Synthesis and domino reactions of polymethylene-3-cyanopyridine-2(1Н)-thiones

Article abstract of DOI:10.1002/jhet.3836

A new and facile three-component method was developed for the synthesis of polymethylene-3-cyanopyridine-2(1Н)-thiones by the domino Knoevenagel → Michael → heterocyclization → dehydrogenation reaction from cycloalkanones, cyanothioacetamide, and polymethoxy-substituted benzaldehydes. The final dehydrogenation step was found to involve arylidenecyanothioacetamide. The resulting pyridinethiones and 4-chloroacetoacetic ester were introduced into the domino S_N2 → Thorpe-Ziegler → Guareschi-Thorpe reaction to synthesize tetracyclic dipyridothiophenes. Starting from these compounds, 8,9-polymethylenepyranothienodipyridines were also synthesized by the domino Knoevenagel → Michael → hetero-Thorpe-Ziegler reaction. Furthermore, a method for the synthesis of thienodipyridine annulated to the steroid skeleton is proposed.

Full text of DOI:10.1002/jhet.3836

Received: 1 July 2019
DOI: 10.1002/jhet.3836
Revised: 12 September 2019
Accepted: 11 November 2019
A R T I C L E
Synthesis and domino reactions of polymethylene-
3-cyanopyridine-2(1Н)-thiones
Anatoliy M. Shestopalov1
| Lyudmila A. Rodinovskaya1 | Andrey A. Zubarev1
|
Vladimir N. Nesterov2 | Bogdan I. Ugrak1 | Tatyana Ya. Dutova1
1N.D. Zelinsky Institute of Organic
Abstract
Chemistry, Russian Academy of Sciences,
Leninsky Prospekt, 47, Moscow, Russia
A new and facile three-component method was developed for the synthesis of
polymethylene-3-cyanopyridine-2(1Н)-thiones by the domino Knoevenagel !
Michael ! heterocyclization ! dehydrogenation reaction from cycloalkanones,
cyanothioacetamide, and polymethoxy-substituted benzaldehydes. The final
dehydrogenation step was found to involve arylidenecyanothioacetamide. The
resulting pyridinethiones and 4-chloroacetoacetic ester were introduced into
the domino SN2 ! Thorpe-Ziegler ! Guareschi-Thorpe reaction to synthe-
size tetracyclic dipyridothiophenes. Starting from these compounds, 8,9-
polymethylenepyranothienodipyridines were also synthesized by the
domino Knoevenagel ! Michael ! hetero-Thorpe-Ziegler reaction. Further-
more, a method for the synthesis of thienodipyridine annulated to the steroid
skeleton is proposed.
2Department of Chemistry, University of
North Texas, Denton, Texas
Correspondence
Anatoliy M. Shestopalov, N.D. Zelinsky
Institute of Organic Chemistry, Russian
Academy of Sciences, Leninsky Prospekt,
47, Moscow 119991, Russia.
Email: amsh@ioc.ac.ru
1 | INTRODUCTION
vary substantially from 30% to 75% even under similar
reaction conditions.
Substituted
5,6-polymethylene-3-cyanopyridine-2(1H)-
Recently, it was demonstrated that some derivatives
thiones (1) were first synthesized via the recyclization reaction
of dithiacyclohexenes (2), which proceeds through the inter-
mediate thioketones (3) and arylidenecyanothioacetamides
of 5,6-polymethylenepyridinethiones can inhibit tubulin
polymerization and that they are considered as cancer
therapeutics.[19] Therefore, a novel synthetic method
that yields 5,6-polymethylene-3-cyanopyridine-2(1H)-
thiones substituted with antimitotic polyalkoxyphenyl
groups is relevant for the discovery of novel antitumor
agents.
Here, we report a convenient method of synthesis of
polymethylenepyridine-2(1Н)-thiones containing pharma-
cologically active polyalkoxyphenyl and 3- and 4-pyridyl
substituents[20–22] and show the utility of these products in
domino reactions. Our work also corrects previous studies by
establishing that the arylidenecyanothioacetamides, and not
the oxygen, act as oxidation agents in the final step of
polymethylenepyridine-2(1H)-thione formation. This discov-
ery was used to optimize the synthetic protocol and signifi-
cantly increase the yield of the final polymethylenepyridine-
2(1H)-thiones.
[2,3]
(4) (Scheme 1).[1] Subsequent studies of this reactions
led to the development of a synthetic method that yields
pyridine-2(1H)-thiones (1) by directly reacting arylidene-
cyanothioacetamides (4) and ketones (5) in the presence of
an organic base.[4,5]
Consequently, this method gained
a
wide-
spread use in the synthesis of the corresponding
5,6-polymethylenepyridinethiones.[3,6–13] The reaction
proceeds through the intermediate 1,4-dihydropyridine,
which was assumed to be oxidized by the molecular
oxygen in air.[5] A derivative of this method was also
applied with various cycloalkanones[4,6,14–16] and in the
recyclization of 2,6-diamino-3,5-dicyanothiopyranes in the
presence of cycloalkanones.[17,18] It is important to high-
light that the yields of the final products in these reactions
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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SHESTOPALOV ET AL.
2 | RESULTS AND DISCUSSION
benzylcyanothioacetamide (10a, Ar = C6H5) from the
reaction mixture. Apparently, compound 10a was pro-
duced from benzylidenecyanothioacetamide (4a) in the
dehydrogenation of pyridine 9 with unsaturated nitrile
4. In order to exclude the effect of atmospheric oxygen
on the dehydrogenation, the reaction was performed
under argon. It appeared that the yield of compounds
1a-I was almost the same, being lower than 50%. The
use of a twofold excess of cyanothioacetamide 6 and
aldehyde 7 in this reaction resulted in a substantial
increase in the yield of pyridinethiones 1 (method B)
(Table 1). Therefore, we found for the first time that
arylidenecyanothioacetamides (4) can serve as oxidizing
agents for hydrogenated pyridinethiones 9. Under these
conditions, pyridinethiones are not oxidized to disulfides.
