New promising methods of synthesis of pyridinecarbothioamides

Article abstract of DOI:10.1134/S1070363215100138

New methods of synthesis of pyridinecarbothioamides from the corresponding cyanopyridines with the use of phosphorus pentasulfide as a thiontion agent were developed. The first method was based on the reaction of cyanopyridine with phosphorus pentasulfide in alcoholic ammonium solution followed by hydrolysis. The method provided the corresponding thioamides in 60-90% yield. The second procedure included the reaction of phosphorus pentasulfide with 4-cyanopyridine in aqueous ammonia solution, which led to the formation of pyridine-4-carbothioamides in quantitative yield.

Full text of DOI:10.1134/S1070363215100138

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 10, pp. 2295–2298. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © N.Yu. Khromova, S.I. Malekin, A.V. Kutkin, V.B. Kondrat’ev, 2015, published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 10,
pp. 1663–1666.
New Promising Methods of Synthesis of Pyridinecarbothioamides
N. Yu. Khromova, S. I. Malekin, A. V. Kutkin, and V. B. Kondrat’ev
The State Research Center of the Russian Federation, State Research Institute of Organic Chemistry and Technology,
sh. Entuziastov 23, Moscow, 111024 Russia
e-mail: dir@gosniiokht.ru
Received April 2, 2015
Abstract—New methods of synthesis of pyridinecarbothioamides from the corresponding cyanopyridines with
the use of phosphorus pentasulfide as a thiontion agent were developed. The first method was based on the
reaction of cyanopyridine with phosphorus pentasulfide in alcoholic ammonium solution followed by
hydrolysis. The method provided the corresponding thioamides in 60–90% yield. The second procedure
included the reaction of phosphorus pentasulfide with 4-cyanopyridine in aqueous ammonia solution, which led
to the formation of pyridine-4-carbothioamides in quantitative yield.
Keywords: thioamides, pyridinecarbothioamide, cyanopyridine, phosphorus pentasulfide
DOI: 10.1134/S1070363215100138
Development of thioamide synthesis procedures is
of significant practical interest. These compounds find
wide technical, agricalturalapplications and are used in
the synthesis of heterocyclic compounds [1]. Among
the biologically active thioamides the pyridinecarbo-
thioamides exhibit a wide range of biologic action [2–5].
We developed a promising preparative method of
synthesis of pyridinecarbothioamides 2a–2f in 60–92%
yield that included the reaction of aromatic nitriles 1a–
1f with phosphorus pentasulfide in alcoholic solution
of ammonia at 30–40°C followed by hydrolysis with
water (method a).
S
(1) MeOH + NH3
(2) H2O
CSNHR1
P2S5
R
CN +
R
NH2
2a−2f
R2
1
R = 4-Py (2а), 2-Py (2b), 2-Cl-3-Py (2c), 4-Cl-2-Py (2d), 6-
Cl-2-Py (2e), (5-Cl-3-Py)CH2 (2f).
N
R1 = H, Et, (CH2)2NMe2, –(CH2)2-2-Py; R2 = Pr, SH,
S-(CH2)2NMe2.
The reaction of phosphorus pentasulfide with the
nitrile solution was found to be exothermic; the
reaction mixture solidified after the process was
finished. The subsequent treatment of the crystalline
mixture with water caused its complete dissolution
with an intensive heating and gas evolution; after that
the target pyridinethiocarbamide precipitated as
crystalline species from the solution. Most probably
O,O-dimethyldithiophosphoric acid ammonium salt in
this case was the thionation agent [18, 19].
Two methods of synthesis of carbothioamides
described in reviews [6–8] are the most widely known.
The first one involved thionation of amides with
phosphorus pentasulfide or Lawesson's reagent; the
second one is the reaction of nitriles with hydrogen
sulfide. Besides that few methods of nitriles conver-
sion to thioamides with the help of such thionation
reagents as thioacetamide [9], alkali metals or ammo-
nium hydrosulfides [10, 11], (P4S10O)2–Na22+ [12], О,О-
dialkyldithiophosphoric acids [13–16], a mixture of
aluminum oxide with ammonium O,O-diethyldithio-
phosphate under microwave irradiation [17] have been
described.
Further we discovered that triethylamine can be
used in the reaction instead of ammonia (method b).
The reaction proceeded under similar conditions and
led to the formation of the target pyridinecarbo-
thioamides 2a–2f in 60–92% yield.
2295

