35

Scheme 13

Alternatively thioiminoesters could be obtained by the addition of Grignard

reagents to aryl isothiocyanates followed by alkylation with methyl iodide. Subsequent

treatment of the iminoesters thus obtained with hydrogen sulphide in acetonitrile afford the

corresponding dithioesters. For example addition the Grignard reagent prepared from 1,3-

peritadienylbromide to phenyl isothiocyanate followed by alkylation with methyl iodide

affords the methyl thioiminoester 37 which on subsequent treatment with hydrogen

sulphide gave the dithioester 38 l 5 (Scheme 14).

a,p-Unsaturated amides also could be converted to the corresponding a,P-

unsaturated dithioesters, though the procedure involves several steps (Scheme 15).

5 SMe

5

Scheme 14

The amide was first alkylated with triethyl oxonium fluroborate to furnish the

ethoxy substituted iminium salt 40 which on treatment with hydrogen sulphide at - I 5°C

gave the thionoester 41. Ethoxy group was then replaced by pyperidine to afford the

thioamide 42. Subsequent alkylation with methyl iodide gave the methylthio substituted

iminium salt 43 which was subjected to treatment with hydrogen sulphide at low

temperature to furnish the dithiocinnimate 44.9

The synthesis of functionalized dithioesters usually involve the reactlon of

functionalized carbanions with carbon disulphide followed by alkylation. Carbanions

derived from a wide variety of substrates undergo addition to carbon disulphide resulting

in the formation of the respective dithiocarboxylic acids 16 Derivatives of malonic acid , phenols, naphthols, hydroxyquinolines",

aldehydes1' k e t ~ n e s ' ~ . ' ~ ~ . ' ~ ' , nitromethane2', pyrrole, indole, pyridine, quinoline and their

derivatives2', ketimines of cyclic ketones22 and pyrazolone derivatives2hre among the

substrates that undergo base catalyzed addition to carbon disulphide leading to the

formation of dithiocarboxylic acids.

2.2.1.4 Reactions of enolates with carbondisulfide

P-0x0 dithiocarboxylic acids and their esters are prepared by the reaction of

enolate anion derived from enolizable ketones on treatment with a strong base with carbon

disulphide. Aliphatic and cyclic ketones react with carbon disulphide in the presence of

sodium t-pentoxide to furnish the corresponding p-0x0 dithiocarboxylic acids2"scheme

16).

46

Scheme 16

Substituted acetophenones undergo addition to carbon disulphide in the presence

of potassium t-butoxide leading to the formation of j3-hydroxy dithiocimamic acids which

could be alkylated to the respective j3-0x0 dithioesters 50 by an ion-pair technique25

(Scheme 17).

48 49 50

Scheme 17

Other active methylene compounds such as diethyl malonate, methyl cyanoacetate,

malononitrile, acetyl acetone, benzoyl acetone and dibenzoyl methane also react similarly

giving the corresponding fi~nctionalized dithioesters.

Konen and co-workers have described a method for the conversion of long chain

carboxylic acids to dithioesters. For example nonanoic acid was first converted to the

lithium enolate, which on reaction with carbon disulphide followed by alkylation with

methyl iodide and subsequent decarboxylation gave methyl dithiooctanonate 53 29 (Scheme

18)

0

53

Scheme 18

Addition of sodium phenoxide to carbon disulphide at high temperature (155-

170 '~ ) in DMF also leads to the formation of dithiocarboxylic acids. For example 3,5-di-

r-butyl dithiosalicylic acid can be prepared by this method."

Scheme 19

2.2.1.5 Reactions of Enolates with Dimethyl trithiocarbonate

Junjappa and co-workers have developed a convenient general method for the

synthesis of hnctionalized dithioesters from active rnethylene compounds This method

works well with aliphatic, cyclic, and aryl alkyl ketones The reaction involves treatment

of the carbanions derived from active methylene compounds in the presence of a base such

as NaH in DMF, with dimethyl trithi~carbonate.~' The synthesis of 13-0x0 dithioesters

employing this protocol is depicted in Scheme 20. /

56 57

Scheme 20

This method has been further extended to the preparation of dithioesters of

sulphones and su~~hoxides .~ ' Methyl chlorodithioformates also undergo similar reactions

with enolates to afford corresponding dithioesters.''