In the synthesis of 4-pyridyl-substituted pyridinethiones
1h,i by the three-component condensation (method B), we
used 3-pyridyl- or 4-pyridylcarbaldehydes (7d,e), cyclohexa-
none (5b), and cyanothioacetamide (6); piperidine served as
the catalyst (Scheme 3). Compounds 1h,i were obtained
under these conditions in 76% and 73% yields.
The method for the synthesis of the targeted
pyridinethiones developed in the present study is based
on the three-component reaction of cycloalkanones (5),
cyanothioacetamide (6), and polymethoxy-substituted
benzaldehydes (7a-c). Apparently, the reaction involves
the Knoevenagel condensation of aldehydes (7) with
cyanothioacetamide (6) as the first step giving rise to
unsaturated thioamide (4). The subsequent Michael reac-
tion affords adduct 8, which is followed by its cyclization
to dihydropyridine 9. The dehydrogenation of compound
9 gives target pyridinethiones 1 (Scheme 2).
The synthesis was performed as a one-pot process by
refluxing an ethanol solution of the starting reagents in
the presence of a mixture of triethylamine and mor-
pholine. In all cases, the yields of compounds 1a-i were
not higher than 40% (method А) (Table 1).
Earlier, hydrogenated pyridines 9 were assumed to be
oxidized by atmospheric oxygen.[5] However, we isolated
According to the literature data, the reaction giving
pyridinethione 1h,i based on 3-pyridyl- or 4-pyridylmethylene
(cyano)thioacetamide and cyclohexanone derivatives can
give either tetrahydroquinoline or tetrahydroisoquinoline
derivatives.[7,8,23–25] In order to unambiguously establish the
structures of products of these reactions, we synthesized
adamantyl derivative 12 (Scheme 3) and studied it using X-ray
diffraction analysis.
The structure of compound 12 established by X-ray
diffraction analysis provides clear evidence that these
reactions give quinolones[7,8] rather than isoquinoline, as
it was erroneously reported earlier.[23–25]
As can be seen in Figure 1, the cyclohexene moiety in
compound 12 adopts a half-chair conformation: the
SCHEME 1 Known methods of synthesis of pyridinethiones 1
SCHEME 2 Three-component
synthesis of pyridinethiones 1

SHESTOPALOV ET AL.
3
TABLE 1 Pyridinethiones 1 by
methods A and B
Yield, %
Product 1
n
2
1
1
2
2
3
3
2
2
Ar
Method Aa
Method Ba
1a
1b
1c
1d
1e
1f
C6H5
37
36
26
24
28
14
14
42
40
56
69
58
61
54
38
41
76
73
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
3-Py
1g
1h
1i
4-Py
aMethod A: Morpholine (15 mmol), Et3N (10 mmol), cyanothioacetamide 6 (10 mmol), aldehyde 7 (10
mmol) and ketone 5 (10 mmol) in EtOH (30 mL). Stirred for 30 min, heated under reflux for 2 h. Method B:
Morpholine (15 mmol), Et3N (10 mmol), cyanothioacetamide 6 (20 mmol), aldehyde 7 (20 mmol) and
ketone 5 (10 mmol) in EtOH (30 mL). Stirred for 30 min, heated under reflux for 2 h.
SCHEME 3 4-(3-Pyridyl-) and 4-(4-pyridyl-)
pyridinethiones 1h,i
FIGURE 1 General view of molecule 12. Hydrogen atoms,
except for the N–H hydrogen atom, are omitted for clarity
С(7) and С(8) atoms deviate from the plane (flat within
0.008 Å) passing through the other four atoms by
−0.408(9) and 0.316(9) Å, respectively. The dihedral
angle between the planar part of the bicyclic moiety and
the pyridyl substituent is 55.1(3)ꢀ. The following torsion
angles describe the mutual spatial arrangement of the
substituents at the sulfur atom: C(19)–S(1)–C(2)–N(1) is
−7.2(3)ꢀ, C(2)–S(1)–C(19)–C(20) is −73.8(3)ꢀ; S(1)–C(19)–
C(20)–O(1) is 164.3(3)ꢀ, S(1)–C(19)–C(20)–N(21) is –17.2
(3)ꢀ, C(22)–N(21)–C(20)–C(19) is 179.1(3)ꢀ, and С(20)–N
(21)–C(22)–C(24) is −108.2(2)ꢀ. The observed geometry of
this moiety leads to the formation of an intramolecular
nonbonding S(1) … H(21A) interaction with a distance of
2.60 Å, which is substantially shorter than the sum of the
van der Waals radii of these atoms.[26] It should be noted,
that in the crystal the hydrogen atom H(21A) forms a
weak intermolecular N(21)–H(21A) … N(15) hydrogen
bond (x, −y + 1/2, z + 1/2) [N(21) … N(15) 3.293(5) Å, N
(21)–H(21A) 0.86 Å, H(21A) … N(15) 2.53 Å, angle N
(21)–H(21A) … N(15) is 148ꢀ], linking molecules 12 into
the infinite chains. The other geometric parameters have
standard values.[27]
We used pyridinethiones 1 in domino reactions for the
synthesis of thienodipyridines containing a polyalkoxyphenyl
substituent. The reaction of pyridinethiones 1 with
4-chloroacetoacetic ester 13 proceeds in ethanol in the
presence of an excess of 10% aqueous KOH as the domino
SN2 ! Thorpe-Ziegler ! Guareschi-Thorpe reaction. We
have described this type of domino reactions relatively
recently,[28] and this reaction only supplements the knowl-
edge of domino reactions.[29] We used this method for the
synthesis of substituted thienodipyridines 14 (Scheme 4,
Table 2).

4
SHESTOPALOV ET AL.
SCHEME 4 Domino synthesis of
substituted thienodipyridines 14
We extended the method of the synthesis of fused
produced by a known method.[30] Compound 15 reacts
with 4-chloroacetoacetic ester (13) in the presence of a
three-fold excess of KOH in ethanol (Scheme 5).
