Synthesis of New Thieno[2,3-b]pyridine Derivatives Based on Fused Thiophenes

Article abstract of DOI:10.1134/S1070428020030094

Abstract: Conditions for the Gewald synthesis of2-amino-5,5-dimethyl-4,7-dihydro-5H-thieno[2,3-c]pyrans from2,2-dimethyltetrahydropyran-4-ones have been optimized, and the yields have beenimproved. A procedure has been developed for the synthesis of newpyrano[4′,3′:4,5]thieno[2,3-b]pyridinesby the Thorpe–Ziegler reaction of thieno[2,3-c]pyrans. Anticonvulsant activity of the synthesized compoundswas studied.

Full text of DOI:10.1134/S1070428020030094

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 3, pp. 422–428. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 3, pp. 414–421.
Synthesis of New Thieno[2,3-b]pyridine Derivatives
Based on Fused Thiophenes
E. G. Paronikyana, A. S. Harutyunyana,*, and R. G. Paronikyana
a Scientific Technological Center of Organic and Pharmaceutical Chemistry, National Academy of Sciences of Armenia,
Yerevan, 0014 Armenia
*e-mail: Harutyunyan_arpi@mail.ru
Received October 18, 2019; revised January 16, 2020; accepted January 17, 2020
Abstract—Conditions for the Gewald synthesis of 2-amino-5,5-dimethyl-4,7-dihydro-5H-thieno[2,3-c]pyrans
from 2,2-dimethyltetrahydropyran-4-ones have been optimized, and the yields have been improved. A procedure
has been developed for the synthesis of new pyrano[4′,3′:4,5]thieno[2,3-b]pyridines by the Thorpe–Ziegler
reaction of thieno[2,3-c]pyrans. Anticonvulsant activity of the synthesized compounds was studied.
Keywords: thiophene, thieno[2,3-c]pyranes, thieno[2,3-b]pyridines, pyrano[4′,3′:4,5]thieno[2,3-b]pyridines,
anticonvulsant activity
DOI: 10.1134/S1070428020030094
Thieno[2,3-b]pyridines and their derivatives display
a broad spectrum of biological activity [1–12]. In
particular, compounds exhibiting antibacterial [5, 6],
antitumor [7, 8], anticonvulsant [9], anti-inflammatory
[10], antidepressant [11], and antiviral activities [12]
have been found in this series. Therefore, there is
an obvious interest in the synthesis and chemical and
biological properties of new fused thieno[2,3-b]pyri-
dine derivatives. The goal of the present work was to
develop preparative procedures for the synthesis of
new pyrano[4′,3′:4,5]thieno[2,3-b]pyridines, study of
their physicochemical properties, and evaluation of the
synthesized compounds for anticonvulsant activity.
with ethyl cyanoacetate, malononitrile, and cyanoacet-
amide. The reactions led to the formation of pyr-
ano[4′,3′:4,5]thieno[2,3-b]pyridines 4 and 6 through
intermediates 3 and 5, respectively, or their tautomers
(Scheme 1).
Aminothiophenes 2a and 2b were also reacted with
active methylene compounds such as ethyl 2-phenyl-
acetate, ethyl acetoacetate, and acetylacetone. The re-
action of 2a with ethyl 2-phenylacetate was carried out
with a view to obtaining fused thieno[2,3-b]pyridine
derivative containing a phenyl substituent. However,
instead of expected product 4c, we isolated N-phenyl-
acetyl derivative 3c. The reaction of 3-cyanothieno-
[2,3-c]pyran 2b with ethyl acetoacetate gave Schiff
base 5d in 40–45% yield. Compound 5d was syn-
thesized in 89–90% yield by condensation of 2b with
ethyl β-aminocrotonate. Intramolecular cyclization of
the latter in the presence of sodium ethoxide afforded
70% of pyrano[4′,3′:4,5]thieno[2,3-b]pyridine 6d. By
acidification of the mother liquor we isolated amino
acid 6e which was also obtained by heating compound
6d in 10% aqueous–alcoholic sodium hydroxide under
reflux (Scheme 1).
The starting compounds were thieno[2,3-c]pyrans
2a and 2b which were synthesized by the Gewald
reaction of 2,2-dimethyltetrahydropyran-4-one (1) with
cyanoacetic acid derivatives and sulfur in basic
medium [13–15]. It should be noted that the reported
synthesis of thieno[2,3-c]pyrans 2a and 2b was charac-
terized by relatively low yields (40–60%) [14] and that
the isolation procedure was quite laborious. We suc-
ceeded in finding optimal conditions for the synthesis
of these compounds. In particular, a mixture of mor-
pholine and diethylamine was used as catalyst, and the
reaction was carried out at a lower temperature (40–
41°C), so that the yield was improved to 75–84% and
less tar was formed (Scheme 1).
