One-Pot Synthesis of Thieno[2,3-b]pyridine and Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine Derivatives

Article abstract of DOI:10.1134/S1070428020060020

Abstract: 2-Acyl-4,5,6-trialkyl-3-aminothieno[2,3-b]pyridines, 8′-ethyl-7′,9′-dimethyl-1′H-spiro[cyclohexane-1,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin]-4′(3′H)-one, and 7,8,9-trimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine have been synthesize

Full text of DOI:10.1134/S1070428020060020

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 6, pp. 974–982. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 6, pp. 859–869.
One-Pot Synthesis of Thieno[2,3-b]pyridine
and Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine Derivatives
I. V. Dyachenkoa, V. D. Dyachenkoa, P. V. Dorovatovskyb,
V. N. Khrustalevc,d, and V. G. Nenajdenkoe,*
a Taras Shevchenko Lugansk National University, Lugansk, 91011 Ukraine
b Kurchatov Institute National Research Center, Moscow, 123182 Russia
c Peoples’Friendship University of Russia, Moscow, 117198 Russia
d Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119991 Russia
e Faculty of Chemistry, Moscow State University, Moscow, 119991 Russia
*e-mail: nenajdenko@gmail.com
Received April 7, 2020; revised April 9, 2020; accepted April 13, 2020
Abstract—2-Acyl-4,5,6-trialkyl-3-aminothieno[2,3-b]pyridines, 8′-ethyl-7′,9′-dimethyl-1′H-spiro[cyclo-
hexane-1,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin]-4′(3′H)-one, and 7,8,9-trimethylpyrido[3′,2′:4,5]thieno-
[3,2-d]pyrimidin-4-amine have been synthesized by one-pot three-component condensation of 3-methyl(ethyl)-
pentane-2,4-diones with cyanothioacetamide and α-halocarbonyl compounds, cyclohexanone, or formamide.
The structures of some of the synthesized thieno[2,3-b]pyridine derivatives have been studied by X-ray analysis.
Keywords: 3-methyl(ethyl)pentane-2,4-diones, cyanothioacetamide, α-halocarbonyl compounds, cyclo-
hexanone, formamide, thieno[2,3-b]pyridines, pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines, X-ray analysis
DOI: 10.1134/S1070428020060020
Functionalized thieno[2,3-b]pyridines are used in
the treatment of central nervous system diseases [1]
and as C-terminal hydrolase L1 (UCH-L1) inhibitors
[2]. They are also promising for the design of anti-
microbial [3] and antitumor agents [4–6]. The main
methods of synthesis of these compounds are based on
fusion of a thiophene ring to pyridine or a pyridine ring
to thiophene [7].
of organic sulfides C that are capable of undergoing
deprotonation in basic medium to give carbanion D.
Intramolecular cyclization with participation of the
cyano group leads to imino derivative E which tauto-
merizes to exhaustively substituted 3-aminothieno-
[2,3-b]pyridine 1 (Scheme 1).
The structures of (3-amino-4,6-dimethylthieno-
[2,3-b]pyridin-2-yl)(thiophen-2-yl)methanone (1a),
Herein, we report a one-pot procedure for the syn-
thesis of 2-acyl-4,5,6-trialkyl-3-aminothieno[2,3-b]-
pyridines 1a–1l that are promising as starting materials
for the preparation of fused polycyclic heterocycles
[8–11]. Compounds 1a–1l were obtained by condensa-
tion of acyclic precursors, pentane-2,4-diones 2a–2c,
cyanothioacetamide (3), and α-halo ketones 4a–4l, in
DMF at 50°C in the presence of an equimolar amount
of sodium ethoxide. A plausible reaction scheme in-
cludes Knoevenagel condensation of cyanothioacet-
amide at one carbonyl group of diketone 2, intra-
molecular cyclization of condensation product A to
sodium pyridine-2-thiolate B, and alkylation of the lat-
ter with α-halocarbonyl compound 4 with the formation
N3
C13
C4
O1
C8
C3
C3A
C2
C5
C6
C9
S2
C7A
C14
C12
S1
C10
C7
C11
Fig. 1. Molecular structure of compound 1a. Non-hydrogen
atoms are shown as 50%-probability anisotropic displace-
ment ellipsoids. Intramolecular hydrogen bond N–H···O is
shown with dashed line.
974

