Synthesis and Cyclizations of N-(Thieno[2,3-b]pyridin-3-yl)cyanoacetamides

Article abstract of DOI:10.1134/S1070363219100062

3-Aminothieno[2,3-b]pyridine-2-carboxylic acid esters readily reacted with 3,5-dimethyl-1-(cyanoacetyl)-1H-pyrazole to give previously unknown N-(thieno[2,3-b]pyridin-3-yl)cyanoacetamides. Reactions of the latter with 2-(arylmethylidene)malononitriles were nonselective, and mixtures of different heterocyclization products were generally formed. The cyclization of ethyl 4,6-dimethyl-3-[(cyanoacetyl)amino]thieno[2,3-b]-pyridine-2-carboxylate afforded 2,4-dihydroxy-7,9-dimethylthieno[2,3-b : 4,5-b′]dipyridine-3-carbonitrile whose tautomeric equilibrium was studied by DFT quantum chemical calculations. In silico analysis of biological activity of the synthesized compounds was performed.

Full text of DOI:10.1134/S1070363219100062

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 10, pp. 2018–2026. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 10, pp. 1520–1530.
Synthesis and Cyclizations
of N-(Thieno[2,3-b]pyridin-3-yl)cyanoacetamides
E. A. Chigorinaa, A. V. Bespalovb, and V. V. Dotsenkob,c*
a Institute of Chemical Reagents and High Purity Chemical Substances of National Research Centre
“Kurchatov Institute,” Moscow, Russia
b Kuban State University, Krasnodar, Russia
*e-mail: victor_dotsenko_@mail.ru
c North-Caucasian Federal University, Stavropol, Russia
Received March 21, 2019; revised March 21, 2019; accepted April 15, 2019
Abstract—3-Aminothieno[2,3-b]pyridine-2-carboxylic acid esters readily reacted with 3,5-dimethyl-1-(cyano-
acetyl)-1H-pyrazole to give previously unknown N-(thieno[2,3-b]pyridin-3-yl)cyanoacetamides. Reactions of
the latter with 2-(arylmethylidene)malononitriles were nonselective, and mixtures of different heterocyclization
products were generally formed. The cyclization of ethyl 4,6-dimethyl-3-[(cyanoacetyl)amino]thieno[2,3-b]-
pyridine-2-carboxylate afforded 2,4-dihydroxy-7,9-dimethylthieno[2,3-b:4,5-b′]dipyridine-3-carbonitrile whose
tautomeric equilibrium was studied by DFT quantum chemical calculations. In silico analysis of biological activity
of the synthesized compounds was performed.
Keywords: cyanoacetylation, cyanoacetylpyrazole, thieno[2,3-b]pyridines, Dieckmann cyclization, thieno[2,3-
b:4,5-b′]dipyridines
DOI: 10.1134/S1070363219100062
Functional derivatives of cyanoacetic acid are among
the most popular building blocks in fine organic syn-
thesis (for reviews, see [1–6]). Numerous examples
of introduction of a cyanoacetyl fragment into or-
ganic molecules have been reported. The most efficient
methods include direct cyanoacetylation of substrates
using acylating agents such as cyanoacetyl chloride,
cyanoacetic acid/DMAP (dimethylaminopyridine)/DCC
(N,N′-dicyclohexylcarbodimide), cyanoacetic acid/acetic
anhydride [4], and 1-(cyanoacetyl)-3,5-dimethylpyrazole
(1) [7]. The latter reagent is exceptionally convenient in
operation and preparatively accessible, and it seems to
be preferred alternative to most of the cyanoacetylating
agents in reactions with nitrogen nucleophiles and various
heterocyclizations [8–12]. Pyrazole 1 reacts with a broad
series of amines, including heterocyclic ones [7]; how-
ever, its reactions with 3-aminothieno[2,3-b]pyridines
have not been reported so far.
In continuation of the series of our studies in the field
of functionalized thienopyridines [21–28], we focused
on the possibility of obtaining previously unknown N-
cyanoacetyl derivatives of 3-aminothieno[2,3-b]pyridine
using pyrazole 1 as cyanoacetylating agent.