The reaction of amino ester 2a with ethyl aceto-
acetate in acetic acid gave compound 6a in a low yield
(path b in Scheme 1). When the reaction was carried
out in alkaline medium, the product was compound 3d
in a mixture with its keto–enol tautomer 7 at a ratio of
4:1 (Scheme 2); attempts to cyclize compound 3d (7)
In continuation of our studies, aminothiophenes 2a
and 2b were involved in the Thorpe–Ziegler reactions
422

SYNTHESIS OF NEW THIENO[2,3-b]PYRIDINE DERIVATIVES
423
Scheme 1.
O
R1
Me
S8, R1CH2CN
Me
NH2
Me
O
S
O
Me
1
2a, 2b
R2
R3
Me
R2
R1
Me
Me
Path a
O
Me
O
O
NH
N
H
O
S
S
3a–3c
4a–4c
R2
R3
Me
R2
R4
R1
Me
Me
Me
Path b
R4
O
N
N
O
S
S
5a–5d
6a–6e
2a, 3a, 3c, 5a, R1 = COOEt; 2b, 3b, 5b–5d, R1 = CN; 3a, 3b, 4a, 4b, 5b, 6b, R2 = CN; 5a, 5d, 6a, 6d, R2 = COOEt;
3c, 4c, R2 = Ph; 5c, 6c, R2 = CONH2; 6e, R2 = COOH; 4a, 4c, 6a, R3 = OH; 4b, 6b–6e, R3 = NH2; 5a, 5d, 6a, 6d, 6e, R4 =
Me; 5b, 5c, 6b, 6c, R4 = NH2.
were unsuccessful. Amino nitrile 2b reacted with
acetylacetone to produce open-chain enamine 5f. Treat-
ment of the latter with sodium methoxide resulted in
the formation of compound 8 containing two thieno-
[2,3-c]pyran fragments (Scheme 3). In the reaction of
2-aminotetrahydro-1-benzothiophene-3-carbonitrile (9)
[16] with ethyl acetoacetate we isolated and identified
1:1 and 2:1 condensation products 10 (40%) and 11
(50%) (Scheme 4). Unlike compound 11, ester 10
underwent cyclization to ethyl 4-amino-2-methyl-
5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-car-
boxylate [15]. The structures of the synthesized com-
carboxymethylcellulose (Viadi-Ingredienty, St. Peters-
burg, Russia) and Tween 80 (Ferak Berlin, Germany).
The anticonvulsant activity was evaluated by the
prevention of clonic twitches and clonic seizure com-
ponent. Thieno[2,3-c]pyran derivative 5f at a dose of
50 mg/kg prevented pentylenetetrazol-induced clonic
seizures in 60% of animals. Among thieno[2,3-b]pyr-
idine derivatives, the most active were compounds 4a,
4b, and 6a–6e, while the other compounds showed no
anticonvulsant activity. In the series of hydroxy nitriles,
a more pronounced effect (40–60%) was observed for
compounds 4a, 4b, and 6a. Ester 6d at a dose of
50 mg/kg showed 60% anticonvulsant activity; com-
pound 5f exerted a similar effect. The activity of car-
boxylic acid 6e was lower. Amines 6b and 6c exhibited
a weak anticonvulsant activity. Compounds 4a, 5f, and
6d also displayed sedative activity.
1
pounds were confirmed by H and 13C NMR, IR, and
mass spectra.
The anticonvulsant activity of the synthesized com-
pounds was assessed by their effect on pentylenetetra-
zol-induced seizures [17] in male and female white
mice with a weight of 18–24 g. Pentylenetetrazol
(Acros organics, NJ, USA) was administered subcuta-
neously at a dose of 90 mg/kg as a suspension with
In summary, we have optimized conditions for the
synthesis of 2-amino-5,5-dimethyl-4,7-dihydro-5H-
thieno[2,3-c]pyrans and obtained new pyrano-
Scheme 2.
EtO
EtO
O
O
O
O
MeC(O)CH2COOEt
NaOEt, EtOH, Δ
O
OH
Me
Me
Me
Me
Me
Me
2a
NH
3d (80%)
NH
7 (20%)
O
O
S
S
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

PARONIKYAN et al.
424
Scheme 3.
