Novel multicomponent synthesis of 6,7-dihydro-5H-cyclopenta[b]pyridine derivatives

Article abstract of DOI:10.1007/s10593-020-02854-7

[Figure not available: see fulltext.] The multicomponent condensation of malononitrile, hydrogen sulfide, aldehydes, 1-(cyclopent-1-en-1-yl)pyrrolidine, and alkylating agents leads to the formation of 6,7-dihydro-5H-cyclopenta[b]pyridine derivatives. The structure of a number of heterocycles obtained on their basis was studied by X-ray structural analysis.

Full text of DOI:10.1007/s10593-020-02854-7

DOI 10.1007/s10593-020-02854-7
Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
Novel multicomponent synthesis of
6,7-dihydro-5H-cyclopenta[b]pyridine derivatives
Ivan V. Dyachenko1, Vladimir D. Dyachenko1, Pavel V. Dorovatovskii2,
Victor N. Khrustalev3,4, Valentine G. Nenajdenko5*
1 Luhansk Taras Shevchenko National University,
2 Oboronna St., Luhansk 91011, Ukraine; e-mail: ivladya87@mail.ru
2 National Research Center ''Kurchatov Institute'',
1 Akademika Kurchatova Sq., Moscow 123182, Russia; e-mail: paulgemini@mail.ru
3 RUDN University,
6 Miklukho-Maklaya St., Moscow 117198, Russia; e-mail: khrustalev-vn@rudn.ru
4 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: vnkhrustalev@gmail.com
5 Lomonosov Moscow State University,
1, Build. 3 Leninskie Gory, Moscow 119991, Russia; e-mail: nenajdenko@gmail.com
Submitted June 13, 2020
Accepted after revision November 19, 2020
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(12), 1592–1598
The multicomponent condensation of malononitrile, hydrogen sulfide, aldehydes, 1-(cyclopent-1-en-1-yl)pyrrolidine, and alkylating
agents leads to the formation of 6,7-dihydro-5H-cyclopenta[b]pyridine derivatives. The structure of a number of heterocycles obtained on
their basis was studied by X-ray structural analysis.
Keywords: aldehydes, alkylating agents, 1-(cyclopent-1-en-1-yl)pyrrolidine, 6,7-dihydro-5H-cyclopenta[b]pyridines, hydrogen sulfide,
malononitrile, multicomponent synthesis, X-ray structural analysis.
Cyclopenta[b]pyridine derivatives are structural frag-
ments of alkaloids1 and exhibit a wide spectrum of
biological activity. Thus, derivatives with hypoglycemic
activity,2 antagonists of calcium channels,3 fluorescent
probes,4 and inhibitors of protein kinase FGFR15 were
found among these compounds. The main methods of the
synthesis of cyclopenta[b]pyridines principally involve
annulation of the pyridine ring to substituted cyclo-
pentanone6 or to its enamine.7 Synthesis of these com-
pounds from linear molecules8 and by intramolecular
recyclization of substituted pyrimidine9 is possible.
multicomponent condensations,11 we studied a novel
version of this type of synthesis based on the reaction of
malononitrile (1), hydrogen sulfide (2), aldehydes 3a–g,
1-(cyclopent-1-en-1-yl)pyrrolidine (4), alkylating agents
5а–h, and Et3N. This reaction represents a profound
structural transformation. According to chromatography
data, cyanothioacetamide (6) is initially formed which then
undergoes the Knoevenagel condensation with aldehydes
3a–g. The resulting alkenes 7 are involved in the Stork
alkylation with enamine 4. The obtained adducts 8 undergo
intramolecular cyclotransamination with the formation of
salts 9 containing the target bicyclic cyclopenta[b]pyridine
structure. The addition of alkylating agents 5а–h to the
reaction mixture leads to the production of thioesters 10
Considering the high practical importance of cyclopenta-
[b]pyridine derivatives, the promise of domino reactions
for organic synthesis,10 in continuation of our studies of
0009-3122/20/56(12)-1592©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
Scheme 1
R
CN
R
CN
S
3a–g
CN
+
CN
Et3N
CN
S
H2S
+
RCHO
+
N
+
Hal
5a–h
Z
NH2
EtOH, 20°C
H2N
S
2
3a–g
N
4
H2N
1
6
7
8
R
R
CN
S
5a–h
CN
NH2
S
Z
N
H
N
H
10
9
(From 3a,b,d–g, 5e–f)
KOH, H2O
(From 3d, 5c)
Ac2O, , 2 h
81%
(From 3c, 5d)
HCONH2, , 4 h
76%
(From 3a, 5a)
(From 3b, 5b)
68%
78%
DMF, 29 h
67–82%
R
Et
OAc
NH2
N
Ph
CN
NC
N
Ph
N
NH2
Z
S
N
S
S
S
N
15a–f
CN
S
N
14
CN
SMe
11
Ph
N
12
N
13
3 a R = Ph, b R = cyclohex-3-enyl, c R = Et, d R = 4-HOC6H4, e R = 4-Me2CHC6H4, f R = 4-ClC6H4, g R = 4-O2NC6H4
5 a Hal = Br, Z = CH2Br; b Hal = Cl, Z = Ph; c Hal = I, Z = H; d Hal = Cl, Z = CN; e Hal = Br, Z = 4-ClC6H4CO; f Hal = Br, Z = PhCO;
g Hal = Cl, Z = CO2Et; h Hal =Cl, Z = CONH2
15 a R = 4-Me2CHC6H4, Z = 4-ClC6H4CO; b R = 4-ClC6H4, Z = PhCO; c R = 4-HOC6H4, Z = 4-ClC6H4CO;
d R = cyclohex-3-enyl, Z = CO2Et; e R = Ph, Z = CONH2; f R = 4-O2NC6H4, Z = CONH2
(Scheme 1), which, by aromatization of the dihydro-
pyridine ring, apparently with atmospheric oxygen, are
converted into various end products, as shown below.