We have found that compounds 2a and 2b readily react
with 1-(cyanoacetyl)-3,5-dimethylpyrazole (1) in boiling
toluene to give previously unknown substituted cyano-
acetamides 3a and 3b in good yields (Scheme 1). Taking
into account the synthetic potential of cyanoacetamides
[1, 2, 4], it seemed reasonable to study reactions of 3a and
3b with 2-(arylmethylidene)malononitriles 4. It is known
that cyanoacetamides generally react with dinitriles 4 to
produce pyridines 5 (Scheme 2) [1, 4, 29–31]. However,
as shown in [32–34], reactions of 4 with anthranilic acid
derivatives 6 can be accompanied by further heterocy-
clization with the formation of polycyclic structures like
7 (Scheme 2).
3-Aminothieno[2,3-b]pyridines contain a privileged
thienopyridine fragment and constitute a popular class
of compounds with a very broad spectrum of biological
activity [13–15]. The chemistry of 3-aminothieno[2,3-b]-
pyridines was the subject of a number of reviews [16–20].
We studied cyclizations of 3a with malononitriles
4. Regardless of the base catalyst used (morpholine or
potassium hydroxide), compound 3a reacted with 4a and
4b in a non-selective manner to give mixtures of com-
pounds 8–12 at different ratios, which we failed to sepa-
2018

SYNTHESIS AND CYCLIZATIONS OF N-(THIENO[2,3-b]PYRIDIN-3-YL)CYANOACETAMIDES
2019
Scheme 1.
N
R3
NH2
CH3
R2
COOR4
O
N
N
+
R1
N
S
CH3
1
2a, 2b
O
R3
N
HN
H3C
CN
R2
R1
toluene, ǻ
CH3
+
COOR4
HN
N
S
3a, 3b
1
3
2
4
1
2
3
4
R = R = CH , R = H, R = Et (ɚ); R + R = (CH ) , R = H, R = CH (b).
3
2 4
3
rate (Scheme 3, Table 1). The products were identified
by HPLC/MS and 1H NMR. Compound 10 was formed
via competing intramolecular Dieckmann cyclization of
the thienopyridine substrate. Dipyridothiophene 10 was
also the only isolated product in the reaction of 3a with
2-(4-nitrobenzylidene)malononitrile (4c). The structure
of the isolated compounds was confirmed by NMR, IR,
and HPLC/MS data, elemental analyses, and independent
synthesis of 10 through sodium isopropoxide-promoted
intramolecular cyclization of 3a.
Scheme 2.
Ar
N
Ar
Ar
NC
O
CN
NC
O
CN
NC
O
[O]
CN
+
NH2
CN
N
R
NH2
NH
R
R
5
4
EWG
EWG
EWG
NH
O
NC
CN
O
CN
Ar
+
N
N
CN
Ar
H
Ar
NC
CN
H2N
O
4
6
CN
NC
O
EWG
[O]
NH
O
CN
Ar
CN
Ar
N
N
X
H2N
CN
CN
7
EWG = CN, CO2Alk; X = O, NH.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

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CHIGORINA et al.
Table 1. Reaction of compound 3a with (arylmethylidene)malononitriles 4
Yield, %
10
Reactants
Reaction conditions
8
~36
~45
Traces
0
9
~9
11
0
12
0
3а + 4а
3а + 4а
3а + 4b
3а + 4c
Morpholine, EtOH, Δ
KOH, DMF, Δ
~22
~45
~5
Traces
~4
Traces
Traces
0
0
KOH, DMF, Δ
~19
0
KОН, EtOH, Δ
0
81
Compound 10 can exist as several tautomers 10A–
10D (Scheme 4). It was impossible to unambiguously
determine the tautomer structure on the basis of NMR
and IR data; therefore, the relative stability of different
tautomers was estimated by quantum chemical calcula-
tions. The calculations were performed in the framework
of the density functional theory with the B3LYP hybrid
functional (Becke exchange functional [35] and Lee–
Yang–Parr correlation functional [36]) and 6-31G(d,p)
split-valence basis set using GAMESS software package.
The obtained structures were visualized using Molekel.