2.2.1.6 Formation of a-Oxodithioesters

While P-0x0 dithioesters could be conveniently prepared from enolizable carbonyl

compounds, direct methods leading to the formation of a-0x0 dithioesters are rare The

reaction of benzaldehyde with carbon disulphide in the presence of potassium cyanide,

followed by alkylation with diazomethane gave the methyl ester of benzoyl

dithiocarboxylic acidg0 (Scheme 21).

58 59

Scheme 21

Didier and Frederic have recently reported another approach for the synthesis of

a-0x0 dithioesters from aryl methyl ketones. The intermediate pyridinium salts obtained

from methyl ketones on treatment with pyridine and iodine, react with sulfur in the

presence of triethyl amine to afford the a-0x0 dithiocarboxylates, which on further

alkylation to furnish the corresponding dithioester~.~'

6 1 62

Scheme 22

The conversion of aryl methyl ketones to the corresponding a-0x0

dithiocarboxylates can also be achived by their. treatment with ethyl disulphide in the

presence of a base such as sodium 1-butoxide. This reaction has been illustrated for

substituted acetophenone in Scheme 23.40

63

Scheme 23

2.2.1.7 Friedel Crafts Type Reactions

Electron rich aromatic substrates undergo Friedel-Crafts type reaction with carbon

disulphide to furnish aromatic dithiocarboxylic acids. Trimethyl silyl methyl

dithiobenzoate 64 has been prepared from benzene following this method as shown in

Scheme 24.3'

64

Scheme 24

Similarly pyrrole derivatives also undergo reaction with carbon disulphidej6 to give

substituted pyrrole dithiocarboxylic acids.

2.2.1.8 Reactions Irivolving 3-Thioxo-l,2-dithiol

3-Thioxo-1,2-dithiol 65 is a valuable substrate for the synthesis of functionalized

dithioesters. The reaction of morpholine with 3-thioxo-l,2-dithiol i n chloroform followed

by alkylation leads to thaformation of 3-morpholino dithioacrylate 67 "(Scheme 25).

65

-. . . .

1 . , . -. i -. / 67 :.

' -.. 1' , ~

Scheme 25

AltemativdY the alkylation of 3-thioxo-1.2-dithiol can be petiormed before h e

reaction with amine. For example the reaction of methyl iodide with 65 gave the salt 68

which on further reaction with amines gave p-amino dithioacylic esters."

68

Scheme 26

El@ x d,: dph I SMe

H

70 7 1

Scheme 27

Other substituted thioxodithiole salts also react similarly with amines to afford P- amino substituted a,P-unsaturated dithioesters. For example amino substituted

cyclopentenyl dithioesters are obtained as shown in scheme above.18 ,

2.2.1.9 Reactions of Dithioenolates

Aliphatic dithiocarboxylic acids on treatment with two equivalents of butyl lithium

afford the corresponding dilithium dithioenolates 72 which undergo sntooth addition to

aldehydes and ketones leading to the formation of P-hydroxy dithiocarboxylic acids73.

Subsequent alkylation with methyl iodide followed by dehydration furnish a,P-unsaturated

dithioesters 75. A synthesis of methyl-3,3-dimethyl dithioacrylate by this protocol is

depicted in Scheme 28.39

SMe

74

Scheme 28

2.2.2 Reactions of dithiocarboxylic acids and esters

Dithiocarboxylic esters can be easily transformed to the corresponding lithium or

sodium enethiolate. The thioenolates are valuable intermediates used in the construction

of new carbon carbon bonds. The thioclaisen rearrangements involving these

intermediates have also attracted attention from several groups. The dithiocarboxylic

acids and esters are also useful intermediates in the synthesis of heterocycles.

2.2.2.1 Reactions of enethiolates

Deprotonation of dithioesters can be accomplished quantitatively by strong bases

such as lithium diisopropyl a~nide. '~ Sulphur has a high aptitude for stabilizing negative

charge, which supports the enthiolate structure to the deprotonated species rather than the

a-metalated structure. Enethiolates have some advantages over the analogous enolates

They have good thermal stability and do not undergo equilibration with proton donors.

Another important feature is that formation of enethiolate is highly stereospccific ris- 45

Isomer is formed exclusively.