ONE-POT SYNTHESIS OF THIENO[2,3-b]PYRIDINE
975
Scheme 1.
Me
Me
N
O
O
R
CN
S
S
EtONa
–H2O
R
CN
+
NC
Me
Me
Hlg
–H2O
NH2
Me
S– Na+
R
Me
O
NH2
2a–2c
3
A
B
O
Me
Me
N
Z
R
CN
R
EtONa
4a–4l
Z
Z
Me
N
S
Me
N
S
O
O
C
D
Me
Me
NH
NH2
R
R
Z
Z
S
S
O
O
Me
N
Me
N
E
1a–1l
1, R = H, Z = thiophen-2-yl (a), 4-ClC6H4 (b), 4-MeOC6H4 (c), BuO (d), 1,3-thiazol-2-ylamino (e), i-PrO (f), PrO (g),
4-AcC6H4NH (h), Me(CH2)7O (i); R = Me, Z = 2-MeC6H4NH (j); R = Et, PhNH (k), 4-BrC6H4 (l). 2, R = H (a), Me (b), Et (c);
4, Hlg = Br, Z = thiophen-2-yl (a), 4-ClC6H4 (b), 4-MeOC6H4 (c), 4-BrC6H4 (l); Hlg = Cl, Z = BuO (d), 1,3-thiazol-2-ylamino (e),
i-PrO (f), PrO (g), 4-AcC6H4NH (h), Me(CH2)7O (i), 2-MeC6H4NH (j), PhNH (k).
(3-amino-4,6-dimethylthieno[2,3-b]pyridin-2-yl)-
(4-chlorophenyl)methanone (1b), and (3-amino-4,6-
dimethylthieno[2,3-b]pyridin-2-yl)(4-methoxyphenyl)-
methanone (1c) were studied by X-ray analysis. The
central 3-amino-4,6-dimethylthieno[2,3-b]pyridin-2-
yl)carbonyl fragment of all molecules 1a–1c is almost
planar [mean-square deviation of non-hydrogen atoms
from the average plane are 0.039 (1a), 0.055 (1b), and
0.045 Å (1c)]. Presumably, the planar structure of that
fragment is stabilized by the formation of extended
conjugation system and fairly strong intramolecular
hydrogen bond N–H···O (Figs. 1–3, Table 1).
The planar thienyl (1a), p-chlorophenyl (1b), and
p-methoxyphenyl (1c) groups are turned through
angles of 28.38(10), 33.00(5), and 37.09(4)°, respec-
tively, relative to the 3-amino-4,6-dimethylthieno-
[2,3-b]pyridin-2-ylcarbonyl fragment. It should be
noted that the methoxy group in molecule 1c is co-
C16
N3
C3
C15
C4
N3
C3
O1
C8
C4
O1
C5
C3A
C3A
C5
C8
C9
C14
C9
C2
C6
C17
C14
C2
C7A
C6
C13
C12
C7A
C10
S1
N7
C13
C12
Cl1
S1
C16
C10
N7
O2
C11
C11
C15
Fig. 2. Molecular structure of compound 1b. Non-hydrogen
atoms are shown as 50%-probability anisotropic displace-
ment ellipsoids. Intramolecular hydrogen bond N–H···O is
shown with dashed line.
Fig. 3. Molecular structure of compound 1c. Non-hydrogen
atoms are shown as 50%-probability anisotropic displace-
ment ellipsoids. Intramolecular hydrogen bond N–H···O is
shown with dashed line.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

