Multicomponent Synthesis of 4-Alkyl(Aryl, Hetaryl)-2-alkoxycarbonyl(aroyl, carbamoyl)- 3,6-diamino-5-cyanothieno[2,3-b]pyridines

Article abstract of DOI:10.1134/S1070428018100019

The condensation of malononitrile with hydrogen sulfide and aldehydes in the presence of triethylamine in ethanol at room temperature afforded 4-alkyl(aryl, hetaryl)-2,6-diamino-3,5-dicyano-4H-thiopyrans. Treatment of the latter in situ with alkali in DMF, followed by addition of an alkylating agent, led to the formation of 4-alkyl(aryl, hetaryl)-2-alkoxycarbonyl(aroyl, carbamoyl)-3,6-diamino-5-cyanothieno[2,3-b]- pyridines.

Full text of DOI:10.1134/S1070428018100019

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 10, pp. 1435–1445. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © I.V. Dyachenko, V.D. Dyachenko, P.V. Dorovatovskii, V.N. Khrustalev, V.G. Nenajdenko, 2018, published in Zhurnal Organicheskoi
Khimii, 2018, Vol. 54, No. 10, pp. 1423–1433.
Multicomponent Synthesis
of 4-Alkyl(Aryl, Hetaryl)-2-alkoxycarbonyl(aroyl, carbamoyl)-
3,6-diamino-5-cyanothieno[2,3-b]pyridines
I. V. Dyachenkoa, V. D. Dyachenkoa, P. V. Dorovatovskiib,
V. N. Khrustalevb, c, and V. G. Nenajdenkod*
a Taras Shevchenko Lugansk National University, ul. Oboronnaya 2, Lugansk, 91000 Ukraine
b National Research Center “Kurchatov Institute,” pl. Akademika Kurchatova 1, Moscow, 123182 Russia
c Peoples’Friendship University of Russia, ul. Miklukho-Maklaya 6, Moscow, 117198 Russia
d Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
*e-mail: nenajdenko@gmail.com
Received July 10, 2018
Abstract—The condensation of malononitrile with hydrogen sulfide and aldehydes in the presence of triethyl-
amine in ethanol at room temperature afforded 4-alkyl(aryl, hetaryl)-2,6-diamino-3,5-dicyano-4H-thiopyrans.
Treatment of the latter in situ with alkali in DMF, followed by addition of an alkylating agent, led to the
formation of 4-alkyl(aryl, hetaryl)-2-alkoxycarbonyl(aroyl, carbamoyl)-3,6-diamino-5-cyanothieno[2,3-b]-
pyridines.
DOI: 10.1134/S1070428018100019
Thieno[2,3-b]pyridine derivatives were found to
exhibit antitumor [1] and antiviral activity [2, 3]; some
compounds of this series act as antidermatophytic
agents [4], selective progesterone receptor agonists [5],
and factor 2 kinase (eEF2-K) inhibitors [6]. Thieno-
pyridines are also promising as intermediate products
in the synthesis of non-nucleoside inhibitors of human
cytomegalovirus and related herpes polymerases [7].
Two strategies can be distinguished among numerous
methods of synthesis of thieno[2,3-b]pyridines: thio-
phene annulation onto 2-thioxopyridine and pyridine
ring fusion to 2-aminothiophene [8].
according to Knoevenagel. Michael addition of CH
acid 1 to the activated C=C double bond of condensa-
tion product B yields adduct C which undergoes
chemoselective intramolecular cyclization to 4-alkyl-
(aryl, hetaryl)-2,6-diamino-3,5-dicyano-4H-thiopyran
5a–5m. Recyclization of the latter by the action of
alkali leads to pyridine-2-thiolate D. The subsequent
regioselective alkylation of D at the sulfur atom with
α-halo carbonyl compound 3a–3m affords sulfide E
whose intramolecular cyclization in the presence of
alkali yields thienopyridine 4a–4s. Compounds 4a–4s
are promising intermediate products for the preparation
of fused polycyclic systems [9–11]. The proposed reac-
tion scheme was confirmed by the isolation of inter-
mediate substituted thiopyrans 5a–5m which were syn-
thesized previously by reaction of arylmethylidene-
malononitrile with cyanothioacetamide [12–14].
We have developed a new method of synthesis of
thieno[2,3-b]pyridine derivatives by multicomponent
condensation of malononitrile (1) with hydrogen
sulfide, aldehyde 2a–2m, and α-halo carbonyl com-
pound 3a–3m in the presence of triethylamine. The
reactions were carried out in ethanol at room tempera-
ture, and the products were 4-alkyl(aryl, hetaryl)-2-
alkoxycarbonyl(aroyl, carbamoyl)-3,6-diamino-5-
cyanothieno[2,3-b]pyridines 4a–4s (Scheme 1).
A probable reaction scheme includes initial addition of
hydrogen sulfide to malononitrile (1) to give cyano-
thioacetamide A which reacts with aldehyde 2a–2m
The structures of 2,6-diamino-3,5-dicyano-4-(4-
ethylphenyl)- and 2,6-diamino-3,5-dicyano-4-cyclo-
hexyl-4H-thiopyrans 5a and 5b were determined by
X-ray analysis (Fig. 1). Despite sterically different
substituents on C4 in molecules 5a (4-ethylphenyl) and
5b (cyclohexyl), crystals formed by these compounds
are almost isostructural (Tables 1, 2; see Experi-
1435

DYACHENKO et al.
1436
Scheme 1.
R
R
NC
CN
1
NH2
Et3N
RCHO (2a–2m)
NC
+
H2S
NH2
NC
CN
NC
S
NH2
HS
S
N
1
A
B
C
R
R
R
HlgCH2C(O)Z
N
NC
CN
NC
CN
NC
3a–3m
KOH, DMF
Z
H2N
S
NH2
H2N
N
S– K+
H2N
N
H
S
H
O
5a–5m
D
E
OCH2Ph
F
PhCH2Cl, EtONa
NH2
R = 4-HOC6H4
Z = 4-FC6H4
NC
R
N
S
O
NH2
H2N
N
H
NC
Z
6
–2[H]
OMe
S
O
H2N
MeO
4a–4s
O
, AcOH, ∆
HN
R = 3,4-(MeO)2C6H3
Z = NH2
NH
O
NC
S
H2N
N
H
7
2, 5, R = 4-EtC6H4 (a), Cy (b), 4-HOC6H4 (c), 4-EtOC6H4 (d), thiophen-2-yl (e), furan-2-yl (f), Ph (g), 3-FC6H4 (h), 4-MeOC6H4 (i),
Et (j), 4-BrC6H4 (k), 4-BuOC6H4 (l), 3,4-(MeO)2C6H3 (m); 3, Hlg = Cl, Z = NH2 (a); Hlg = Br, 4-MeOC6H4 (b), 4-ClC6H4 (c),
4-FC6H4 (d), 4-BrC6H4 (e); Hlg = Cl, Z = EtO (f), 2-MeC6H4NH (g), MeO (h); Hlg = Br, Z = 4-O2NC6H4 (i); Hlg = Cl, Z =
4-BrC6H4NH (j); Hlg = Br, Z = 4-BuC6H4 (k), naphthalen-2-yl (l), 2,4,5-Me3C6H2 (m); 4, R = Cy, Z = NH2 (a), 4-MeOC6H4 (b);
R = 3,4-(MeO)2C6H3, Z = Ph (c), NH2 (d); R = 4-EtOC6H4, Z = 4-ClC6H4 (e); R = thiophen-2-yl, Z = 4-BrC6H4 (f); R = 4-EtC6H4,
Z = EtO (g), 2-MeC6H4NH (h), MeO (i); R = furan-2-yl, Z =NH2 (j), 4-O2NC6H4 (k), 4-BrC6H4NH (l), 4-ClC6H4 (m); R = Ph, Z =
4-BuC6H4 (n); R = 3-FC6H4, Z = naphthalen-2-yl (o); R = 4-MeOC6H4, Z = NH2 (p); R = BuOC6H4, Z = MeO (q); R = 4-BrC6H4,
Z = NH2 (r); R = Et, Z = 2,4,5-Me3C6H2 (s).
mental). The central thiopyran ring in both molecules
has a boat conformation with the S1 and C4 atoms
deviating from the plane formed by the other ring
atoms by 0.439(2), 0.482(2) (5a) and 0.374(2),
0.409(2) Å (5b), respectively. The N1 atom in 5a and
N4 in 5b have planar configuration with the sum of the
bond angles equal to 360(5) and 359(4)°, respectively,
whereas the N4 atom in 5a and N1 atom in 5b are
slightly pyramidalized [bond angle sum 353(5) and
352(4)°, respectively]. The bulky substituents on C4 in
both molecules 5a and 5b occupy less favorable axial
position, which is likely to be determined by the reac-
tion direction. Molecules 5a and 5b in crystal are
linked through fairly strong N–H···N hydrogen bonds
to form corrugated layers along the 100 crystallo-
graphic plane (Fig. 2; Tables 1, 2). The layers are
packed in a zipper-like fashion.
