A new route to highly substituted thieno[2,3-b]pyridines via cascade heterocyclization of 2-acyl-1,1,3,3-tetracyanopropenide salts

Article abstract of DOI:10.1007/s10593-017-2044-6

[Figure not available: see fulltext.] 2-Acyl-1,1,3,3-tetracyanopropenides undergo cascade heterocyclization under the action of mercaptoacetic esters, leading to the formation of new 3,6-diamino-4-aroyl-5-cyanothieno[2,3-b]pyridine-2-carboxylates. The fast and convenient synthetic way to highly substituted thieno[2,3-b]pyridine scaffold is described.

Full text of DOI:10.1007/s10593-017-2044-6

DOI 10.1007/s10593-017-2044-6
Chemistry of Heterocyclic Compounds 2017, 53(2), 230–235
A new route to highly substituted thieno[2,3-b]pyridines via
cascade heterocyclization of 2-acyl-1,1,3,3-tetracyanopropenide salts
Arthur A. Grigor'ev1, Sergey V. Karpov1*, Yakov S. Kayukov1,
Oleg E. Nasakin1, Iuliia A. Gracheva2, Victor A. Tafeenko3
1
Chuvash State University named after I. N. Ulyanov,
15 Moskovsky Ave., Cheboksary 428015, Russia; e-mail: serg31.chem@mail.ru
2
Nizhni Novgorod State University,
23 Gagarina Ave., Nizhni Novgorod 603950, Russia; e-mail: yulia17gra4ova@mail.ru
Lomonosov Moscow State University,
1-3 Leninskie Gory, Moscow 119991, Russia; e-mail: tafeenko-victor@yandex.ru
3
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2017, 53(2), 230–235
Submitted October 19, 2016
Accepted November 28, 2016
R1
O
R1
O
C
NH2
O
Py
OR2
NC
O
+
NC
CN
K+
, ~3 h
HS
OR2
S
CN CN
H2N
N
ATCN
One-step synthesis
Up to 79% yield
2-Acyl-1,1,3,3-tetracyanopropenides undergo cascade heterocyclization under the action of mercaptoacetic esters, leading to the
formation of new 3,6-diamino-4-aroyl-5-cyanothieno[2,3-b]pyridine-2-carboxylates. The fast and convenient synthetic way to highly
substituted thieno[2,3-b]pyridine scaffold is described.
Keywords: organic nitriles, tetracyanopropenides, thieno[2,3-b]pyridines, cyano group.
Currently, there is a considerable interest in the thieno-
[2,3-b]pyridine molecular scaffolds. These compounds
exhibit a broad range of biological activities, such as
anticancer,1 anti-inflammatory,2 antiviral,3 antimicrobial,4
antidiabetic,5 osteogenic,6 and neuroprotective.7,8 Addi-
tionally, representative compounds have been recognized
as death-associated protein kinase inhibitors,9 multidrug
resistance,10 and mGluR5 receptor11 modulators.
The most popular routes for the synthesis of thieno[2,3-b]-
pyridine core are the reaction between 2-aminothiophene-
3-carbonitriles and 1,1-dimethoxy-N,N-dimethylethan-
amine,1a the alkylation of 2-thioxo-1,2-dihydropyridine-
3-carbonitriles followed by Thorpe–Ziegler cycliza-
tion,1b–d,2b,3b,5a,b,6b,7b,10,11,12 and the heteroannulation of
2-halonicotinonitriles using methyl/ethyl thioglycolate.1g,9
In this work, we described a fast and convenient
synthesis of novel methyl/ethyl 3,6-diamino-4-aroyl-
5-cyanothieno[2,3-b]pyridine-2-carboxylates. These com-
pounds contain a carbonyl substituent in position 4 of the
pyridine ring, which reveals broad opportunities for
targeted annulation to pyridine [d]-bond and other
modifications.
Thieno[2,3-b]pyridines 2 were obtained via the reaction
of readily available potassium 2-acyl-1,1,3,3-tetracyano-
propenides (ATCN)13 1 with mercaptoacetic esters 3 in
pyridine (Scheme 1, Table 1). Pyridine was used as
solvent, as stronger bases give rise to other products.14
Using of weaker bases leads to low yields.15 The method is
limited to aromatic and heteroaromatic acyl groups, ATCN
with aliphatic acyl groups produce dihydrofuran deriva-
tives.16 A proposed mechanism for this reaction involves
nucleophilic addition of thiol to ATCN cyano group and
subsequent Thorpe–Ziegler cyclization of the intermediate
pyridine B.
The formation of intermediate alkyl 2-[(6-amino-4-aroyl-
3,5-dicyanopyridin-2-yl)sulfanyl]acetates A was confirmed
by decreasing refluxing time to 1 h. In this case, the
resulting isolated precipitate contains
a mixture of
compounds 4 and 2 in variable ratio, according to 1H NMR
spectroscopy. In our opinion, the Thorpe–Ziegler cycliza-
tion proceeds significantly faster than formation of pyridine
ring under reaction conditions.
However, compounds 4 can be obtained in 61−72%
yields by the reaction between 2-amino-4-acyl-6-chloro-
0009-3122/17/53(02)-0230©2017 Springer Science+Business Media New York
230

Chemistry of Heterocyclic Compounds 2017, 53(2), 230–235
Scheme 1
Table 1. Substituents and yields of alkyl 3,6-diamino-4-aroyl-
5-cyanothieno[2,3-b]pyridine-2-carboxylates 2a–h
Yield, %
Оne-step method* Two-step method**
Com-
pound
R1
R2
Ph
Me
Et
64
67
76
73
79
77
68
65
44
43
38
41
47
49
32
37
2a
2b
2c
2d
2e
2f
Ph
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
2-Thienyl
2-Thienyl
Me
Et
Me
Et
Me
Et
2g
2h
* ATCN 1 (10 mmol), mercaptoacetic ester 3 (15 mmol), pyridine
(10 ml), reflux, 2.5–3 h.