Polyannulated steroid 16 was successfully synthesized
in 68% yield by performing the reaction under reflux for
a short period of time followed by the cooling of the reac-
tion mixture and its acidification with 10% HCl.
heterocyclic compounds containing the annulated
cyclopentane moiety to the more complex 3β-oxy-5-cyano-
2-methylandrost-5-eno[17,16-c]pyridine-6(1Н)-thione (15)
TABLE 2 Substituted thienodipyridines 14
Resulting thienodipyridines 14a-e contain the
4-oxopyridine moiety and can be used in subsequent syn-
thesis. Thus, based on these compounds, we synthesized
polyannulated 2-amino-3-cyanopyrans (18) by the three-
component condensation with malononitrile 17 and aro-
matic aldehydes 7. The synthesis was performed by
heating a mixture of reagents in ethanol in the presence
of triethylamine (Scheme 6, Table 3). The scheme of the
Product 14
14a
n
1
2
2
3
3
Ar
Yield, %
3,4-(OCH3)2-C6H3
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
53
68
82
78
69
14b
14c
14d
14e
SCHEME 5 Synthesis of thienodipyridine
16 annulated with steroid system
SCHEME 6 Synthesis of
annulated pyrans 18

SHESTOPALOV ET AL.
5
TABLE 3 Annulated pyrans 18
Product
18a
n
1
2
2
3
3
Ar
3,4-(OCH3)2-C6H3
Ar1
Yield, %
C6H5
C6H5
31
66
41
68
37
18b
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
3,4-(OCH3)2-C6H3
3,4,5-(OCH3)3-C6H2
18c
4-CH3O-C6H4
C6H5
18d
18e
4-CH3O-C6H4
reaction giving annulated 2-amino-4Н-pyrans 18 can be
represented as the domino Knoevenagel ! Michael !
hetero-Thorpe-Ziegler reaction.
was 3 μL/min; nitrogen as the nebulizer gas (4 L/min);
the interface temperature was 180ꢀС.
4.2 | X-ray diffraction study
3 | CONCLUSION
Yellow monoclinic crystals of compound 12 were
obtained by the slow evaporation of an ethanolic solu-
tion. The X-ray diffraction data were collected at T =
25ꢀС: a = 15.410(6) Å, b = 13.643(3) Å, c = 13.119(5) Å, β
= 111.94(3)ꢀ, V = 2558(2) Å3, dcalc = 1.263 г/cm3, Z =
4, space group P21/с.
The unit cell parameters and the intensities of 4565
independent reflections were measured on a Siemens
P3/PC four-circle automated diffractometer (γMoKα,
graphite monochromator, θ/2θ-scanning technique to
θmax = 25ꢀ). The structure was solved by direct methods,
which revealed all nonhydrogen atoms. The structure
was refined by the full-matrix least-squares method with
anisotropic displacement parameters for nonhydrogen
atoms. The hydrogen atoms were positioned geometri-
cally and refined with fixed coordinates and thermal
parameters. The final values of the R factors were R1 =
0.0713 based on 2814 reflections with I > 2σ and Rw =
0.1898 based on 4387 reflections. All calculations were
performed using the SHELXTL program package.
To summarize, it was shown for the first time that
4-aryl-3-cyano-5,6-polymethylenepyridine-2(1Н)-thiones
can be synthesized by the three-component condensa-
tions of cycloalkanones, cyanothioacetamide, and
polymethoxy-substituted benzaldehydes. It was found
that the intermediate dihydropyridinethione is oxidized by
arylidenecyanothioacetamide that is present in the reac-
tion mixture. Pyridinethiones were transformed into
8,9-polymethylenepyranothienodipyridines by the follow-
ing two successive processes: domino SN2 ! Thorpe-
Ziegler ! Guareschi-Thorpe and domino Knoevenagel !
Michael ! hetero-Thorpe-Ziegler reactions. The method
was also successfully extended to the preparation of
thienodipyridine annulated to the steroid skeleton.
4 | EXPERIMENTAL
4.1 | General
The atomic coordinates were deposited at the Cam-
bridge Crystallographic Data Centre, deposition number
CCDC 1057468. These data can be obtained free of
charge from the Cambridge Crystallographic Data Cen-
tre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.
ccdc.cam.ac.uk/conts/retrieving.html.
The melting points were measured on a Kofler hot stage.
The IR spectra were measured on a Bruker Alpha spec-
1
trometer in KBr pellets. The Н and 13С NMR spectra
were recorded on the Jeol JNM − ECX400 (at 400 and
100 MHz, respectively), Bruker AM 300 (at 300
and 75 MHz, respectively), Bruker AM 200 (at 200 and
50 MHz, respectively), spectrometers in DMSO-d6. The
mass spectra were obtained on a Kratos MS-30 instru-
ment (70 eV). High-resolution electrospray ionization
4.3 | 4-Aryl-3-cyano-
5,6-polymethylenepyridine-2(1Н)-thiones
(1a-i)
(ESI) mass spectra were measured on
a Bruker
micrOTOF II instrument in positive (capillary voltage
was set at 4500 V) and negative (capillary voltage was set
at 3200 V) ion modes. The scan range was m/z 50 to
3000 D, the external or internal calibration (electrospray
calibrant solution, Fluka). Solutions in acetonitrile, meth-
anol, or water were supplied by a syringe; the flow rate
4.3.1 | Method А (general procedure)
Morpholine (1.3 mL, 15 mmol) and Et3N (1.4 mL,
10 mmol) were added to a mixture of cyanothioacetamide
6 (1 g, 10 mmol), the corresponding aldehyde 7a-e

6
SHESTOPALOV ET AL.
(10 mmol) and ketone 5a-c (10 mmol) in EtOH (30 mL).
In the synthesis of compounds 1h,i, piperidine (1.0 mL,
10 mmol) was used as the catalyst. The reaction mix-
ture was stirred for 30 minutes, heated under reflux for
2 hours, cooled, and neutralized with concentrated
HCl (2.2 mL, 25 mmol). The precipitate that formed
was filtered off and washed with EtOH (20 mL) and
hexane.