The ground state energies were calculated with prelimi-
nary geometry optimization with a similar basis set. Non-
specific solvation of tautomers in DMSO was taken into
account in terms of the conducting polarizable continuum
model (CPCM) [37].
were obtained by PCM for DMSO. In this case, the most
stable was tautomer 10A, though the energy difference
between 10A and 10B was as small as 5.2 kJ/mol. These
findings allowed us to presume that compound 10 in the
crystalline state has structure 10B which can be converted
to tautomer 10A upon dissolution in DMSO, since the lat-
ter is solvated more effectively. The strongest solvation by
DMSO was predicted for tautomer 10C; however, its en-
ergy still remains fairly high (the difference is 20.2 kJ/mol
relative to 10A). Structure 10D is the least favorable both
in the gas phase and in DMSO solution and seems there-
fore hardly probable. In the future, we plan to perform
a more detailed study of tautomeric transformations of
similar dipyridothiophenes.
Compounds 3a, 3b, and 10 were evaluated in silico for
drug likeness, and theirADMET (absorption, distribution,
metabolism, excretion, toxicity) parameters and probable
biological activity were predicted using OSIRIS Property
Explorer [38], SwissADME [39], SwissTargetPrediction
[40], PASS Online [41], and Molinspiration Property
Calculation Service [42]. OSIRIS Property Explorer was
used to estimate the lipophilicity (c Log P), solubility
(log S), topological polar surface area (TPSA), and toxi-
cological parameters (risks of side mutagenic, oncogenic,
and reproductive effects), drug likeness, and drug score
[38]. This online service makes it possible to perform
primary analysis of a structure for its correspondence to
Lipinski’s rule of five [c Log P ≤ 5.0, molecular weight
(MW) ≤ 500, TPSA≤ 140, number of hydrogen bond ac-
ceptors ≤ 10, number of hydrogen donors ≤ 5] [43–45].
The results of calculations by OSIRIS Property Explorer
are collected in Table 2.
The calculated energies of tautomers 10A–10D are
given in the figure. The most stable tautomer in the gas
phase is 10B, and the energy of tautomer 10A is higher
by 25.8 kJ/mol. It should be noted that different results
120
100
1
80
60
40
2
20
0
It is seen that cLog P values for 3a, 3b, and 10 do
not exceed 3.0 (Table 2), indicating their probable good
absorption and permeability [43–45]. The molecular
weight of all compounds is lower than 350, which is also
consistent with Lipinski’s rule of five. However, none of
these compounds showed positive drug likeness or high
10A
10B
10C
10D
Tautomer
Relative energies of tautomers 10A–10D calculated (1) with
account taken of non-specific solvation in DMSO and (2) for
the gas phase; the energy of the most stable tautomer (10A)
in DMSO was assumed to be zero.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

SYNTHESIS AND CYCLIZATIONS OF N-(THIENO[2,3-b]PYRIDIN-3-YL)CYANOACETAMIDES
2021
Scheme 3.
Ar
NC
Ar
O
CN
CN
Me
N
Me
N
O
HN
S
CN
CO2Et
Me
CN
ꢄɚ–4c
N
N
OH
CN
+
NH2
CO2Et
Me
S
Me
S
ꢀɚ–8c
Me
N
OH
Ar
3a
10
i-PrONa
i-PrOH
CN
NC
O
Ar
CN
Me
Me
N
CN
O
N
OH
CN
N
Me
N
+
NH2
NH
Me
N
S
Me
S
CO2Et
OH
S
O
Me
N
N
10
ꢁɚ–9c
11a–11c
+
CN
O
Ar
Me
CN
NH
Me
N
S
O
ꢂꢃɚ–12c
Ar = 4-MeOC H (ɚ), Ph (b), 4-NO C H (c).
6
4
2 6 4
drug score (>0.5). On the other hand, low probability of
toxicity was predicted for 3a, 3b, and 10.
able targets of 3a are microtubule-associated protein tau
(MAPT) and TDP1 (tyrosyl-DNA phosphodiesterase
1), of 3b, MAPT and MBNL (muscleblind-like splicing
regulator) protein family, and of 10, MBNLproteins. The
bioavailability index of all compounds was equal to 0.55,
in keeping with the Lipinski rule of five [46].