** 1) Pyridine 4 (10 mmol), mercaptoacetic ester 3 (10 mmol), Et3N
(10 mmol), 1,4-dioxane (10 ml), rt, 5–10 min; 2) compound 4 (5 mmol),
Et3N (7 mmol), 1,4-dioxane (10 ml), reflux, 30 min. Yields are given for
the conversion of compounds 1 to compounds 2.
Figure 1. Molecular structure of compound 2f with atoms repre-
sented by thermal vibration ellipsoids of 50% probability.
In conclusion, the novel methyl/ethyl 3,6-diamino-
4-aroyl-5-cyanothieno[2,3-b]pyridine-2-carboxylates were
obtained via two routes. The one-step synthesis via
refluxing a mixture of 2-acyl-1,1,3,3-tetracyanopropenides
with thioglycolates is a more convenient procedure due to
the exclusion of isolation of intermediates, which
positively affects the yield. Due to their structure, the
obtained thieno[2,3-b]pyridines may be interesting in the
targeted synthesis of biologically active compounds.
pyridine-3,5-dicarbonitriles 517 and thioglycolates 3 in the
presence of Et3N (Scheme 1). This reaction was carried out
in order to characterize compounds 4a–h. Compounds 4a–h
can be readily transformed to thieno[2,3-b]pyridines 2a–h
by refluxing in 1,4-dioxane for ~30 min in the presence of
Et3N (Table 1).
The structure of compound 2f was established by single
crystal X-ray diffraction analysis (Fig. 1). The crystal is tri-
clinic with the space group P-1. Intramolecular hydrogen bond
lengths are 2.943 (N(4)···O(1)) and 2.788 Å (N(4)···O(3)).
Each of the two molecules in the unit is connected into a centro-
symmetric dimer via two intermolecular N(1)···H–N(2i)
hydrogen bonds with lengths 3.061 Å; symmetry codes:
(i) 1 – x, 2 – y, –z.
Experimental
IR spectra were recorded in samples dispersed in
mineral oil on a OKB Spectr FTIR spectrophotometer
1
FSM-1202. Н and 13C NMR spectra were registered on a
Bruker Avance III HD spectrometer (400 and 100 МHz,
respectively) in DMSO-d6, internal standard was TMS.
231

Chemistry of Heterocyclic Compounds 2017, 53(2), 230–235
Mass spectra were recorded on a Finnigan МАТ INCOS-50
C 58.85; H 3.87; N 15.18. C18H14N4O3S. Calculated, %:
instrument (electron impact energy 70 eV). Elemental
analysis was performed on a varioMICROcube CHN-
analyzer. Melting points were determined using an Electro-
thermal IA 9000 series II apparatus. The reaction progress
and purity of the obtained compounds were controlled by
TLC on Sorbfil PTSH-AF-A-UF plates (eluent EtOAc),
visualization under UV light, with iodine vapor, or thermal
decomposition.
C 59.01; H 3.85; N 15.29.
Methyl 3,6-diamino-5-cyano-4-(4-methylbenzoyl)thieno-
[2,3-b]pyridine-2-carboxylate (2c). Yield 76% (method I),
38% (method II), yellow powder, mp 271–272°С (decomp.).
IR spectrum, ν, cm–1: 3336 (NH2), 3269 (NH2), 2218 (CN),
1
1746 (CO2Me), 1670 (COAr). H NMR spectrum, δ, ppm
(J, Hz): 2.41 (3H, s, CH3); 3.71 (3H, s, OCH3); 5.82 (2H, s,
NH2); 7.41 (2Н, d, J = 8.0, H Ar); 7.71 (2Н, br. s, NH2);
7.80 (2Н, d, J = 8.1, H Ar). 13C NMR spectrum, δ, ppm:
22.0; 51.9; 86.6; 92.1; 112.3; 115.1; 130.6; 130.8; 132.2;
147.4; 147.7; 150.0; 158.9; 164.8; 165.7; 193.0. Mass
spectrum, m/z (Irel, %): 366 [M]+ (21), 351 [M–CH3]+ (6),
335 [M–CH3O]+ (5), 291 (19), 119 [CH3C6H4CO]+ (43), 91
[CH3C6H4]+ (100). Found, %: C 58.89; H 3.88; N 15.20.
C18H14N4O3S. Calculated, %: C 59.01; H 3.85; N 15.29.
Ethyl 3,6-diamino-5-cyano-4-(4-methylbenzoyl)thieno-
[2,3-b]pyridine-2-carboxylate (2d). Yield 73% (method I),
41% (method II), yellow powder, mp 252–253°С (decomp.).
IR spectrum, ν, cm–1: 3328 (NH2), 3289 (NH2), 2213 (CN),
Synthesis of alkyl 3,6-diamino-4-aroyl-5-cyanothieno-
[2,3-b]pyridine-2-carboxylates 2a–h (General methods).
Method I: one-step. Potassium ATCN 1a–d (10 mmol) and
mercaptoacetic ester 3a,b (15 mmol) were dissolved in
pyridine (10 ml). The reaction mixture was refluxed for
2.5–3 h (TLC control), then cooled and poured into
saturated aqueous KCl (50 ml). The dark-orange precipitate
was filtered off, recrystallized from AcOH, and dried in
vacuo.
Method II: two-step. 4-Acyl-2-amino-6-chloropyridine-
3,5-dicarbonitrile 5a–d (10 mmol), prepared by a published
method,17 mercaptoacetic ester 3a,b (10 mmol), and Et3N
(1.0 g, 10 mmol) were dissolved in 1,4-dioxane (10 ml).