4-(3,4-Dimethoxyphenyl)-2-thioxo-
1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (1d)
M.p. = 272-274ꢀC. IR (ν/cm−1): 3249 (NH), 2221 (CN). 1H
NMR (DMSO-d6, 300 MHz, δ, ppm, J/Hz): 1.52-1.75 (m,
4H, 2 CH2), 2.17 (m, 2H, CH2), 2.78 (m, 2H, CH2), 3.77 (s,
3H, CH3O), 3.82 (s, 3H, CH3O), 6.87 (d, J = 8.4, 1H, Ar),
6.94 (s, 1H, Ar), 7.08 (d, J = 8.4, 1H, Ar), 13.89 (s, 1H,
NH). 13C NMR (DMSO-d6, 50 MHz, δ, ppm): 25.6, 26.7,
30.7, 32.5, 60.8, 61.0, 116.8, 117.1, 118.1, 119.3, 121.9,
125.7, 126.4, 132.5, 153.9, 154.8, 157.5, 180.6. Found
(%): C, 66.05; H, 5.78; N, 8.28.C18H18N2O2S. Calculated
(%): C, 66.23; H, 5.56; N, 8.58.
4.3.2 | Method B (general procedure)
Morpholine (1.3 mL, 15 mmol) and Et3N (1.4 mL,
10 mmol) were added to
a
mixture of cyan-
2-Thioxo-4-(3,4,5-trimethoxyphenyl)-
othioacetamide 6 (2 g, 20 mmol), the corresponding
aldehyde 7a-e (20 mmol) and ketone 5a-c (10 mmol) in
EtOH (30 mL). In the synthesis of compounds 1h,i,
piperidine (1.0 mL, 10 mmol) was used as the catalyst.
The reaction mixture was stirred for 30 minutes,
heated under reflux for 2 hours, cooled, and neutral-
ized with concentrated HCl (2.2 mL, 25 mmol). The
precipitate that formed was filtered off and washed
with EtOH (20 mL) and hexane.
1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (1e)
M.p. = 285-290ꢀC (decomp.). IR (ν/cm−1): 3174 (NH),
2227 (CN). 1H NMR (DMSO-d6, 300 MHz, δ, ppm, J/Hz):
1.52-1.75 (m, 4H, 2 CH2), 2.20 (m, 2H, CH2), 2.78 (m, 2H,
CH2), 3.72 (s, 3H, CH3O), 3.78 (s, 6H, 2 CH3O), 6.65 (s,
2H, Ar), 13.91 (s, 1H, NH). 13C NMR (DMSO-d6,
50 MHz, δ, ppm): 25.7, 26.7, 30.5, 32.5, 61.5 (2C), 65.4,
110.4 (2C), 119.2, 121.8, 126.0, 135.7, 143.0, 157.5,
158.3 (2C), 163.0, 180.6. Found (%): C, 64.22; H,
5.47; N, 7.99.C19H20N2O3S. Calculated (%): C,
64.02; H, 5.66; N, 7.86.
4-Phenyl-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-
3-carbonitrile (1a)
The spectroscopic characteristics are identical to those
described in the study,[1] m.p. = 265-267ꢀC (lit.
268ꢀC [1]).
4-(3,4-Dimethoxyphenyl)-2-thioxo-2,5,6,7,8,9-hexahydro-
1H-cyclohepta[b]pyridine-3-carbonitrile (1f)
M.p. = 253-255ꢀC. IR (ν/cm−1): 3159 (NH), 2220 (CN). 1H
NMR (DMSO-d6, 300 MHz, δ, ppm, J/Hz): 1.47 (m, 2H,
CH2), 1.59-1.79 (m, 4H, 2 CH2), 2.37 (m, 2H, CH2), 3.00
(m, 2H, CH2), 3.76 (s, 3H, CH3O), 3.82 (s, 3H, CH3O),
6.83 (d, J = 8.1, 1H, Ar), 6.89 (s, 1H, Ar), 7.09 (d, J = 8.1,
1H, Ar), 13.95 (s, 1H, NH). 13C NMR (DMSO-d6,
50 MHz, δ, ppm): 30.3, 31.4, 33.5, 36.1, 37.8, 60.79,
60.95, 116.9, 117.1, 119.1, 125.8, 129.1, 132.1, 133.1,
153.9, 154.6, 162.5, 164.1, 179.8. Found (%): C, 67.43; H,
5.88; N, 8.53. C19H20N2O2S. Calculated (%): C, 67.03; H,
5.92; N, 8.23.
4-(3,4-Dimethoxyphenyl)-2-thioxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b]pyridine-3-carbonitrile (1b)
M.p. = 255-258ꢀC. IR (ν/cm−1): 3182 (NH), 2218 (CN). 1H
NMR (DMSO-d6, 300 MHz, δ, ppm, J/Hz): 2.03 (m, 2H,
CH2), 2.64 (m, 2H, CH2), 2.97 (m, 2H, CH2), 3.79 (s, 3H,
CH3O), 3.83 (s, 3H, CH3O), 7.05-7.15 (m, 3H, Ar), 14.27
(s, 1H, NH). 13C NMR (DMSO-d6, 50 MHz, δ, ppm): 27.6,
34.8, 36.9, 60.8, 60.9, 116.8, 117.2, 122.7, 126.6, 132.0,
134.7, 137.7, 153.7, 155.4, 159.3, 164.0, 182.2. Found
(%): C, 65.55; H, 5.13; N, 9.12. C17H16N2O2S. Calculated
(%): C, 65.36; H, 5.16; N, 8.97.