The log S parameter indicated relatively low predicted
solubility of these compounds. It should be noted that the
log S value of 80% of commercially available drugs is
no less than –4 [38]. According to the PASS Online data,
compound 10 should inhibit insulinase with a probability
of 0.711. Molinspiration Property Calculation Service
predicted possible kinase inhibitory activity of 3a, 3b,
and 10 (Molinspiration bioactivity score –0.34, –0.29,
and 0.14, respectively; the higher the score, the higher
the probability of biological activity).
In summary, N-(thieno[2,3-b]pyridin-3-yl)cyanoacet-
amides can be synthesized by direct cyanoacetylation
of 3-aminothieno[2,3-b]pyridine-2-carboxylates with
1-(cyanoacetyl)-3,5-dimethylpyrazole. However, in con-
trast to published data for structurally related compounds,
the obtained cyanoacetamides react with 2-(arylmethyli-
dene)malononitriles in a non-selective manner, obviously
depending on the reaction conditions and unsaturated
nitrile structure. Studies aimed at optimizing the reaction
conditions and developing selective procedures for the
synthesis of polycyclic structures based on N-(thieno[2,3-
High gastrointestinal absorption, no BBB (blood–
brain barrier) permeability, and inhibition of a series
of proteins of the cytochrome P450 family (CYP) were
predicted for all compounds (Table 3). According to the
data of SwissTargetPrediction analysis, the most prob-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2022
CHIGORINA et al.
Scheme 4.
ꢂꢅȺ
10B
Me
N
Me
N
H
N
N
OH
CN
O
Me
S
Me
S
CN
OH
OH
10C
10D
Me
N
Me
N
H
N
H
N
O
OH
CN
Me
S
CN
Me
S
O
O
b]pyridin-3-yl)cyanoacetamides are now in progress.
In silico analysis of possible biological activity of the
synthesized compounds indicated correspondence to
bioavailability criteria for oral administration and prob-
able broad spectrum of action.
(λ 254 nm) and Sedex 75 ELSD detectors and coupled
with a PE SCIEXAPI 150EX mass spectrometer (ES-API,
positive ion detection). The elemental compositions were
determined using a Carlo Erba 1106 elemental analyzer.
The purity of the synthesized compounds was checked
by TLC on Silufol UV254 plates using acetone–hexane
(1 : 1) as eluent; spots were visualized by treatment with
iodine vapor or under UV light.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
Initial 1-(cyanoacetyl)-3,5-dimethylpyrazole (1) was
synthesized from cyanoacetohydrazide and acetylacetone
according to the procedure described in [47].
DPX-400 spectrometer at 400.4 MHz using DMSO-d6 as
solvent; the chemical shifts were measured relative to the
residual proton signal of the solvent or tetramethylsilane.
The IR spectra were recorded on Thermo Nicolet Magna
750 IR and LOMO IKS-29 (3, 10) instruments from
samples prepared as KBr pellets. The HPLC/MS analysis
was performed with a Shimadzu LC-10AD liquid chro-
matograph equipped with Shimadzu SP D-10A UV–Vis
3-[(Cyanoacetyl)amino]thieno[2,3-b]pyridine-
2-carboxylates 3a and 3b (general procedure). A hot
solution of 15 mmol of thienopyridine 2a or 2b in
25–30 mL of anhydrous toluene was added dropwise to
a solution of 3.00 g (18.4 mmol) of 1-(cyanoacetyl)-3,5-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

SYNTHESIS AND CYCLIZATIONS OF N-(THIENO[2,3-b]PYRIDIN-3-YL)CYANOACETAMIDES
2023
Table 2. Toxicity risks and physicochemical characteristics of compounds 3a, 3b, and 10, predicted by OSIRIS Property Explorer
Toxicity risksa
Physicochemical parameters
Comp. no.
сLogP
logS
MW
TPSA
drug likeness
drug Score
3a
3b
10
–
–
–
–
–
–
–
–
–
–
–
–
2.24
2.71
2.11
–4.81
–5.21
–4.64
317.0
343.0
271.0
120.3
120.3
118.2
–7.53
–12.79
–5.36
0.36
0.322
0.376
a “–” No toxicity prediction.