O
H2N
Me
Me
Me
Me
O
O
N
S
Me
Me
MeC(O)CH2COMe
TsOH, EtOH, Δ
6f
CN
Me
Me
2b
Me
Me
NH
O
NC
Me
S
Me
O
Me
5f
NaOMe
CN
O
S
N
S
N
H
Me
8
[4′,3′:4,5]thieno[2,3-b]pyridines based thereon. The re-
action of 2-amino-4,5,6,7-tetrahydro-1-benzothio-
phene-3-carbonitrile with ethyl acetoacetate has been
found to afford a mixture of 1:1 and 2:1 condensation
products. Analogous 2 : 1 adduct was formed on at-
tempted cyclization of 5,5-dimethyl-2-{[(1E)-1-meth-
yl-3-oxobut-1-en-1-yl]amino}-4,7-dihydro-5H-thieno-
[2,3-c]pyran-3-carbonitrile. Some of the synthesized
compounds (4a, 5f, and 6d) showed a pronounced anti-
convulsant activity in combination with low toxicity
and insignificant side effects.
tal compositions were determined with a Euro EA 3000
elemental analyzer (Germany), as well as by the
Korshun−Klimova (C, H) and Dumas–Pregl methods
(N). The melting points were measured on a Boetius
micro hot stage. Analytical thin-layer chromatography
was performed on Silufol UV-254 plates; spots were
visualized by treatment with iodine vapor. Commer-
cially available reagents were purchased from Fluka
(Germany), Aldrich, and Sigma (USA). The solvents
used were purified according to standard procedures.
Compounds 2a and 2b (general procedure).
A suspension of 12.8 g (10 mmol) of 2,2-dimethyltetra-
hydropyran-4-one (1), 10 mmol of ethyl cyanoacetate
or malononitrile, and 3.2 g (10 mmol) of sulfur powder
in 50 mL of 96% ethanol was heated to 30–40°C, and
a mixture of 3 mL of diethylamine and 5 mL of
morpholine in 10 mL of ethanol was added dropwise
with stirring over a period of 30 min. The mixture was
stirred at 40–41°C for 3 h, cooled with ice water, and
left overnight in a refrigerator. The crystalline solid
was filtered off, washed with water, dried, and recrys-
tallized from ethanol.
EXPERIMENTAL
The IR spectra were recorded on a Nicolet Avatar
330 FT-IR spectrometer (USA) from samples dispersed
in mineral oil. The mass spectra (electron impact,
50 eV) were obtained on an MKh-1321A spectrometer
(USSR) with direct sample admission into the ion
source; the batch inlet probe temperature was set 15–
20°C lower than the melting point of a sample. The
1H and 13C NMR spectra were recorded on a Varian
Mercury 300 VX spectrometer (USA) at 300.08 and
75.462 MHz, respectively, using DMSO-d6, DMSO-d6–
CCl4 (1:3), DMSO-d6–CF3COOD, or CDCl3 as solvent
and tetramethylsilane as internal standard. The elemen-
Ethyl 2-amino-5,5-dimethyl-4,7-dihydro-5H-
thieno[2,3-c]pyran-3-carboxylate (2a). Yield 21.5 g
(84%) [14].
Scheme 4.
O
NC
CN
OEt
Me
O
MeC(O)CH2COOEt
NH2
CN
CN
+
S
N
H
S
NH
S
N
H
Me
11
S
9
10
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

SYNTHESIS OF NEW THIENO[2,3-b]PYRIDINE DERIVATIVES
425
2-Amino-5,5-dimethyl-4,7-dihydro-5H-thieno-
[2,3-c]pyran-3-carbonitrile (2b). Yield 15.7 g
(76%) [14].
4-Hydroxy-6,6-dimethyl-2-oxo-1,5,6,8-tetrahy-
dro-2H-pyrano[4′,3′:4,5]thieno[2,3-b]pyridine-3-
carbonitrile (4a). Ethyl cyanoacetate, 3.4 g (30 mmol),
and compound 2a, 2.55 g (10 mmol), were added to
a solution of sodium ethoxide prepared from 1 g
(43 mmol) of sodium and 40 mL of anhydrous ethanol
(99.95%). The mixture was refluxed for 1 h, cooled,
poured into 150 mL of cold water, and acidified with
aqueous HCl. The crystalline solid was filtered off,
washed with water, and recrystallized from DMF. Yield
2.5 g (89%), mp 341–344°C, Rf 0.64 (chloroform–
ethanol–hexane, 1:1:3). IR spectrum, ν, cm–1: 3390 br
(NH), 3480 br (OH), 2230 v.s (C=N), 1640 s (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.28 s (6H,
CH3), 2.80 t (2H, CH2, J = 1.9 Hz), 4.60 t (2H, OCH2,
J = 1.9 Hz), 12.40 br.s (2H, NH, OH). Found, %:
C 56.07; H 4.49; N 10.22; S 12.06. C13H12N2O3S.
Calculated, %: C 56.51; H 4.38; N 10.14; S 11.6.
Ethyl 5,5-dimethyl-2-[(phenylacetyl)amino]-4,7-
dihydro-5H-thieno[2,3-c]pyran-3-carboxylate (3c).
