A mild and versatile synthesis of thioamides

Article abstract of DOI:10.1055/s-0029-1217711

Aliphatic and aromatic nitriles react with thioacetic acid in the presence of calcium hydride to give the corresponding thioamides in good to excellent yields. The examples studied include haloaryl nitriles in which the halogen is facile towards S_NAr reactions under other conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217711

2338
LETTER
A Mild and Versatile Synthesis of Thioamides
A
Mi ld
a
nd Vers a
t
.
il e
S
ynthesis
A
of Thioami des . Mahammed,a,b V. P. Jayashankara,a N. Premsai Rai,a K. Mohana Raju,b P. N. Arunachalam*a
a
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra-Jigani Road, Bangalore 560 100, India
E-mail: pn.arunachalam@syngeneintl.com
Synthetic Polymer Laboratories, Department of Polymer Science, Sri Krishnadevaraya University, Anantapur 515 003, India
b
Received 13 May 2009
S
Abstract: Aliphatic and aromatic nitriles react with thioacetic acid
in the presence of calcium hydride to give the corresponding thio-
amides in good to excellent yields. The examples studied include
haloaryl nitriles in which the halogen is facile towards SNAr reac-
tions under other conditions.
MeCOSH, CaH2
R
CN
R
NH2
80 °C, solvent-free
1
2
R = aryl and alkyl
76–95%
Key words: thioamides, nitriles, thioacetic acid, calcium hydride
Scheme 1 Synthesis of thioamides from various nitrilies 2a–w
Attempts to use other bases, such as carbonates or hydrox-
ides of other alkali or alkaline earth metals, resulted in
various byproducts, and their general applicability was
minimal as other functional groups got affected. For ex-
ample, thioacetic acid in the presence of sodium hydrox-
ide resulted in the decomposition of ethyl cyanoacetate
and no thioamide was observed.
Aromatic and aliphatic thioamides are regarded as versa-
tile intermediates in organic synthesis.1 They are the key
intermediates in the synthesis of molecules which are of
varied utilities such as pesticides2 and pharmaceuticles.3–5
Many methods are available in the literature for the syn-
thesis of thioamide. They are synthesized either from the
corresponding amides using Lawesson reagent,5c or from
the corresponding nitriles using alkali metal hydrogen sul-
fide or ammonium sulfide under high pressure.6 In addi-
tion reagents such as phosphorus decasulfide,7 thioacids,8
thioacetic acid in combination with Lewis acid,9a thioace-
tic acid in benzylamine,9b thioacetamide,10 DowexSH,11
O-dialkyldithiophosphates,12 diphenylphosphinodithioac-
ids,13 sodium trimethylsilanethiolate,14 sodium hydrosul-
fide hydrate and diethyl amine hydrochloride,15 sodium
hydrosulfide hydrate and magnesium chloride hexahy-
drate,16 and (P4S11)Na2,17,18 are also widely used in their
synthesis from the corresponding nitriles. In special cases,
thioamides are synthesized using elemental sulfur in the
presence of morpholine19a and ammonium sulfide19b un-
der microwave conditions.
In this paper we report a simple and efficient synthesis of
a wide variety of thioamides which were synthesized from
the corresponding nitriles. The nitrile compounds reacted
with excess thioacetic acid in the presence of calcium hy-
dride at 80 °C to afford good to excellent yields of respec-
tive thioamides within a short reaction time of 1.0–1.5
hours (Table 1).20 In Scheme 2 we had depicted a plausi-
ble mechanism for this reaction. Calcium hydride reacts
with thioacetic acid, resulting in the formation of nucleo-
philic calcium thiolate which attacks the nitrile group.
Subsequent aqueous workup hydrolyzes this intermediate
resulting in the thioamides.
It is worth mentioning that the same process was success-
fully extended to the synthesis of other halo-substituted
thioamide derivatives; for example, halo-substituted ben-
zonitriles reacted smoothly under the specified conditions
to afford excellent yields of 92%, 86%, and 90%, respec-
tively (entries 2–4 Table 1). These halo benzonitriles nor-
mally give rise to halogen-displaced side products with
sulfide reagents. Additionally, substituted benzyl cya-
nides (entries 5–7, 9, and 10) also gave the corresponding
thioamides 2e–g,i,j in good to excellent yields. The pyri-
donitriles (entries 12–14) also gave the corresponding car-
bothioamides in excellent yields. It is interesting to note
that the yields are usually in the range of 50–60% by using
Lawesson reagent21 or by using hydrogen sulfide–triethyl
amine combination over 15–20 hours.21 Similarly,
thiophene-3-carbonitrile also gets converted into
thiophene-3-thioamide 2o (entry 15) in 85% yield. The
methodology is widely applicable to aliphatic moieties as
well. For example, aliphatic nitriles 1r–w gave the corre-
sponding thioamides 2r–w in very good yields. The con-
ditions tolerated easily hydrolyzable groups such as
As part of our current research program, we were in need
of halogen-substituted aromatic thioamides. When some
of the halogen substituted aryl nitriles were reacted with
phosphorous pentasulfide or others sulfide-based reagents
they resulted in various side products and required prod-
uct formed in less than 10% yield. We tried to explore a
condition which tolerates most of the functional groups.