DYACHENKO et al.
976
in a “head-to-tail” fashion with conservation of the
polar direction (polar space group Cc), whereas the
crystal structures of 1b and 1c are characterized by
head-to-head orientation of stacks along the same
direction, so that an inversion center appears (centro-
symmetric space group P21/c). Therefore, compounds
1a–1c can be expected to form the corresponding
polymorphic modifications, namely, in the centrosym-
metric space group P21/c for 1a and polar space group
Cc for 1b and 1c.
a
c
0
The condensation of 3-methylpentane-2,4-dione
(2b) with cyanothioacetamide (3) in DMF in the pres-
ence of sodium ethoxide at 50°C, followed by addition
of chloroacetonitrile (5) and heating of the product in
boiling formamide for 1 h, afforded 7,8,9-trimethyl-
pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine (6).
Thienopyridine F was obviously formed as inter-
mediate product in this multicomponent process
(Scheme 2). Likewise, the condensation of 3-ethyl-
pentane-2,4-dione (2c), cyanothioacetamide (3),
chloroacetamide (7), and cyclohexanone under similar
conditions led to the formation of 8′-ethyl-7′,9′-di-
methyl-1'H-spiro[cyclohexane-1,2′-pyrido[3′,2′:4,5]-
thieno[3,2-d]pyrimidin]-4′(3′H)-one (8) which is a po-
tential intermediate product in the synthesis of anti-
microbial [12], anti-asthmatic [13], and analgesic
agents [14]. It is reasonable to presume intermediate
formation of substituted thienopyridine G in this
reaction (Scheme 2).
b
The spectral parameters of 1a–1l, 6, and 8 were
Fig. 4. Crystal packing of compound 1a.
consistent with their structures (see Experimental).
1
Their H NMR spectra showed signals from aliphatic
planar to the benzene ring. Molecules 1a, 1b, and 1c in
crystal are packed in stacks along the a crystallographic
axis (Figs. 4–6). The stacked molecules are oriented
approximately parallel to the (1 0 –2) plane. No short
intermolecular contacts were observed in the crystal
structures of 1a–1c.
substituents at proper positions with expected multi-
plicities, as well as broadened singlets of NH and NH2
protons. The formation of spirocyclic fragment in 8
confirmed vicinal position of the amino and carbamoyl
groups, which is typical of such systems [15].
It should be noted that compounds 1b and 1c are
isostructural and that compound 1a is isotypical to 1b
and 1c. Obviously, this is related to the different mutual
arrangement of stacks. In the crystal structure of 1a,
the stacks are aligned along the b crystallographic axis
EXPERIMENTAL
The unit cell parameters and reflections intensities
for compounds 1a–1c were measured on a BELOK
synchrotron station at the Kurchatov Institute National
Table 1. Hydrogen bonds in the crysatal structures of compounds 1a–1c
Compound no.
D–H···A, Å
N3–H3A···O1
N3–H3A···O1
N3–H3A···O1
d(D–H), Å
0.90(5)
d(H···A), Å
2.01(5)
d(D···A), Å
2.712(5)
Angle DHA, deg
133(4)
1a
1b
1c
0.85(2)
2.04(2)
2.697(2)
133.6(19)
0.84(2)
2.08(2)
2.693(2)
129.7(17)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

ONE-POT SYNTHESIS OF THIENO[2,3-b]PYRIDINE
977
a
a
c
0
0
c
b
b
Fig. 5. Crystal packing of compound 1b.
Fig. 6. Crystal packing of compound 1c.
Research Center using a Rayonix SX165 CCD two-
coordinate detector (temperature 100 K, λ 0.96990 Å,
φ-scanning with a step of 1.0°). The data were
processed by iMOSFLM program included in CCP4
package [16]. A correction for absorption of X-rays
was applied using SCALA program [17]. The principal
crystallographic data and structure refinement param-
eters are collected in Table 2. The structures were
solved by the direct method and were refined against
F2 by the full-matrix least squares method in aniso-
tropic approximation for non-hydrogen atoms. Hydro-
gen atoms of the amino groups were localized by the
difference Fourier syntheses and were refined in iso-
tropic approximation with fixed thermal displacement
parameters [Uiso(H) = 1.2Ueq(N)]. The positions of the
other hydrogen atoms for all compounds were calcu-
lated geometrically and were refined according to the
riding model with fixed positional parameters and
isotropic thermal displacement parameters [Uiso(H) =
1.5Ueq(C) for methyl groups Uiso(H) = 1.2Ueq(C) for
other hydrogens]. All calculations were performed
using SHELXTL software package [18]. The tabulated
Scheme 2.
Me
N
Me
N
NH2
O
HCONH2, Δ
3
N
Me
Me
Me
Me
2b
+
Cl
–H2O
CN
CN
NH2
S
S
N
5
F
6
O
Me
NH2
, AcOH, Δ
O
Me
3
Et
HN
S
NH2
O
2c
+
Cl
NH
Et
–H2O
NH2
S
Me
N
O
Me
N
7
G
8
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