The reaction mixture was stirred at room temperature for
5–10 min (TLC control), then poured into water (30 ml).
The white alkyl 2-[(6-amino-4-aroyl-3,5-dicyanopyridin-
2-yl)sulfanyl]acetate 4a–h was filtered off, recrystallized
from AcOH–H2O, 1:1, and dried in vacuo. Compound 4a–h
(5 mmol) and Et3N (0.7 g, 7.0 mmol) were dissolved in
1,4-dioxane (10 ml). The reaction mixture was refluxed for
30 min (TLC control), then cooled and poured into water
(30 ml). The dark-orange precipitate 2a–h was filtered off,
recrystallized from AcOH, and dried in vacuo.
1
1739 (CO2Et), 1666 (COAr). H NMR spectrum, δ, ppm
(J, Hz): 1.21 (3H, t, J = 7.1, CH3); 2.40 (3H, s, CH3); 4.18
(2Н, q, J = 7.0, OCH2); 5.81 (2H, s, NH2); 7.41 (2Н, d,
J = 8.0, H Ar); 7.71 (2Н, br. s, NH2); 7.80 (2Н, d, J = 8.0,
H Ar). 13C NMR spectrum, δ, ppm: 14.8; 21.9; 60.6; 86.6;
92.5; 112.4; 115.1; 130.6; 130.8; 132.2; 147.3; 147.7;
149.9; 158.9; 164.5; 165.7; 193.1. Mass spectrum, m/z (Irel, %):
380 [M]+ (65), 352 [M–C2H4]+ (12), 335 [M–C2H5O]+ (5),
305 (37), 119 [CH3C6H4CO]+ (54), 91 [CH3C6H4]+ (100).
Found, %: C 59.86; H 4.26; N 14.63. C19H16N4O3S.
Calculated, %: C 59.99; H 4.24; N 14.73.
Methyl 3,6-diamino-5-cyano-4-(4-methoxybenzoyl)-
thieno[2,3-b]pyridine-2-carboxylate (2e). Yield 79%
(method I), 47% (method II), orange powder, mp 275–
276°С (decomp.). IR spectrum, ν, cm–1: 3331 (NH2), 3292
(NH2), 2224 (CN), 1751 (CO2Me), 1682 (COAr). 1H NMR
spectrum, δ, ppm (J, Hz): 3.71 (3H, s, OCH3); 3.87 (3H, s,
OCH3); 5.84 (2H, s, NH2); 7.12 (2Н, d, J = 8.9, H Ar); 7.68
(2Н, br. s, NH2); 7.87 (2Н, d, J = 8.5, H Ar). 13C NMR
spectrum, δ, ppm: 51.9; 56.4; 86.7; 91.9; 112.2; 115.1;
115.4; 127.6; 133.4; 147.4; 150.1; 158.9; 164.8; 165.7;
165.8; 191.5. Mass spectrum, m/z (Irel, %): 382 [M]+ (20),
367 [M–CH3]+ (9), 351 [M–CH3O]+ (7), 307 (28), 135
[CH3OC6H4CO]+ (37), 107 [CH3OC6H4]+ (100). Found, %:
C 56.39; H 3.72; N 14.52. C18H14N4O4S. Calculated, %:
C 56.54; H 3.69; N 14.65.
Methyl 3,6-diamino-4-benzoyl-5-cyanothieno[2,3-b]-
pyridine-2-carboxylate (2a). Yield 64% (method I), 44%
(method II), orange powder, mp 258–259°С (decomp.).
IR spectrum, ν, cm–1: 3343 (NH2), 3279 (NH2), 2221 (CN),
1
1752 (CO2Me), 1672 (COAr). H NMR spectrum, δ, ppm
(J, Hz): 3.71 (3H, s, OCH3); 5.83 (2H, s, NH2); 7.61 (2Н, t,
J = 7.2, H Ph); 7.73 (2Н, br. s, NH2); 7.81 (1Н, t, J = 6.7,
H Ph); 7.91 (2Н, d, J = 7.3, H Ph). 13C NMR spectrum,
δ, ppm: 51.9; 86.6; 92.3; 112.3; 115.0; 130.0; 130.6; 134.6;
136.5; 147.4; 149.8; 158.9; 164.8; 165.8; 193.7. Mass
spectrum, m/z (Irel, %): 352 [M]+ (24), 337 [M–CH3]+ (7),
321 [M–CH3O]+ (6), 277 (23), 105 [C6H5CO]+ (42), 77
[C6H5]+ (100). Found, %: C 57.99; H 3.45; N 15.86.
C17H12N4O3S. Calculated, %: C 57.95; H 3.43; N 15.90.
Ethyl
3,6-diamino-4-benzoyl-5-cyanothieno[2,3-b]-
Ethyl
3,6-diamino-5-cyano-4-(4-methoxybenzoyl)-
pyridine-2-carboxylate (2b). Yield 67% (method I), 43%
(method II), orange powder, mp 234–236°С (decomp.).