The structure of 4a–4s was confirmed by spectral
data and chemical transformations. The condensation
with 4-hydroxybenzaldehyde gave 4-hydroxyphenyl-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

MULTICOMPONENT SYNTHESIS OF 4-ALKYL(ARYL, HETARYL)-...
(a)
1437
(b)
C16
C11
C15
C10
C14
C11
C12
C13
C9
C10
C12
C13
C8
C9
C8
N2
C7
C3
C4
N2
C4
C7
C5
C14
C3
N3
N3
C16
C2
C5
C6
N1
C2
C6
N1
S1
S1
N4
N4
Fig. 1. Molecular structures of (a) 2,6-diamino-4-(4-ethylphenyl)-4H-thiopyran-3,5-dicarbonitrile (5a) and (b) 2,6-diamino-4-cyclo-
hexyl-4H-thiopyran-3,5-dicarbonitrile (5b) according to the X-ray diffraction data. Non-hydrogen atoms are shown as anisotropic
displacement ellipsoids with a probability of 50%.
(a)
(b)
a
a
c
0
0
c
b
b
Fig. 2. Crystal packings of (a) 2,6-diamino-4-(4-ethylphenyl)-4H-thiopyran-3,5-dicarbonitrile (5a) and (b) 2,6-diamino-4-cyclo-
hexyl-4H-thiopyran-3,5-dicarbonitrile (5b) according to the X-ray diffraction data.
substituted thienopyridine 4 which was alkylated in
situ with benzyl chloride to obtain the corresponding
ether 6. This reaction was used to synthesize 3-(4-al-
koxyphenyl)-2-(4-arylthiazol-2-yl)acrylonitrile [15]
and 7-benzyloxybenzo[b]pyran derivatives [16].
The vicinal position of the amino and carbamoyl
groups with respect to each other was confirmed by the
synthesis of a spiro heterocyclic system, spiro[cyclo-
hexane-1,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]
7, from thienopyridine 4d and cyclohexanone [17–19].
The IR spectra of 4a–4s characteristically showed
absorption bands due to stretching and bending vibra-
tions of the amino groups at 3445–3220 and 1648–
1635 cm–1, respectively, and C≡N stretching band at
2224–2217 cm–1. In the 1H NMR spectra of 4a–4s we
observed signals from protons of aromatic substituents
(see Experimental) and a broadened singlet at δ 5.48–
7.90 ppm due to protons of the NH2 groups.
The structure of 3,6-diamino-5-cyano-4-cyclo-
hexylthieno[2,3-b]pyridine-2-carboxamide (4a) was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

DYACHENKO et al.
1438
Table 1. Hydrogen bonds in the crystal structure of 2,6-di-
amino-4-(4-ethylphenyl)-4H-thiopyran-3,5-dicarbonitrile (5a)
strong intra- and intermolecular hydrogen bonds
(Table 3) formed in the crystal structure. The amide
group is turned through an angle of 11.01(11)° with
respect to the thiophene ring and is involved in strong
intramolecular hydrogen bond N2–H2A···O1 (Fig. 3,
Table 3). The N1 and N4 atoms have planar configura-
tion with the sum of the bond angles equal to 359(4)
and 360(5)°, respectively, while the N2 atom is pyra-
midal [sum of the bond angles 340(4)°]. Molecules 4a
in crystal are linked through fairly strong intermolec-
ular hydrogen bonds N–H···O to form double-deck
layers parallel to the 100 crystallographic plane (Fig. 4,
Table 3).
D–H···A
D–H, Å H···A, Å D···A, Å ∠DHA, deg
N1–H1A···N2 a 0.89(2) 2.49(2) 3.206(2) 138.5(17)
N1–H1B···N3 b 0.87(2) 2.26(2) 3.121(2) 170.9(18)
N4–H4A···N2 c 0.88(2) 2.10(2) 2.976(2) 173.4(18)
N4–H4B···N3 a 0.89(2) 2.32(2) 3.133(2) 152.4(17)
a
b
c
Symmetry operation: x, y + 1, z.
Symmetry operation: x, –y + 1/2, z + 1/2.
Symmetry operation: x, –y + 1/2, z – 1/2.
Table 2. Hydrogen bonds in the crystal structure of 2,6-di-
amino-4-cyclohexyl-4H-thiopyran-3,5-dicarbonitrile (5b)
EXPERIMENTAL
∠DHA,
deg
D–H···A
D–H, Å H···A, Å D···A, Å
The X-ray diffraction data for compounds 4a, 5a,
and 5b were obtained on a Belok synchrotron station
with a Rayonix SX165 two-coordinate CCD detector
at the “Kurchatov Institute” National Research Center
(100 K, λ 0.96990 Å, ω-scanning with a step of 1.0°).
The data were processed using iMOSFLM program
implemented in CCP4 package [20]. A correction for
absorption was applied by SCALA program [21]. The
principal crystallographic data and structure refine-
ment parameters are collected in Table 4. The struc-
tures were solved by the direct method and were
refined against F2 by the full-matrix least-squares
method in anisotropic approximation for non-hydrogen
atoms. The ethyl substituent in molecule 5a is dis-
ordered by two positions with equal populations.
Hydrogen atoms of the amino groups were localized
from the difference Fourier maps, and their positions
were refined in isotropic approximation with fixed iso-
tropic displacement parameters [Uiso(H) = 1.2Ueq(N)].
The positions of the other hydrogens were calculated
geometrically and refined according to the riding
model with fixed positional parameters and isotropic
displacement parameters Uiso(H) = 1.5Ueq(C) for
methyl groups and Uiso(H) = 1.2Ueq(C) for other
hydrogens. All calculations were performed using
SHELXTL software package [22]. The tabulated coor-
dinates of atoms, bond lengths, bond and torsion
angles, and anisotropic displacement parameters for
compounds 4a, 5a, and 5b were deposited to the
Cambridge Crystallographic Data Centre; CCDC entry
nos. 1853572 (4a), 1853573 (5a), 1853574 (5b).
N1–H1A···N2 a 0.892(17) 2.406(17) 3.2373(17) 155.1(14)
N1–H1B···N3 b 0.860(17) 2.119(18) 2.9730(17) 172.1(16)
N4–H4A···N3 a 0.881(18) 2.672(18) 3.3447(18) 133.9(14)
N4–H4B···N2 c 0.883(18) 2.355(18) 3.2226(18) 167.6(15)
a
b
c
Symmetry operation: x, y + 1, z.
Symmetry operation: x, –y + 1/2, z – 1/2.
Symmetry operation: x, –y + 1/2, z + 1/2.
unambiguously determined by X-ray analysis (Fig. 3).