2296
KHROMOVA et al.
1H and 13C NMR spectroscopy data (DMSO-d6) for thioamides 2a–2f, and 3
Comp.
δН, ppm (J, Hz)
no.
δC, ppm
121.1, 146.7, 150.0, 198.0
2a
2b
2c
2d
7.68 m, 8.61 m, 9.74 s, 10.10 s
7.55 m, 7.94 m, 8.47 m, 8.56 m, 9.89 s, 10.03 s
7.42 m, 7.77 d.d (J 7.2, 1.4), 8.35 m, 9.83 s, 10.20 s
124.6, 126.5, 137.5, 147.7, 151.7, 195.0
123.5, 137.7, 139.0, 144.0, 149.0, 198.4
124.3, 126.1, 143.8, 149.3, 153.5, 193.2
7.74 d.d (J 5.7, 2.4), 8.47 d (J 1.8), 8.57 d (J 5.4), 9.95 s,
10.32 s
2e
2f
3
7.71 d (J 7.2), 8.01 t (J 7.9), 8.40 d (J 7.9), 9.76 s, 10.20 s
7.74 d (J 8.4), 7.78 d (J 8.4), 8.31 s, 3.83 s, 9.47 s, 9.57 s
7.56 m, 8.56 m, 1.21 t (J 7.8), 3.67 m, 10.53 s
125.0, 128.3, 140.0, 146.9, 163.6, 194.1
46.6, 123.7, 132.7, 140.0, 148.6, 150.0, 204.0
12.9, 41.6, 121.6, 148.4, 150.1, 194.9
S
admixtures that significantly facilitated the process of
their isolation and purification. Carrying out the
reaction with aqueous ammonia did not require the use
of organic solvents. The thionation reagent in all the
reactions was most probably ammonium dithiophos-
phate.
(1) MeOH + Et3N
(2) H2O
P2S5
CN +
R
R
NH2
1
2a, 2b
By an example of 4-cyanopyridine we showed that
N-substituted thioamides can be prepared similarly
using in this case diethylamine instead of triethyl-
amine. The reaction led to the formation of N-ethyl-
pyridin-4-carbothioamide 3 in 54% yield.
EXPERIMENTAL
We used 2- and 4-pyridinecarbonitriles, 2-chloro-3-
pyridinecarbonitrile, 6-chloro-3-pyridinecarbonitrile,
and 2-chloro-4-pyridinecarbonitrile purchased from
Aldrich.
S
NH2
CN
NH4OH
1H, 13C and 31P NMR spectra were recorded on a
Bruker AM-360 spectrometer at 360.13, 90.58, and
145.78 MHz respectively. Tetramethylsilane was used
+ P2S5
N
N
2a
1
as an internal reference for H and 13C NMR spectra;
S
NHEt
for 31P NMR spectra 85% phosphoric acid was used as
an external reference. The reaction progress was
monitored by the means of TLC on Kieselgel 60 F254
(Merck) plates eluting with a mixture methylene
chloride–methanol, 9 : 1.
(1) MeOH + Et2NH
(2) H2O
N
3
Pyridine-4-carbothioamide (2a). a. Ground phos-
phorus pentasulfide (115 g, 0.5 mol) was added to a
solution of 4-cyanopyridine (52 g, 0.5 mol) in 250 mL
of 20% ammonium in methanol under vigorous stirring
maintaining the reaction mixture temperature below
35–40°C. The reaction mixture was kept at room
temperature for 12 h, and then 150 mL of water was
added that caused dissolution of the solid and intensive
exothermic gas liberation. After cooling of the reaction
mixture to room temperature the precipitate was
filtered off, washed with water, and dried. Yield 92%
(64 g), Rf = 0.39, mp = 209°С (mp = 209–210°С [20]).
The reaction of 4-cyanopyridine with phosphorus
pentasulfide can proceed in aqueous solution of
ammonium without methanol. In this case the reaction
afforded pyridine-4-carbothioamide 2a in 98% yield.
The structure of all prepared compounds was
confirmed by NMR spectroscopy data (see table).
The elaborated procedure simplified preparation of
pyridinecarbothioamides and may be applied to the
synthesis of various compounds of this class. The
target pyridinecarbothioamides crystallized easily from
the reaction mixture and almost did not contain any
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 10 2015