Compound 2a, 2.6 g (10 mmol), and ethyl 2-phenyl-
acetate, 5.0 g (30 mmol), were added to a solution of
sodium ethoxide prepared from 0.46 g (20 mmol) of
sodium and 10 mL of anhydrous ethanol. The mixture
was refluxed for 2 h and allowed to cool down, and the
precipitate was filtered off, washed with diethyl ether
and water, dried, and recrystallized from ethanol. Yield
3.2 g (86%), mp 105–107°C, Rf 0.56 (acetone–pentane,
1:2). IR spectrum, ν, cm–1: 3285, 3200 br (NH, OH),
1680, 1653 s (C=O). 1H NMR spectrum (DMSO-d6), δ,
ppm: 1.22 s (6H, CH3), 1.32 t (3H, CH2CH3, J =
7.1 Hz), 2.62 t (2H, CH2, J = 1.6 Hz), 3.81 s (2H,
PhCH2), 4.23 q (2H, OCH2CH3, J = 7.1 Hz), 4.58 t
(2H, OCH2, J = 1.6 Hz), 7.41–7.21 m (5H, Ph),
11.00 br.s (1H, NH). Mass spectrum, m/z (Irel, %):
373 (97) [M]+, 374 (23), 315 (29), 254 (56), 197
(47), 125 (31). Found, %: C 64.24; H 6.12; N 3.87;
S 8.65. C20H23NO4S. Calculated, %: C 64.32; H 6.21;
N 3.75; S 8.59.
4-Amino-6,6-dimethyl-2-oxo-1,5,6,8-tetrahydro-
2H-pyrano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carbo-
nitrile (4b). Ethyl cyanoacetate, 1.13 g (10 mmol), and
compound 2b, 2.08 g (10 mmol), were added to a solu-
tion of sodium ethoxide prepared from 0.8 g (35 mmol)
of sodium and 25 mL of anhydrous ethanol. The
mixture was refluxed for 2.5 h, cooled, diluted with
200 mL of water, and filtered, and the filtrate was
acidified with glacial acetic acid. The crystalline solid
was filtered off, washed with water, dried, and recrys-
tallized from DMF. Yield 2.2 g (82%), mp 346–350°C,
Rf 0.63 (DMF–ethanol, 3:2). IR spectrum, ν, cm–1:
3500 br (NH), 3330, 3240 br (NH2), 2206 v.s (C≡N),
Ethyl 5,5-dimethyl-2-(3-oxobutanamido)-4,7-di-
hydro-5H-thieno[2,3-c]pyran-3-carboxylate (3d).
A solution of 0.7 g (5.5 mmol) of ethyl acetoacetate
and 0.05 g of triethanolamine in 5 mL of xylene was
heated to the boiling point, and a solution of 1.3 g
(5 mmol) of compound 2a in 5 mL of xylene was
added dropwise. The mixture was refluxed for 1 h and
was then cooled with stirring. The crystalline solid was
filtered off, washed with water, dried, and recrystallized
from ethanol. Yield 1.1 g (65%, a mixture of tautomers
3d and 7 at a ratio of 4:1), mp 119–121°C, Rf 0.60
(acetone–pentane, 1:3). IR spectrum, ν, cm–1: 3240,
3190 br (NH, OH), 1730, 1680, 1650 s (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.25 s (6H,
CH3), 1.39 t (0.6H, CH2CH3, J = 7.0 Hz, 7), 1.40 t
(2.4H, CH2CH3, J = 7.1 Hz, 3d), 2.00 s (0.6H, CH3, 7),
2.26 s (2.4H, CH3, 3d), 2.66 t (0.4H, CH2, J = 1.6 Hz,
7), 2.68 t (1.6H, CH2, J = 1.7 Hz, 3d), 3.77 s (1.6H,
CH2Ac, 3d), 4.31 q (0.4H, CH2CH3, J = 7.0 Hz, 7),
4.36 q (1.6H, CH2CH3, J = 7.1 Hz, 3d), 4.65 t
(0.4H, OCH2, J = 1.6 Hz, 7), 4.65 t (1.6H, OCH2, J =
1.7 Hz, 3d), 5.23 s (0.2H, CH, 7), 11.04 br.s
(0.2H, NH, 7), 11.51 br.s (0.8H, NH, 3d), 11.04 br.s
(0.2H, OH, 7). Found, %: C 56.75; H 6.35; N 4.06;
S 9.34. C20H23NO4S. Calculated, %: C 56.62; H 6.24;
N 4.13; S 9.45.
1
1640 s (C=O). H NMR spectrum (DMSO-d6–CCl4,
1:3), δ, ppm: 1.28 s (6H, CH3), 2.82 s (2H, CH2), 4.60 s
(2H, OCH2), 6.48 s (2H, NH2), 11.95 br.s (1H, NH).
Found, %: C 56.61; H 4.59; N 15.37; S 11.71.
C13H13N3O2S. Calculated, %: C 56.72; H 4.76;
N 15.26; S 11.65.