2-Thioxo-4-(3,4,5-trimethoxyphenyl)-
2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridine-
3-carbonitrile (1g)
2-Thioxo-4-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-
1H-cyclopenta[b]pyridine-3-carbonitrile (1c)
M.p. = 264-266ꢀC. IR (ν/cm−1): 3171 (NH), 2221 (CN). 1H
NMR (DMSO-d6, 300 MHz, δ, ppm, J/Hz): 1.50 (m, 2H,
CH2), 1.58-1.78 (m, 4H, 2 CH2), 2.37 (m, 2H, CH2), 3.02
(m, 2H, CH2), 3.73 (s, 3H, CH3O), 3.78 (s, 6H, 2 CH3O),
6.63 (s, 2H, Ar), 13.98 (s, 1H, NH). 13C NMR (DMSO-d6,
50 MHz, δ, ppm): 30.2, 31.3, 33.6, 36.2, 37.7, 61.3 (2C),
65.4, 110.5 (2C), 118.8, 122.1, 132.1, 136.4, 142.9, 158.2,
162.4, 164.3 (2C), 179.7. Found (%): C, 65.04; H, 5.73; N,
7.44. C20H22N2O3S. Calculated (%): C, 64.84; H,
5.99; N, 7.56.
M.p. = 275-280ꢀC (decomp.). IR (ν/cm−1): 3173 (NH),
2224 (CN). 1H NMR (DMSO-d6, 300 MHz, δ, ppm, J/Hz):
2.04 (m, 2H, CH2), 2.67 (m, 2H, CH2), 2.98 (m, 2H, CH2),
3.74 (s, 3H, CH3O), 3.80 (s, 6H, 2 CH3O), 6.86 (s, 2H, Ar),
14.37 (s, 1H, NH). 13C NMR (DMSO-d6, 75 MHz, δ, ppm):
21.6, 29.9, 31.0, 55.6 (2C), 59.6, 105.4 (2C), 111.6, 116.7,
126.1, 129.3, 138.0, 152.3 (2C), 153.5, 158.4, 176.4. Found
(%): C, 63.04; H, 5.44; N, 8.35. C18H18N2O3S. Calculated
(%): C, 63.14; H, 5.30; N, 8.18.

SHESTOPALOV ET AL.
7
4-(3-pyridyl)-2-thioxo-2,5,6,7-tetrahydro-1H-cyclopenta
[b]pyridine-3-carbonitrile (1h)
37.9 (3C, Ad), 52.7, 104.1, 115.0, 123.7, 126.4, 131.0, 136.1,
148.3, 150.2, 157.6, 161.6, 166.1, 177.8. Found (%): C
71.38, H 6/95, N 11.42. C29H34N4OS: Calculated (%): C
71.57, H 7.04, N 11.51.
M.p. = 274-276ꢀC (lit. 273-275ꢀC [25]), the spectroscopic
characteristics are identical to those described in the
study.[7]
4-(4-Pyridyl)-2-thioxo-2,5,6,7-tetrahydro-1H-cyclopenta
[b]pyridine-3-carbonitrile (1i)
4.6 | Synthesis of 4-aryl-3-cyano-
5,6-polymethylenedipyridothiophenes
(14a-e) (general procedure)
M.p. = 309-311ꢀC (284ꢀC [25]), the spectroscopic charac-
teristics are identical to those described in the study.[7]
A 20% aqueous KОН solution (0.4 mL, 1.4 mmol) was
added to a suspension of pyridinethione 1c-g (1 mmol) in
EtOH (10 mL). Then 4-chloroacetoacetic ester 13 (0.14
mL, 1 mmol) was added dropwise, and the mixture was
stirred for 20 minutes. A 20% aqueous KОН solution (0.4
mL, 1.4 mmol) in water was added to the reaction mix-
ture containing a precipitate. The mixture was refluxed
for 1.5 hours, cooled, neutralized with concentrated HCl,
and diluted with water (3-4 mL). The precipitate that
formed was filtered off, washed with water, a water-
ethanol mixture, and hexane.
4.4 | 2-Cyano-
3-phenylpropanethioamide (10a)
In the synthesis of 4-phenyl-2-thioxo-1,2,5,6,7,8-hexa-
hydroquinoline-3-carbonitrile (1a) using the method А,
the reaction mixture obtained after the separation of the
reaction product was allowed to stand for 48 hours at
8ꢀС. The precipitate that formed was filtered off and rec-
rystallized twice from AcOEt. Benzylcyanothioacetamide
(10a) was obtained in a yield of 28%.
M. p. = 148-150ꢀС. IR (ν/cm−1): 3379, 3262, 3166
(NH2); 2247 (CN). 1H NMR (DMSO-d6, 400 MHz, δ, ppm,
J/Hz): 3.16 (m, 2H, CH2); 4.29 (t, J = 10.6; lH, CH);
7.18-7.35 (m, 5H, Ph); 9.51 (s, 1Н, NH2), 9.92 (s, 1Н,
NH2). 13C NMR (DMSO-d6, 100 MHz, δ, ppm): 39.4, 47.5,
118.9, 127.7, 129.1 (2C), 129.6 (2C), 136.9, 198.6. Found
(%): C, 63.31; H, 5.18; N, 14.89. C20H22N2O3S. Calculated
(%): C, 63.13; H, 5.30; N, 14.72.
4.6.1 | 4-Hydroxy-10-(3,4-
dimethoxyphenyl)-8,9-dihydro-1H-
cyclopenta[e]thieno[2,3-b:4,5-b0]dipyridin-2
(7H)-one (14a)
M.p. = 285-290ꢀC (decomp.). IR (ν/cm−1): 3578 (OH),
1
3347 (NH), 1631 (CO). H NMR (DMSO-d6, 400 MHz, δ,
ppm, J/Hz): 2.03 (m, 2H, CH2), 2.72 (m, 2H, CH2), 3.01
(m, 2H, CH2), 3.73 (s, 3H, OCH3), 3.85 (s, 3H, OCH3),
5.70 (s, 1H, CH), 7.01 (dd, J = 8.1, J = 2.0, 1H, Ar), 7.13
(d, J = 2.0, 1H, Ar), 7.15 (br. s, 1H, OH, OH protons are
associated with water and overlapped with the signal of
Ar), 7.16 (d, J = 8.1, 1H, Ar), 11.7 (br. s, 1H, NH, NH protons
are associated with water). 13C NMR (DMSO-d6, 100 MHz, δ,
ppm): 23.3, 29.4, 34.5, 56.1, 56.3, 96.9, 109.2, 112.4, 112.6,
118.9, 121.1, 126.9, 134.1, 141.3, 149.1, 149.7, 149.9, 159.7,
162.7, 162.9, 167.0. Found (%): C, 63.87; H, 4.78; N, 7.08.