Scheme 29

Aldol reactions of enethiolates derived from dithiocarboxylates were mentioned

earlier in connection with the preparation of a,P-unsaturated dithioesters. Addition of

enethiolates generated from dithioesters to aldehydes at low temperature (to avoid retro-

aldol reaction) provide good yields of P-hydroxy d i th i~es te r s .~~ The reaction is highly

steriospecific and cis-enethiolate give the wr-aldol.45b AS mentioned earlier dehydration

of P-hydroxydithioesters give a,P-unsaturated dithiocarboxylates. 46c.47

Lithium enethiolates are reactive towards a,P-unsaturated carbonyl compounds.48

The addition takes place in Michael fashion to afford 6-keto dithioesters which find hrther

application in synthesis.49 The Michael reaction of the enethiolates derived from

dithiocarboxylates proceed stereospecifically, under kinetically controlled conditions.

Thus the addition of cis-enethiolate to i;;-enone furnishes the anti-adduct Jld.50

Epoxides also react with enethiolates generated from dithioesters, though the

reaction is sluggish. However it is the sulphur end of the ambident nucleophile that opens

the epoxide rings'

79

Scheme 30

Scheme 31

The reaction of ene-thiolates with alkylating agents also furnish products with

alkylation at sulphur. Base catalysed alkylation of dithioesters lead to the formation of the

corresponding ketene dithioacetals. 49.32 Alkylation of the thiolate anion derived from

dithioesters or dithiocarboxylic acids with functionalized alkylating agents may lead to the

formation of heterocycles. Several such reactions involving P-0x0 dilhioesters and p-0x0

dithiocarboxylic acids are described along with similar reactions involving 13-0x0

thioamide (vide supra)

Alkylation of dithiocarboxylic acids with allylic halides furnish S-ally1

dithiocarboxylates. The lithium enethiolates derived from these S-allyl dithiocarboxylates

undergo a facile 3,3-sigmatropic shift leading to the formation of lithium salt of a-allyl

dithiocarboxylic acids '-' S-Alkenyl dithioesters are also formed in this reaction as a result of the base

catalyzed migration of the double bond. S-Allyl a-0x0 ketenedithioacetals also undergo

base catalyzed thio-Claisen rearrangement." This method has been used for the synthesis

of a-ally1 ketene dithioacetals as shown in scheme 33.

90

Scheme 33

2.2.2.2 Synthesis of 2H-thiopyran-2-thiones

Pradere and co-workers have described the reactions of p-0x0 dithiocarboxylic

acids with a-acetylenic ketones and p-chlorovinyl aldehydes. Substituted 2H-thiopyran-2-

5 s thiones 93 and 95 are obtained respectively from these reactions (Scherne 34 and

Scheme 35)

R' = Aryl or Alkyl; R'= Aryl or Alkyl.

Scheme 34

0

94 92

R' = Aryl; R2 = Aryl.

Scheme 35

P-Chlorovinyl ketones also react similarly with p-0x0 thiocarboxylic acids to

afford 2H-thiopyran-2-thione derivative^.'^ The reaction of dimethyl acetylene

dicarboxylate with p-0x0 thioamides also afford 2H-thiopyran-2-one derivatives." Acyl

dithioacetate react with dithiolium salts to give 3-acyl substituted 2H-thiopyran-2-one

derivative^.'^ (Scheme 36)

97 98

Scheme 36

2.2.2.3 Formation of Other Heterocycles

13-Oxodithioesters react with functionalized electrophiles leading to the formation

of several heterocyles particularly thiophene derivatives. These reactions would be

described along with similar reactions of 9-0x0 thioamides. A few examples of reactions

leading to the formation of other heterocyclic systems are described here. 13-0x0

dithiocarboxylic acids can be transformed in to substituted 3-thioxo-l,2-dithiols on

treatment with trimethyl silyl sulfide in presence of N-chlorosuccinirnide and i m i d a z o ~ e . ~ ~