Table 3. ADMET parameters and biological activity of compounds 3a, 3b, and 10, predicted by SwissADME and SwissTarget-
Predictiona
Cytochrome P450 inhibition
Comp.
no.
Probable
targets
Bioavailability
inde
CYP1A2 CYP2C19 CYP2C9 CYP2D6 CYP3A4
МАРТ,
TDP2
0.55
0.55
3a
3b
High
High
–
–
+
+
+
+
+
+
–
–
–
МАРТ,
MBNL1,
MBNL2,
MBNL3
+
MBNL1,
MBNL2,
MBNL3
0.55
10
High
–
+
–
+
–
+
а The signs “+” or “–” denote the presence or absence of effect.
dimethylpyrazole 1 in 10 mL of anhydrous toluene.
The resulting solution was refluxed for 5 h (TLC); after
~20 min, the product began to precipitate. The mixture
was cooled, and the white solid was filtered off, washed
with toluene and ethanol, and dried.
56.73; H 4.85; N 13.21. C15H15N3O3S. Calculated, %: C
56.77; H 4.76; N 13.24.
Methyl 3-[(cyanoacetyl)amino]-5,6,7,8-tetra-
hydrothieno[2,3-b]quinoline-2-carboxylate (3b). Yield
70%, colorless crystals. IR spectrum, ν, cm–1: 3250 br
(N–H), 2250 w (C≡N), 1710 s and 1665 s (C=O). 1H NMR
spectrum, δ, ppm: 1.70–1.82 m (2H, CH2), 1.85–1.90 m
(2H, CH2), 2.85–2.87 m (2H, CH2), 2.94–2.97 m (2H,
CH2), 3.76 s (3H, OCH3), 4.01 s (2H, CH2CN), 8.26
s (1H, 4-H), 10.40 s (1H, NH). Found, %: C 58.30; H
4.65; N 12.71. C16H15N3O3S. Calculated, %: C 58.34; H
4.59; N 12.76.
Ethyl 3-[(cyanoacetyl)amino]-4,6-dimethylthi-
eno[2,3-b]pyridine-2-carboxylate (3a). Yield 71%,
colorless crystals pourly soluble in acetone and insoluble
in boiling ethanol. An analytical sample was obtained
by recrystallization from ethanol–acetic acid (1 : 3). IR
spectrum, ν, cm–1: 3240 br (N–H), 2250 w (C≡N), 1715
s and 1670 s (C=O). 1H NMR spectrum, δ, ppm: 1.31 t
(3H, CH2CH3, 3J = 6.9 Hz), 2.55 s (3H, CH3), 2.58 s (3H,
CH3), 3.96 s (2H, CH2CN), 4.31 q (2H, OCH2, 3J = 6.9
Hz), 7.19 s (1H, 5-H), 10.35 s (1H, NH). Found, %: C
Reaction of compound 3a with 2-(4-methoxyben-
zylidene)malononitrile (4a) in the presence of mor-
pholine. Morpholine, 1.0 mL (0.011 mol), was added to
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

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CHIGORINA et al.
a mixture of 427 mg (1.345 mmol) of cyanoacetamide 3a
and 287 mg (1.56 mmol) of dinitrile 4a in 15 mL of etha-
nol. The mixture was refluxed with stirring for 2 h; amide
3a gradually dissolved, and the product began to precipi-
tate after ~30 min. The mixture was cooled, and the pre-
cipitate was filtered off, washed with ethanol, and dried.
The product was 370 mg of green–brown finely crystal-
line solid poorly soluble in ethanol and acetone. Accord-
ing to the 1H NMR and HPLC/MS data, it was a mixture
of ethyl 3-[6-amino-3,5-dicyano-4-(4-methoxyphenyl)-
2-oxopyridin-1(2H)-yl]-4,6-dimethylthieno[2,3-b]-
pyridine-2-carboxylate (8a), 3-(4-methoxyphenyl)-9,11-
dimethyl-1,6-dioxo-5,6-dihydro-1H-pyrido[1,2-a]pyri-
do[3′,2′ : 4,5]thieno[2,3-e]pyrimidine-2,4-dicarbonitrile
(9a), and 2,4-dihydroxy-7,9-dimethylthieno[2,3-b :
4,5-b′]dipyridine-3-carbonitrile (10) at a molar ratio of
~100 : 24 : 61. Yield ~36% (8a), ~9% (9a), ~22% (10).