The thiophene and pyridine rings in molecule 4a are
planar, but their planes form a dihedral angle of
6.77(10)° due to steric effects of the substituents and
C12
C13
C14
C11
C10
N2
C9
C4
O2
N3
C15
C3
C3A
C5
C2
C8
C6
N1
N4
C7A
S1
N7
Fig. 3. Molecular structure of 3,6-diamino-5-cyano-4-cyclo-
hexylthieno[2,3-b]pyridine-2-carboxamide (4a) according to
the X-ray diffraction data. Non-hydrogen atoms are shown
as anisotropic displacement ellipsoids with a probability of
50%. The N–H···O intramolecular hydrogen bond is shown
as dashed line.
The IR spectra were recorded on an IKS-40 spec-
trometer from samples dispersed in mineral oil. The
1H and 13C NMR spectra were measured on a Varian
VXR-400 spectrometer at 399.97 and 100 MHz,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

MULTICOMPONENT SYNTHESIS OF 4-ALKYL(ARYL, HETARYL)-...
1439
a
0
c
b
Fig. 4. Crystal packing of 3,6-diamino-5-cyano-4-cyclohexylthieno[2,3-b]pyridine-2-carboxamide (4a) according to the X-ray
diffraction data.
respectively, using DMSO-d6 as solvent and tetra-
methylsilane as internal standard. The mass spectra
of 4a, 4g, 4o–4q, 5a, and 5b were obtained on
an Orbitrap Elite high-resolution mass spectrometer.
Samples were dissolved in 1 mL of DMSO, diluted by
a factor of 100 with 1% formic acid in acetonitrile, and
introduced into the electrospray ionization source
using a syringe pump (flow rate 40 μL/min). Gas
fluxes in the ion source were turned off; needle voltage
3.5 kV, capillary temperature 275°C; positive and nega-
tive ions were detected in an orbital trap with a resolu-
tion of 480000; [2DMSO + H]+ (m/z 157.03515) and
dodecyl sulfate anion (m/z 265.14789) were used as
internal calibrants for positive and negative ions,
respectively. The mass spectra of the other compounds
were recorded on an Agilent 1100 Series LC/MSD
instrument (electron impact, 70 eV; samples were
introduced as solutions in acetic acid). The elemental
compositions were determined with a Perkin Elmer
CHN analyzer. The melting points were measured on
a Kofler hot stage. The progress of reactions was
monitored, and the purity of products was checked, by
TLC on Silufol UV-254 plates using acetone–hexane
(3:5) as eluent; spots were visualized by treatment
with iodine vapor and by UV irradiation.
Compounds 4a–4s (general procedure). An Erlen-
meyer flask was charged with a solution of 0.66 g
(10 mmol) of malononitrile (1) in 20 mL of ethanol,
and three drops of triethylamine were added with
Table 3. Hydrogen bonds in the crystal structure of 3,6-di-
amino-5-cyano-4-cyclohexylthieno[2,3-b]pyridine-2-car-
boxamide (4a)
D–H···A
D–H, Å H···A, Å D···A, Å ∠DHA, deg
N1–H1A···O1 a 0.85(2) 2.20(2) 3.040(2) 175.9(18)
N1–H1B···N7 b 0.91(2) 2.23(2) 3.116(2) 166.2(18)
N2–H2A···O1 0.92(2) 2.24(2) 2.895(2) 127.7(15)
N2–H2B···O1 c 0.86(2) 2.62(2) 3.249(2) 131.3(17)
N4–H4A···O1 d 0.85(2) 2.20(2) 2.993(2) 155.3(19)
a
b
c
d
Symmetry operation: –x + 1, –y + 3, –z + 1.
Symmetry operation: –x + 1, y + 1/2, –z + 1/2.
Symmetry operation: x, y – 1, z.
Symmetry operation: x, –y + 3/2, z – 1/2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

DYACHENKO et al.
1440
Table 4. Crystallographic data for compounds 4a, 5a, and 5b
Parameter
4a
5a
5b
Formula
C15H17N5OS
315.40
C15H14N4S
282.36
C13H16N4S
260.36
Molecular weight
Single crystal dimensions, mm
0.10×0.10×0.25
Monoclinic
P21/c
0.05×0.05×0.07
Monoclinic
P21/c
0.15×0.15×0.15
Monoclinic
P21/c
Crystal system
Space group
a, Å
17.270(4)
0005.2501(10)
17.830(4)
115.21(3)
1462.7(7)
4
13.837(3)
0006.6701(13)
16.820(3)
108.41(3)
1472.9(6)
4
11.500(2)
0006.7300(13)
17.187(3)
105.07(3)
1284.4(4)
4
b, Å
c, Å
β, deg
V, Å3
Z
d
calc, g/cm3
1.432
1.273
1.346
F(000)
μ, mm–1
664
592
552
0.532
0.496
0.555
2θmax, deg
76.98
76.88
76.87
Total number of reflections
Number of independent reflections (Rint)
Number of reflections with I > 2σ(I)
Number of variables
17214
15371
16066
3120 (0.066)
2614
3107 (0.059)
2569
2673 (0.077)
2392
217
199
176
R1, wR2 [reflections with I > 2σ(I)]
R1, wR2 (all independent reflections)
Goodness of fit with respect to F2
Extinction coefficient
0.047, 0.114
0.057, 0.121
1.045
0.045, 0.108
0.055, 0.114
1.016
0.040, 0.096
0.048, 0.100
1.083
–
0.0074(19)
0.960, 0.970
0.005(1)
0.912, 0.912
T
min, Tmax
0.870, 0.940
stirring using a magnetic stirrer. The mixture was
cooled to 10°C on a water bath, and gaseous hydrogen
sulfide generated by hydrolysis of Al2S3 was passed
through the mixture at a moderate flow rate. The mix-
ture was stirred for 15–20 min after cyanothioacet-
amide A began to crystallize therefrom, and 10 mmol
of aldehyde 2a–2m was added with stirring at room
temperature. The mixture became homogeneous for
some time, and alkene B separated over a period of
3–8 min. An additional portion of malononitrile (1),
0.66 g (10 mmol), was then added while continuously
stirring, and the mixture was stirred for 10–15 min
until it became homogeneous again and left to stand
for 4–6 h. The mixture was diluted with an equal
volume of DMF, 5.6 mL (10 mmol) of 10% aqueous
potassium hydroxide was added, and the mixture was
left to stand for 24 h. Alkylating agent 3a–3m,
10 mmol, was added, the mixture was stirred for 3 h,
and 5.6 mL (10 mmol) of 10% aqueous potassium
hydroxide was added again. After 2 h, the mixture was
diluted with an equal volume of water, and the precip-
itate was filtered off and washed with water, ethanol,
and hexane.
3,6-Diamino-5-cyano-4-cyclohexylthieno[2,3-b]-
pyridine-2-carboxamide (4a). Yield 2.3 g (74%),
yellow plates, mp 248–250°C (from BuOH). IR spec-
trum, ν, cm–1: 3415, 3330, 3297, 3280 (NH2), 2218
1
(C≡N), 1668 (CONH2), 1638 (δNH2). H NMR spec-
trum, δ, ppm: 1.16–1.28 m (1H, Cy), 1.29–1.47 m (2H,
Cy), 1.52–1.78 m (5H, Cy), 2.11–2.16 m (2H, Cy),
3.61–3.77 m (1H, Cy), 6.69 br.s (2H, 3-NH2), 7.04 br.s
13
(2H, 6-NH2), 7.06 br.s (2H, CONH2). C NMR spec-
trum, δC, ppm: 25.6, 26.4 (2C), 29.9 (2C), 38.1, 96.2,
115.9, 118.1, 149.2, 160.0, 160.4, 164.2, 167.4 (2C).
Mass spectrum: m/z 316.1227 [M + H]+. C15H17N5OS.
Calculated: M 316.1154.
3,6-Diamino-4-cyclohexyl-2-(4-methoxybenzoyl)-
thieno[2,3-b]pyridine-5-carbonitrile (4b). Yield 3.2 g
(79%), yellow powder fluorescing under UV irradia-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

MULTICOMPONENT SYNTHESIS OF 4-ALKYL(ARYL, HETARYL)-...