Ethyl (2E)-3-[(3-cyano-5,5-dimethyl-4,7-dihydro-
5H-thieno[2,3-c]pyran-2-yl)amino]but-2-enoate
(5d). a. A mixture of 2.1 g (10 mmol) of 2-amino-5,5-
dimethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carbo-
nitrile (2b), 1.3 g (10 mmol) of ethyl β-aminocrotonate,
and 0.1 g of p-toluenesulfonic acid in 20 mL of toluene
was refluxed for 16 h. The mixture was cooled and
filtered, excess solvent was distilled off, 10 mL of
ethanol was added to the residue, and the mixture was
left overnight in a refrigerator. The crystalline solid
was filtered off, washed with cold ethanol and water,
dried, and recrystallized from ethanol–water (3:1).
Yield 2.23 g (89%).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

PARONIKYAN et al.
426
b. A mixture of 2.1 g (10 mmol) of compound 2b,
OCH2), 14.04 br.s (1H, NH). Found, %: C 59.6;
H 6.03; N 4.25; S 10.07. C16H19NO4S. Calculated, %:
C 59.79; H 5.96; N 4.36; S 9.98.
1.3 g (10 mmol) of ethyl acetoacetate, and 0.1 g of
p-toluenesulfonic acid in 20 mL of anhydrous benzene
was refluxed in a flask equipped with a Dean–Stark
trap until water no longer separated. The solvent was
distilled off, and the residue was treated with 10 mL of
ethanol and left overnight in a refrigerator. The crys-
talline solid was filtered off, washed with cold ethanol
and water, dried, and recrystallized from ethanol–water
(3:1). Yield 1.1 g (45%). mp 125–127°C, Rf 0.57
(chloroform–ethanol, 1:2). IR spectrum, ν, cm–1: 3510,
3350 br (NH2), 2200 v.s (C≡N), 1670 s (C=O).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.34 m (9H,
CH3, CH2CH3), 2.07 s (3H, CH3), 2.60 s (2H, CH2),
4.20 q (2H, CH2CH3, J = 7.0 Hz), 4.65 s (2H, OCH2),
4.90 s (1H, CH), 11.03 s (1H, NH). Found, %: C 60.08;
H 6.17; N 8.68; S 10.13. C16H20N2O3S. Calculated, %:
C 59.98; H 6.29; N 8.74; S 10.01.
2,4-Diamino-6,6-dimethyl-5,8-dihydro-6H-pyr-
ano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carbonitriles
6b and 6c (general procedure). Compound 2b, 2.1 g
(10 mmol), and malononitrile or cyanoacetamide
(10 mmol) were added to a solution of sodium ethoxide
prepared from 0.25 g (11 mmol) of sodium and 12 mL
of anhydrous ethanol (99.9%). The mixture was
refluxed for 3–4.5 h and allowed to cool down, and the
crystalline solid was filtered off, washed with water,
dried, and recrystallized from ethanol.
2,4-Diamino-6,6-dimethyl-5,8-dihydro-6H-pyr-
ano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carbonitrile
(6b). Yield 1.7 g (63%), mp 276–278°C, Rf 0.62
(chloroform–ethanol, 2:3). IR spectrum, ν, cm–1: 3454–
3125 br (NH2), 2260 v.s (C≡N), 1641 s (C=O).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.30 s (6H, CH3), 2.89 s (2H, CH2), 3.94 s (2H, NH2),
4.72 t (2H, OCH2, J = 1.9 Hz), 6.90 br.s (1H, NH2).
Found, %: C 56.76; H 4.99; N 20.57; S 11.78.
C13H14N4OS. Calculated, %: C 56.92; H 5.14;
N 20.42; S 11.69.
5,5-Dimethyl-2-{[(2E)-4-oxopent-2-en-2-yl]-
amino}-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carbo-
nitrile (5f). A mixture of 2.1 g (10 mmol) of compound
2b, 1.5 g (15 mmol) of acetylacetone, and 0.05 g of
p-toluenesulfonic acid in 10 mL of anhydrous toluene
was refluxed in a flask equipped with a Dean–Stark
trap until water no longer separated (2 h). The mixture
was cooled and left overnight in a refrigerator, and the
precipitate was filtered off, washed with ethanol and
water, dried, and recrystallized from ethanol. Yield
2.9 g (82%), mp 157–158°C, Rf 0.59 (ethyl acetate–
methanol, 1:1). IR spectrum, ν, cm–1: 3407, 3186 br
2,4-Diamino-6,6-dimethyl-5,8-dihydro-6H-pyr-
ano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carboxamide
(6c). Yield 1.4 g (48%), mp 234–235°C, Rf 0.66
(chloroform–ethanol, 2:3). IR spectrum, ν, cm–1: 3450–
3125 br (NH2), 2215 v.s (C≡N), 1650 s (C=O).
1H NMR spectrum (DMSO-d6–CCl4, 1:3), δ, ppm:
1.26 s (6H, CH3), 2.89 t (2H, CH2, J = 1.9 Hz), 3.48 s
(2H, NH2), 4.73 t (2H, OCH2, J = 1.9 Hz), 6.83 br.s
(1H, NH2), 6.93 br.s and 7.43 br.s (1H each, CONH2).