The use of 1,2-dibromoethane (5а) as an alkylating
agent makes it possible to synthesize 2,2'-[ethane-
1,2-diylbis(sulfanediyl)]bis(4-phenyl-6,7-dihydro-5H-cyclo-
penta[b]pyridine-3-carbonitrile) (11), whereas the use of
benzyl chloride (5b) leads to the formation of
2-benzylsulfanyl-4-(cyclohex-3-en-1-yl)-6,7-dihydro-5H-
cyclopenta[b]pyridine-3-carbonitrile (12).
When p-hydroxybenzaldehyde (3d) and MeI (5c) are
introduced into this multicomponent reaction and its
product is heated under reflux in Ac2O, esterification of the
hydroxy group of the phenol substituent occurs with the
formation of 4-(3-cyano-2-methylsulfanyl-6,7-dihydro-5H-
cyclopenta[b]pyridin-4-yl)phenyl acetate (13).
The use of chloroacetonitrile (5d) as an alkylating agent
and heating of the reaction product under reflux in
formamide results in the formation of the tetracyclic system
10-ethyl-8,9-dihydro-7H-cyclopenta[5',6']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidin-4-amine (14).
Substituted 3-amino-6,7-dihydro-5H-cyclopenta[b]thieno-
[3,2-e]pyridines 15a–f are easily formed when active
methylene halogen derivatives 5e–f are used as alkylating
agents. The closure of the thiophene ring is catalyzed by an
aqueous KOH in DMF.
The spectral data confirm the structure of the synthe-
sized compounds 11–14, 15a–f. IR spectra contain
characteristic absorption bands of the stretching vibrations
of the conjugated cyano group, amino and carbonyl moieties.
1
The H NMR spectra exhibit signals of the protons of
the trimethylene moiety, aromatic substituents, amino
group, and alkylsulfanyl group with the characteristic
splitting patterns and chemical shifts. 13C NMR spectra
contain signals of all carbon atoms with the typical
chemical shift values.
Of note is the doubling of some signals in the 1H and 13C
NMR spectra of compound 14 which can apparently be
explained by tautomerism of the aminopyrimidine frag-
ment.
To elucidate the mechanism of the considered multi-
component reaction and unambiguously establish the
structure of its products, compounds 11, 12, and 15a,b
were studied by X-ray structural analysis (Figs. 1–4)
Compound 11 exists as a dimer in which two
6,7-dihydro-5H-cyclopenta[b]pyridine fragments are joined
via an ethylene disulfide bridge and which has its own
inversion center. A solvate 1,4-dioxane molecule was
revealed in the solid state occupying a particular position in
the inversion center. The central 6,7-dihydro-5H-cyclo-
penta[b]pyridine fragments in compounds 11 and 12 have a
characteristic structure with a cyclopentene ring in the
envelope conformation.4 The phenyl substituent in
compound 11 is rotated relative to the basal plane of the
central bicyclic fragment (standard deviation is 0.018 Å) by
52.58(6)°. The ethylene disulfide bridge conformation is
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Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
Figure 1. Molecular structure of compound 11·C4H8O2 with
atoms represented as thermal vibration ellipsoids of 50%
probability. Dashed lines show alternative positions of disordered
fragments.
g-t-g (t – trans, 180°; g – gauche,
60°), which is
Figure 3. Molecular structure of compound 15a with atoms
represented as thermal vibration ellipsoids of 50% probability
(one of six crystallographically independent molecules is
presented). Dotted lines depict intramolecular hydrogen bonds
N–H···O and N–H···π.
described by the three torsion angles C(2)–S(1)–C(1)–C(1A),
S(1)–C(1)–C(1A)–S(1A), and C(1)–C(1A)–S(1A)–C(2A),
respectively.4 The cyclohexene ring in compound 12 has
the half-chair conformation with a carbon atom C(15) out
of the plane drawn through the rest of the ring atoms (the
standard deviation is 0.016 Å) by 0.432(8)Å. The angle
between the basal planes of the cyclohexene ring and the
central bicyclic fragment in compound 12 is 87.15(16)°.2
The benzylsulfide substituent is trans-arranged with respect
to the central bicyclic fragment, and the angle between the
plane of the benzyl substituent and the basal plane of the
central bicyclic structure is 60.96(8)°. In the solid state, the
molecules of compounds 11 and 12 are stacked along the
crystallographic a axis and are located at the distances of
the van der Waals radii.