1441
tion, mp 238–240°C (from BuOH). IR spectrum, ν,
cm–1: 3445, 3315, 3286 (NH2), 2224 (C≡N), 1703
(C=O), 1648 (δNH2). H NMR spectrum, δ, ppm:
3,6-Diamino-2-(4-bromobenzoyl)-4-(thiophen-2-
yl)thieno[2,3-b]pyridine-5-carbonitrile (4f). Yield
3.3 g (73%), yellow crystals, mp 341–343°C (from
1,4-dioxane), sublimes at 280°C. IR spectrum, ν, cm–1:
3412, 3330, 3300, 3285 (NH2), 2220 (C≡N), 1695
1
1.28–1.40 m (1H, Cy), 1.51–1.64 m (2H, Cy), 1.73–
1.92 m (5H, Cy), 2.16–2.27 m (2H, Cy), 3.51–3.61 m
(1H, Cy), 3.81 s (3H, Me), 6.97 d (2H, Harom, J =
8.5 Hz), 7.11 br.s (2H, 3-NH2), 7.66 d (2H, Harom, J =
8.5 Hz), 7.90 br.s (2H, 6-NH2). Mass spectrum:
m/z 407.1 (Irel 100%) [M + 1]+. Found, %: C 64.88;
H 5.36; N 13.60. C22H22N4O2S. Calculated, %:
C 65.00; H 5.46; N 13.78. M 406.51.
1
(C=O), 1641 (δNH2). H NMR spectrum, δ, ppm:
6.83 br.s (2H, 3-NH2), 7.35 t (1H, 4′-H, J = 3.7 Hz),
7.46 d (1H, 3′-H, J = 2.2 Hz), 7.61 d (2H, C6H4, J =
8.3 Hz), 7.62–7.74 m (4H, Harom, 6-NH2), 8.01 d
(1H, 5′-H, J = 4.7 Hz). Mass spectrum: m/z 456.0
(Irel 100%) [M + 1]+. Found, %: C 50.03; H 2.34;
N 12.25. C19H11BrN4OS2. Calculated, %: C 50.12;
H 2.43; N 12.30. M 455.36.
3,6-Diamino-2-benzoyl-4-cyclohexylthieno-
[2,3-b]pyridine-5-carbonitrile (4c). Yield 3.5 g
(81%), yellow powder, mp 230–232°C (from AcOH).
IR spectrum, ν, cm–1: 3407, 3332, 3294 (NH2), 2220
Ethyl 3,6-diamino-5-cyano-4-(4-ethylphenyl)-
thieno[2,3-b]pyridine-2-carboxylate (4g). Yield 2.9 g
(80%), yellow powder fluorescing under UV irradia-
tion, mp 219–220°C (from AcOH). IR spectrum, ν,
cm–1: 3404, 3382, 3305, 3288 (NH2), 2222 (C≡N),
1716 (C=O), 1641 (δNH2). 1H NMR spectrum, δ, ppm:
1.19 t (3H, MeCH2O, J = 7.1 Hz), 1.23 t (3H, Me, J =
7.5 Hz), 2.69 q (2H, CH3CH2, J = 7.5 Hz), 4.14 q (2H,
CH2O, J = 7.1 Hz), 5.48 br.s (2H, 3-NH2), 7.38 d (2H,
1
(C≡N), 1698 (C=O), 1644 (δNH2). H NMR spectrum,
δ, ppm: 3.80 s (3H, Me), 3.87 s (3H, Me), 7.04–7.22 m
(4H, 3-NH2, Harom), 7.43–7.72 m (7H, 6-NH2, Harom),
8.07 d (1H, Harom, J = 8.7 Hz). Mass spectrum:
m/z 429.1 (Irel 100%) [M – 1]+. Found, %: C 64.05;
H 4.14; N 12.91. C23H18N4O3S. Calculated, %:
C 64.17; H 4.21; N 13.02. M 430.49.
H
arom, J = 6.2 Hz), 7.43 br.s (4H, 6-NH2, Harom).
3,6-Diamino-5-cyano-4-(3,4-dimethoxyphenyl)-
thieno[2,3-b]pyridine-2-carboxamide (4d). Yield
2.7 g (72%), yellow powder, mp 250–252°C (from
BuOH). IR spectrum, ν, cm–1: 3399, 3286, 3268, 3220
(NH2), 2219 (C≡N), 1671 (CONH2), 1635 (δNH2).
1H NMR spectrum, δ, ppm: 3.76 s (3H, Me), 3.84 s
(3H, Me), 5.76 br.s (2H, 3-NH2), 6.95 br.s (2H, 6-NH2),
6.99 d (1H, Harom, J = 8.5 Hz), 7.08 s (1H, Harom),
7.13 d (1H, Harom, J = 8.5 Hz), 7.25 br.s (2H, CONH2).
Mass spectrum: m/z 370.0 (Irel 100%) [M + 1]+. Found,
%: C 55.13; H 3.95; N 18.80. C17H15N5O3S. Calculat-
ed, %: C 55.28; H 4.09; N 18.96. M 369.40.
13C NMR spectrum, δC, ppm: 14.9, 15.5, 28.4, 60.2,
90.2, 90.9, 113.7, 116.1, 128.4 (2C), 128.9 (2C), 131.0,
146.2, 148.7, 153.5, 159.2, 164.4, 165.2. Mass spec-
trum: m/z 367.1226 [M + H]+. C19H18N4O2S. Cal-
culated: M 367.1150.
3,6-Diamino-5-cyano-4-(4-ethylphenyl)-
N-(2-methylphenyl)thieno[2,3-b]pyridine-2-carbox-
amide (4h). Yield 2.8 g (66%), green powder,
mp 230–232°C (from BuOH). IR spectrum, ν, cm–1:
3419, 3395, 3301, 3296 (NH2), 2224 (C≡N), 1668
1
(C=O), 1638 (δNH2). H NMR spectrum, δ, ppm:
1.26 t (3H, Me, J = 7.4 Hz), 2.18 s (3H, Me), 2.71 q
(2H, CH2, J = 7.4 Hz), 5.69 br.s (2H, 3-NH2), 7.12 t
(1H, Harom, J = 7.2 Hz), 7.16 t (1H, Harom, J = 7.1 Hz),
7.23 t (2H, Harom, J = 8.1 Hz), 7.38 br.s (2H, 6-NH2),
7.42 d (2H, Harom, J = 7.7 Hz), 7.45 d (2H, Harom, J =
7.7 Hz), 9.01 br.s (1H, CONH). 13C NMR spectrum,
δC, ppm: 15.5, 18.4, 28.4, 90.9, 93.6, 114.5, 116.3,
126.2, 126.3, 127.4 (2C), 128.5 (2C), 128.9, 130.6,
131.4, 134.5, 136.9, 146.1, 147.4, 153.0, 159.1, 164.1,
164.2. Mass spectrum: m/z 428.1 (Irel 100%) [M + 1]+.
Found, %: C 67.35; H 4.88; N 16.25. C24H21N5OS.
Calculated, %: C 67.43; H 4.95; N 16.38. M 427.53.
3,6-Diamino-2-(4-chlorobenzoyl)-4-(4-ethoxy-
phenyl)thieno[2,3-b]pyridine-5-carbonitrile (4e).
Yield 3.7 g (82%), light yellow powder fluorescing
under UV irradiation, mp 240–242°C (from AcOH). IR
spectrum, ν, cm–1: 3415, 3388, 3310, 3247 (NH2),
1
2219 (C≡N), 1711 (C=O), 1630 (δNH2). H NMR
spectrum, δ, ppm: 1.39 t (3H, Me, J = 6.1 Hz), 4.15 q
(2H, CH2, J = 6.1 Hz), 6.79 br.s (2H, 3-NH2), 7.17 br.s
(2H, 6-NH2), 7.46 d (2H, Harom, J = 8.3 Hz), 7.57 br.s
13
(4H, Harom), 7.69 d (2H, Harom, J = 8.3 Hz). C NMR
spectrum, δC, ppm: 15.1, 63.8, 91.7, 99.7, 113.1 (2C),
115.7, 125.3, 129.0 (2C), 129.1 (2C), 129.4 (2C),
129.5, 129.9 (2C), 152.2, 154.5, 159.9, 160.3, 166.8,
186.6. Mass spectrum: m/z 449.0 (Irel 100%) [M + 1]+.
Found, %: C 61.42; H 3.75; N 12.35. C23H17ClN4O2S.