Mass spectrum, m/z (Irel, %): 292 (36) [M]+, 249 (43),
234 (16), 192 (16), 191 (100), 151 (15), 150 (24).
Found, %: C 53.61; H 5.39; N 19.27; S 11.85.
C13H16N4O2S. Calculated, %: C 53.41; H 5.52;
N 19.16; S 10.97.
1
(NH), 2202 v.s (C≡N), 1615 s (C=O). H NMR spec-
trum (DMSO-d6), δ, ppm: 1.29 m (6H, CH3), 2.10 s
(3H, CH3), 2.15 d (3H, CH3, J = 0.6 Hz), 2.55 t (2H,
CH2, J = 1.7 Hz), 4.59 t (2H, OCH2, J = 1.9 Hz), 5.39 d
(1H, CH, J = 0.6 Hz), 13.15 br.s (1H, NH). Found, %:
C 61.98; H 6.17; N 9.78; S 11.13. C15H18N2O2S.
Calculated, %: C 62.04; H 6.25; N 9.65; S 11.04.
Ethyl 4-hydroxy-2,6,6-trimethyl-5,8-dihydro-6H-
pyrano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carbox-
ylate (6a). A mixture of 2.6 g (10 mmol) of compound
2a and 1.43 g (11 mmol) of ethyl acetoacetate in 30 mL
of acetic acid was refluxed for 2 h. The solvent was
distilled off, the residue was treated with 10 mL of
ethanol, and the mixture was left overnight in a refrig-
erator. The precipitate was filtered off and washed with
cold ethanol and water. Yield 1.8 g (57%), mp 293–
295°C, Rf 0.58 (acetone–pentane, 1:3). IR spectrum, ν,
cm–1: 3970 br (OH), 1680 s (C=O). 1H NMR spectrum
(DMSO-d6), δ, ppm: 1.20 s (6H, CH3), 1.37 t (3H,
CH2CH3, J = 7.1 Hz), 2.09 s (3H, CH3), 2.65 s (2H,
CH2), 4.32 q (2H, OCH2CH3, J = 7.0 Hz), 4.53 s (2H,
Ethyl 4-amino-2,6,6-trimethyl-5,8-dihydro-6H-
pyrano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carbox-
ylate (6d). Compound 5d, 3.2 g (10 mmol), was added
to a solution of sodium ethoxide prepared from 0.35 g
(15 mmol) of sodium and 50 mL of anhydrous ethanol.
The mixture was left to stand for 12 h at room tem-
perature and was then refluxed for 3 h. After cooling,
the mixture was kept for 2 days in a refrigerator, and
the precipitate was filtered off, washed with ethanol
and water, dried, and recrystallized from ethanol. Yield
2.2 g (70%), mp 160–161°C, Rf 0.61 (ethyl acetate–
chloroform–pentane, 1:1:1). IR spectrum, ν, cm–1:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

SYNTHESIS OF NEW THIENO[2,3-b]PYRIDINE DERIVATIVES
427
3510, 3350 br (NH2), 1670 s (C=O). 1H NMR spectrum
(DMSO-d6), δ, ppm: 1.33 s (6H, CH3), 1.35 m (3H,
CH2CH3), 2.63 s (3H, CH3), 2.80 s (2H, CH2), 4.35 q
(2H, CH2CH3, J = 6.1 Hz), 4.70 s (2H, OCH2), 6.77 s
(2H, NH2). Found, %: C 59.89; H 6.39; N 8.85; S 9.92.
C16H20N2O3S. Calculated, %: C 59.98; H 6.29; N 8.74;
S 10.01.
13C NMR spectrum (DMSO-d6–CCl4, 1:3), δC, ppm:
20.74, 25.68, 35.03, 58.83, 70.13, 101.35, 102.13,
113.25, 126.65, 130.04, 153.31, 159.64. Found, %:
C 62.34; H 5.76; N 11.75; S 13.22. C25H28N4O2S2.
Calculated, %: C 62.47; H 5.87; N 11.66; S 13.34.
Compounds 10 and 11. A mixture of 1.8 g
(10 mmol) of compound 9, 1.3 g (10 mmol) of ethyl
acetoacetate, and 0.1 g of p-toluenesulfonic acid in
20 mL of anhydrous benzene was refluxed in a flask
equipped with a Dean–Stark trap until water no longer
separated. After cooling, the crystals of 11 were filtered
off, washed with ethanol and water, dried, and recrys-
tallized from ethanol. The solvent was distilled off
from the filtrate, the residue was treated with 10 mL of
ethanol, and the mixture was left overnight in a refrig-
erator. The crystals of 10 were filtered off, washed with
cold ethanol and water, dried, and recrystallized from
ethanol.