2297
NEW PROMISING METHODS OF SYNTHESIS OF PYRIDINECARBOTHIOAMIDES
Found, %: С 52.05; H 4.29; N 20.32; S 23.34.
C6H6N2S. Calculated, %: С 52.15; H 4.38; N 20.27; S
23.20.
dried. Yield 60%, mp 180°С (decomp.). Found, %: С
41.82; H 3.05; Cl 20.29; N 16.22; S 18.62. C6H5ClN2S.
Calculated, %: С 41.74; H 2.92; Cl 20.54; N 16.23; S
18.57.
b. Phosphorus pentasulfide (6 g, 0.028 mol) was
added to a solution of 4-cyanopyridine (3 g, 0.028 mol)
and triethylamine (8 g, 0.079 mol) in 30 mL of
methanol under vigorous stirring at 30–40°C. The
reaction mixture was kept for 12 h at room temperature
then 50 mL of water was added. The formed pre-
cipitate was filtered off and dried. Yield 58% (2.3 g).
2-(Chloropyrid-2-yl)thioacetamide (2f) was prepared
similarly according to method a. After the end of
reaction 150 mL of water was added and the mixture
was heated at 70–75°C with the help of a water bath
till the gas evolution stopped. After cooling the
precipitate was filtered off, washed with water, and
dried. Yield 60%, mp 170°С (decomp.). Found, %: С
45.15; H 3.70; Cl 18.90, N 15.11; S 17.14. C7H7ClN2S.
Calculated, %: С 45.04; H 3.78; Cl 18.99; N 15.01; S
17.18.
c. Ground phosphorus pentasulfide (7 g, 0.031 mol)
was added to a solution of 4-cyanopyridine (3.2 g,
0.03 mol) in 40 mL of 23% aqueous ammonia at
stirring. Warming of the reaction mixture up to 70–75°C
was observed. After cooling the precipitate was filtered
off, washed with water, and dried. Yield 91% (3.8 g).
N-Ethylpyridine-4-carbothioamide (3). Phosphorus
pentasulfide (36 g, 0.16 mol) was added to a solution
of 4-cyanopyridine (16 g, 0.15 mol) and diethyamine
(30 g) in 100 mL of methanol at stirring at 35–40°C.
The reaction mixture was kept at room temperature for
12 h. Then 100 mL of water was added, and the
reaction mixture was heated at 60–70°C by the water
bath. After cooling the precipitate was filtered off,
washed with water, and dried. Yield 54% (13.7 g), Rf
0.55, mp 102°С. Found, %: С 57.83; H 5.99; N 16.79;
S 19.39. C8H10N2S. Calculated, %: С 57.80; H 6.06; N
16.85; S 19.29.
d. Phosphorus pentasulfide (4.8 g, 0.022 mol) was
added to 25 mL of 23% aqueous ammonia. The
reaction mixture warmed up to 60°C. Then 4-cyano-
pyridine (2.2 g, 0.02 mol) was added to the obtained
solution, and then the reaction mixture was stirred at
40–50°C for 0.5 h. After cooling the precipitate was
filtered off, washed with water, and dried. Yield 98%
(2.7 g).
Pyridine-2-carbothioamide (2b) was prepared
similarly according to method a. After the reaction
ended, 150 mL of water was added and the mixture
was heated up to 70–75°C by water bath till the gas
evolution stopped. After cooling the precipitate was
filtered off, washed with water, and dried. Yield 89%
(61.8 g), Rf 0.45, mp 137°С (136–137°С [21]). Found,
%: С 52.09; H 4.31; N 20.30; S 23.30. C6H6N2S.
Calculated, %: С 52.15; H 4.38; N 20.27; S 23.20.
REFERENCES
1. Jagodzinski, T.S., Chem. Rev., 2003, vol. 103, p. 197.
DOI: 10.1021/cr0200015.
2. Lekarstvennye sredstva (Drugs), Mashkovskii, M.V.,
Ed., Moscow: Novaya Volna, 2012.
3. Ubiali, D., Pagani, G., and Pregnolato, M., Bioorg. Med.
Chem. Lett., 2002, vol. 12, p. 2541. DOI: 10.1016/
S0960-894X(02)00490-0.
4. Kinney, W.A., Lee, N.E., and Blank, R.M., J. Med.
Chem., 1990, vol. 33, p. 327. DOI: 10.1021/jm00163a053.
5. Klimesova, V., Svoboda, M., and Waisser, K.,
Farmaco, 1999, vol. 54, p. 666. DOI: 10.1016/S0014-
827X(99)00078-6.
2-Chloro-3-carbothioamide (2c) was prepared
similarly according to method a. Yield 78%, Rf 0.55,
mp 165°С (decomp.).
6-Chloropyridine-2-carbothioamide (2d) was pre-
pared similarly according to method a. Yield 94%, mp
176°С (decomp.). Found, %: С 41.69; H 2.96; Cl
20.56; N 16.19; S 18.60. C6H5ClN2S. Calculated, %: С
41.74; H 2.92; Cl 20.54; N 16.23; S 18.57.
6. Walter, W. and Bode, K.-D., Angew. Chem. Int. Ed.,
1966, vol. 5, no. 5, p. 447. DOI: 10.1002/anie.196604471.
4-Chloropyridine-2-carbothioamide (2e) was pre-
pared similarly according to method a. After the end of
reaction 150 mL of water was added and the mixture
was heated at 70–75°C with the help of a water bath
till the gas evolution stopped. After cooling the
precipitate was filtered off, washed with water, and
7. Scheibye, S., Pedersen, B.S., and Lawesson, S.O., Bull.
Soc. Chim. Belg., 1978, vol. 87, p. 229.
8. Petrov, K.A. and Andreev, L.N., Russ Chem. Rev.,
1969, vol. 38, no, 1, p. 21.
9. Taylor, E.C. and Zoltewicz, J.A., J. Am. Chem. Soc.,
1960, vol. 82, p. 2656. DOI: 10.1021/ja01495a078.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 10 2015

