Synthesis of polyfunctional 2-thionicotinonitriles

Article abstract of DOI:10.1134/S1070428016110087

Reaction of 2-amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitriles with sulfur in benzonitrile affords 4-amino-6-aryl-2-thio-1,2-dihydropyridine-3,5-dicarbonitriles. They also are synthesized by an authentic synthesis from 4-amino-6-aryl-2-bromopyridine-3,5-

Full text of DOI:10.1134/S1070428016110087

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 11, pp. 1600–1602. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © I.N. Bardasov, D.L. Mikhailov, M.Yu. Belikov, A.Yu. Alekseeva, O.V. Ershov, 2016, published in Zhurnal Organicheskoi Khimii,
2016, Vol. 52, No. 11, pp. 1607–1609.
Synthesis of Polyfunctional 2-Thionicotinonitriles
I. N. Bardasov,* D. L. Mikhailov, M. Yu. Belikov, A. Yu. Alekseeva, and O. V. Ershov
I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
*e-mail: bardasov.chem@mail.ru
Received April 25, 2016
Abstract—Reaction of 2-amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitriles with sulfur in benzonitrile affords 4
-amino-6-aryl-2-thio-1,2-dihydropyridine-3,5-dicarbonitriles. They also are synthesized by an authentic
synthesis from 4-amino-6-aryl-2-bromopyridine-3,5-dicarbonitriles and sodium hydrosulfide.
DOI: 10.1134/S1070428016110087
Compounds with 2-thionicotinonitrile as the main
structural fragment are traditionally interesting due to
the wide range of their biologic activity and the
possibility of application to the fine organic synthesis
and also to production from them dyes, pigments, acid-
base indicators, and other practically important
substances [1–3]. For instance, among these com-
pounds substances were found possessing anticancer
[4, 5], neurotropic [6], cardiotonic [7], antiepileptic
[8], antiarrhythmic [9] action. In the fine organic
synthesis the 2-thionicotinonitrile fragment is used for
the targeted preparation of thieno[2,3-b]pyridines with
antitumor activity [10–14].
4-amino-6-aryl-2-thioxo-1,2-dihydropyridine-3,5-
dicarbonitriles 2a–2d in 34–70% yields (Scheme 1).
The structure of compounds 2a–2d was confirmed
1
by the IR, Н, 13С NMR, and mass spectra. The IR
spectra contained strong absorption bands of
conjugated cyano groups at 2214–2223 cm–1 and
stretching vibrations of amino group in the region
3256–3338 cm–1. In the 1Н NMR spectra proton
signals of the NH fragment of the dihydropyridine ring
appear at 13.28–13.37 ppm, of NH2 group, at 7.89–
8.04 ppm, and also the signals from aryl substituents
are present. The mass spectra are characterized by the
presence of molecular ion [M]+ of 78–95% intensity.
The main approach to the synthesis of 2-
thionicotinonitriles consists in the reaction of thiocyan-
acetamide with ylidene derivative of methylene-active
compounds and the three-component reaction between
aldehyde, methylene-active compound, and thiocyan-
acetamide [1–3].
As solvents for the synthesis of thioxonicotino-
nitriles 2a–2d only high boiling liquids are suitable
like DMF, DMSO, xylene, yet the yields of reaction
products were below 50%. In dioxane,THF, ethanol,
and 2-propanol only trace amounts of thioxopyridines
2a–2d were formed. The highest yields were obtained
in benzonitrile.
Arylylidene derivatives of malononitrile dimer are
promising precursors for building up the pyridine ring
[15–19], in particular, of nicotinonitrile. At treating
with hydrogen bromide of 2-amino-4-arylbuta-1,3-
diene-1,1,3-tricarbonitriles 1a–1d in the presence of an
oxidant 2-bromonicotinonitrile derivatives were
formed [20], and treating with sodium methylate in
methanol afforded 2-methoxynicotinonitrile [21]. In
extension of the studies on the preparation of highly
The application of amines as catalysts, in particular,
diethylamine, piperidine, and morpholine which
Scheme 1.
NH2
NH2
NC
Ar
CN
S
S
CN
functionalized nicotinonitriles we developed
a
Ar
PhCN
procedure for the synthesis of their 2-thioxo
derivatives. The reaction of 2-amino-4-arylbuta-1,3-
diene-1,1,3-tricarbonitriles 1a–1d with sulfur in
benzonitrile led to the formation of the corresponding
N
H
CN
CN
1a_1d
2a_2d
Ar = Ph (a), 3,4-Cl2C6H3 (b), 4-FC6H4 (c), 4-MeC6H4 (d).
1600