One of the published methods utilized thioacetic acid in
the presence of Lewis acid or light, but it is not compatible
with other acid-sensitive groups such as acetals or tert-
butyl esters. We observed that under basic conditions
thioacetic acid could bring about desired transformation
of nitriles to thioamide without any noticeable side reac-
tions (Scheme 1).
SYNLETT 2009, No. 14, pp 2338–2340
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Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217711; Art ID: G15309ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Mild and Versatile Synthesis of Thioamides
2339
R
S
–N
Ca2+
S
O
(MeCOS)2Ca
H2O
Ca(OAc)2
+
RCN
S
R
R
NH2
N–
O
not isolated
Scheme 2 Plausible mechanism
Table 1 Conversion of Nitriles to Thioamides in the Presence of
Thioacetic Acid (continued)
esters. Ethyl cyanoacetate, for example, afforded a good
yield of ethyl 3-amino-3-thioxopropanoate 2s without af-
fecting the ester group.
S
MeCOSH, CaH2
R CN
R
C
NH2
80 °C, solvent-free
Table 1 Conversion of Nitriles to Thioamides in the Presence of
1
2
Thioacetic Acid
R = aryl and alkyl
S
MeCOSH, CaH2
Entry Nitrile
Product
Time Yield
R CN
R
C
NH2
(h)a
(%)b
80 °C, solvent-free
1
2
R = aryl and alkyl
CN
13
2m22f
1.5
90
Entry Nitrile
Product
Time Yield
(h)a
(%)b
N
14
2n22f
2o22g
2p22h
1.5
1.0
1.0
92
85
92
CN
N
1
2a22a
1.0
95
CN
15
S
Cl
CN
2
2b (new)
1.0
1.0
92
86
CN
Br
16
MeO2C
CN
F
17
2q22i
2r22j
1.0
1.0
89
76
HO2C
CN
CN
3
2c22b
CN
18
F
O
19
2s22k
1.25
88
CN
Cl
CN
4
5
6
2d (new)
2e22c
1.0
1.5
1.5
90
94
90
O
CN
CN
CN
20
2t (new)
1.0
1.0
84
80
O2N
21
22
23
2u22l
MeO
Cl
CN
CN
2v (new)
1.0
1.0
87
2f (new)
CN
Cl
MeCN
2w22m
80c
a Reactions were monitored by LC-MS, GC,c and TLC analysis.
b Yields refer to the isolated pure products after flash chromatogra-
phy.
7
8
9
2g (new)
2h22d
1.0
95
87
85
I
CN
c Reaction was carried out at 50 °C.
CN
1.5
O
Br
Acknowledgment
2i (new)
1.25
OCF3
NC
The authors thank Dr. Goutam Das, President, Syngene Internatio-
nal Ltd., Bangalore, for permitting the use of resources and Dr.
Arvind Mathur, Associate Director, Bristol Myers Squibb Pharma-
ceutical Research Institute, New Jersey, for valuable suggestions.
2j22e
1.25
90
Me
Me
10
CN
References and Notes
11
12
2k22f
1.25
1.5
92
88
(1) Metzner, P. Synthesis 1992, 1185.
CN
(2) Herbert Haller, L. J.; Barthel, W. F. US 2,358,925, 1994.
(3) Leresque, C. L. US 2,560,296, 1951.
(4) Kureha Chemical Industry Co. Ltd Jpn. Kokai Tokyo 81 12
315, 1981.
2l22f
N
CN
Synlett 2009, No. 14, 2338–2340 © Thieme Stuttgart · New York

2340
K. A. Mahammed et al.
LETTER
(5) (a) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
(b) Lawesson, S. O.; Perregaard, J.; Scheibye, S.; Meyer,
H. J.; Thompson, I. Bull. Soc. Chim. Belg. 1977, 679.
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(b) Zbruyev, O. I.; Stiasni, N.; Kapper, C. O. J. Comb. Chem.
2003, 5, 145.
C7H5ClN2O2S: C, 33.81; H, 2.33; N, 12.93. Found: C, 33.76;
H, 2.38; N, 12.96. MS: m/z = 214.9 [M+].