Scheme 37

Scheme 38

The dithioester 108 derived from dimedone 101 undergo selective addition of

aniline to one of the carbonyl group to afford the P-phenylamino substituted a,P-

unsaturated dithioester 103 which cyclize to 104 on heating in diphenyl ether 60

2.2.2.4 Oxidation Reactions

Oxidation reactions of sulfur compounds lead to the formation of corresponding

sulfoxides or sulfones depending on the reaction conditions. Oxidation of functionalized

dithioesters should provide access to functionalized sulfones or sulfoxides which are

valuable intermediates in organic synthesis. Aliphatic dithioesters can be oxidized to

sulphines by treating them with m-chloroperbenzoic acid in methylene chloride. However

these sulphines have been found to undergo facile rearrangement to corresponding

dithioperoxy esters at room temperat~re.~'

106

Scheme 39

Oxidation of dithiocarboxylates with benzene selinic anhydride furnish thiol esters

as the products.43

(Ph-SeO)20 + PhSeSePh

R

Scheme 40

2.3 Thioamides

Thioamides are also among very common. intermediates in organic synthesis while

thiocarbonyl compounds are unstable in general these amides are fairly stable. They are

widely used in the synthesis of heterocycles and as synthetic intermediate^.'^'.'^'.^^^

2.3.1 Synthesis of thioamides

Thioacylation reactions, addition of nucleophiles to isothiocyanates 104.93a.75. and 10s thionation of amides are among the most common methods used in the synthesis of

thioamides. A survey of some of the important methods is presented here.

Simple thioamides can be prepared by thioacylation of amines. Thiocarboxylates,

3H-1,2-dithiol-3-ones, dithiocarboxylates, thioamides, thioketenes and carbon disulfide are

the commonely used substrates for the thioacylation reaction with amines. A few

examples of the synthesis of thioamides involving tl~ioacylation protocol are described

here.

Nucleophilic attack of ammonia or secondary amines on 0-alkylthiocarboxylate

110 provide thioamides. A large number of reports describe synthesis of thioamides

employing this method. 61 However under some conditions for example when the reaction

was carried out in polar protic solvents such as ethanol some unwanted side reactions are

favoured. If the reaction is performed at high temperature there 1s a possibility of the

rearrangement of the 0-alkylthiocarboxylates to the S-alkylthiocarboxylates thus resulting

in the formation of of simple amides rather than th i~amides .~~" Besides when primary

amine is used there is a tendency to form amidines or imidates instead of the the

t h i ~ a m i d e s . ~ ' ~

Scheme 41

The S-S bond cleavage of 3H-1.2-dithiol-3-ones 112 by nucleophiles such as

Grignard reagent affords malonic acid monothioamide 113.~'

112 113

Scheme 42

Active methylene compounds, for example camphor react with carbon disulfide in

the presence of excess base to provide dianions of dithiocarboxylic acid 115 which on

neutralization with HCI and addition of primary amines yield 3-oxonorbornane

thiocarboxamide 116 with undefined steriochemistry (Scheme 43 ).

NaNH2,G2, % h 2 0 0 r G H b HQwH2.J$o

S NHR 0 S

115

Scheme 43

A Friedel-Crafts type reaction involving electron rich aromatic substrates with

thiocarbamoyl chloride lead to the formation of aryl substituted thioamides." Thus the

reaction of anisol with N,N-dimethyl thiocarbamoyl chloride 118 afford the corresponding

thioamide 119 in 77% yield.(Scheme 44)

117 118

Scheme 44

Carbanions derived from active methylene compounds undergo condensation

reaction with thiocarbamoyl chloride to afford functionalized thioamides (~cheme45) .~ '

3

+ EWG CI A NR2

R i N ~ E W G S EWG

120 121 122

Scheme 45

Dithiocarboxylates react with amines faster than the corresponding 0-alkyl

t h i o c a r b ~ x ~ l a t e s . ~ ~ This pronounced reactivity may lead to the in situ reaction of the

dithioester generated by the thiolysis of thioimidate with liberated ammonia to give a

primary thioamide.

124

Scheme 46

Transamidation is another method for the formation of thioamides by which

another thioamide is treated with amines and the reactivity depends on the nuclec>philicity

of the incoming amine and the leaving group ability of the amine to be replaced Thus 67 some N-thioacylated heterocycles such as benzoxasole derivative , succinimideGX and

azoles 69 etc. are exceptionally good substrates for transamidation.