SYNTHESIS OF POLYFUNCTIONAL 2-THIONICOTINONITRILES
1601
Scheme 2.
NH2
NH2
NC
Ar
CN
S
NC
Ar
CN
S
H2S
S
H2S
1
2
_
N
H
H2N
A
B
according to published data accelerate the processes
involving sulfur [22] led to the acceleration of the
reaction, but it resulted in a mixture of products. In this
case the target compounds 2 should be isolated by
chromatography. Therefore it is better to carry out the
synthesis without the basic catalysis, for the yields do
not grow in the catalytic process. At the acid catalysis
the reaction rate did not change and the yield
decreased.
these compounds promising substrates for targeted
organic synthesis.
EXPERIMENTAL
IR spectra were recorded on a Fourier spectrometer
1
FSM-1202 from thin film (or mull in mineral oil). Н
and 13С NMR spectra were registered on a spec-
trometer Bruker DRX-500 (500.13 and 125.76 МHz
respectively) in DMSO-d6, internal reference TMS.
Mass spectra were obtained on an instrument Finnigan
MAT INCOS-50 (electron impact, 70 eV). Melting
points were measured on an instrument OptiMelt
MPA100. The purity of synthesized compounds was
checked by TLC on Silufol UV-254 plates,
development under UV irradiation, in iodine vapor, or
by thermal decomposition.
The formation of thioxopyridines 2a–2d apparently
occurs via a succession of transformations presented in
Scheme 2. Evidently in the initial stage hydrogen
sulfide formed that added to the terminal cyano group
(Scheme 2). Further the formed thioxoamide А
underwent an intramolecular heterocyclization
resulting in a tetrahydropyridine ring B. In the final
stage the oxidation occurs under the action of sulfur
accompanied with hydrogen sulfide evolution; the
latter can take part in transformations.
4-Amino-2-thioxo-6-phenyl-1,2-dihydropyridine-
3,5-dicarbonitrile (2а). а. A slurry of 0.220 g (1 mmol)
of 2-amino-4-phenylbuta-1,3-diene-1,1,3-tricarbonitrile
1 and 0.064 g (2 mmol) of elemental sulfur in 1 mL of
benzonitrile was boiled at reflux for 16 h, then the
solution was diluted with 2-propanol. The separated
dark-brown crystalline precipitate was filtered off and
recrystallized from dioxane. Yield 0.156 g (62%).
2-Thioxonicotinonitriles 2a–2d were also prepared
by an authentic synthesis from 4-amino-6-aryl-2-
bromopyridine-3,5-dicarbonitriles 3a–3d (Scheme 3)
[9]. The bromine substitution was performed in 1,4-
dioxane at treating with sodium hydrosulfide. As a
result 2-thioxopyridines 2a–2d were isolated in yields
up to 99%.
b. To a solution of 0.298 g (1 mmol) of 4-amino-2-
bromo-6-phenylpyridine-3,5-dicarbonitrile 3а in 3 mL
of 1,4-dioxane was added dropwise a solution of 0.062 g
(1.1 mmol) of sodium hydrosulfide in 1 mL of water.
The mixture was stirred at 50°С till the completion of
the reaction (TLC monitoring), then the solution was
diluted with water and neutralized with conc.
hydrochloric acid. The separated yellow crystalline
precipitate was filtered off, washed with water, with a
little ethanol and hot benzene. Yield 0.237 g (94%),
mp 280–281°С (decomp.). IR spectrum, ν, cm–1: 3338
(NН2), 2223 (С≡N). 1Н NMR spectrum, δ, ppm: 7.55 t
(2Н, С6Н5, J 7.5 Hz), 7.60–7.66 m (3Н, С6Н5), 7.93 s
(2Н, NH2), 13.35 s (1H, NH). 13С NMR spectrum, δ,
ppm: 86.61, 93.78 (С3, С5), 114.20, 115.70 (2CN),
128.41, 129.16, 130.35, 131.72 (C6H5), 155.70, 157.55
Scheme 3.
NH2
NC
Ar
CN
Br
HBr, Br2
NaSH
1a_1d
2a_2d
N
3a_3d
Ar = Ph (a), 3,4-Cl2C6H3 (b), 4-FC6H4 (c), 4-MeC6H4 (d).
Hence we developed two procedures of the
preparation of polyfunctional 2-thioxonicotinonitriles
containing in their structure fragments convenient for
further transformations, namely, enaminonitrile and 3-
cyanopyridine-2(1Н)-thione moieties, thus making
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 11 2016