DYACHENKO et al.
978
Table 2. Crystallographic data for compounds 1a–1c
Parameter
1a
1b
1c
Formula
C14H12N2OS2
288.38
C16H13ClN2OS
316.79
C17H16N2O2S
312.38
Molecular weight
Single crystal dimensions, mm
0.05×0.15×0.25
Monoclinic
Cc
0.10×0.10×0.25
Monoclinic
P21/c
0.10×0.10×0.20
Monoclinic
P21/c
Crystal system
Space group
a, Å
6.9652(14)
25.630(5)
7.2852(15)
97.37(3)
1289.8(5)
4
7.1131(14)
27.840(6)
7.2401(14)
100.67(3)
1409.0(5)
4
7.1300(14)
28.265(6)
7.2850(15)
100.89(3)
1441.7(5)
4
b, Å
c, Å
β, deg
V, Å3
Z
dcalc, g/cm3
1.485
1.493
1.439
F(000)
600
656
656
μ
0.956
0.988
0.537
2θ
76.76
76.86
76.98
Total number of reflections
Number of independent reflections (Rint)
Number of reflections with I > 2σ(I)
Number of variables
R1; wR2 [reflections I > 2σ(I)]
R1; wR2 (all independent reflections)
Goodness of fit with respect to F2
Extinction coefficient
Tmin; Tmax
6331
18340
25378
2054 (0.054)
1947
3017 (0.104)
2548
2995 (0.070)
2645
181
199
209
0.041; 0.090
0.048; 0.097
1.046
0.048; 0.123
0.057; 0.130
1.080
0.039; 0.097
0.046; 0.102
1.055
0.004(1)
0.770; 0.940
0.013(2)
0.770; 0.900
0.006(1)
0.770; 0.900
coordinates of atoms, bond lengths, bond and torsion
angles, and anisotropic displacement parameters for
compounds 1a–1c were deposited to the Cambridge
Crystallographic Data Centre [entry nos. 1880 558
(1a), 1880559 (1b), and 1880560 (1c)].
perature 275°C; positive and negative ion detection,
Orbitrap resolution 480 000; internal calibrants
[2DMSO + H]+ ion (m/z 157.03515) for positive ions
and dodecyl sulfate anion (m/z 265.14789) for negative
ions. The mass spectra of 1d, 1g, 1j–1l, and 8 (electron
impact, 70 eV) were recorded using an Agilent 1100
Series liquid chromatograph coupled with an Agilent
LC/MSD LS mass-selective detector (samples were
introduced in acetic acid). Elemental analysis was
performed with a Perkin Elmer CHN analyzer. The
melting points were measured on a Kofler hot stage.
The progress of reactions was monitored, and the
purity of the isolated compounds was checked, by TLC
on Silufol UV-254 plates using acetone–hexane (3:5)
as eluent; spots were visualized by treatment with
iodine vapor and under UV light.
The IR spectra were recorded on an IKS-40 spec-
trometer from samples dispersed in mineral oil. The
1H and 13C NMR spectra were measured on a Varian
VXR–400 spectrometer at 399.97 and 100 MHz,
respectively, using DMSO-d6 as solvent (unless other-
wise stated) and tetramethylsilane as internal standard.
The mass spectra of 1a–1c, 1e, 1f, 1h, 1i, and 6 were
obtained on an Orbitrap Elite high-resolution mass
spectrometer; samples were dissolved in 1 mL of
DMSO, and the solutions were diluted 100-fold with
1% HCOOH in CH3CN and introduced into the elec-
trospray ionization source at a flow rate of 40 μL/min
using a syringe pump; ion source gas supply was
turned off; capillary voltage 3.5 kV, capillary tem-
2-Acyl-4,5,6-trialkyl-3-aminothieno[2,3-b]pyri-
dines 1a–1l (general procedure). A solution prepared
from 0.23 g (10 mmol) of metallic sodium and 20 mL
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