C21H18N2O4S. Calculated (%): C, 63.95; H, 4.60; N, 7.10.
4.5 | N-(1-(adamantan-1-yl)ethyl)-
2-((3-cyano-4-(pyridin-3-yl)-
5,6,7,8-tetrahydroquinolin-2-yl)thio)
acetamide (12)
A 10% aqueous KОН solution (5.6 mL) was added to a
solution of pyridinethione 1h (2.29 g, 10 mmol) in DMF
(15 mL). The reaction mixture was stirred for 10 minutes,
and then N-(1-(adamantan-1-yl)ethyl)-2-chloroacetamide
11 (2.56 g, 10 mmol) was added. The reaction mixture
was stirred for 30 minutes and diluted with water (10-15
mL). The precipitate was filtered off, washed with water,
and recrystallized from ethanol to obtain 12 (4.38 g, 90%)
4.6.2 | 4-Hydroxy-11-(3,4-
dimethoxyphenyl)-7,8,9,10-tetrahydropyrido
[20,30:4,5]thieno[2,3-b]quinolin-2(1H)-
one (14b)
1
as a yellow solid; m.p. = 178-179ꢀС. H NMR (DMSO-d6,
300 MHz, δ, ppm, J/Hz): 0.95 (d, 3H, CH3, J = 6.7 Hz),
1.44-1.91 (m, 19H, CH2-CH2, Ad), 2.36 (m, 2H, CH2), 2.93
(s, 2H, S-CH2), 3.52 (m, 1H, CH), 4.00 (m, 2H, SH2), 7.59
(m, 1H, Py), 7.67 (d, J = 9.4 Hz, 1H, Py), 7.85 (d, J = 7.7
Hz, 1H, Py), 8.57 (s, 1H, Py), 8.72 (d, J = 4.4 Hz, 1H,
NH). 13C NMR (DMSO-d6, 75 MHz, δ, ppm): 14.1, 21.6,
21.6, 26.2, 27.8 (3C, Ad), 33.1, 33.8, 35.6, 36.6 (3C, Ad),
M.p. > 300ꢀC. IR (ν/cm−1): 3507 (OH), 3363, 3377 (NH),
1
3175 (NH), 1634 (CO). H NMR (DMSO-d6, 400 MHz, δ,
ppm, J/Hz): 1.66 (m, 2H, CH2), 1.80 (m, 2H, CH2), 2.47
(m, 2H, CH2), 2.98 (m, 2H, CH2), 3.72 (s, 3H, OCH3), 3.84
(s, 3H, OCH3), 5.64 (s, 1H, CH), 6.92(d, J = 8.1, 1H, Ar),

8
SHESTOPALOV ET AL.
7.02 (s, 1H, Ar), 7.19 (d, J = 8.1, 1H, Ar), 7.45 (br. s, 1H,
OH, OH protons are associated with water), 11.77 (br. s,
1H, NH, NH protons are associated with water). 13C
NMR (DMSO-d6, 100 MHz, δ, ppm): 22.6, 22.7, 26.6, 33.6,
56.2, 56.4, 97.4, 109.0, 112.1, 112.9, 119.5, 119.6, 120.7, 126.8,
128.4, 144.9, 149.8, 150.0, 157.6, 158.8, 162.7, 162.8. Found
(%): C, 64.77; H, 4.80; N, 6.94.C22H20N2O4S. Calculated
(%): C, 64.69; H, 4.94; N, 6.86.
2H, CH2), 2.60 (m, 2H, CH2), 3.12(m, 2H, CH2), 3.74 (s, 6H,
2OCH3), 3.82 (s, 3H, OCH3), 5.61 (s, 1H, CH), 6.76 (s, 2H, Ar),
7.42 (s, 1H, OH), 11.88 (s, 1H). 13C NMR (DMSO-d6, 100 MHz,
δ, ppm): 26.7, 27.7, 29.1, 31.9, 39.6, 56.9 (2C), 61.0, 97.5, 106.3
(2C), 109.0, 119.2, 130.7, 133.7, 135.3, 138.4, 143.6, 154.2 (2C),
156.8, 162.8 (2C), 164.8. Found (%): C, 63.69; H, 5.66; N, 6.13.
C24H24N2O5S. Calculated (%): C, 63.70; H, 5.35; N, 6.19.
4.7 | Synthesis of 70-methyl-3β,40-
dioxyandrost-5-eno[17,16-с]thieno[20,30-
b:40,50-b0]dipyridin-20(1H)-one (16)
4.6.3 | 4-Hydroxy-11-(3,4,5-
trimethoxyphenyl)-7,8,9,10-tetrahydropyrido
[20,30:4,5]thieno[2,3-b]quinolin-2(1H)-one (14c)
A 10% aqueous KOH solution (0.18 mL, 0.45 mmol) and then
4-chloroacetoacetic ester 13 (0.075 g, 0.45 mmol) were added to
a solution of thione 15 (0.18 g, 0.45 mmol) in ethanol (5 mL).
The reaction mixture was stirred for 30 minutes, and then 10%
aqueous KOH (0.36 mL, 0.9 mmol) was added. The reaction
mixture was heated under reflux for 2 hours and then cooled,
H2O (5 mL) was added, the mixture was acidified with HCl to
acidic pH values, and the precipitate that formed was filtered
off. Thienodipyridine 16 was obtained in a yield of 0.146 g
(68%) M.p. > 300ꢀC. IR (ν/cm−1): 3396 (br, OH, NH), 1629
M.p. > 300ꢀC. IR (ν/cm−1): 3549 (OH), 3365 (NH), 1636
(CO). H NMR (DMSO-d6, 400 MHz, δ, ppm, J/Hz): 1.69
1
(m, 2H, CH2), 1.82 (m, 2H, CH2), 2.54 (m, 2H, CH2), 3.00
(m, 2H, CH2), 3.75 (m, 9H, 3OCH3), 5.65 (s, 1H, CH),
6.75 (s, 2H, Ar), 7.47 (s, 1H, OH), 11.79 (br. s, 1H, NH).