IR spectrum, ν, cm–1: 3339 (NH2), 3286 (NH2), 2227 (CN),
thieno[2,3-b]pyridine-2-carboxylate (2f). Yield 77%
(method I), 49% (method II), yellow powder, mp 238–
239°С (decomp.). IR spectrum, ν, cm–1: 3334 (NH2), 3286
1
1
1758 (CO2Et), 1664 (COAr). H NMR spectrum, δ, ppm
(NH2), 2230 (CN), 1748 (CO2Et), 1681 (COAr). H NMR
(J, Hz): 1.22 (3H, t, J = 7.1, CH3); 4.19 (2Н, q, J = 7.1,
OCH2); 5.82 (2H, s, NH2); 7.61 (2Н, t, J = 7.8, H Ph); 7.72
(2Н, br. s, NH2); 7.80 (1Н, t, J = 7.4, H Ph); 7.90 (2Н, d,
J = 7.4, H Ph). 13C NMR spectrum, δ, ppm: 14.8; 60.6;
86.9; 92.6; 112.4; 115.0; 130.0; 130.6; 134.6; 136.4; 147.3;
149.7; 158.8; 164.5; 165.7; 193.7. Mass spectrum, m/z (Irel, %):
366 [M]+ (26), 338 [M–C2H4]+ (8), 321 [M–C2H5O]+ (5),
291 (21), 105 [C6H5CO]+ (46), 77 [C6H5]+ (100). Found, %:
spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.1, CH3); 3.87
(3H, s, OCH3); 4.18 (2H, q, J = 7.1, OCH2); 5.82 (2H, s,
NH2); 7.11 (2Н, d, J = 8.9, H Ar); 7.68 (2Н, br. s, NH2);
7.87 (2Н, d, J = 8.5, H Ar). 13C NMR spectrum, δ, ppm:
14.8; 56.4; 60.5; 86.7; 92.3; 112.3; 115.1; 115.4; 127.6;
133.4; 147.3; 150.1; 158.9; 164.5; 165.7; 165.8; 191.5.
Mass spectrum, m/z (Irel, %): 396 [M]+ (54), 368 [M–C2H4]+
(6), 351 [M–C2H5O]+ (4), 321 (15), 135 [CH3OC6H4CO]+
232

Chemistry of Heterocyclic Compounds 2017, 53(2), 230–235
(51), 107 [CH3OC6H4]+ (100). Found, %: C 57.46; H 4.08;
(10), 279 [M–CH2CO2C2H5]+ (23), 105 [C6H5CO]+ (100),
77 [C6H5]+ (21). Found, %: C 58.85; H 3.87; N 15.17.
C18H14N4O3S. Calculated, %: C 59.01; H 3.85; N 15.29.
Methyl 2-{[6-amino-3,5-dicyano-4-(4-methylbenzoyl)-
pyridin-2-yl]sulfanyl}acetate (4c). Yield 61%, white
powder, mp 183–184°С. IR spectrum, ν, cm–1: 3322 (NH2),
3231 (NH2), 2218 (CN), 1761 (CO2Me), 1632 (COAr).
1H NMR spectrum, δ, ppm (J, Hz): 2.42 (3H, s, CH3); 3.69
(3H, s, OCH3); 4.21 (2H, s, SCH2); 7.43 (2Н, d, J = 8.1,
H Ar); 7.85 (2Н, d, J = 8.2, H Ar); 8.32 (2H, br. s, NH2).
13C NMR spectrum, δ, ppm: 21.9; 32.2; 53.1; 83.5; 90.0;
114.2; 114.3; 130.6; 130.7; 131.1; 147.7; 157.1; 159.5;
166.4; 168.8; 190.8. Mass spectrum, m/z (Irel, %): 366 [M]+
(49), 351 [M–CH3]+ (10), 293 [M–CH2CO2CH3]+ (14), 119
[CH3C6H4]+ (100), 91 [CH3C6H4]+ (22). Found, %:
C 59.06; H 3.88; N 15.20. C18H14N4O3S. Calculated, %:
C 59.01; H 3.85; N 15.29.
Ethyl 2-{[6-amino-3,5-dicyano-4-(4-methylbenzoyl)-
pyridin-2-yl]sulfanyl}acetate (4d). Yield 63%, white
powder, mp 165–166°С. IR spectrum, ν, cm–1: 3335 (NH2),
3236 (NH2), 2224 (CN), 1758 (CO2Et), 1639 (COAr).
1H NMR spectrum, δ, ppm (J, Hz): 1.21 (3H, t, J = 7.1,
CH3); 2.42 (3H, s, CH3); 4.14 (2H, q, J = 7.1, OCH2); 4.20
(2H, s, SCH2); 7.43 (2Н, d, J = 8.0, H Ar); 7.83 (2Н, d,
J = 8.1, H Ar); 8.29 (2H, br. s, NH2). 13C NMR spectrum,
δ, ppm: 14.5; 21.9; 32.4; 61.9; 83.5; 90.0; 114.2; 114.3;
130.6; 130.7; 131.2; 147.7; 157.1; 159.5; 166.5; 168.3;
190.8. Mass spectrum, m/z (Irel, %): 380 [M]+ (52), 351
[M–C2H4]+ (12), 293 [M–CH2CO2C2H5]+ (21), 119 [CH3C6H4]+
(100), 91 [CH3C6H4]+ (26). Found, %: C 59.79; H 4.27;
N 14.62. C19H16N4O3S. Calculated, %: C 59.99; H 4.24;
N 14.73.
Methyl 2-{[6-amino-3,5-dicyano-4-(4-methoxybenzoyl)-
pyridin-2-yl]sulfanyl}acetate (4e). Yield 71%, white
powder, mp 139–140°С. IR spectrum, ν, cm–1: 3334 (NH2),
3238 (NH2), 2226 (CN), 1752 (CO2Me), 1629 (COAr).
1H NMR spectrum, δ, ppm (J, Hz): 3.68 (3H, s, OCH3);
3.89 (3H, s, OCH3); 4.21 (2H, s, SCH2); 7.13 (2Н, d,
J = 8.8, H Ar); 7.90 (2Н, d, J = 8.7, H Ar); 8.28 (2H, br. s,
NH2). 13C NMR spectrum, δ, ppm: 32.2; 53.1; 56.4; 83.5;
90.0; 114.2; 114.4; 115.5; 126.5; 133.2; 157.4; 159.5;
165.8; 166.3; 168.9; 189.3. Mass spectrum, m/z (Irel, %):
382 [M]+ (56), 367 [M–CH3]+ (16), 309 [M–CH2CO2CH3]+
(19), 135 [CH3OC6H4CO]+ (100), 107 [CH3OC6H4]+ (12).