2-(3,4-Dichlorophenyl)ethanethioamide (2f)
1H NMR (400 MHz, DMSO-d6): d = 3.8 (s, 2 H), 7.2 (d, 1
H), 7.5 (s, 1 H), 7.6 (d, 1 H), 9.4 (s, 1 H), 9.5 (s, 1 H) ppm.
13C NMR (100 MHz, DMSO-d6): d = 50.5, 129.6, 129.8,
130.6, 131.1, 131.2, 138.8, 204.9 ppm. Anal. Calcd (%) for
C8H7Cl2NS: C, 43.65, H, 3.21, N, 6.36. Found: C, 43.76, H,
3.28, N, 6.34; MS: m/z = 219.9 [M+].
(7) Brillion, D. Synth. Commun. 1992, 1397.
(8) Albert, A. Ber. Dtsch. Chem. Ges. 1915, 48, 470.
(9) (a) Gauthier, J. Y.; Lebel, H. Phosphorus, Sulfur Silicon
Relat. Elem. 1994, 325. (b) Ikeda, K.; Sato, K.; Nishino, R.;
Aoyama, S.; Suzuki, T.; Sato, M. Bioorg. Med. Chem. 2008,
16, 6783.
3-(4-Iodophenyl)propanethioamide (2g)
1H NMR (400 MHz, DMSO-d6): d = 3.7 (s, 2 H), 7.1 (d, 2
H), 7.6 (d, 2 H), 9.3 (br s, 1 H), 9.4 (br s, 1 H) ppm. 13
C
NMR: (100 MHz, DMSO-d6): d = 50.7, 93.0, 131.6, 137.3,
137.6, 205.4 ppm. Anal. Calcd (%) for C8H8INS: C, 34.67;
H, 2.91; N, 5.05. Found: C, 34.65; H, 2.98; N, 5.11. MS:
m/z = 277.8 [M+].
(10) Taylor, E. C.; Zoltewicz, J. A. J. Am. Chem. Soc. 1960, 82,
2656.
(11) Liboska, R.; Zyka, D.; Bobek, M. Synthesis 2002, 1649.
(12) (a) Yousif, N. M. Tetrahedron 1989, 45, 4599. (b)Pudovik,
A. N.; Cherkasov, R. A.; Zimin, M. G.; Zabirov, N. G. Bull.
Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1979, 28,
805.
(13) Benner, S. A. Tetrahedron Lett. 1981, 22, 1851.
(14) (a) Shiao, M. J.; Lai, L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R.
J. Org. Chem. 1993, 58, 4742. (b) Lin, P. Y.; Ku, W. S.;
Shiao, M. J. Synthesis 1992, 1219.
(15) Boys, M. L.; Downs, V. L. Synth. Commun. 2006, 295.
(16) Manaka, A.; Sato, M. Synth. Commun. 2005, 761.
(17) Brillon, D. Synth. Commun. 1992, 1397.
(18) Rapaport, E.; Cass, M. W.; White, E. H. J. Am. Chem. Soc.
1972, 94, 3153.
2-[4-(Trifluoromethoxy)phenyl]ethanethioamide (2i)
1H NMR (400 MHz, DMSO-d6): d = 3.8 (s, 2 H), 7.2 (d, 2
H), 7.4 (d, 2 H), 9.4 (br s, 1 H), 9.5 (br s, 1 H) ppm. 13C NMR
(100 MHz, DMSO-d6): d = 50.5, 116.7, 131.0, 131.3, 136.8,
137.3, 147.6, 147.7, 205.4 ppm. Anal. Calcd (%) for
C9H8F3NOS: C, 45.95; H, 3.43; N, 5.95. Found: C, 45.98; H,
3.48; N, 5.98. MS: m/z = 235.8 [M+].
Propanethioamide (2t)
1H NMR (400 MHz, DMSO-d6): d = 1.2 (t, 3 H) 2.6 (q, 2 H),
7.2 (s, 1 H), 8.0 (s, 1 H) ppm. 13C NMR (100 MHz, DMSO-
d6): d = 15.0, 42.1, 208.6 ppm. Anal. Calcd (%) for C3H7NS:
C, 40.41; H, 7.91; N, 15.71. Found: C, 40.45; H, 7.98; N,
15.78. GC-MS: m/z = 89.1 [M+].
2,2-Dimethylpropanethioamide (2v)
(19) (a) Moghaddam, F. M.; Hojabri, L.; Dohendou, M. Synth.
Commun. 2003, 4279. (b) Bagley, M. C.; Chapaneri, K.;
Glover, C.; Merritt, E. A. Synlett 2004, 2615.