127

Scheme 47

In some reactions thioamides are converted to other thioamides by C-C bond

forming reactions. For example, when N,N-Dimethyl thioformamide was treated with

lithium diisopropyl amide to afford the corresponding C-lithiated species, which on

subsequent treatment with electrophiles gave thioamide 130 (Scheme 48)'"

Scheme 48

The reaction of N,N-diisopropyl carbamoyl or N,N-diniethyl thiocarbamoyl

chloride with excess of lithium powder and catalytic amount of naphthalene in the

presence of a carbonyl compound at -78' to -20°C undergo Barbier type reaction give the

corresponding a-hydroxyamides or thioamides in 40-80% yields71

131 132 133

Scheme 49

Treatment of the thioenolates derived from thioamides with electrophiles also

afford novel hnctionalized thioamides For example the thioenolates obtained from 134

on treatment with aldehydes lead to the stereoselective formation of the P-hydroxy

thioamide as the erythro isorner.12

134 135

Scheme 50

Enolizable thioamides may be transformed to the corresponding

enaminothioketones by heating with N.N-dimethyl formamide 0. N-acetal. The reaction

involves a sequence of electrophilic attack and e~imination.'~

134 136

Scheme 51

The S-silylated derivatives of thioamides react with electrophiles in the presence of

Lewis acids. The addition of the silyl enol thioether 137 with Schiff base yields fl-amino

thioamides 138 as a mixture of dia~tereomers.'~

(I) LDA (u) Me,SiCI

NMe2

137

Scheme 52

Thioketenes, though highly unstable, can be generated by a variety of methods7'

and are valuable intermediates in synthesis. Amines give a smooth reaction with

thioketenes to afford thioanlides under mild non-reducing conditions. Sensitive functional

groups such as cyano, nitro or sulfonyl residues remain ~ n a f f e c t e d . ~ ' ~ Scheme 53 shows

the reaction of a secondary amine with a-nitrothioketene.

140

Scheme 53

Alkynyl thiolates 142 react with excess of diethyl amine to generate the thioketene *

143 which would be trapped by the diethyl amine itself to afford the thioamide (Scheme

54) 144 76

142 143 144

Scheme 54

Amides can be directly transformed to thioamides on treatment with thionating 107,108

agents like Lawesson's reagentlo6 or phosphorous pentasulfide. Thioamides can be

obtained conveniently by the thiolysis of imidoyl chlorides. Scheme 55 shows the

formation of N-sulfonyl thioamides from the corresponding imidoyl chloride as well "

The imidoyl chlorides can be prepared from the corresponding amides on treatment with

phosgene

145 146

Scheme 55

The chlorosubstituted iminium salts, derived from amides and lactams on treatment

with POCI,, triphosgene or oxalyl chloride, can be transformed to corresponding

thioamides or thiolactams on treatment with hexamethyl disilathiane. Secondary and

tertiary amides and lactams gave good to excellent yields in this reaction while the yields

of primary thioamides were poor.78

148

Scheme 56

The reaction of benzimidium chloride 150 with dithiocarbamate 151 yields the

thioimidate 152 as the primary product which on rearrangement give the thioacylated

thiobenzamide 153 in quantitative yield. l9

150 151 152 153

Scheme 57

Thiolysis of imidates is of limited application in the synthesis of thioamides.

Imidates are usually prepared from nitriles. But nitriles can be directly transformed to

thioamides in one step. However for the synthesis of thiolactams, the corresponding

lactams are first converted to imidates and then subjected to thio~~sis,"'

15s

Scheme 58

Benzyl triethyl ammonium tetrathiomolybdate has also been shown to be an

effective sulfur transfer agent, useful in the conversion of amides and lactams to the

corresponding thioamides and thiolactams through their chlorosubstituted iminiunl salt

intermediates."

N,N-Disubstituted amidines 157 can be transformed into tertiary thioamide 1-58'~

on treatment with hydrogen sulfide in the presence of pyridine. However thiolysis of N-

mono substituted amidines give a mixture of thioamides.