Found, %: C 56.38; H 3.72; N 14.51. C18H14N4O4S.
Calculated, %: C 56.54; H 3.69; N 14.65.
N 14.04. C19H16N4O4S. Calculated, %: C 57.57; H 4.07;
N 14.13.
Methyl 3,6-diamino-5-cyano-4-(thiophene-2-carbonyl)-
thieno[2,3-b]pyridine-2-carboxylate (2g). Yield 68%
(method I), 32% (method II), orange powder, mp 243–
244°С (decomp.). IR spectrum, ν, cm–1: 3343 (NH2), 3266
(NH2), 2225 (CN), 1741 (CO2Me), 1662 (COAr). 1H NMR
spectrum, δ, ppm (J, Hz): 3.72 (3H, s, OCH3); 5.93 (2H, s,
NH2); 7.30 (1Н, t, J = 4.4, H thienyl); 7.72 (2Н, s, NH2);
7.82 (1Н, d, J = 3.9, H thienyl); 8.37 (1Н, d, J = 4.8,
H thienyl). 13C NMR spectrum, δ, ppm: 51.9; 87.0; 92.2;
112.0; 115.1; 130.4; 140.2; 140.9; 141.3; 147.3; 148.8;
158.9; 164.8; 165.8; 185.1. Mass spectrum, m/z (Irel, %):
358 [M]+ (29), 343 [M–CH3]+ (10), 327 [M–CH3O]+ (8),
283 (19), 111 [C5H3SCO]+ (51), 83 [C5H3S]+ (100). Found, %:
C 50.17; H 2.83; N 15.49. C15H10N4O3S2. Calculated, %:
C 50.27; H 2.81; N 15.63.
Ethyl 3,6-diamino-5-cyano-4-(thiophene-2-carbonyl)-
thieno[2,3-b]pyridine-2-carboxylate (2h). Yield 65%
(method I), 37% (method II), yellow powder, mp 234–
235°С (decomp.). IR spectrum, ν, cm–1: 3334 (NH2), 3270
1
(NH2), 2228 (CN), 1749 (CO2Et), 1671 (COAr). H NMR
spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.1, CH3); 4.19
(2H, q, J = 7.1, OCH2); 5.91 (2H, s, NH2); 7.23–7.35 (1Н,
m, H thienyl); 7.72 (2Н, br. s, NH2); 7.81 (1Н, d, J = 3.1,
H thienyl); 8.37 (1Н, d, J = 4.8, H thienyl). 13C NMR
spectrum, δ, ppm: 14.8; 60.6; 87.0; 92.6; 112.1; 115.1;
130.4; 140.1; 140.9; 141.3; 147.2; 148.8; 158.9; 164.5;
165.8; 185.1. Mass spectrum, m/z (Irel, %): 372 [M]+ (51),
344 [M–C2H4]+ (9), 327 [M–C2H5O]+ (6), 297 (19), 110
[C5H3SCO]+ (56), 83 [C5H3S]+ (100). Found, %: C 51.50;
H 3.27; N 14.94. C19H12N4O3S2. Calculated, %: C 51.60;
H 3.25; N 15.04.
Methyl 2-[(6-amino-4-benzoyl-3,5-dicyanopyridin-2-yl)-
sulfanyl]acetate (4a). Yield 69%, white powder, mp 209–
210°С. IR spectrum, ν, cm–1: 3330 (NH2), 3226 (NH2),
2223 (CN), 1751 (CO2Me), 1632 (COAr). 1H NMR
spectrum, δ, ppm (J, Hz): 3.69 (3H, s, OCH3); 4.22 (2H, s,
SCH2); 7.63 (2Н, t, J = 7.8, H Ph); 7.82 (1Н, t, J = 7.4,
H Ph); 7.95 (2Н, d, J = 7.4, H Ph); 8.33 (2H, br. s, NH2).
13C NMR spectrum, δ, ppm: 32.2; 53.1; 83.5; 89.9; 114.1;
114.3; 130.1; 130.5; 133.5; 136.5; 156.8; 159.5; 166.4;
168.8; 191.4. Mass spectrum, m/z (Irel, %): 352 [M]+ (52),
337 [M–CH3]+ (13), 279 [M–CH2CO2CH3]+ (17), 105
[C6H5CO]+ (100), 77 [C6H5]+ (19). Found, %: C 57.99;
H 3.46; N 15.87. C17H12N4O3S. Calculated, %: C 57.95;
H 3.43; N 15.90.
Ethyl 2-[(6-amino-4-benzoyl-3,5-dicyanopyridin-2-yl)-
sulfanyl]acetate (4b). Yield 64%, white powder, mp 161–
162°С. IR spectrum, ν, cm–1: 3329 (NH2), 3233 (NH2),
2219 (CN), 1760 (CO2Et), 1634 (COAr). 1H NMR
spectrum, δ, ppm (J, Hz): 1.21 (3H, t, J = 7.1, CH3); 4.13
(2H, q, J = 7.0, OCH2); 4.21 (2H, s, SCH2); 7.63 (2Н, t,
J = 7.7, H Ph); 7.82 (1Н, t, J = 7.4, H Ph); 7.94 (2Н, d,
J=7.7, H Ph); 8.32 (2H, br. s, NH2). 13C NMR spectrum,
δ, ppm: 14.5; 32.4; 61.9; 83.5; 90.0; 114.1; 114.3; 130.1;
130.5; 133.5; 136.5; 156.9; 159.5; 166.5; 168.2; 191.4.