4-Amino-2,6,6-trimethyl-5,8-dihydro-6H-pyr-
ano[4′,3′:4,5]thieno[2,3-b]pyridine-3-carboxylic
acid (6e). a. Compound 2b, 3.2 g (10 mmol), was
added to a freshly prepared solution of 0.68 g
(10 mmol) of sodium ethoxide in 20 mL of anhydrous
ethanol. The mixture was refluxed for 8 h, cooled,
poured into 50 mL of cold water, acidified with con-
centrated aqueous HCl, and left overnight in a refrig-
erator. The precipitate was filtered off, washed with
ethanol and water, dried, and recrystallized from
ethanol. Yield 1.65 g (57%).
Ethyl 4-amino-2-methyl-5,6,7,8-tetrahydro[1]-
benzothieno[2,3-b]pyridine-3-carboxylate (10).
Yield 2.23 g (40%) [15].
b. Compound 6d, 3.2 g (10 mmol), was added to
a solution of sodium ethoxide prepared from 0.23 g
(10 mmol) of sodium and 20 mL of ethanol. The
mixture was refluxed for 3 h and was then treated as
described above in a. Yield 2.25 g (78%), mp 226–
228°C, Rf 0.68 (ethyl acetate–chloroform–pentane,
1:1:2). IR spectrum, ν, cm–1: 3500, 3350 br (NH2),
(2E)-N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothio-
phen-2-yl)-3-[(3-cyano-4,5,6,7-tetrahydro-1-benzo-
thiophen-2-yl)amino]but-2-enamide (11). Yield
2.13 g (50%), mp 266–267°C, Rf 0.68 (acetone–
pentane, 1:2). IR spectrum, ν, cm–1: 3240, 3170 br
1
3310 br (OH), 1660 s (C=O). H NMR spectrum
1
(NH), 2206 v.s (C≡N), 1680 s (C=O). H NMR spec-
(DMSO-d6), δ, ppm: 1.33 s (6H, CH3), 2.62 s (3H,
CH3), 2.95 t (2H, CH2, J = 1.9 Hz), 3.03 br.s (1H, OH),
4.71 t (2H, OCH2, J = 1.9 Hz), 6.80 br.s (2H, NH2).
Mass spectrum, m/z (Irel, %): 292 (15) [M]+, 247 (13),
235 (15), 234 (76), 219 (32), 217 (21), 193 (31).
Found, %: C 57.45; H 5.60; N 9.47; S 17.06.
C14H16N2O3S. Calculated, %: C 57.52; H 5.52; N 9.58;
S 10.97.
trum (DMSO-d6), δ, ppm: 1.78–1.91 m (8H, CH2),
2.16 d (3H, CH3, J = 0.8 Hz), 2.53–5.67 m (8H, CH2),
5.46 q (1H, CH, J = 0.8 Hz), 10.96 br.s (1H, NH),
11.57 br.s (1H, NH). Found, %: C 62.68; H 5.17;
N 13.17; S 15.23. C22H22N4OS2. Calculated, %:
C 62.53; H 5.25; N 13.26; S 15.18.
CONFLICT OF INTEREST
The authors declare the absence of conflict of interest.
REFERENCES
2-({(2E,3E)-4-[(3-Cyano-5,5-dimethyl-4,7-dihy-
dro-5H-thieno[2,3-c]pyran-2-yl)amino]methylpent-
3-en-2-ylidene}amino)-5,5-dimethyl-4,7-dihydro-
5H-thieno[2,3-c]pyran-3-carbonitrile (8). Compound
2b, 2.9 g (10 mmol), was added to a solution of sodium
methoxide prepared from 0.25 g (11 mmol) of sodium
and 25 mL of anhydrous methanol. The mixture was
refluxed for 15 min and was left to stand for 12 h. The
crystalline solid was filtered off, washed with cold
methanol and water, dried, and recrystallized from
methanol. Yield 1.0 g (21%), mp 259–260°C, Rf 0.63
(ethyl acetate–methanol, 3:1). IR spectrum, ν, cm–1:
1. Naguib, B.H. and El-Nassan, H.B., J. Enzyme Inhib. Med.
Chem., 2016, vol. 31, p. 1718.
https://doi.org/10.3109/14756366.2016.1158711
2. Abdelaziz, M.E., El-Miligy, M.M.M., Fahmy, S.M.,
Mahran, M.A., and Hazzaa, A.A., Bioorg. Chem., 2018,
vol. 80, p. 674.
https://doi.org/10.1016/j.bioorg.2018.07.024
3. Binsaleh, N.K., Wigley, C.A., Whitehead, K.A., van
Rensburg, M., Reynisson, J., Pilkington, L.I., Barker, D.,
Jones, S., and Dempsey-Hibbert, N.C., Eur. J. Med.
Chem., 2018, vol. 143, p. 1997.