1H NMR spectrum (identified signals), δ, ppm: 8a: 1.28
4-(4-methoxyphenyl)-2-oxo-3,4-dihydropyridin-1(2H)-
yl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate
(11a) were also detected by HPLC/MS. IR spectrum, ν,
cm–1: 3509 br, 3273 br, 3150 br (N–H, O–H); 2227 s,
2212 s (C≡N); 1723 s, 1672 s (C=O). 1H NMR spectrum
(identified signals), δ, ppm: 8a: 1.23 t (3H, CH2CH3,
3J = 7.0 Hz), 2.30 s (3H, CH3), 2.61 s (3H, CH3), 3.86 s
(3H, MeO), 4.30 q (2H, OCH2, 3J = 7.0 Hz), 7.14 d (2H,
m-H, 3J = 8.3 Hz), 7.30 s (1H, 5-H), 7.57 d (2H, o-H, 3J =
8.3 Hz), 8.47 br. s (2H, NH2); 10: 2.56 s (3H, CH3), 2.88
s (3H, CH3), 7.22 s (1H, 5-H). Mass spectrum, m/z: 273.1
[M + H]+ (10), 453.8 [M + H]+ (9a), 472.0 [M + NH4]+
(9a), 500.3 [M + H]+ (8a), 502.0 [M + H]+ (11a), 543.0
[2M + H]+ (10), 813.8 [3M + H]+ (10), 999.0 [2M + H]+
(8a), 1001.0 [2M + H]+ (11a), 1084.9 [4M + H]+ (10).
Reaction of compound 3a with 2-benzylidenemalo-
nonitrile (4b) in the presence of potassium hydroxide.
Powdered potassium hydroxide, 110 mg (1.96 mmol), was
added to a suspension of 251 mg (0.79 mmol) of cyano-
acetamide 3a and 197 mg (1.28 mmol) of dinitrile 4b in
10 mL of ethanol. The mixture was heated to the boiling
point, and the resulting yellow solution was refluxed for
25 min with stirring. The product precipitated from the
solution during the process. The mixture was cooled and
treated in succession with 1 mL of acetic acid and 1 mL
of 10% aqueous HCl, and the precipitate was filtered off,
washed with ethanol, and dried. The product was 89 mg
of yellow–orange powder poorly soluble in ethanol and
acetone. According to the 1H NMR and HPLC/MS data,
it was a mixture of compound 10, 9,11-dimethyl-1,6-
dioxo-3-phenyl-5,6-dihydro-1H-pyrido[1,2-a]pyri-
do[3′,2′ : 4,5]thieno[2,3-e]pyrimidine-2,4-dicarbonitrile
(9b), and 9,11-dimethyl-1,6-dioxo-3-phenyl-2,3,5,6-
tetrahydro-1H-pyrido[1,2-a]pyrido[3′,2′ : 4,5]thieno[2,3-
e]pyrimidine-2,4-dicarbonitrile (12b) at a molar ratio of
~2.5 : 2 : 9. Yield ~5% (10), ~4% (9b), ~19% (12b). The
product also contained ~3–4 mol % of 8b and/or 11b (1H
3
t (3H, CH2CH3, J = 7.0 Hz), 2.32 s (3H, CH3), 2.62 s
3
(3H, CH3), 3.88 s (3H, MeO), 4.31 q (2H, OCH2, J =
7.0 Hz), 7.12 d (2H, m-H, 3J = 8.3 Hz), 7.24 s (1H, 5-H),
7.54 d (2H, o-H, 3J = 8.3 Hz), 8.36 br.s (2H, NH2); 9a:
2.61 s (3H, CH3), 2.97 s (3H, CH3), 3.87 s (3H, MeO),
7.26 s (1H, 5-H), 8.02 d (2H, o-H, 3J = 8.8 Hz); 10: 2.59
s (3H, CH3), 2.91 s (3H, CH3), 6.28*1 br.s (1H, OH), 7.19
s (1H, 5-H), 11.44* br.s (OH, NH). Mass spectrum, m/z:
272.5 [M + H]+ (10), 389.3 [M – MeOC6H4 + MeCN +
H]+ (9a), 472.0 [M + NH4]+ (9a), 500.5 [M + H]+ (8a),
543.3 [2M + H]+ (10), 999.3 [2M + H]+ (8a).