Mass spectrum, m/z (Irel, %): 366 [M]+ (48), 337 [M–C2H4]+
Ethyl 2-{[6-amino-3,5-dicyano-4-(4-methoxybenzoyl)-
pyridin-2-yl]sulfanyl}acetate (4f). Yield 72%, white powder,
mp 122–123°С. IR spectrum, ν, cm–1: 3331 (NH2), 3239
1
(NH2), 2220 (CN), 1757 (CO2Et), 1630 (COAr). H NMR
spectrum, δ, ppm (J, Hz): 1.21 (3H, t, J = 7.1, CH3); 3.89
(3H, s, OCH3); 4.14 (2H, q, J = 7.1, OCH2); 4.20 (2H, s,
SCH2); 7.13 (2Н, d, J = 8.9, H Ar); 7.90 (2Н, d, J = 8.8,
H Ar); 8.28 (2H, br. s, NH2). 13C NMR spectrum, δ, ppm:
14.5; 32.4; 56.4; 61.9; 83.5; 90.1; 114.2; 114.4; 115.5;
126.5; 133.2; 157.4; 159.5; 165.8; 166.4; 168.3; 189.3.
Mass spectrum, m/z (Irel, %): 396 [M]+ (51), 367 [M–C2H4]+
(9), 309 [M–CH2CO2C2H5]+ (17), 135 [CH3OC6H4CO]+
(100), 107 [CH3OC6H4]+ (25). Found, %: C 57.40; H 4.09;
233

Chemistry of Heterocyclic Compounds 2017, 53(2), 230–235
N 14.04. C19H16N4O4S. Calculated, %: C 57.57; H 4.07;
N 14.13.
Methyl 2-{[6-amino-3,5-dicyano-4-(thiophene-2-carbonyl)-
were performed with the SHELX program, and the
molecular graphics were prepared by using the
DIAMOND19 software. The complete X-ray structural data
set for compound 2f was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1502502).
pyridin-2-yl]sulfanyl}acetate (4g). Yield 64%, white
powder, mp 119–120°С. IR spectrum, ν, cm–1: 3336 (NH2),
3229 (NH2), 2217 (CN), 1760 (CO2Me), 1636 (COAr).
1H NMR spectrum, δ, ppm (J, Hz): 3.68 (3H, s, OCH3);
4.21 (2H, s, SCH2); 7.34 (1Н, t, J = 4.4, H thienyl); 7.97
(1Н, d, J = 3.7, H thienyl); 8.30 (2H, br. s, NH2); 8.36 (1Н,
d, J = 4.8, H thienyl). 13C NMR spectrum, δ, ppm: 32.2;
53.1; 83.6; 90.0; 114.1; 114.3; 130.4; 140.0; 140.2; 140.7;
156.1; 159.5; 166.4; 168.8; 183.0. Mass spectrum, m/z (Irel, %):
358 [M]+ (51), 343 [M–CH3]+ (15), 284 [M–CH2CO2CH3]+
(21), 111 [C5H3SCO]+ (100), 83 [C5H3S]+ (9). Found, %:
C 50.16; H 2.83; N 15.52. C15H10N4O3S2. Calculated, %:
C 50.27; H 2.81; N 15.63.
This work was supported by the Russian Foundation for
Basic Research (research project No. 15-33-21087
'mol_a_ved'). The X-ray study was supported in part by
Lomonosov Moscow State University Program of
Development.
References
1. (a) Willemann, C.; Grünert, R.; Bednarski, P. J.; Troschütz, R.
Bioorg. Med. Chem. 2009, 17, 4406. (b) Zeng, X.-X.;
Zheng, R.-L.; Zhou, T.; He, H.-Y.; Liu, J.-Y.; Zheng, Y.;
Tong, A.-P.; Xiang, M.-L.; Song, X.-R.; Yang, S.-Y.; Yu, L.-T.;
Wei, Y.-Q.; Zhao, Y.-L.; Yang, L. Bioorg. Med. Chem. Lett.
2010, 20, 6282. (c) Sleebs, B. E.; Levit, A.; Street, I. P.; Falk, H.;
Hammonds, T.; Wong, A. C.; Charles, M. D.; Olson, M. F.;
Baell, J. B. MedChemComm 2011, 2, 977. (d) Pevet, I.; Brulé, C.;
Tizot, A.; Gohier, A.; Cruzalegui, F.; Boutin, J. A.; Goldstein, S.
Bioorg. Med. Chem. 2011, 19, 2517. (e) Dai, X.-Y.; Zeng, X.-X.;
Peng, F.; Han, Y.-Y.; Lin, H.-J.; Xu, Y.-Z.; Zhou, T.; Xie, G.;
Deng, Y.; Mao, Y.-Q.; Yu, L.-T.; Yang, L.; Zhao, Y.-L. Cell.
Physiol. Biochem. 2012, 29, 281. (f) Feng, L.; Reynisdóttir, I.;
Reynisson, J. Eur. J. Med. Chem. 2012, 54, 463.
(g) Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Preti, D.;
Tabrizi, M. A.; Bassetto, M.; Brancale, A.; Hamel, E.;
Castagliuolo, I.; Bortolozzi, R.; Basso, G.; Viola, G. J. Med.
Chem. 2013, 56, 2606. (h) Arabshahi, H. J.; Leung, E.;
Barker, D.; Reynisson, J. MedChemComm 2014, 5, 186.
(i) Hung, J. M.; Arabshahi, H. J., Leung, E.; Reynisson, J.;
Barker, D. Eur. J. Med. Chem. 2014, 86, 420. (j) Leung, E.;
Hung, J. M.; Barker, D.; Reynisson, J. MedChemComm 2014,
5, 99. (k) 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.;
Reynisson, J. MedChemComm 2015, 6, 1987.
2. (a) Tumey, L. N.; Boschelli, D. H.; Lee, J.; Chaudhary, D.
Bioorg. Med. Chem. Lett. 2008, 18, 4420. (b) Boschelli, D. H.;
Wu, B.; Barrios Sosa, A. C.; Chen, J.; Asselin, M.; Cole, D. C.;
Lee, J.; Yang, X.; Chaudhary, D. Bioorg. Med. Chem. Lett.