Figure 4. Molecular structure of compound 15b with atoms
represented as thermal vibration ellipsoids of 50% probability
(one of six crystallographically independent molecules is
presented). Dotted lines depict intramolecular hydrogen bonds
N–H···O and N–H···π(С=С).
Figure. 2. Molecular structure of compound 12 with atoms
represented as thermal vibration ellipsoids with 40% probability.
Compound 15a crystallizes with six crystallographically
independent molecules in the unit cell, differing mainly in
the orientation of the chlorophenyl substituent relative to
the central tricyclic 6,7-dihydro-5H-cyclopenta[b]thieno-
[3,2-e]pyridine fragment: in three molecules, the
corresponding interplanar angle is 50.39(7), 50.55(7), and
50.58(7)°, while in the other three it is respectively 134.81(7),
134.78(7), and 134.71(7)°. It is important to note that the
conformation of molecule 15b corresponds to an orienta-
tion with the interplanar angle of 53.98(5)°.
The structure of molecules 15a,b is largely determined
by the presence of quite strong intramolecular hydrogen
bonds N–H···O and N–H···π(C=C) (Table 1). As a result,
the amino and carbonyl groups in both compounds are
practically coplanar to the thieno[3,2-e]pyridine fragment.
The cyclopentene rings in compounds 15a,b assume the
typical envelope conformations, and 4-phenyl substituents
are rotated relative to the basal plane of the central tricyclic
fragment (the standard deviations are 0.025, 0.024, 0.045,
0.025, 0.045, and 0.044 Å for six crystallographically
1594

Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
Table 1. Hydrogen bonds and their characteristics
(bond lengths and angles) in structures 15a,b
DHA angle,
d(D–H), d(H···A), d(D···A),
D–H···A
Å
Å
Å
°
Compound 15a
N(3)–H(3B) ··O(1)
0.82(3)
0.82(3)
0.87(3)
0.87(3)
0.93(3)
2.15(3)
2.744(3)
2.951(3)
2.746(3)
2.948(3)
2.718(3)
3.063(3)
2.963(3)
2.760(3)
2.723(3)
3.060(3)
3.055(3)
2.721(3)
129(2)
140(2)
127(2)
140(2)
124(2)
152(2)
143(3)
124(3)
130(2)
147(2)
154(2)
124(2)
N(3)–H(3B) ··O(1)*
N(26)–H(26B)···O(2)
N(26)–H(26B) ··O(4)**
N(49)–H(49B) ··O(3)
2.28(3)
2.13(3)
2.23(3)
2.09(2)
2.21(3)
2.30(3)
2.25(3)
2.09(3)
2.30(3)
2.26(3)
2.15(3)
N(49)–H(49B) ··O(3)*** 0.93(3)
N(72)–H(72B) ··O(2)*4
N(72)–H(72B) ··O(4)
N(95)–H(95B) ··O(5)
N(95)–H(95B) ··O(6)
N(118)–H(11H) ··O(5)
N(118)–H(11H) ··O(6)
0.78(3)
0.78(3)
0.86(3)
0.86(3)
0.85(3)
0.85(3)
Figure 6. Centrosymmetric dimers of compound 15b. Dotted
lines depict intra- and intermolecular hydrogen bonds.
Compound 15b
To conclude, the multicomponent reaction of malono-
nitrile, hydrogen sulfide, aldehydes, 1-(cyclopent-1-en-
1-yl)pyrrolidine, alkylating agents, and triethylamine leads
to the formation of new derivatives of 2-alkylsulfanyl-
6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitriles, 3-ami-
no-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridines and
the heterocyclic system 10-ethyl-8,9-dihydro-7H-cyclo-
penta[5',6']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine.
N(3)–H(3B) ··O(1)
0.87(2)
0.87(2)
2.12(2)
2.36(2)
2.753(2)
2.897(2)
130(2)
121(2)
N(3)–H(3B) ··O(1)*5
* Symmetry operations: –x + 1, –y + 1, –z.
** Symmetry operations: x + 1, y + 1, z.
*** Symmetry operations: –x, –y, –z.
*4 Symmetry operations: x – 1, y – 1, z.
*5 Symmetry operations: –x + 1, –y + 1, –z + 1.
independent 15a molecules, respectively) at angles of
66.47(7), 66.55(7), 66.89(6), 66.54(7), 67.11(7), and 67.30(7)°
(for six crystallographically independent molecules 15a,
respectively), and 56.30(6)° (for molecule 15b).
Experimental
IR spectra were registered on a IKS-40 spectrometer in
petroleum jelly. 1H and 13C NMR spectra were acquired on
a Varian VXR-400 spectrometer (400 and 100 MHz,
1
respectively) in DMSO-d6 (CDCl3 for H NMR spectrum
of compound 15f), with TMS as internal standard. High-
resolution mass spectra were recorded on an Orbitrap Elite
mass spectrometer. Samples for mass spectrometry were
dissolved in DMSO (1 ml), diluted 100 times with 1%
HCOOH in MeCN, injected with a syringe pump at a rate
of 40 μl/min into the electrospray ionization source. The
source gas flows were turned off, the voltage across the
needle was 3.5 kV, and the capillary temperature was 275°С.