13C NMR (DMSO-d6, 100 MHz, δ, ppm): 22.6, 22.7, 26.4,
33.6, 56.7, 56.9, 60.9, 97.6, 105.9, 108.9, 119.2, 128.0,
130.1, 135.1, 138.4, 144.7, 148.5, 153.6, 154.1, 154.3, 157.5,
158.8, 162.8. Found (%): C, 62.85; H, 5.29; N, 6.48.
C23H22N2O5S. Calculated (%): C, 63.00; H, 5.06; N, 6.39.
1
(С С, СО). H NMR (δ, ppm, J/Hz): 1.00 (s, 3Н, С(18)Н3);
1.04 (s, 3Н, С(19)Н3); 1.15-1.40 (m, 5Н, СН, СН2); 1.60-1.85
(m, 8Н, СН, СН2); 2.05-2.23 (m, 4Н, СН, СН2); 2.60 (s, 3Н,
С(70)СН3); 4.19 (m, 1Н, СНОН); 5.36 (m, 1Н, С СН); 6.15 (s,
1Н, (30)Н); 12.04 (s, 1Н, NH). Due to the hydrogen/deuterium
solvent exchange, the signals of protons of ОН groups are not
observed in the spectrum. High-resolution MS (ESI, m/z):
Calculated: C28H32N2OS [M + Na] 499.2026, Found: 499.2017.
4.6.4 | 4-Hydroxy-12-(3,4-
dimethoxyphenyl)-8,9,10,11-tetrahydro-1H-
cyclohepta[e]thieno[2,3-b:4,5-b0]dipyridin-2
(7H)-one (14d)
M.p. > 300ꢀC. IR (ν/cm−1): 3349 (NH), 1632 (CO). 1H NMR
(DMSO-d6, 400 MHz, δ, ppm, J/Hz): 1.53 (m, 2H, CH2),
1.68 (m, 2H, CH2), 1.78 (m, 2H, CH2), 2.61 (m, 2H, CH2),
3.14 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
5.64 (s, 1H, CH), 6.90 (dd, J = 7.3, J = 2.0, 2H, Ar), 6.98
(d, 1H, J = 2.0, Ar), 7.20 (d, J = 7.3, 2H, Ar), 7.41 (br. s, 1H,
OH, OH protons are associated with water), 11.53 (br. s,
1H, NH). 13C NMR (DMSO-d6, 100 MHz, δ, ppm): 26.6,
27.7, 29.0, 31.7, 39.3, 56.5, 56.7, 97.5, 109.3, 113.1, 113.4,
119.7, 121.2, 127.7, 133.9, 143.5, 143.6, 150.1, 150.2, 157.1,
162.7, 162.8, 164.6. Found (%): C, 65.31; H, 5.39; N, 6.44.
C23H22N2O4S. Calculated (%): C, 65.39; H, 5.25; N, 6.63.
4.8 | Synthesis of polyannulated pyrans
(18a-e) (general procedure)
A solution of malononitrile 17 (0.066 g, 1 mmol), the
corresponding pyridinone 14a-e (1 mmol), aldehyde 7a,f
(1 mmol), and triethylamine (0.1 mL, 0.5 mmol) in EtOH
(10 mL) was refluxed with stirring for 1 hour. Then the
reaction mixture was cooled, neutralized with HBr, and
diluted with water. The precipitate was filtered off and
washed with hot water, ethanol, and hexane.
4.6.5 | 4-Hydroxy-12-(3,4,5-
4.8.1 | 2-Amino-3-cyano-7-(3,4-
trimethoxyphenyl)-8,9,10,11-tetrahydro-1H-
cyclohepta [e]thieno[2,3-b:4,5-b0]dipyridin-2
(7H)-one (14e)
dimethoxyphenyl)-4-phenyl-
4,8,9,10-tetrahydrocyclopenta[e]pyrano[2,3-d0]
thieno[2,3-b:4,5-b0]dipyridin-5(6H)-one (18a)
M.p. > 300ꢀC. IR (ν/cm−1): 3570 (OH), 3374, 3359 (NH),
3183 (NH), 1637 (CO). H NMR (DMSO-d6, 400 MHz, δ,
M.p. = 265-267ꢀC. IR (ν/cm−1): 3543 (OH), 3351 (NH2),
3193 (NH), 2200 (CN), 1675 (CO). H NMR (DMSO-d6,
1
1
ppm, J/Hz): 1.54 (m, 2H, CH2), 1.66 (m, 2H, CH2), 1.80 (m,
300 MHz, δ, ppm, J/Hz): 2.13 (m, 2H, CH2), 2.85 (m, 2H,

SHESTOPALOV ET AL.
9
CH2), 3.17 (m, 2H, CH2), 3.77 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 4.42 (s, 1H, CH), 7.20-7.05 (m, 11H, Ar + NH2),
8.27 (s, 1H, NH). Found (%): C, 67.65; H, 4.33; N, 10.18.
C31H24N4O4S. Calculated (%): C, 67.87; H, 4.41; N, 10.21.
ppm, J/Hz): 1.56 (m, 2H, CH2), 1.74-1.82 (m, 4H,
CH2,CH2), 2.65 (m, 2H, CH2), 3.46 (m, 2H, CH2),
3.70-3.86 (m, 6H, 2OCH3), 4.38 (s, 1H, CH), 6.97-7.24 (m,
10H, Ar + NH2), 7.70 (s, 1H, NH). Found (%): C,
68.55; H, 5.01; N, 9.64. C33H28N4O4S. Calculated (%): C,
68.73; H, 4.89; N, 9.72.