2008, 18, 2850. (c) Madhusudana, K.; Shireesha, B.; Modi
Naidu, V. G.; Ramakrishna, S.; Narsaiah, B.; Rao, A. R.;
Diwan, P. V. Eur. J. Pharmacol. 2012, 678, 48. (d) Liu, H.;
Li, Y.; Wang, X.-Y.; Wang, B.; He, H.-Y.; Liu, J.-Y.;
Xiang, M.-L.; He, J.; Wu, X.-H.; Yang, L. Bioorg. Med.
Chem. Lett. 2013, 23, 2349.
3. (a) Schnute, M. E.; Anderson, D. J.; Brideau, R. J.; Ciske, F. L.;
Collier, S. A.; Cudahy, M. M.; Eggen, M.; Genin, M. J.;
Hopkins, T. A.; Judge, T. M.; Kim, E. J.; Knechtel, M. L.;
Nair, S. K.; Nieman, J. A.; Oien, N. L.; Scott, A.; Tanis, S. P.;
Vaillancourt, V. A.; Wathen, M. W.; Wieber, J. L. Bioorg.
Med. Chem. Lett. 2007, 17, 3349. (b) Wang, N.-Y.; Zuo, W.-Q.;
Xu, Y.; Gao, C.; Zeng, X.-X.; Zhang, L.-D.; You, X.-Y.;
Peng, C.-T.; Shen, Y.; Yang, S.-Y.; Wei, Y.-Q.; Yu, L.-T.
Bioorg. Med. Chem. Lett. 2014, 24, 1581.
Ethyl 2-{[6-amino-3,5-dicyano-4-(thiophene-2-carbonyl)-
pyridin-2-yl]sulfanyl}acetate (4h). Yield 71%, white
powder, mp 107–108°С. IR spectrum, ν, cm–1: 3331 (NH2),
3230 (NH2), 2219 (CN), 1758 (CO2Me), 1634 (COAr).
1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.2,
CH3); 4.16 (2H, q, J = 7.2, OCH2); 4.22 (2H, s, SCH2);
7.36 (1Н, t, J = 4.3, H thienyl); 7.97 (1Н, d, J = 3.9,
H thienyl); 8.33 (2H, br. s, NH2); 8.37 (1Н, d, J = 4.7,
H thienyl). 13C NMR spectrum, δ, ppm: 14.5; 32.4; 61.9;
83.6; 90.1; 114.1; 114.3; 130.4; 139.9; 140.2; 140.6; 156.1;
159.5; 166.5; 168.2; 183.0. Mass spectrum, m/z (Irel, %):
372 [M]+ (48), 344 [M–C2H4]+ (12), 285 [M–CH2CO2C2H5]+
(19), 111 [C5H3SCO]+ (100), 83 [C5H3S]+ (8). Found, %:
C 51.52; H 3.26; N 15.06. C16H12N4O3S2. Calculated, %:
C 51.60; H 3.25; N 15.04.
2-Amino-6-chloro-4-(thiophene-2-carbonyl)pyridine-
3,5-dicarbonitrile (5d). Yield 76%, white powder, mp 255–
257 °С (decomp.). IR spectrum, ν, cm–1: 3211 (NH2); 2217
1
(C≡N); 1662 (C=O). H NMR spectrum, δ, ppm (J, Hz):
7.38 (1H, dd, J = 4.2, J = 4.8, H Ar); 8.05 (1H, d, J = 3.8,
H Ar); 8.40 (1H, d, J = 4.8, H Ar); 8.45 (1H, br. s) and 8.97
(1H, br. s, NH2). 13C NMR spectrum, δ, ppm: 87.1; 96.2;
113.6; 115.3; 130.4; 138.0; 140.6; 141.0; 148.3; 157.2;
160.2; 182.3. Mass spectrum, m/z (Irel, %): 290 [М(37Cl)]+
(5), 288 [М(35Cl)]+ (14), 111 [C4H3SCO]+ (100), 116 (12),
83 [C4H3S]+ (11). Found,%: C 49.98; H 1.79; N 19.51.
C12H5ClN4OS. Calculated, %: C 49.92; H 1.75; N 19.41.
X-ray structural investigation of compound 2f.
A syngle crystal of compound 2f for X-ray diffraction
purposes was obtained by slow evaporation of acetic acid
solution in air at room temperature. The X-ray data of
compound 2f collected by using a STOE diffractometer
Pilatus100K detector, focusing mirror collimation, CuKα
(1.54086 Å) radiation, rotation method mode. The STOE
X-AREA 1.67 software was used for unit refinement and
data reduction, as well as for the data collection and image
processing. Intensity data were scaled with the LANA
program (part of X-Area package) in order to minimize
differences of intensities of symmetry-equivalent
reflections (multiscan method). The structures were solved
and refined with the SHELX18 program. The non-hydrogen
atoms were refined by using the anisotropic full-matrix
least-square procedure. Molecular geometry calculations
4. (a) Rolim Bernardino, A. M.; da Silva Pinheiro, L. C.; Rangel
Rodrigues, C..; Loureiro, N. I.; Castro, H. C.; Lanfredi-
Rangel, A.; Sabatini-Lopes, J.; Borges, J. C.; Carvalho, J. M.;
Alves Romeiro, G.; Ferreira, V. F.; Frugulhetti, I. C. P. P.;
Vannier-Santos, M. A. Bioorg. Med. Chem. 2006, 14, 5765.
(b) Al-Trawneh, S. A.; El-Abadelah, M. M.; Zahra, J. A.;
234

Chemistry of Heterocyclic Compounds 2017, 53(2), 230–235
Al-Taweel, S. A.; Zani, F.; Incerti, M.; Cavazzoni, A.; Vicini, P.