Mass spectra were recorded in the positive and negative ion
modes in an orbital trap with a resolution of 480,000.
Internal calibrant was 2DMSO+Н+ ion (m/z 157.03515).
The mass spectrum of compound 15е was registered on an
Agilent 1100 mass spectrometer with an Agilent LS/
MSDLS selective detector (the sample was injected in an
AcOH matrix, EI ionization, 70 eV). Melting points were
determined on a Kofler bench. Monitoring of the reaction
progress and assessment of the purity of synthesized
compounds were done by TLC on Silufol UV-254 plates,
eluent hexane–Me2CO, 5:3, visualization by iodine vapor
and UV light.
Figure 5. Centrosymmetric dimers of compound 15a (one of six
crystallographically independent dimers is presented). Dotted
lines depict intra- and intermolecular hydrogen bonds.
In the solid state, the molecules of compounds 15a,b
form centrosymmetric dimers due to intermolecular
hydrogen bonds N–H···O (Table 1, Figs. 5 and 6). Dimers
are packed in stacks along the crystallographic axis a (in
the case of compound 15a) and b (in the case of compound
15b) and are located at the distances of the van der Waals
radii.
2,2'-[Ethane-1,2-diylbis(sulfanediyl)]bis(4-phenyl-6,7-
dihydro-5Н-cyclopenta[b]pyridine-3-carbonitrile (11).
A moderate stream of H2S (2) was bubbled through a
solution of malononitrile (1) (0.7 g, 10 mmol) and Et3N
(3 drops) in EtOH (50 ml) at 20°С for 1 h until
crystallization of cyanothioacetamide 6 started. At this
point, bubbling was stopped, and benzaldehyde (3а) (1 ml,
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Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
10 mmol) was added to the mixture. The mixture was
СН2СН3); 2.94 (2Н, t, J = 7.8, СН2); 2.99 (2Н, t, J = 7.8,
СН2); 3.26–3.37 (2Н, m, СН2); 7.42 (2Н, br. s, NH2); 8.30*
and 8.47 (1Н, s, Н-2). 13C NMR spectrum, δ, ppm: 18.9,
19.1*; 27.3; 27.6; 32.7; 39.1; 116.6; 126.3*; 128.0, 128.5*;
138.5, 138.8*; 152.0; 152.5*, 152.6; 157.1*; 159.8*, 160.1;
162.6; 163.5; 165.6*; 165.9*; 172.7; 172.9*. Found, m/z:
271.1021 [M+H]+. C14H15N4S. Calculated, m/z: 271.1012.
2,4-Substituted 3-amino-6,7-dihydro-5Н-cyclopenta-
[b]thieno[3,2-е]pyridines 15a–f were prepared similarly
from the corresponding aldehyde 3a,b,d–f (10 mmol) and
the alkylating agent 5e–f (10 mmol). The resulting
precipitate was filtered off and dissolved in DMF (25 ml).
10% Aqueous KOH (5.6 ml, 10 mmol) was added with
stirring, the stirring was continued for 5 h, and the mixture
was kept for 24 h, then diluted with an equal volume of
H2O. The formed precipitate was filtered off, washed with
H2O (20 ml), followed by EtOH (20 ml), and hexane (10 ml).
[3-Amino-4-(4-isopropylphenyl)-6,7-dihydro-5Н-cyclo-
penta[b]thieno[3,2-e]pyridin-2-yl](4-chlorophenyl)metha-
none (15a). Yield 3.1 g (70%), yellow crystals (fluoresce
under UV light), mp 147–149°С (BuOH). IR spectrum,
ν, cm–1: 3288–3415 (NН2), 1705 (С=О), 1633 (δ NН2).
1H NMR spectrum, δ, ppm (J, Hz): 1.25 (6Н, d,
J = 6.9, 2СН3); 1.99–2.14 (2Н, m, СН2); 2.47 (2Н, t,
J = 5.5, СН2); 2.84–2.96 (1Н, m, СН(СН3)2); 3.04 (2Н, t,
J = 7.6, СН2); 6.76 (2Н, br. s, NH2); 7.36 (2Н, d, J = 8.0,
Н Ar.); 7.45 (2Н, d, J = 8.0, Н Ar.); 7.57 (2Н, d, J = 8.7,
Н Ar); 7.72 (2Н, d, J = 8.7, Н Ar). Found, m/z: 447.1297
[M+H]+. C26H24ClN2OS. Calculated, m/z: 447.1292.