Reaction of compound 3a with 2-(4-methoxy-
benzylidene)malononitrile (4a) in the presence of
potassium hydroxide. Powdered potassium hydroxide,
110 mg (1.96 mmol), was added to a suspension of
291 mg (0.92 mmol) of cyanoacetamide 3a and
169 mg (0.92 mmol) of dinitrile 4a in 2.5 mL of DMF.
The mixture was heated to the boiling point, and the
resulting red–orange solution was heated for 3–4 min
with stirring. The product precipitated during this period.
The mixture was cooled and treated in succession with
1 mL of acetic acid and 1 mL of 10% aqueous HCl. The
precipitate was filtered off, washed with ethanol, and
dried. The product was 320 mg of yellow–orange powder
poorly soluble in EtOH, DMSO, and acetone. According
to the 1H NMR and HPLC/MS data, it was a mixture of 8a
and 10 at a ratio of ~1 : 1. Yield ~45% (8a), ~45% (10).
Traces (<5%) of 9a and ethyl 3-[6-amino-3,5-dicyano-
3
1
NMR: δ 1.22 ppm, t, J = 7.0 Hz). H NMR spectrum
(identified signals), δ, ppm: 9b: 2.61 s (3H, CH3), 2.96 s
(3H, CH3), 7.24 s (1H, 5-H), 7.65–7.66 m (3H, Ph), 7.99–
8.01 m (2H, Ph); 10: 2.58 s (3H, CH3), 2.92 s (3H, CH3),
6.20* br.s (1H, OH), 7.19 s (1H, 5-H); 12b: 2.58 s (3H,
CH3), 2.90 s (3H, CH3), 3.96 d (CHCN, 1H, 3J = 12.4 Hz),
7.15 s (1H, 5-H), 7.53–7.59 m (5H, Ph), 10.07* br.s (1H,
NH). Mass spectrum, m/z: 261.6 [M – 164]+ (12b), 272.5
[M + H]+ (10), 359.8 [M – NCCH=C=O + H]+ (12b),
398.5 [M – CO + H]+ (9b), 413.8 [M – 2HCN + MeCN +
H]+ (12b), 424.5 [M + H]+ (9b), 426.5 [M + H]+ (12b),
1 (*) The signal intensity is underestimated, presumably because of
H–D exchange.
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SYNTHESIS AND CYCLIZATIONS OF N-(THIENO[2,3-b]PYRIDIN-3-YL)CYANOACETAMIDES
2025
543.7 [2M + H]+ (10), 717.5 [2M – 2 NCCH=C=O +
H]+ (12b), 795.5 [2M – 2CO + H]+ (12b), 814.8 [3M +
H]+ (10), 825.8 [2 M – 4 HCN + 2 MeCN + H]+ (12b),
847.3 [2M + H]+ (9b).
https://doi.org/10.1134/S1070428008110018
2. Fadda, A.A., Bondock, S., Rabie, R., and Etman, H.A.,
Turk. J. Chem., 2008, vol. 32, no. 3, p. 259.
3. Bondock, S., Tarhoni, A.E.G., and Fadda, A.A., Arkivoc,
2006, part (ix), p. 113.
2,4-Dihydroxy-7,9-dimethylthieno[2,3-b:4,5-b′]-
dipyridine-3-carbonitrile (10). a. Reaction of 3a with
2-(4-nitrobenzylidene)malononitrile (4c) in the pres-
ence of KOH. Powdered potassium hydroxide, 110 mg
(1.96 mmol), was added to a suspension of 173 mg
(0.55 mmol) of cyanoacetamide 3a and 160 mg
(0.80 mmol) of dinitrile 4c in 10 mL of DMF. The
mixture was refluxed for 1 h with stirring, and a solid
precipitated. The mixture was cooled, treated in succes-
sion with 1 mL of acetic acid and 1 mL of 10% aqueous
HCl, and the precipitate was filtered off, washed with
ethanol, and dried. Yield 120 mg (81%), yellow powder
poorly soluble in ethanol and acetone. IR spectrum, ν,
cm–1: 3500–3150 br (N–H, O–H), 2220 s (C≡N), 1650
s (C=O). 1H NMR spectrum, δ, ppm: 2.59 s (3H, CH3),
2.91 s (3H, CH3), 6.12* br.s (1H, OH), 7.16 s (1H, 5-H),
11.58* br.s (OH or NH). Mass spectrum, m/z: 272.5 [M +
H]+, 543.5 [2M + H]+, 815.0 [3M + H]+. Found, %: C
57.64; H 3.48; N 15.33. C13H9N3O2S. Calculated, %: C
57.55; H 3.34; N 15.49.