10. Krauze, A.; Grinberga, S.; Krasnova, L.; Adlere, I.; Sokolova, E.;
Domracheva, I.; Shestakova, I.; Andzans, Z.; Duburs, G.
Bioorg. Med. Chem. 2014, 22, 5860.
11. Nógrádi, K.; Wágner, G.; Domány, G.; Bobok, A.; Magdó, I.;
Kolok, S.; Mikó-Bakk, M.; Vastag, M.; Sághy, K.; Gyertyán, I.;
Kóti, J.; Gál, K.; Farkas, S.; Keserű, G. M.; Greiner, I.;
Szombathelyi, Z. Bioorg. Med. Chem. Lett. 2015, 25, 1724.
12. Bondarenko, S. P.; Zhitnetskyi, I. V.; Semenov, S. V.;
Frasinyuk, M. S. Chem. Heterocycl. Compd. 2016, 52, 262.
[Khim. Geterotsikl. Soedin. 2016, 262.]
13. Karpov, S. V.; Grigor'ev, A. A.; Kayukov, Ya. S.; Karpova, I. V.;
Nasakin, O. E.; Tafeenko, V. A. J. Org. Chem. 2016, 81, 6402.
14. Kayukov, Ya. S.; Bardasov, I. N.; Karpov, S. V.; Ershov, O. V.;
Nasakin, O. E.; Kayukova, O. V.; Tafeenko, V. A. Russ.
J. Org. Chem. 2012, 48, 1447. [Zh. Org. Khim. 2012,
48, 1463.]
15. Grigor'ev, A. A.; Karpov, S. V.; Kayukov, Ya. S.;
Belikov, M. Yu.; Nasakin, O. E. Tetrahedron Lett. 2015, 56,
6279.
16. Karpov, S. V.; Kayukov, Ya. S.; Bardasov, I. N.; Ershov, O. V.;
Nasakin, O. E.; Kayukova, O. V. Russ. J. Org. Chem. 2011,
47, 1161. [Zh. Org. Khim. 2011, 47, 1144.]
17. (a) Karpov, S. V.; Kayukov, Ya. S.; Bardasov, I. N.;
Kayukova, O. V.; Lipin, K. V.; Nasakin, O. E. Russ. J. Org.
Chem. 2011, 47, 1492. [Zh. Org. Khim. 2011, 47, 1467.]
(b) Kayukov, Ya. S.; Karpov, S. V.; Kayukova, O. V.;
Ershov, O. V.; Nasakin, O. E. Russ. J. Org. Chem. 2014, 50,
1097. [Zh. Org. Khim. 2014, 50, 1116.]
Bioorg. Med. Chem. 2011, 19, 2541.
5. (a) Bahekar, R. H.; Jain, M. R.; Goel, A.; Patel, D. N.;
Prajapati, V. M.; Gupta, A. A.; Jadav, P. A.; Patel, P. R.
Bioorg. Med. Chem. 2007, 15, 3248. (b) Bahekar, R. H.;
Jain, M. R.; Jadav, P. A.; Prajapati, V. M.; Patel, D. N.;
Gupta, A. A.; Sharma, A.; Tom, R.; Bandyopadhya, D.; Modi, H.;
Patel, P. R. Bioorg. Med. Chem. 2007, 15, 6782.
6. (а) Ohba, S.; Nakajima, K.; Komiyama, Y.; Kugimiya, F.;
Igawa, K.; Itaka, K.; Moro, T.; Nakamura, K.; Kawaguchi, H.;
Takato, T.; Chung, U. Biochem. Biophys. Res. Commun.
2007, 357, 854. (b) Saito, K.; Nakao, A.; Shinozuka, T.;
Shimada, K.; Matsui, S.; Oizumi, K.; Yano, K.; Ohata, K.;
Nakai, D.; Nagai, Y.; Naito, S. Bioorg. Med. Chem. 2013, 21,
1628.
7. (a) Le, U.; Melancon, B. J.; Bridges, T. M.; Vinson, P. N.;
Utley, T. J.; Lamsal, A.; Rodriguez, A. L.; Venable, D.;
Sheffler, D. J.; Jones, C. K.; Blobaum, A. L.; Wood, M. R.;
Daniels, J. S.; Conn, P. J.; Niswender, C. M.; Lindsley, C. W.;
Hopkins, C. R. Bioorg. Med. Chem. Lett. 2013, 23, 346.
(b) Szabo, M.; Herenbrink, C. K.; Christopoulos, A.; Lane, J. R.;
Capuano, B. J. Med. Chem. 2014, 57, 4924. (c) Szabo, M.;
Huynh, T.; Valant, C.; Lane, J. R.; Sexton, P. M.;
Christopoulos, A.; Capuano, B. MedChemComm 2015, 6, 1998.
8. Mohler, E. G.; Shacham, S.; Noiman, S.; Lezoualc'h, F.;
Robert, S.; Gastineau, M.; Rutkowski, J.; Marantz, Y.;
Dumuis, A.; Bockaert, J.; Gold, P. E.; Ragozzino, M. E.
Neuropharmacol. 2007, 53, 563.
9. (a) Leonczak, P.; Gao, L.-J.; Ramadori, A. T.; Lescrinier, E.;
Rozenski, J.; De Jonghe, S.; Herdewijn, P. ChemMedChem.
2014, 9, 2587. (b) Gao, L.-J.; Kovackova, S.; Šála, M.;
Ramadori, A. T.; De Jonghe, S.; Herdewijn, P. J. Med. Chem.
2014, 57, 7624.
18. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112.
19. Putz, H.; Brandenburg, K. Diamond – Crystal and Molecular
Structure Visualization; Release 2.1d; Crystal Impact –GbR:
Bonn, 2000. http://www.crystalimpact.com/diamond
235