stirred for 30 min until crystallization of benzylidene-
cyanothioacetamide 7, and enamine 4 (1.4 g, 10 mmol) was
added. The mixture was stirred for 20 min and kept for
24 h. 1,2-Dibromoethane (5а) (0.45 ml, 5 mmol) was
added to the mixture with stirring. After stirring for 2 h, the
mixture was kept for 24 h. The mixture was then diluted
with H2O (50 ml), the formed precipitate was filtered off
and washed with H2O (20 ml), EtOH (10 ml), and hexane
(10 ml). Yield 1.8 g (68%), colorless crystals (fluoresce
under UV light), mp 223–225°С (1,4-dioxane). IR spect-
1
rum, ν, cm–1: 2218 (C≡N). H NMR spectrum, δ, ppm
(J, Hz): 1.86–2.15 (4Н, m, 2СН2); 2.75 (4Н, t, J = 7.5,
2СН2); 3.00 (4Н, t, J = 7.7, 2СН2); 3.67 (4Н, s, 2SCH2);
7.38–7.54 (10Н, m, H Ph). 13C NMR spectrum, δ, ppm:
22.6 (2C); 29.8 (2С); 30.3 (2С); 35.3 (2С); 103.7 (2С);
116.1 (2С); 128.7 (2С); 129.1 (4С); 129.9 (4С); 132.2
(2С); 135.1 (2С); 149.7 (2С); 160.8 (2С); 170.1 (2С).
Found, m/z: 531.1674 [M+H]+. C32H27N4S2. Calculated,
m/z: 531.1672.
2-Benzylsulfanyl-4-(cyclohex-3-en-1-yl)-6,7-dihydro-
5Н-cyclopenta[b]pyridine-3-carbonitrile
(12)
was
prepared similarly from cyclohex-3-ene-1-carbaldehyde
(3b) (1.2 ml, 10 mmol) and benzyl chloride (5b) (1.2 ml,
10 mmol). Yield 2.7 g (78%), yellow crystals, mp 107–
1
109°С (МеОН) (mp 111–113°С7b). H NMR spectrum
matches the published spectrum.7b 13C NMR spectrum,
δ, ppm: 22.4; 25.6; 25.8; 29.2; 29.7; 33.9; 34.8; 39.3;
102.8; 116.3; 126.1; 127.4; 127.6; 128.8 (2С); 129.6 (2С);
131.8; 138.0; 154.9; 161.1; 170.2. Found, m/z: 347.1579
[M+H]+. C22H23N2S. Calculated, m/z: 347.1577.
[3-Amino-4-(4-chlorophenyl)-6,7-dihydro-5Н-cyclo-
penta[b]thieno[3,2-e]pyridin-2-yl](phenyl)methanone
(15b). Yield 3.3 g (82%), yellow crystals (fluoresce under
UV light), mp 187–189°С (i-BuOH). IR spectrum, ν, cm–1:
4-(3-Cyano-2-methylsulfanyl-6,7-dihydro-5Н-cyclo-
penta[b]pyridin-4-yl)phenyl acetate (13) was prepared
similarly from p-hydroxybenzaldehyde (3d) (1.2 g,
10 mmol) and MeI (5c) (0.62 ml, 10 mmol). Then, the
precipitate was filtered off and heated under reflux in Ac2O
(20 ml) for 2 h. After cooling, the cotton-like colorless
precipitate was washed with Et2O (10 ml) to obtain
chromatographically pure product. Yield 2.6 g (81%),
mp 177–179°С. IR spectrum, ν, cm–1: 2219 (C≡N), 1712
1
3290–3412 (NН2), 1707 (С=О), 1630 (δ NН2). H NMR
spectrum, δ, ppm (J, Hz): 2.02–2.18 (2Н, m, СН2); 2.64
(2Н, t, J = 7.4, СН2); 3.05 (2Н, t, J = 7.7, СН2); 6.70 (2Н,
br. s, NH2); 7.43–7.58 (5Н, m, H Ph); 7.63 (2Н, d, J = 8.5,
Н Ar.); 7.70 (2Н, d, J = 6.5, Н Ar.). 13C NMR spectrum,
δ, ppm: 23.0; 29.1; 34.6; 103.7; 119.5; 127.6 (2С); 128.8
(2С); 129.7 (2С); 130.5 (2С); 131.4; 133.8; 133.9; 134.5;
141.3; 142.2; 150.7; 161.4; 169.5; 189.5. Found, m/z:
405.0827 [M+H]+. C23H18ClN2OS. Calculated, m/z:
405.0823.
1
(С=О). H NMR spectrum, δ, ppm (J, Hz): 1.82–2.17 (2Н,
m, СН2); 2.28 (3Н, s, SCH3); 2.58 (3Н, s, CH3); 2.75 (2Н,
t, J = 7.6, СН2); 3.02 (2Н, t, J = 7.6, СН2); 7.29 (2Н, d,
J = 7.4, Н Ar.); 7.54 (2Н, d, J = 7.4, Н Ar). 13C NMR
spectrum, δ, ppm: 13.5; 21.3; 22.7; 29.8; 35.3; 103.1;
116.4; 122.6 (2C); 130.3 (2С); 131.7; 132.4; 148.6; 151.7;
162.1; 169.4; 170.2. Found, m/z: 325.1012 [M+H]+.
C18H17N2О2S. Calculated, m/z: 325.1005.