157 159

Scheme 59

Thioamides can be prepared from nitriles by thiolysis under acid catalyzed or base

catalyzed conditions. Aromatic or heteroaromatic nitriles react with hydrogen sulfide in

the presence of triethyl amine or pyridine to give the thioamides in excellent yields '' However base catalyzed solvolysis of aliphatic nitriles often give low yields Better yields

are obtained when the reaction is carried out in the presence of phase transfer catalysts

and under high pressure of hydrogen s~l f ide .~ '

R - - . s N H2S H'or Base

R 1 N H2

159 160

Scheme 60

A reagent prepared by reacting phosphorous decasulfide with sodium sulfide ( I : I

ratio) has been found to be very efficient for the rapid conversion of nitriles to thioamides,

at -20Oc.~~

159 160

Scheme 61

Heating of nitriles 159 with dithiocarbamate 160 gives good yields of N.N-

dimethyl thioamide 161. 87

160 161

Scheme 62

Thioacetamide 162 is a convenient source of H2S. An equilibrium is established

which is shifted to the right ifthe liberated acetonitrile is removed by di~tillation.'~

159 162 163

Scheme 63

Successive reactions of Grignard's Reagents with carbondisulfide, I-trifluoro

methyl sulfonyl triazole and amines afford the corresponding N,N-disubstituted thio

amides in good yields (Scheme 64).89

165 166

Scheme 64

Transition metal catalysed cross-coupling reaction of Grignard's reagents with N-

N dimethylthiocarbamoyl chloride provide a very simple method for the synthesis of

various thioamides (Scheme 65)" '

166

Scheme 65

2.3.2 Reactions of thioamides

Thiocarbonyl compounds are usually unstable due to the ineficient overlap of n-

orbitals in the carbon-sulfur double bond 91 But thioamides are fairly stable due to the

delocalization of C=S bond resulting from the resonance interaction between the rr-bond

and the non-bonding electron pair on nitrogen (Scheme 66).

Scheme 66

They have been widely used as synthetic intermediatesy2.'" and in heterocyclic

synthesis.93 A few examples to illustrate the reactivity patterns of thioamides would be

discussed here.

Alkylation of thioamides using dialkoxy carbenium salts introduces the alkyl group

selectively on the sulfur leading to the formation of thioamides. The reaction of diethoxy

carbenium tetrafluoroborate with thiobenzamide has been shown in scheme 67.

S SEt

(RO),CH. BF,

(%I2&, RT, 2h, 100%

67

Scheme 67

Thioamides having tertiary amino substituents can be alkylated with methyl iodide

as well. It has been shown that the intermediate formed on alkylation can be transformed

in to carboxylic esters on basic hydrolysis (Scheme 68).95

169

Scheme 68

A classic example, on the application of thioamides in organic synthesis. is

Eschenmoser's sulfide contraction, which also involve an initial alkylation on the sulfur

An example, illustrating the reaction of bromomalonate with the thioamide 170 to give

vinylogous urethanes 172 has been shown in scheme 69.

C02Me M e O ) P S ~r--( 1 2) X i 2h 12C12 * ofoMe

0 H C02Me 0

OMe

170 171

Scheme 69

Though triphenyl phosphine is usually used to facilitate removal of sulfur, the

sulfkr extrusion is spontaneous in some c a ~ e s . ' ~

A reaction of tertiary amino substituted thioamides with benzene sulfonyl

isocyanate leads to a formal (2+2) cycloaddition followed by fragmentation and removal

of COS resulting in the N-protonated amidines (Scheme 70).~'Though this would appear

to be a convenient method for the synthesis of amidines, the harsh condition needed to

deprotect the benzene sulfonyl group may often destroy the iminoderivatives.

173 174

Scheme 70

Deprotonation at the methylene group adjacent to nitrogen is particularly facile

due to co-ordination offered by the sulfur to the metal atom. Several thioamides could be

conveniently deprotected by S-BuLi. Subsequent addition to electrophiles followed by

hydrolysis would afford substituted amines (Scheme 7 1 ) . ~ ~

Me B u ~ - 7 8 0 ~ ~ Bu N ' TMEDA. THF 0

I 1-Bu Me Me OH

176 177

Scheme 71

Thioamides can be transformed in nitriles by a variety of methods. They include

dehydration by diphosphorous tetraiodide (P&) 99, Oxidation with benzene telluric 100 anhydride and treatment with phosgene followed by a base such as pyridine.'o'

Thioamides can also be converted to corresponding amines by desulfurization with sodiunl

borohydride in the presence of a Ni(ii) salt.Io2 Reaction of functionalyzed thioamides

leading to the formation of heterocycles have been discussed in chapter 4.

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