4.8.2 | 2-Amino-3-cyano-7-(3,4-
dimethoxyphenyl)-4-phenyl-4,6,8,9,10,11-
hexahydro-5H-pyrano[200,300:40,50]pyrido
[20,30:4,5]thieno[2,3-b]quinolin-5-one (18b)
4.8.5 | 2-Amino-3-cyano-
7-(3,4,5-trimethoxyphenyl)-
4-(4-methoxyphenyl)-
4,8,9,10,11,12-hexahydrocyclohepta[e]
pyrano[2,3-d0]thieno[2,3-b:4,5-b0]dipyridin-5
(6H)-one (18e)
M.p. = 238-241ꢀC. IR (ν/cm−1): 3360 (NH2), 3182 (NH),
1
2196 (CN), 1673 (CO). H NMR (DMSO-d6, 400 MHz, δ,
ppm, J/Hz): 1.72 (m, 4H, CH2CH2), 2.47 (m, 2H, CH2), 2.98
(m, 2H, CH2), 3.62, 3,71 (s, s, 3H, OCH3), 3.77, 3.79 71 (s, s,
3H, OCH3), 4.30 (s, 1H, CH), 6.83-7.24 (m, 10 H, Ar + NH2),
7.71 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz, δ, ppm):
22.6 (2C), 26.5, 33.6, 37.5, 56.3, 56.5, 58.7, 105.7, 109.0, 112.3,
112.4, 113.2, 119.1, 119.9, 120.4, 120.8, 127.3, 128.0, 128.1,
128.8 (2C), 134.7, 144.4, 144.5, 150.1, 150.3, 152.1, 157.5,
159.0, 159.5, 159.6. Found (%): C, 68.39; H, 4.47; N, 10.17.
C32H26N4O4S. Calculated (%): C, 68.31; H, 4.66; N, 9.96.
M.p. = 223-225ꢀC. IR (ν/cm−1): 3568 (OH), 3353 (NH2),
3176 (NH), 2200 (CN), 1672 (CO). H NMR (DMSO-d6,
1
400 MHz, δ, ppm, J/H): 1.58 (m, 2H, CH2), 1.76 (m, 4H,
CH2CH2), 2.66 (m, 2H, CH2), 3.18 (m, 2H, CH2), 3.68
(s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.77 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 4.35 (s, 1H, CH), 6.66 (s, 1H, Ar), 6.71
(s, 1H, Ar), 6.77 (d, J = 8.8, 2H, Ar0), 6.85 (s, 2H, NH2),
7.08 (d, J = 8.8, 2H, Ar0), 7.74 (s, 1H, NH). 13C NMR
(DMSO-d6, 100 MHz, δ, ppm): 26.6, 27.7, 29.1, 31.5,
36.8, 39.3, 55.7, 57.2, 57.4, 59.8, 61.0, 106.2, 107.2,
107.4, 109.4, 114.5 (2C), 119.2, 119.6, 128.5, 129.1 (2C),
130.3, 133.9, 136.6, 139.6, 143.7, 152.0, 154.5 (2C),
157.1, 159.0, 159.1, 159.8, 165.3. Found (%): С,
66.11; H, 5.18; N, 9.01. C35H32N4O6S. Calculated (%):
С, 66.02; H, 5.07; N, 8.80.
4.8.3 | 2-Amino-3-cyano-
4-(4-methoxyphenyl)-
7-(2,3,4-trimethoxyphenyl)-
4,6,8,9,10,11-hexahydro-5H-pyrano
[200,300:40,50]pyrido[20,30:4,5]thieno[2,3-b]
quinolin-5-one (18c)
M.p. = 272-274ꢀC. IR (ν/cm−1): 3353, 3319 (NH2), 3191 (NH),
2208 (CN), 1674 (CO). H NMR (DMSO-d6, 400 MHz, δ,
ORCID
1
Anatoliy M. Shestopalov https://orcid.org/0000-0003-
ppm, J/Hz): 1.76 (m, 4H, CH2CH2), 2.52 (m, 2H, CH2), 3.04
(m, 2H, CH2), 3.62 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.71
(s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.29 (s, 1H, CH), 6.72
(s, 1H, Ar), 6.75 (s, 1H, Ar), 6.77 (d, J = 8.8, 2H, Ar1), 7.05
1539-3938
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(d, J = 8.8, 2H, Ar1), 7.21 (s, 2H, NH2), 7.75 (s, 1H, NH). 13
C
[2] Litvinov, V. P.; Sharanin, Yu. A.; Shestopalov, A. M. Sulfur
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NMR (DMSO-d6, 100 MHz, δ, ppm): 22.5, 22.6, 26.3, 33.7,
36.8, 55.7, 57.2, 57.3, 59.7, 61.0, 105.9, 106.8, 107.0, 109.4,
114.5 (2C), 119.1, 119.7, 128.6, 129.1 (2C), 129.8, 134.6, 136.6,
139.6, 144.7, 152.0, 154.6 (2C), 157.7, 158.9, 159.2, 159.6,
159.8. Found (%): C, 65.42; H, 4.97; N, 9.11.
C34H30N4O6S. Calculated (%): C, 65.58; H, 4.86; N, 9.00.
[3] Sharanin, Yu. A.; Litvinov, V. P.; Shestopalov, V. P.; Nesterov, V. N.;
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4.8.4 | 2-Amino-3-cyano-7-(3,4-
dimethoxyphenyl)-4-phenyl-4,8,9,10,11,12-
hexahydrocyclohepta[e]pyrano[2,3-d0]thieno
[2,3-b:4,5-b0]dipyridin-5(6H)-one (18d)
M.p. = 248-250ꢀC. IR (ν/cm−1): 3370 (NH2), 3200 (NH),
1
2207 (CN), 1677 (CO). H NMR (DMSO-d6, 300 MHz, δ,

10
SHESTOPALOV ET AL.
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How to cite this article: Shestopalov AM,
Rodinovskaya LA, Zubarev AA, Nesterov VN,
Ugrak BI, Dutova TY. Synthesis and domino
reactions of polymethylene-3-cyanopyridine-2(1Н)-
thiones. J Heterocyclic Chem. 2019;1–10. https://
doi.org/10.1002/jhet.3836