Calculated, %: C 61.54; H 3.82; N 12.48. M 448.93.
Methyl 3,6-diamino-5-cyano-4-(4-ethylphenyl)-
thieno[2,3-b]pyridine-2-carboxylate (4i). Yield 2.4 g
(68%), bright yellow powder, mp 265–267°C (from
BuOH). IR spectrum, ν, cm–1: 3396, 3310, 3295, 3287
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

DYACHENKO et al.
1442
(NH2), 2219 (C≡N), 1714 (C=O), 1646 (δ NH2).
1H NMR spectrum, δ, ppm: 1.31 t (3H, Me, J =
7.6 Hz), 2.75 q (2H, CH2, J = 7.6 Hz), 3.80 s (3H,
MeO), 5.51 br.s (2H, 3-NH2), 7.25 br.s (2H, 6-NH2),
7.33 d (2H, Harom, J = 8.1 Hz), 7.40 d (2H, Harom, J =
8.1 Hz). Mass spectrum: m/z 353.0 (Irel 100%) [M + 1]+.
Found, %: C 61.28; H 4.44; N 15.76. C18H16N4O2S.
Calculated, %: C 61.35; H 4.58; N 15.90. M 352.41.
C 50.11; H 2.53; N 15.34. C19H12BrN5O2S. Calculated,
%: C 50.23; H 2.66; N 15.42. M 454.31.
3,6-Diamino-2-(4-chlorobenzoyl)-4-(furan-2-yl)-
thieno[2,3-b]pyridine-5-carbonitrile (4m). Yield
3.1 g (79%), yellow powder, mp 246–248°C (from
AcOH). IR spectrum, ν, cm–1: 3398, 3330, 3300, 3296
(NH2), 2221 (C≡N), 1713 (C=O), 1641 (δ NH2).
1H NMR spectrum, δ, ppm: 6.77 d (1H, 3′-H, J =
1.2 Hz), 6.82 s (1H, 4′-H), 7.10 br.s (2H, 3-NH2),
7.48 br.s (2H, 6-NH2), 7.68 d (2H, Harom, J = 7.8 Hz),
7.83 d (2H, Harom, J = 7.8 Hz), 8.01 d (1H, 5′-H). Mass
spectrum, m/z 395.4 (Irel 100%) [M + 1]+. Found, %:
C 57.68; H 2.72; N 14.05. C19H11ClN4O2S. Calculated,
%: C 57.80; H 2.81; N 14.19. M 394.84.
3,6-Diamino-5-cyano-4-(furan-2-yl)thieno[2,3-b]-
pyridine-2-carboxamide (4j). Yield 2.3 g (77%),
yellow powder, mp 293–295°C (from 1,4-dioxane). IR
spectrum, ν, cm–1: 3448, 3396, 3330, 2288 (NH2),
1
2222 (C≡N), 1671 (C=O), 1638 (δNH2). H NMR
spectrum, δ, ppm: 6.17 br.s (2H, 3-NH2), 6.81 d (1H,
3′-H, J = 1.6 Hz), 7.08 br.s (3H, 6-NH2, 4′-H), 7.39 br.s
13
3,6-Diamino-2-(4-butylphenyl)-4-phenylthieno-
[2,3-b]pyridine-5-carbonitrile (4n). Yield 3.3 g
(77%), yellow powder, mp 203–205°C (from AcOH).
IR spectrum, ν, cm–1: 3407, 3391, 3335, 3298 (NH2),
(2H, CONH2), 8.04 s (1H, 5′-H). C NMR spectrum,
δC, ppm: 89.8, 94.4, 112.8, 114.5, 115.2, 116.4, 140.2,
145.1, 146.2, 146.6, 159.1, 164.4, 167.3. Mass spec-
trum: m/z 300.0 (Irel 100%) [M + 1]+. Found, %:
C 52.03; H 2.97; N 23.32. C13H9N5O2S. Calculated, %:
C 52.17; H 3.03; N 23.40. M 299.31.
1
2224 (C≡N), 1703 (C=O), 1646 (δNH2). H NMR
spectrum, δ, ppm: 0.95 t (3H, Me, J = 7.2 Hz), 1.27–
1.43 m (2H, CH2), 1.54–1.69 m (2H, CH2), 2.66 t (2H,
CH2, J = 7.5 Hz), 6.70 br.s (2H, 3-NH2), 7.25 d (2H,
Harom, J = 7.7 Hz), 7.45 br.s (2H, 6-NH2), 7.49 d (2H,
Harom, J = 8.1 Hz), 7.58 d (2H, Harom, J = 7.7 Hz), 7.66 t
(3H, Harom, J = 7.8 Hz). Mass spectrum: m/z 427.1
(Irel 100%) [M + 1]+. Found, %: C 70.29; H 5.14;
N 13.02. C25H22N4OS. Calculated, %: C 70.40; H 5.20;
N 13.14. M 426.54.
3,6-Diamino-4-(furan-2-yl)-2-(4-nitrobenzoyl)-
thieno[2,3-b]pyridine-5-carbonitrile (4k). Yield 2.7 g
(67%), yellow powder fluorescing under UV irradia-
tion, mp 265–267°C (from AcOH). IR spectrum, ν,
cm–1: 3411, 3387, 3310, 3285 (NH2), 2223 (C≡N),
1
1644 (δNH2), 1635 (NO2). H NMR spectrum, δ, ppm:
6.88 s (1H, 3′-H), 7.20 s (1H, 4′-H), 7.35 br.s (2H,
3-NH2), 7.53 br.s (2H, 6-NH2), 7.68 d (4H, Harom, J =
6.8 Hz), 8.12 s (1H, 5′-H). 13C NMR spectrum, δC,
ppm: 90.3, 100.4, 112.3, 113.0, 115.9, 116.2, 127.6
(2C), 129.0 (2C), 131.4, 141.5, 141.6, 144.7, 146.8,
151.6, 159.9, 167.2, 188.3. Mass spectrum: m/z 406.1
(Irel 100%) [M + 1]+. Found, %: C 56.18; H 2.62;
N 17.19. C19H11N5O4S. Calculated, %: C 56.29;
H 2.74; N 17.28. M 405.40.
3,6-Diamino-4-(3-fluorophenyl)-2-(naphthalen-
2-ylcarbonyl)thieno[2,3-b]pyridine-5-carbonitrile
(4o). Yield 3.3 g (76%), yellow crystals, mp 298–
300°C (from AcOH). IR spectrum, ν, cm–1: 3412,
3388, 3315, 3282 (NH2), 2218 (C≡N), 1704 (C=O),
1
1643 (δNH2). H NMR spectrum, δ, ppm: 6.70 br.s
(2H, 3-NH2), 7.39 d (1H, Harom, J = 7.6 Hz), 7.42–
7.73 m (8H, Harom, 6-NH2), 7.82–8.15 m (3H, Harom),
8.27 s (1H, Harom). 13C NMR spectrum, δC, ppm:
91.2, 100.4, 112.8, 115.7, 115.9, 117.7, 124.6, 127.4,
127.5, 128.1, 128.2, 128.7, 129.3, 132.2, 132.4, 134.2,
138.7, 151.5, 152.8, 159.5, 161.4, 163.8, 166.7, 172.4,
188.0. Mass spectrum: m/z 439.1025 [M + H]+.
C25H15FN4OS. Calculated: M 439.0951.