1H NMR (400 MHz, DMSO-d6): d = 1.3 (s, 9 H) 7.0 (br s, 1
H), 7.7 (br s, 1 H) ppm. 13C NMR: (100 MHz, DMSO-d6):
d = 32.5, 48.8, 221.8 ppm. Anal. Calcd (%) for C5H11NS: C,
51.23; H, 9.46; N, 11.95. Found: C, 51.31; H, 9.48; N, 11.98.
MS: m/z = 118.0 [M+].
(20) General Procedure for the Synthesis of Thioamide
To a mixture of aryl nitrile (1 equiv) and CaH2 (1 equiv) was
taken in a two-necked 50 mL round-bottomed flask, and the
content was cooled to 0 °C and added thioacetic acid (1.5
equiv). After stirring for 15 min the reaction mixture was
heated in an oil bath at 80 °C for the given period of time
(Table 1). After the completion of the reaction, the contents
were cooled to r.t., 50% aq EtOAc (2 × 10 mL) was added
and stirred for some time till the layers separated. Extraction
was done once again with EtOAc, and the combined organic
layer was filtered through Celite pad, and concentrated under
reduced pressure to get the crude product. It was then
purified by crystallization using PE and EtOAc (9:1). All the
novel products were characterized by NMR and MS
analysis.
(21) Sivakumar, M.; Senthilkumar, P.; Pandit, A. B. Synth.
Commun. 2001, 2583.
(22) (a) Liboska, R.; Zyka, D.; Bobek, M. Synthesis 2002, 1649.
(b) Oliver, J. E.; DeMilo, A. B.; Cohen, C. F.; Shortino,
T. J.; Robbins, W. E. J. Agric. Food Chem. 1976, 24, 1065.
(c) Takikawa, Y.; Shimada, K.; Sato, K.; Sato, S.; Takizawa,
S. Bull. Chem. Soc. Jpn. 1985, 58, 995. (d) Abdel-Lateef,
M. F.-A.; Eckstein, Z. Bull. Acad. Pol. Sci., Ser. Sci. Chim.
1971, 19, 705. (e) Miwatashi, S.; Arikawa, Y.; Naruo, K.;
Igaki, K.; Watanabe, Y.; Kimura, H.; Kawamoto, T.;
Ohkawa, S. Chem. Pharm. Bull. 2005, 53, 410. (f) Lin,
P. Y.; Ku, W. S.; Shiao, M. J. Synthesis 1992, 1219.
(g) Matsuda, K.; Yanagisawa, I.; Isomura, Y.; Mase, T.;
Shibanuma, T. Synth. Commun. 1997, 2393. (h) Sakai,
T. T.; Rama, K. N. Bioorg. Med. Chem. 1999, 7, 1559.
(i) Chihiro, M.; Nagamoto, H.; Takemura, I.; Kitano, K.;
Komatsu, H.; Sekiguchi, K.; Tabusa, F.; Mori, T.;
Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1995, 38, 353.
(j) Kindler, V. K. Justus Liebigs Ann. Chem. 1927, 452, 107.
(k) Erlenmeyer, H.; Junod, J.; Guex, W.; Erne, M. Helv.
Chim. Acta 1948, 31, 1342. (l) Lehr, H.; Guex, W.;
Erlenmeyer, H. Helv. Chim. Acta 1944, 27, 970.
(m) Edward, J. T.; Derdall, G. D.; Wong, S. C. Can. J. Chem.
1977, 55, 2331.
4-Bromo-2-chlorobenzenecarbothioamide (2b)
1H NMR (400 MHz, DMSO-d6): d = 7.31 (d, 1 H), 7.50 (q,
1 H), 7.75 (s, 1 H), 9.73 (br s, 1 H), 10.23 (br s, 1 H) ppm.
13C NMR (100 MHz, DMSO-d6): d = 126.5, 129.1, 129.7,
133.3, 136.6, 141.3, 188.5 ppm. Anal. Calcd (%) for
C7H5BrClNS: C, 33.56; H, 2.01; N, 5.59. Found: C, 33.54;
H, 2.22; N, 5.55. MS: m/z = 251.0 [M+].
4-Chloro-3-nitrobenzenecarbothioamide (2d)
1H NMR (400 MHz, DMSO-d6): d = 7.8 (d, 1 H), 8.1 (d, 1
H), 8.5 (s, 1 H), 9.8 (br s, 1 H), 10.2 (br s, 1 H) ppm.
13C NMR (100 MHz, DMSO-d6): d = 124.7, 128.0, 131.8,
132.4, 139.6, 147.2, 196.5 ppm. Anal. Calcd (%) for
Synlett 2009, No. 14, 2338–2340 © Thieme Stuttgart · New York