BARDASOV et al.
1602
(С4, С6), 179.45 (C1). Mass spectrum, m/z (Irel, %): 252
(81) [M]+. Found, %: C 61.92; H 3.10; N 22.27.
C13H8N4S. Calculated, %: C 61.89; H 3.20; N 22.21. M
252.30.
6. Krauze, A., Germane, S., Eberlin, O., Sturms, I., Klusa, V.,
and Duburs, G., Eur. J. Med. Chem., 1999, p. 34.
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2005, vol. 40, p. 1405.
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Compounds 2b–2d were similarly obtained.
Abdulla, M.M., Monatsh. Chem., 2003, vol. 134, p. 1395.
9. Abdulla, M.M., Monatsh. Chem., 2008, vol. 139, p. 69.
4-Amino-2-thioxo-6-(3,4-dichlorophenyl)-1,2-
dihydropyridine-3,5-dicarbonitrile (2b). Yield 44%
(а), 99% (b), mp 233–234°С (decomp.). IR spectrum,
10. Szabo, M., Huynh, T., Valant, C., Lane, J.R., Sexton, P.M.,
Christopoulos, A., and Capuano, B., Med. Chem.
Commun., 2015, vol. 6, p. 1998.
1
ν, cm–1: 3288 (NН2), 2214 (С≡N). Н NMR spectrum,
11. Arabshahi, H.J., Van Rensburg, M., Pilkington, L.I.,
Jeon, C.Y., Song, M., Gridel, L.-M., Leung, E., Barker, D.,
Vuica-Ross, M., Volcho, K.P., Zakharenko, A.L.,
Lavrik, O.I., and Reynisson, J., Med. Chem. Commun.,
2015, vol. 6, p. 1987.
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Zheng, Y., Tong, A.-P., Xiang, M.-L., Song, X.-R.,
Yang, S.-Y., Yu, L.-T., Wei, Y.-Q., Zhao, Y.-L., and
Yang, L., Bioorg. Med. Chem. Lett., 2010, vol. 20,
p. 6282.
δ, ppm: 7.68 d.d (1Н, С6Н3, J 2.0, 8.5 Hz), 7.86 d (1Н,
С6Н3, J 8.5 Hz), 8.02 d (1Н, С6Н3, J 2.0 Hz), 8.04 s
(2Н, NH2), 13.45 s (1H, NH). Mass spectrum, m/z (Irel,
%): 320 (87) [M]+. Found, %: C 48.70; H 1.80; N
17.52. C13H6Cl2N4S. Calculated, %: C 48.62; H 1.88;
N 17.44. M 321.18.
4-Amino-6-(4-tolyl)-2-thioxo-1,2-dihydropyridi-
ne-3,5-dicarbonitrile (2c). Yield 95%, mp 227–229°С
(decomp.). IR spectrum, ν, cm–1: 3268 (NН2), 2220
1
13. Leung, E., Hung, J.M., Barker, D., and Reynisson, J.,
(С≡N). Н NMR spectrum, δ, ppm: 7.36 d (2Н, С6Н4,
Med. Chem. Commun., 2014, vol. 5, p. 99.
J 8.1 Hz), 7.54 d (2Н, С6Н4, J 8.2 Hz), 7.89 s (2Н,
NH2), 13.28 s (1H, NH). Mass spectrum, m/z (Irel, %):
266 (95) [M]+. Found, %: C 63.14; H 3.78; N 21.04.
C14H10N4S. Calculated, %: C 63.06; H 3.88; N 21.12.
M 266.32.
14. Hung, J.M., Arabshahi, H.J., Leung, E., Reynisson, J.,
and Barker, D., Eur. J. Med. Chem., 2014, vol. 86,
p. 420.
15. Bardasov, I.N., Alekseeva, A.U., Ershov, O.V., and
Belikov, M.Yu., Tetrahedron Lett., 2015, vol. 56,
p. 5434.
16. Bardasov, I.N., Alekseeva, A.U., Mihailov, D.L.,
Ershov, O.V., and Grishanov, D.A., Tetrahedron Lett.,
2015, vol. 56, p. 1830.
4-Amino-2-thioxo-6-(4-fluorophenyl)-1,2-dihyd-
ropyridine-3,5-dicarbonitrile (2d). Yield 97%, mp
239–240°С (decomp.). IR spectrum, ν, cm–1: 3256 (NН2),
1
2221 (С≡N). Н NMR spectrum, δ, ppm: 7.41 t (2Н,
17. Bardasov, I.N., Alekseeva, A.U., Mihailov, D.L.,
Ershov, O.V., Nasakin, O.E., and Tafeenko, V.A.,
Tetrahedron Lett., 2014, vol. 55, p. 2730.
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Ershov, O.V., and Nasakin, O.E., Russ. J. Org. Chem.,
2013, vol. 49, p. 1715.
С6Н4, J 8.9 Hz), 7.54 d.d (2Н, С6Н4, J 5.5, 8.9 Hz),
7.96 s (2Н, NH2), 13.37 s (1H, NH). Mass spectrum,
m/z (Irel, %): 270 (78) [M]+. Found, %: C 57.66; H
2.70; N 20.71. C13H7FN4S. Calculated, %: C 57.77; H
2.61; N 20.73. M 270.29.
The study was carried out under the financial
support of the Russian Foundation for Basic Research
(grant no. 15-33-21087 mol_a_ved).
19. Melekhin, E.A., Bardasov, I.N., Ershov, O.V., Erem-
kin, A.V., Kayukov, Ya.S., and Nasakin, O.E., Russ.
J. Org. Chem., 2006, vol. 42, p. 622.
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Ershov, O.V., and Nasakin, O.E., Tetrahedron Lett.,
2013, vol. 54, p. 21.
21. Alekseeva, A.Yu., Mikhailov, D.L., Bardasov, I.N.,
Ershov, O.V., Nasakin, O.E., and Lyshchikov, A.N.,
Russ. J. Org. Chem., 2014, vol. 50, p. 244.
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s organicheskimi soedineniyami (The Reactions of
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