3,6-Diamino-N-(4-bromophenyl)-5-cyano-4-
(furan-2-yl)thieno[2,3-b]pyridine-2-carboxamide
(4l). Yield 3.1 g (82%), yellow crystals, mp 252–
254°C (from AcOH). IR spectrum, ν, cm–1: 3400,
3382, 3313, 3285 (NH, NH2), 2225 (C≡N), 1666
1
(C=O), 1639 (δNH2). H NMR spectrum, δ, ppm:
6.33 br.s (2H, 3-NH2), 6.84 t (1H, 4′-H, J = 1.4 Hz),
7.11 d (1H, 3′-H, J = 3.3 Hz), 7.47 d (2H, Harom, J =
8.8 Hz), 7.51 br.s (2H, 6-NH2), 7.63 d (2H, Harom, J =
8.8 Hz), 8.08 s (1H, 5′-H), 9.47 br.s (1H, CONH).
13C NMR spectrum, δC, ppm: 90.2, 93.6, 112.8, 114.0,
115.4, 116.3, 123.4 (2C), 131.6 (2C), 138.9, 140.4,
145.0, 146.5, 148.2, 159.3, 164.2, 164.8, 172.5. Mass
spectrum: m/z 455.0 (Irel 100%) [M + 1]+. Found, %:
3,6-Diamino-5-cyano-4-(4-methoxyphenyl)-
thieno[2,3-b]pyridine-2-carboxamide (4p). Yield
2.4 g (70%), yellow powder, mp 275–277°C (from
BuOH). IR spectrum, ν, cm–1: 3439, 3335, 3302, 3296
(NH2), 2222 (C≡N), 1666 (C=O), 1629 (δ NH2).
1H NMR spectrum, δ, ppm: 3.82 s (3H, Me), 5.66 br.s
(2H, 3-NH2), 6.94 br.s (2H, 6-NH2), 7.11 d (2H, Harom
,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

MULTICOMPONENT SYNTHESIS OF 4-ALKYL(ARYL, HETARYL)-...
1443
J = 8.7 Hz), 7.26 br.s (2H, CONH2), 7.39 d (2H, Harom
,
addition of KOH and DMF. The precipitate was
filtered off and washed with ethanol and hexane.
J = 8.7 Hz). 13C NMR spectrum, δC, ppm: 55.72, 90.9,
93.3, 114.8 (2C), 116.4, 116.6, 125.9, 130.0 (2C),
146.7, 152.7, 158.9, 160.6, 163.8, 167.2. Mass spec-
trum: m/z 340.0862 [M + H]+. C16H13N5O2S. Calculat-
ed: M 340.0790.
2,6-Diamino-4-(4-ethylphenyl)-4H-thiopyran-
3,5-dicarbonitrile (5a). Yield 2.1 g (76%), yellow
crystals, mp 175–177°C (from AcOH); published data
[23]: mp 181–183°C. 13C NMR spectrum, δC, ppm:
16.0, 28.2, 43.5, 72.6 (2C), 119.3, 127.0 (2C), 128.2,
128.5 (2C), 141.2, 143.0, 151.5 (2C). Mass spectrum:
m/z 283.0810 [M + H]+. C15H14N4S. Calculated:
M 283.0939.
Methyl 3,6-diamino-4-(4-butoxyphenyl)-5-
cyanothieno[2,3-b]pyridine-2-carboxylate (4q).
Yield 3.0 g (75%), light yellow powder, mp 248–
250°C (from EtOH), sublimes at 200°C to form rod-
like crystals fluorescing under UV irradiation. IR spec-
trum, ν, cm–1: 3399, 3385, 3312, 3276 (NH2), 2219
(C≡N), 1714 (C=O), 1645 (δNH2). 1H NMR spectrum,
δ, ppm: 0.93 t (3H, Me, J = 7.4 Hz), 1.32–1.51 m (2H,
CH2), 1.58–1.74 m (2H, CH2), 3.66 s (3H, MeO),
4.02 t (2H, OCH2, J = 7.8 Hz), 5.22 br.s (2H, 3-NH2),
7.10 d (2H, Harom, J = 6.8 Hz), 7.38 d (2H, Harom, J =
6.8 Hz), 7.42 br.s (2H, 6-NH2). 13C NMR spectrum, δC,
ppm: 14.2, 19.2, 31.2, 51.6, 67.8, 91.1, 113.8, 115.4
(2C), 116.2, 116.6, 125.4, 130.0 (2C), 148.9, 153.4,
159.3, 160.3, 164.8, 165.2. Mass spectrum:
m/z 397.1330 [M + 1]+. C20H20N4O3S. Calculated:
M 397.1256.
2,6-Diamino-4-cyclohexyl-4H-thiopyran-3,5-di-
carbonitrile (5b). Yield 2.1 g (81%), yellow crystals,
mp 207–209°C (from AcOH); published data [23]:
mp 215–217°C. 13C NMR spectrum, δC, ppm: 26.0
(2C), 26.3, 30.4 (2C), 44.6, 45.5, 71.0 (2C), 120.2
(2C), 153.0 (2C). Mass spectrum: m/z 261.0967
[M + H]+. C13H16N4S. Calculated: M 261.1096.
2,6-Diamino-4-(4-hydroxyphenyl)-4H-thiopyran-
3,5-dicarbonitrile (5c). Yield 1.9 g (71%), yellow
powder, mp 165–167°C (from AcOH). IR spectrum, ν,
cm–1: 3446 (OH), 3404, 3307, 3208 (NH2), 2202
1
(C≡N), 1645 (δNH2). H NMR spectrum, δ, ppm:
4.13 s (1H, 4-H), 6.72 d (2H, Harom, J = 8.4 Hz),
6.80 br.s (4H, NH2), 7.03 d (2H, Harom, J = 8.4 Hz),
9.33 br.s (1H, OH). Mass spectrum: m/z 271.2
(Irel 100%) [M + 1]+. Found, %: C 57.61; H 3.64
N 20.65. C13H10N4OS. Calculated, %: C 57.76; H 3.73;
N 20.73. M 270.31.
3,6-Diamino-4-(4-bromophenyl)-5-cyanothieno-
[2,3-b]pyridine-2-carboxamide (4r). Yield 2.5 g
(65%), yellow powder, mp 263–265°C (from AcOH).
IR spectrum, ν, cm–1: 3434, 3319, 3295, 3281 (NH2),
1
2223 (C≡N), 1669 (C=O), 1638 (δNH2). H NMR
spectrum, δ, ppm: 5.63 br.s (2H, 3-NH2), 6.84 br.s (2H,
6-NH2), 7.16 br.s (2H, CONH2), 7.41 d (2H, Harom, J =
7.4 Hz), 7.76 d (2H, Harom, J = 7.4 Hz). Mass spec-
trum: m/z 389 (Irel 100%) [M + 1]+. Found, %: C 46.35;
H 2.48; N 17.89. C15H10BrN5OS. Calculated, %:
C 46.41; H 2.60; N 18.04. M 388.25.
2,6-Diamino-4-(4-ethoxyphenyl)-4H-thiopyran-
3,5-dicarbonitrile (5d). Yield 2.3 g (79%), yellow
powder, mp 181–183°C (from EtOH); published data
[24]: mp 183–185°C.
2,6-Diamino-4-(thiophen-2-yl)-4H-thiopyran-
3,5-dicarbonitrile (5e). Yield 2.1 g (80%), yellow
powder, mp 160–162°C (from EtOH); published data
[25]: mp 162–165°C.
3,6-Diamino-4-ethyl-2-(2,4,5-trimethylbenzoyl)-
thieno[2,3-b]pyridin-5-carbonitrile (4s). Yield 3.0 g
(83%), yellow powder fluorescing under UV irradia-
tion, mp 228–230°C (from BuOH). IR spectrum, ν,
cm–1: 3412, 3396, 3334, 3285 (NH2), 2220 (C≡N),
2,6-Diamino-4-(furan-2-yl)-4H-thiopyran-3,5-
dicarbonitrile (5f). Yield 1.6 g (66%), yellow powder,
mp 161–163°C (from EtOH); published data [26]:
mp 162–164°C.