[3-Amino-4-(4-hydroxyphenyl)-6,7-dihydro-5Н-cyclo-
penta[b]thieno[3,2-e]pyridin-2-yl](4-chlorophenyl)metha-
none (15c). Yield 2.8 g (67%), yellow powder, mp 282–
284°С (1,4-dioxane). IR spectrum, ν, cm–1: 3415 (ОН),
1
3150–3395 (NН2), 1704 (С=О), 1648 (δ NН2). H NMR
10-Ethyl-8,9-dihydro-7Н-cyclopenta[5',6']pyrido-
[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (14) was
prepared similarly from propionaldehyde (3c) (0.73 ml,
10 mmol) and chloroacetonitrile (5d) (0.73 ml, 10 mmol).
The resulting precipitate was filtered off and heated under
reflux in formamide (20 ml) for 4 h. After cooling, the
yellow powder was filtered off, washed with Et2O (10 ml)
to obtain chromatographically pure product. Yield 2.1 g
(76%), mp 305–307°С. IR spectrum, ν, cm–1: 3195, 3311,
spectrum, δ, ppm (J, Hz): 2.05 (2Н, t, J = 7.4, СН2); 2.68
(2Н, t, J = 7.4, СН2); 3.04 (2Н, t, J = 7.6, СН2); 6.77 (2Н,
br. s, NH2); 6.95 (2Н, d, J = 8.0, Н Ar); 7.25 (2Н, d,
J = 8.0, Н Ar); 7.58 (2Н, d, J = 8.4, Н Ar); 7.74 (2Н, d,
J = 8.4, Н Ar); 9.95 (1Н, br. s, ОН). 13C NMR spectrum,
δ, ppm: 23.4; 28.2; 34.9; 102.9; 117.2 (2С); 119.9; 124.6;
128.6 (2С); 129.3 (2С); 129.4 (2С); 133.8; 136.7; 139.8; 143.9;
152.1; 158.0; 161.7; 169.6; 187.2. Found, m/z: 421.0779
[M+H]+. C23H18ClN2O2S. Calculated, m/z: 421.0772.
1
3338 (NН2), 1645 (δ NН2). H NMR spectrum, δ, ppm
* The signals of the minor tautomer are marked with an asterisk.
(J, Hz): 1.13 (3Н, t, J = 7.3, СН3); 2.05 (2Н, t, J = 7.3,
1596

Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
Ethyl 3-amino-4-(cyclohex-3-en-1-yl)-6,7-dihydro-5Н-
fragment and cyclopentene rings are disordered over two
positions with populations 0.70:0.30 and 0.75:0.25,
respectively. The positions of hydrogen atoms were
calculated geometrically and included in the refinement
with fixed positional parameters (the rider model) and
isotropic displacement parameters (Uiso(H) = 1.2Ueq(C)).
The final probability factors R1 0.054 for 2799 independent
reflections with I ≥ 2σ(I) and wR2 0.141 for all independent
reflections, S 1.079. Maximum and minimum values of the
peaks of residual electron density were 0.46 and –0.62 e/Å3,
respectively. The full set of X-ray structural data for
compound 11·C4H8O2 was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 2008389).
Compound 12. Yellow needles (C22H22N2S, M 346.47),
monoclinic, space group P21/c; a 10.484(2), b 19.995(4),
c 9.5601(19) Å; β 112.311(15)°; V 1854.0(7) Å3; Z 4;
dcalc 1.241 g/cm3; F(000) 736; μ 0.412 mm–1. A total of
23906 reflections were collected (3975 independent
reflections, Rint 0.082, 2θ 76.96°). The structure was solved
by direct methods and refined by the least squares
technique against F2 in the full-matrix anisotropic
approximation for non-hydrogen atoms. The positions of
hydrogen atoms were calculated geometrically and
included in the refinement with fixed positional parameters
(the rider model) and isotropic displacement parameters
(Uiso(H) = 1.2Ueq(C)). The final probability factors
R1 0.085 for 2687 independent reflections with I ≥ 2σ(I)
and wR2 0.233 for all independent reflections, S 1.058.
Maximum and minimum values of the peaks of residual
electron density were 0.66 and –0.53 e/Å3, respectively.
The full set of X-ray structural data for compound 12 was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 2008390).
Compound 15a. Yellow prisms (C26H23ClN2OS,
M 446.97), triclinic, space group P-1; a 16.730(3), b 17.270(4),
c 24.100(5) Å; α 102.55(3), β 102.60(3), γ 90.86(3)°;
V 6619(3) Å3; Z 12; dcalc 1.346 g/cm3; F(000) 2808;
μ 0.675 mm–1. A total of 58383 reflections were collected
(22544 independent reflections, Rint 0.070, 2θ 76.84°). The
structure was solved by direct methods and refined by the
least squares technique against F2 in the full-matrix aniso-
tropic approximation for non-hydrogen atoms. Hydrogen
atoms of amino groups are localized objectively in
difference Fourier syntheses and included in the refinement
with fixed positional parameters (the rider model) and
isotropic displacement parameters (Uiso(H) = = 1.2Ueq(N)).