1
3190 br (NH), 2219, 2205 v.s (C=N). H NMR spec-
trum (DMSO-d6–CCl4, 1:3), δ, ppm: 1.30 s (12H,
CH3), 2.24 s (6H, CH3), 2.45–2.62 m (4H, CH2), 4.63 s
(4H, OCH2), 5.27 s (1H, CH), 13.20 br.s (1H, NH).
https://doi.org/10.1016/j.ejmech.2017.11.014
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

PARONIKYAN et al.
428
4. Buryi, D.S., Dotsenko, V.V., Aksenov, N.A., Akseno-
va, I.V., Krivokolysko, S.G., and Dyadyuchenko, L.V.,
Russ. J. Gen. Chem., 2019, vol. 89, p. 1575.
10. Pevet, I., Brulé, C., Tizot, A., Gohier, A., Cruzalegui, F.,
Boutin, J.A., and Goldstein, S., Bioorg. Med. Chem.,
2011, vol. 19, p. 2517.
https://doi.org/10.1016/j.bmc.2011.03.021
https://doi.org/10.1134/S1070363219080061
11. Lockman, J.W., Reeder, M.D., Suzuki, K., Ostanin, K.,
Hoff, R., Bhoite, L., Austin, H., Baichwal, V., and
Willardsen, J.A., Bioorg. Med. Chem. Lett., 2010,
vol. 20, p. 2283.
5. Kumar, C.N.S.S.P., Srihari, E., Ravinder, M.,
Kumar, K.P., Murthy, U.S.N., and Rao, V.J., J. Heterocycl.
Chem., 2013, vol. 50, p. E131.
https://doi.org/10.1002/jhet.1091
https://doi.org/10.1016/j.bmcl.2010.02.005
6. Pinheiro, L.C.S., Abreu, P.A., Afonso, I.F., Leal, B.,
Corrêa, L.C.D., Borges, J.C., Marques, I.P.,
Lourenço, A.L., Sathler, P., dos Santos, A.L.,
Medeiros, C.A., Cabral, L.M., Júnior, M.L.O.,
Romeiro, G.A., Ferreira, V.F., Rodrigues, C.R.,
Castro, H.C., and Bernardino, A.M.R., Curr. Microbiol.,
2008, vol. 57, p. 463.
12. Pinheiro, L.C.S., Borges, J.C., Oliveira, C.D.,
Ferreira, V.F., Romeiro, G.A., Marques, I.P., Abreu, P.A.,
Frugulheti, I.C.P.P., Rodrigues, C.R.,Albuquerque, M.G.,
Castro, H.C., and Bernardino, A.M.R., Arkivoc, 2008,
vol. 2008, part (xiv), p. 77.
https://doi.org/10.3998/ark.5550190.0009.e09
13. Gewald, K., Schinke, E., and Böttcher, H., Chem. Ber.,
1966, vol. 99, p. 94.
https://doi.org/10.1007/s00284-008-9234-5
7. Zeng, X.X., Zheng, R.L., Zhou, T., He, H.Y., Liu, J.Y.,
Zheng, Y., Tong, A.P., Xiang, M.L., Song, X.R.,
Yang, S.Y., Yu, L.T., Wei, Y.Q., Zhao, Y.L., and Yang, L.,
Bioorg. Med. Chem. Lett., 2010, vol. 20, p. 6282.
https://doi.org/10.1016/j.bmcl.2010.08.088
https://doi.org/10.1002/cber.19660990116
14. Noravyan, A.S., Mkrtchyan, A.P., Dzhagatspanyan, I.A.,
Nazaryan, I.M., Akopyan, N.E., and Vartanyan, S.A.,
Pharm. Chem. J., 1977, vol. 11, p. 839.
https://doi.org/10.1007/BF00778174
8. Mohareb, R.M., Abdallah, A.E.M., and Abdelaziz, M.A.,
Med. Chem. Res., 2014, vol. 23, p. 564.
15. Schaefer, H., Gewald, K., Mueller, H., and Jescheke, T.,
DD Patent no. 285356 A5, 1990; Chem. Abstr., 1991,
vol. 114, no. 228888d.
https://doi.org/10.1007/s00044-013-0664-7
9. Paronikyan, E.G., Ogannisyan, A.V., Paronikyan, R.G.,
Dzhagatspanyan, I.A., Nazaryan, I.M., Akopyan, A.G.,
and Minasyan, N.S., Pharm. Chem. J., 2019, vol. 52,
p. 839.
16. Lalezari, I., J. Heterocycl. Chem., 1979, vol. 16, p. 603.
https://doi.org/10.1002/jhet.5570160341
17. Drug Discovery and Evaluation. Pharmacological
Assays, Vogel, H.G. and Vogel, W.H., Eds., Berlin:
Springer, 1997, p. 246.
https://doi.org/10.1007/s11094-019-1911-0
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020