1
1709 (C=O), 1646 (δNH2). H NMR spectrum, δ, ppm:
1.33 t (3H, Me, J = 7.4 Hz), 2.21 s (3H, Me), 2.23 s
(3H, Me), 2.25 s (3H, Me), 3.11 q (2H, CH2, J =
7.4 Hz), 6.99 s (1H, Harom), 7.03 s (1H, Harom), 7.22 br.s
(2H, 3-NH2), 8.02 br.s (2H, 6-NH2). Mass spectrum:
m/z 367.0 (Irel 100%) [M + 1]+. Found, %: C 65.40;
H 5.38; N 15.14. C20H20N4OS. Calculated, %: C 65.55;
H 5.50; N 15.29. M 366.47.
2,6-Diamino-4-phenyl-4H-thiopyran-3,5-dicar-
bonitrile (5g). Yield 2 g (78%), yellow crystals,
mp 180–182°C (from EtOH); published data [27]:
mp 181–183°C.
2,6-Diamino-4-(3-fluorophenyl)-4H-thiopyran-
3,5-dicarbonitrile (5h). Yield 1.9 g (69%), yellow
powder, mp 164–166°C (from EtOH); published data
[28]: mp 166–168°C.
Compounds 5a–5m. The procedure was the same
as described above for the synthesis of 4a–4s until the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

DYACHENKO et al.
1444
2,6-Diamino-4-(4-methoxyphenyl)-4H-thio-
glacial acetic acid was refluxed for 2 h. The mixture
was cooled, and the precipitate was filtered off and
washed with diethyl ether. Yield 3.5 g (78%), yellow
powder, mp 320–322°C (from 1,4-dioxane). IR spec-
trum, ν, cm–1: 3396, 3314, 3277, 3205 (NH2, NH),
pyran-3,5-dicarbonitrile (5i). Yield 2.2 g (77%),
yellow powder, mp 153–154°C (from EtOH); pub-
lished data [27]: mp 155–156°C.
2,6-Diamino-4-ethyl-4H-thiopyran-3,5-dicarbo-
nitrile (5j). Yield 1.3 g (65%), yellow crystals,
mp 150–152°C (from EtOH); published data [29]:
mp 150–152°C.
1
2218 (C≡N), 1672 (C=O), 1633 (δNH2). H NMR
spectrum, δ, ppm: 0.52–0.73 m (2H, CH2), 0.84–
1.13 m (1H, Cy), 1.24–1.32 m (3H, Cy), 1.34–1.48 m
(3H, Cy), 1.77–1.83 m (1H, Cy), 3.79 s (3H, Me),
3.84 s (3H, Me), 4.18 br.s (1H, N1H), 7.08 d (1H,
2,6-Diamino-4-(4-bromophenyl)-4H-thiopyran-
3,5-dicarbonitrile (5k). Yield 2.6 g (78%), yellow
powder, mp 182–184°C (from EtOH); published data
[27]: mp 183°C.
H
arom, J = 6.8 Hz), 7.19 d (1H, Harom, J = 6.8 Hz),
7.22 s (1H, Harom), 7.42 br.s (2H, NH2), 7.64 br.s (1H,
NHCO). Mass spectrum: m/z 450.1 (Irel 100%) [M + 1]+.
Found, %: C 61.36; H 5.02; N 15.42. C23H23N5O3S.
Calculated, %: C 61.45; H 5.16; N 15.58. M 449.53.
2,6-Diamino-4-(4-butoxyphenyl)-4H-thiopyran-
3,5-dicarbonitrile (5l). Yield 2.3 g (71%), yellow
powder, mp 156–158°C (from EtOH); published data
[30]: mp 156–158°C.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (program 5-100 for increasing the
rating of PFUR). The X-ray diffraction data were
obtained using the unique Kurchatov Synchrotron
Radiation Source under financial support by the
Ministry of Education and Science of the Russian
Federation (project ID RFMEFI61917X0007).
2,6-Diamino-4-(3,4-dimethoxyphenyl)-4H-thio-
pyran-3,5-dicarbonitrile (5m). Yield 2.3 g (75%),
yellow powder, mp 193–195°C (from EtOH); pub-
lished data [25]: mp 193–195°C.
3,6-Diamino-4-(4-benzyloxy)-2-(4-fluoroben-
zoyl)thieno[2,3-b]pyridine-5-carbonitrile (6) was
synthesized according to the general procedure de-
scribed above for compounds 4. The precipitate of
thienopyridine 4 obtained from 4-hydroxybenzalde-
hyde was dissolved in 20 mL of DMF, and a solution
of 0.23 g (10 mmol) of metallic sodium in 20 mL of
anhydrous ethanol and 1.15 mL (10 mmol) of benzyl
chloride were added in succession with stirring at
20°C. The mixture was stirred for 4 h and diluted with
an equal volume of water, and the precipitate was
filtered off and washed with water, ethanol, and
hexane. Yield 3.5 g (71%), yellow powder, mp 266–
268°C (from 1,4-dioxane). IR spectrum, ν, cm–1: 3418,
3380, 3311, 3295 (NH2), 2219 (C≡N), 1698 (C=O),
REFERENCES
1. Furuya, S., Chon, N., Suzuki, N., and Imado, T.,
US Patent no. 6329388, 2001; Ref. Zh., Khim., 2002,
no. 20-19O.73P.
2. Thorarensen, A., US Patent no. 6620810, 2003; Ref. Zh.,
Khim., 2004, no. 04.21-19O.120P.
3. Thorarensen, A., US Patent no. 6924283, 2006; Ref. Zh.,
Khim., 2006, no. 06.05-19O.89P.
4. Gaber, H.M. and Ouf, S.A., Afinidad, 2005, vol. 62,
p. 337.
5. Wang, Y., Duraiswanic, C., Madaus, K.P., Tran, T.B.,
Williams, S.P., Deng, S.-J., Graybill, T.L., Hammond, M.,
Jones, D.G., Crygielko, E.T., Bray, D.J., and Thomp-
son, S.K., Bioorg. Med. Chem. Lett., 2009, vol. 19,
p. 4916.
1
1645 (δNH2). H NMR spectrum, δ, ppm: 5.21 s (2H,
CH2), 6.79 br.s (2H, 3-NH2), 7.28 d (2H, Harom, J =
8.6 Hz), 7.34 t (2H, Harom, J = 8.8 Hz), 7.38 d (1H,
H
arom, J = 7.2 Hz), 7.44 t (2H, Harom, J = 7.5 Hz), 7.51 t
6. Lockman, J.W., Reeder, M.D., Suzuki, K., Ostanin, K.,
Hoff, R., Bhoite, L., Austin, H., Baichwall, V., and
Willardsen, A.J., Bioorg. Med. Chem. Lett., 2010, vol. 20,
p. 2283.
(4H, Harom, J = 8.8 Hz), 7.63 br.s (2H, 6-NH2), 7.74 d
(1H, Harom, J = 5.8 Hz), 7.76 d (1H, Harom, J = 5.8 Hz).
Mass spectrum: m/z 495.1 (Irel 100%) [M + 1]+. Found,
%: C 67.88; H 3.72; N 11.18. C28H19FN4O2S. Calculat-
ed, %: C 68.00; H 3.87; N 11.33. M 494.546.
7. Schnute, M.E., Cudany, M.M., Bridean, R.J., Homa, F.L.,
Hopkins, T.A., Knechtel, M.L., Oien, N.L., Pitts, T.W.,
Poorman, R.A., Wathen, M.W., and Wieder, J.L., J. Med.
Chem., 2005, vol. 48, p. 5794.