2298
KHROMOVA et al.
10. Wang, C.H., Hwang, F.Y., Horng, J.M., and Chen, C.T.,
Heterocycles, 1979, vol. 12, p. 1191. DOI: 10.3987/R-
1979-09-1191.
sov, R.A., Russ. Chem. Rev., 1991, vol. 60, no. 10,
p. 1128.
17. Kaboudin, B., Elhamifar, D., and Farjadian, F., Org.
Prep. Proc. Intern., 2006, vol. 38, no. 4, p. 412. DOI:
10.1080/00304940609356003.
11. Yakhontov, L.N., Azimov, V.A., and Sycheva, T.P.,
Khim.-Farm. Zh., 1976, no. 2, p. 96.
12. Brillon, D., Synth. Commun., 1992, vol. 22, p. 1397.
18. France Patent 2005609, 1970, C. A., 1970, vol. 73,
DOI: 10.1080/00397919208021604.
p. 14176.
13. Nakanishi, A. and Oae, S., Chem. Ind., 1973, vol. 17,
19. Kaboudin, B. and Norouzi, H., Synthesis, 2004,
p. 274.
p. 2035. DOI: 10.1055/S-2004-829176.
14. Shabana, R., Meyer, H.J., and Lawesson, S.-O.,
Phosphorus and Sulfur, 1985, vol. 25, p. 297. DOI:
10.1080/03086648508072745.
15. Yousif, N.M., Tetrahedron, 1989, vol. 45, no. 14,
p. 4599. DOI: 10.1016/S0040-4020(01)89095-5.
16. Zabirov, N.G., Shamsevaleev, F.M., and Cherka-
20. Gardner, T.S. and Lee, G.H., J. Org. Chem., 1954,
vol. 19, nos. 5–6, p. 753. DOI: 10.1021/jo01370a009.
21. Stephens, C.E., Tanious, F., Kim, S., Wilson, W.D.,
Schell, W.A., Perfect, J.R., Franzblau, S.G., and
Boykin, D.W., J. Med. Chem., 2001, vol. 44, p. 1741.
DOI: 10.1021/jm000413a.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 10 2015