The remaining hydrogen atoms, the positions of which
were calculated geometrically, were included in the refine-
ment with fixed positional parameters (the rider model) and
isotropic displacement parameters (Uiso(H) = 1.5Ueq(C) for
CH3 group and Uiso(H) = 1.2Ueq(C) for the remaining
groups). The final probability factors R1 0.052 for 6381
independent reflections with I ≥ 2σ(I) and wR2 0.152 for all
independent reflections, S 0.890. Maximum and minimum
values of the peaks of residual electron density were 0.542
and −0.54 e/Å3, respectively. The full set of X-ray
structural data for compound 15a was deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
2008391).
cyclopenta[b]thieno[3,2-e]pyridine-2-carboxylate (15d).
Yield 2.3 g (68%), yellow powder (fluoresce under UV
light), mp 218–220°С (EtOH). IR spectrum, ν, cm–1: 3172–
3411 (NН2), 1712 (С=О), 1649 (δ NН2). 1H NMR
spectrum, δ, ppm (J, Hz): 1.25 (3Н, t, J = 7.1, СН3); 1.72–
1.81 (1Н, m), 1.91–2.12 (4Н, m), 2.19–2.23 (2Н, m), 2.29–
2.42 (1Н, m) and 2.82–2.94 (2Н, m, 5СН2); 3.04 (2Н, t,
J = 6.9, СН2); 3.75–3.86 (1Н, m, CH); 4.23 (2Н, q, J = 7.1,
СН2О); 5.65–5.79 (2Н, m, СН=СНСН2); 6.57 (2Н, br. s,
NH2). 13C NMR spectrum, δ, ppm: 14.8; 23.8; 25.6; 26.6;
29.7; 31.5; 33.7; 35.4; 60.6; 116.6; 121.9; 126.5; 127.5;
132.4; 149.5; 151.2; 160.2; 165.4; 169.2. Found, m/z:
343.1476 [M+H]+. C19H23N2O2S. Calculated, m/z:
343.1475.
3-Amino-4-phenyl-6,7-dihydro-5Н-cyclopenta[b]thi-
eno[3,2-e]pyridine-2-carboxamide (15е). Yield 2.2 g
(70%), yellow powder (fluoresce under UV light), mp 238–
240°С (BuOH). IR spectrum, ν, cm–1: 3288–3415 (NН2),
1
1660 (СОNH), 1628 (δ NН2). H NMR spectrum, δ, ppm
(J, Hz): 1.95–2.16 (2Н, m, СН2); 2.63 (2Н, t, J = 5.6, СН2);
3.05 (2Н, t, J = 7.1, СН2); 5.67 (2Н, br. s, NH2); 7.02 (2Н,
br. s, NH2); 7.28–7.53 (5Н, m, H Ph). 13C NMR spectrum,
δ, ppm: 23.1; 29.2; 34.4; 97.7; 120.7; 128.6 (2С); 129.3
(3С); 133.1; 135.6; 142.2; 146.1; 158.5; 167.0; 167.5. Mass
spectrum m/z (Irel, %): 310 [M+Н]+ (100). Found, %:
С 65.92; Н 4.77; N 13.49. C17H16N3OS. Calculated, %:
С 66.00; Н 4.89; N 13.58.
3-Amino-4-(4-nitrophenyl)-6,7-dihydro-5Н-cyclopenta-
[b]thieno[3,2-e]pyridine-2-carboxamide (15f). Yield 2.7 g
(77%), yellow powder, mp 315–317°С (AcOH). IR spect-
rum, ν, cm–1: 3296–3433 (NН2), 1668 (СОNH), 1632
1
(δ NН2). H NMR spectrum, δ, ppm (J, Hz): 2.00–2.18
(2Н, m, СН2); 2.63 (2Н, t, J = 5.5, СН2); 3.05 (2Н, t,
J = 7.7, СН2); 5.70 (2Н, br. s, NH2); 7.17 (2Н, br. s, NH2);
7.70 (2Н, d, J = 8.6, Н Ar); 8.36 (2Н, d, J = 8.6, Н Ar).
13C NMR spectrum, δ, ppm: 23.2; 29.2; 34.3; 120.3; 124.3
(2С); 132.9 (2С); 134.3; 140.1; 142.3; 146.7; 148.4; 158.5;
164.6; 166.8; 167.5. Found, m/z: 355.0860 [M+H]+.
C17H15N4O3S. Calculated, m/z: 355.0859.