7′-Amino-9′-(3,4-dimethoxyphenyl)-4′-oxo-
3′,4′-dihydro-1′H-spiro[cyclohexane-1,2′-pyrido-
[3′,2′:4,5]thieno[3,2-d]pyrimidine]-8′-carbonitrile
(7). A mixture of 1.9 g (5 mmol) of thienopyridine 4d
and 0.5 mL (5 mmol) of cyclohexanone in 20 mL of
8. Litvinov, V.P., Dotsenko, V.V., and Krivokolysko, S.G.,
Khimiya tienopiridinov i rodstvennykh sistem (Chemistry
of Thienopyridines and Related Systems), Moscow:
Nauka, 2006.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

MULTICOMPONENT SYNTHESIS OF 4-ALKYL(ARYL, HETARYL)-...
1445
9. Dyachenko, V.D., Dyachenko, I.V., and Nenajden-
12. Elgemeie, G.E.H., Mohamed, S.M.M., Sherif, S.M., and
ko, V.G., Russ. Chem. Rev., 2018, vol. 87, p. 1.
Elnagdi, M.H., Heterocycles, 1985, vol. 23, p. 3107.
10. Antipin, I.S., Kazymova, M.A., Kuznetsov, M.A.,
Vasilyev, A.V., Ishchenko, M.A., Kiryushkin, A.A.,
Kuznetsova, L.M., Makarenko, S.V., Ostrovskii, V.A.,
Petrov, M.L., Solod, O.V., Tri-shin, Yu.G., Yakov-
lev, I.P., Nenaidenko, V.G., Beloglazkina, E.K., Belets-
kaya, I.P., Ustynyuk, Yu.A., Solov’ev, P.A., Ivanov, I.V.,
Malina, E.V., Sivova, N.V., Negrebetskii, V.V., Bau-
kov, Yu.I., Pozharskaya, N.A., Traven’, V.F., Shchekoti-
khin, A.E., Varlamov, A.V., Borisova, T.N., Lesi-
na, Yu.A., Krasnokutskaya, E.A., Rogozhnikov, S.I.,
Shurov, S.N., Kustova, T.P., Klyuev, M.V., Khelevi-
na, O.G., Stuzhin, P.A., Fedorov, A.Yu., Gushchin, A.V.,
Dodonov, V.A., Kolobov, A.V., Plakhtinskii, V.V.,
Orlov, V.Yu., Kriven’ko, A.P., Fedotova, O.V., Pchelin-
tseva, N.V., Charushin, V.N., Chupakhin, O.N., Kli-
mochkin, Yu.N., Klimochkina, A.Yu., Kuryatni-
kov, V.N., Malinovskaya, Yu.A., Levina, A.S., Zhurav-
lev, O.E., Voronchikhina, L.I., Fisyuk, A.S., Akse-
nov, A.V., Aksenov, N.A., and Aksenova, I.V., Russ. J.
Org. Chem., 2017, vol. 53, p. 1275.
13. Elgemeie, G.E., Sherif, S.M., Abd-El, M.A.F., and
Elnagdi, M.H., Z. Naturforsch., 1986, vol. 41, p. 781.
14. Quintela, J.M., Moreira, M.J., and Peinador, C.,
Heterocycles, 2000, vol. 52, p. 333.
15. Dyachenko, V.D., Russ. J. Org. Chem., 2006, vol. 42,
p. 724.
16. Dyachenko, V.D., Russ. J. Gen. Chem., 2005, vol. 75,
p. 1537.
17. Bakhite, E.A., J. Chem. Res., Synop., 2000, p. 500.
18. Bakhite, E.A., Abdel-Rahman, A.E., and Al-Taifi, E.A.,
Phosphorus, Sulfur Silicon Relat. Elem., 2004, vol. 179,
p. 513.
19. Dyachenko, V.D. and Dyachenko, A.D., Russ. J. Org.
Chem., 2008, vol. 44, p. 412.
20. Battye, T.G.G., Kontogiannis, L., Johnson, O.,
Powell, H.R., and Leslie, A.G.W., Acta Crystallogr.,
Sect. D, 2011, vol. 67, p. 271.
21. Evans, P., Acta Crystallogr., Sect. D, 2006, vol. 62,
p. 72.
11. Konovalov, A.I., Antipin, I.S., Burilov, V.A., Madzhi-
dov, T.I., Kurbangalieva, A.R., Nemtarev, A.V.,
Solovieva, S.E., Stoikov, I.I., Mamedov, V.A., Zakharo-
va, L.Ya., Gavrilova, E.L., Sinyashin, O.G., Balo-
va, I.A., Vasilyev, A.V., Zenkevich, I.G., Krasa-
vin, M.Yu., Kuznetsov, M.A., Molchanov, A.P.,
Novikov, M.S., Nikolaev, V.A., Rodina, L.L.,
Khlebnikov, A.F., Beletskaya, I.P., Vatsadze, S.Z.,
Gromov, S.P., Zyk, N.V., Lebedev, A.T., Lemenov-
skii, D.A., Petrosyan, V.S., Nenaidenko, V.G., Negre-
betskii, V.V., Baukov, Yu.I., Shmigol’, T.A., Korlyu-
kov, A.A., Tikhomirov, A.S., Shchekotikhin, A.E.,
Traven’, V.F., Voskresenskii, L.G., Zubkov, F.I.,
Golubchikov, O.A., Semeikin, A.S., Berezin, D.B.,
Stuzhin, P.A., Filimonov, V.D., Krasnokutskaya, E.A.,
Fedorov, A.Yu., Nyuchev, A.V., Orlov, V.Yu., Begu-
nov, R.S., Ru-sakov, A.I., Kolobov, A.V., Kofanov, E.R.,
Fedotova, O.V., Egorova, A.Yu., Charushin, V.N.,
Chupakhin, O.N., Klimochkin, Yu.N., Osyanin, V.A.,
Reznikov, A.N., Fisyuk, A.S., Sagitullina, G.P., Akse-
nov, A.V., Aksenov, N.A., Grachev, M.K., Maslen-
nikova, V.I., Koroteev, M.P., Brel’, A.K., Lisina, S.V.,
Medvedeva, S.M., Shikhaliev, Kh.S., Suboch, G.A.,
Tovbis, M.S., Mironovich, L.M., Ivanov, S.M., Kurba-
tov, S.V., Kletskii, M.E., Burov, O.N., Kobrakov, K.I.,
and Kuznetsov, D.N., Russ. J. Org. Chem., 2018,
vol. 54, p. 157.
22. Sheldrick, G.M., Acta Crystallogr., Sect. C, 2015,
vol. 71, p. 3.
23. Dyachenko, V.D., Chernega, A.N., and Garasevich, S.G.,
Russ. J. Gen. Chem., 2005, vol. 75, p. 1610.
24. Dyachenko, V.D., Zh. Org. Farm. Khіm., 2007, no. 5,
p. 14.
25. Matrosova, S.V., Zav’yalova, V.K., Litvinov, V.P., and
Sharanin, Yu.A., Russ. Chem. Bull., 1991, vol. 40,
p. 1456.
26. Sharanin, Yu.A., Promonenkov, V.K., Shestopa-
lov, A.M., Nesterov, V.N., Melenchuk, S.N., Shklo-
ver, V.E., and Struchkov, Yu.T., Zh. Org. Khim., 1989,
vol. 25, p. 622.
27. Sharanin, Yu.A., Shestopalov, A.M., Nesterov, V.N.,
Melenchuk, S.N., Promonenkov, V.K., Shklover, V.E.,
Struchkov, Yu.T., and Litvinov, V.P., Zh. Org. Khim.,
1989, vol. 25, p. 1323.
28. Dyachenko, V.D., Krivokolysko, S.G., Sharanin, Yu.A.,
and Litvinov, V.P., Russ. J. Org. Chem., 1997, vol. 33,
p. 1014.
29. Dyachenko, V.D., Krivokolysko, S.G., and Litvi-
nov, V.P., Chem. Heterocycl. Compd., 1996, vol. 32,
no. 9, p. 1055.
30. Dyachenko, V.D. and Litvinov, V.P., Chem. Heterocycl.
Compd., 1998, vol. 34, no. 2, p. 188.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018