Dithiocarboxylic esters and Thioamides: Synthesis and...
Transcript of Dithiocarboxylic esters and Thioamides: Synthesis and...
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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