4. Fadda, A.A. and Rabie, R., Res. Chem. Intermed.,
2016, vol. 42, no. 2, p. 771.
https://doi.org/10.1007/s11164-015-2055-9
5. Shestopalov,A.M.,Shestopalov,A.A.,Rodinovskaya,L.A.,
Synthesis, 2008, no. 1, p. 1.
https://doi.org/10.1055/s-2007-990942
6. Litvinov, V.P., Russ. Chem. Rev., 1999, vol. 68, no. 9,
p. 737.
https://doi.org/10.1070/RC1999v068n09ABEH000533
7. Chigorina, E.A. and Dotsenko, V.V., Chem. Heterocycl.
Compd., 2012, vol. 48, no. 8, p. 1133.
https://doi.org/10.1007/s10593-012-1116-x
8. Chigorina, E.A., Synlett, 2014, vol. 25, no. 3,
p. 453.
https://doi.org/10.1055/s-0033-1340469
9. Edraki, N., Firuzi, O., Foroumadi, A., Miri, R., Madad-
kar-Sobhani, A., Khoshneviszadeh, M., and Shafiee, A.,
Bioorg. Med. Chem., 2013, vol. 21, no. 8,
p. 2396.
https://doi.org/10.1016/j.bmc.2013.01.064
b. Intramolecular cyclization of 3a. A hot solu-
tion of sodium isopropoxide, prepared from 100 mg
(4.35 mmol) of sodium and 10 mL of anhydrous propan-
2-ol, was added to a suspension of 330 mg (1.04 mmol)
of cyanoacetamide 3a in 8 mLof anhydrous propan-2-ol.
The mixture was refluxed for 3 h with stirring, and it
thickened due to formation of a gel-like sodium salt. The
mixture was cooled and treated in succession with 1 mLof
acetic acid and 1 mL of 10% aqueous HCl, and the light
yellow solid was filtered off, washed with ethanol, and
dried. Yield 233 mg (83%). The spectral characteristics of
the product were identical to those of a sample prepared
as described above in a.
10. Hebishy, A.M., Abdelhamid, I.A., and Elwahy, A.H.,
Arkivoc, 2018, part (v), p. 109.
https://doi.org/10.24820/ark.5550190.p010.498
11. Dotsenko, V.V., Krivokolysko, S.G., and Litvinov,
V.P., Monatsh. Chem., 2007, vol. 138, no. 6, p. 607.
https://doi.org/10.1007/s00706-007-0664-8
12. Frolov, K.A., Dotsenko, V.V., Krivokolysko, S.G.,
and Litvinov, V.P., Chem. Heterocycl. Compd., 2012,
vol. 48, no. 3, p. 442.
https://doi.org/10.1007/s10593-012-1012-4
13. Comprehensive Medicinal Chemistry III, Chackalaman-
nil, S., Rotella, D., and Ward, S., Eds., Amsterdam: Else-
vier, 2017, vol. 1, p. 124.
FUNDING
14. Buchstaller, H.P., Siebert, C.D., Steinmetz, R., Frank, I.,
Berger, M.L., Gottschlich, R., Leibrock, J., Krug, M.,
Steinhilber, D., and Noe, C.R., J. Med. Chem., 2006,
vol. 49, no. 3, p. 864.
This study was performed under financial support
by the Ministry of Science and Higher Education of
the Russian Federation (project no. 4.5547.2017/8.9;
V.V. Dotsenko).
https://doi.org/10.1021/jm0503493
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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