X-ray structural analysis of compounds 11, 12, and
15a,b was performed on the BELOK synchrotron station of
National Research Center ''Kurchatov Institute'' using a
Rayonix SX165 CCD two-dimensional detector (100.0(2) K,
λ 0.96990 Å, φ-scanning with a 1.0° step). Experimental
data were processed using the iMOSFLM program
included in the CCP4 software package.12 The correction
for X-ray absorption for the obtained data was done using
the SCALA software.13 All calculations were performed
using the SHELXTL software package.14
Compound 11. Colorless prisms (C32H26N4S2·C4H8O2,
M 618.79), monoclinic, space group C2/c; a 21.983(4),
b 13.640(3), c 10.860(2) Å; β 93.220(12)°; V 3251.2(11) Å3;
Z 4; dcalc 1.264 g/cm3; F(000) 1304; μ 0.464 mm–1. A total
of 20510 reflections were collected (3365 independent
reflections, Rint 0.059, 2θ 76.90°). The structure was solved
by direct methods and refined by the least squares
technique against F2 in the full-matrix anisotropic
approximation for non-hydrogen atoms. The SCH2CH2S
1597

Chemistry of Heterocyclic Compounds 2020, 56(12), 1592–1598
5. Starosila, S. А.; Protopopov, M. V.; Dyachenko, I. V.;
Compound 15b. Yellow prisms (C23H17ClN2OS,
M 404.90), monoclinic, space group C2/c; a 19.080(4),
b 12.780(3), c 17.200(3) Å; β 112.95(3)°; V 3862.1(16)Å3;
Z 8; dcalc 1.393 g/cm3; F(000) 1680; μ 0.755 mm–1. A total
of 16750 reflections were collected (3633 independent
reflections, Rint 0.069, 2θ 76.76°). The structure was solved
by direct methods and refined by the least squares
technique against F2 in the full-matrix anisotropic approxi-
mation for non-hydrogen atoms. Hydrogen atoms of the
amino group are localized objectively in difference Fourier
syntheses and included in the refinement with fixed
positional parameters (the rider model) and isotropic
displacement parameters (Uiso(H) = 1.2Ueq(N)). The
remaining hydrogen atoms, the positions of which were
calculated geometrically, were included in the refinement
with fixed positional parameters (the rider model) and
isotropic displacement parameters (Uiso(H) = = 1.2Ueq(C)).
The final probability factors R1 0.046 for 3144 independent
reflections with I ≥ 2σ(I) and wR2 0.104 for all independent
reflections, S 1.064. Maximum and minimum values of the
peaks of residual electron density were 0.30 and −0.41 e/Å3,
respectively. The full set of X-ray structural data for
compound 15b was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 2008392).
Balanda, А. О.; Dyachenko, V. D.; Yarmolyuk, S. M. Ukr.
Bioorg. Acta 2013, 11(2), 32.
6. (a) Ershov, O. V.; Maksimova, V. N.; Lipin, K. V.;
Belikov, M. Yu.; Ievlev, M. Yu.; Tafeenko, V. A.; Nasakin, O. E.
Tetrahedron 2015, 71, 7445. (b) Abdel-Rahman, A. E.;
Bakhite, E. A.; Mohamed, O. S.; Thabet, E. A. Phosphorus,
Sulfur Silicon Relat. Elem. 2000, 166, 149. (c) Gürdere, M. B.;
Yilmaz, B.; Budak, Y. Synth. Commun. 2014, 44, 981.
7. (a) Dyachenko, V. D.; Dyachenko, A. D. Russ. J. Org. Chem.
2007, 43, 280. [Zh. Org. Khim. 2007, 43, 286.]
(b) Dyachenko, V. D. Russ. J. Gen. Chem. 2005, 75, 1537.
[Zh. Obshch. Khim. 2005, 75, 1612.] (c) Dyachenko, V. D.
Ukr. Khim. Zh. 2006, 72(2), 116. (d) Dyachenko, V. D.;
Karpov, E. N.; Dyakonenko, V. V.; Shishkin, O. V. Russ. J.
Gen. Chem. 2010, 80, 2032. [Zh. Obsh. Khim. 2010, 80,
1723.] (e) Dyachenko, A. D.; Desenko, S. M.; Dyachenko, V. D.
Chem. Heterocycl. Compd. 2002, 38, 747. [Khim. Geterotsikl.
Soedin. 2002, 845.]
8. Xie, L.-G.; Shaaban, S. S.; Chen, X.; Maulide, N. Angew.
Chem., Int. Ed. 2016, 55, 12864.
9. Martin, R. E.; Morawitz, F.; Kuratli, C.; Alker, A. M.;
Alanine, A. I. Eur. J. Org. Chem. 2012, 47.
10. Tittse, L.; Brashe, G.; Gerike, K. Domino-reaktsii
v
organicheskom sinteze (Domino Reactions in Organic Synthesis
[in Russian]); Moscow: BINOM. Laboratoriya znanii, 2010.
11. (a) Dyachenko, I. V.; Dyachenko, V. D.; Dorovatovskii, P.
V.; Khrustalev, V. N.; Nenajdenko, V. G. Chem. Heterocycl.
Compd. 2019, 55, 442. [Khim. Geterotsikl. Soedin. 2019, 55,
442.] (b) Dyachenko, I. V.; Kalashnik, I. N.; Dyachenko, V. D.;
Dorovatovskii, P. V.; Khrustalev, V. N.; Nenajdenko, V. G.
Russ. J. Org. Chem. 2019, 55, 1019. [Zh. Org. Khim. 2019,
55, 1127.] (c) Dyachenko, I. V.; Dyachenko, V. D.;
Dorovatovskii, P. V.; Khrustalev, V. N.; Nenajdenko, V. G.
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This study was carried out with the financial support of
the Ministry of Science and Higher Education of the
Russian Federation (project FSSF-2020-0017).
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