ONE-POT SYNTHESIS OF THIENO[2,3-b]PYRIDINE
979
of ethanol was added with stirring at 20°C to a mixture
of 10 mmol of 1,3-diketone 2a–2c and 1.0 g (10 mmol)
of cyanothioacetamide (3) in 20 mL of DMF. The mix-
ture was heated to 50°C, 10 mmol of α-halocarbonyl
compound 4a–4l was added, and the mixture was
stirred at 20°C for 5 h and left to stand for 24 h. The
mixture was diluted with an equal volume of water,
and the precipitate was filtered off and washed in
succession with water, ethanol, and hexane.
mp 118–120°C (from BuOH). IR spectrum, ν, cm–1:
3418, 3388, 3005 (NH2), 1722 (C=O), 1634 (δNH2).
1H NMR spectrum, δ, ppm: 0.91 t (3H, Me, J =
7.4 Hz), 1.32–1.46 m (2H, CH2), 1.57–1.74 m (2H,
CH2), 2.48 s (3H, Me), 2.71 s (3H, Me), 4.22 t (2H,
OCH2, J = 6.5 Hz), 6.76 br.s (2H, NH2), 7.05 s (1H,
5-H). 13C NMR spectrum, δC, ppm: 14.1, 19.2, 20.2,
24.3, 30.9, 64.1, 94.1, 122.2, 122.7, 145.5, 150.5,
160.0, 160.6, 165.3. Mass spectrum: m/z 279.0
(Irel 100%) [M + 1]+. Found, %: C 60.32; H 6.41;
N 9.92. C14H18N2O2S. Calculated, %: C 60.41; H 6.52;
N 10.06. M 278.4.
(3-Amino-4,6-dimethylthieno[2,3-b]pyridin-2-
yl)(thiophen-2-yl)methanone (1a). Yield 2.2 g (77%),
yellow rod-like crystals, mp 230–232°C (from AcOH).
IR spectrum, ν, cm–1: 3413, 3390, 3295 (NH2), 1698
3-Amino-4,6-dimethyl-N-(1,3-thiazol-2-yl)-
thieno[2,3-b]pyridine-2-carboxamide (1e). Yield
2.4 g (80%), light yellow plates fluorescing under UV
light, mp 248–250°C (from BuOH); sublimes at 210°C
to form to cubic crystals. IR spectrum, ν, cm–1: 3418–
3295 (NH, NH2), 1673 (C=O), 1644 (δNH2). 1H NMR
spectrum, δ, ppm: 2.48 s (3H, Me), 2.72 s (3H, Me),
6.86–7.05 m (4H, 4′-H, 5′-H, NH2), 7.41 s (1H, 5-H),
1
(C=O), 1648 (δ NH2). H NMR spectrum, δ, ppm:
2.47 s (3H, Me), 2.72 s (3H, Me), 7.07 s (1H, 5-H),
7.22–7.26 m (1H, 4′-H), 7.88–7.94 m (2H, 3′-H, 5′-H),
8.10 br.s (2H, NH2). 13C NMR spectrum, δC, ppm:
20.6, 24.4, 101.2, 121.7, 122.6, 128.9, 130.9, 133.2,
145.7, 146.4, 154.1, 161.5, 161.6, 179.3. Mass spec-
trum: m/z 289.0466 [M + H]+. C14H12N2OS2. Calcu-
lated: M + H 289.0391.
13
12.58 br.s (1H, CONH). C NMR spectrum, δC, ppm:
(3-Amino-4,6-dimethylthieno[2,3-b]pyridin-2-
yl)(4-chlorophenyl)methanone (1b). Yield 2.6 g
(81%), yellow needles, mp 191–193°C (from AcOH).
IR spectrum, ν, cm–1: 3410–3305 (NH2), 1684 (C=O).
1H NMR spectrum, δ, ppm: 2.48 s (3H, Me), 2.73 s
(3H, Me), 7.07 s (1H, 5-H), 7.57 d (2H, Harom, J =
8.0 Hz), 7.74 d (2H, Harom, J = 8.0 Hz), 8.06 br.s (2H,
20.3, 23.0, 93.9, 111.8, 115.1, 122.0 (2C), 128.8,
132.1, 145.1, 146.3, 159.3, 160.5. Mass spectrum:
m/z 305.0526 [M + H]+. C13H12N4OS2. Calculated:
M + H 305.0453.
Propan-2-yl 3-amino-4,6-dimethylthieno[2,3-b]-
pyridine-2-carboxylate (1f). Yield 2.0 g (77%), light
yellow crystals fluorescing under UV light, mp 103–
105°C (from i-PrOH). IR spectrum, ν, cm–1: 3407–
13
NH2). C NMR spectrum, δC, ppm: 20.6, 24.5, 102.5,
121.9, 122.5, 129.0 (2C), 129.7 (2C), 136.2, 140.0,
146.6, 153.5, 161.5, 162.1, 187.9. Mass spectrum:
m/z 317.0514 [M + H]+. C16H13ClN2OS. Calculated:
M + H 317.0437.
1
3300 (NH2), 1719 (C=O), 1635 (δ NH2). H NMR
spectrum, δ, ppm: 1.25 d (6H, Me, J = 6.2 Hz), 2.47 s
(3H, Me), 2.68 s (3H, Me), 5.02–5.16 m (1H, OCH),
6.72 br.s (2H, NH2), 7.01 s (1H, 5-H). 13C NMR spec-
trum, δC, ppm: 20.2, 22.3 (2C), 24.3, 67.9, 94.5, 122.2,
122.7, 145.5, 150.3, 160.0, 160.5, 164.9. Mass spec-
trum: m/z 265.1006 [M + H]+. C13H16N2O2S. Calculat-
ed: M + H 265.0932.
(3-Amino-4,6-dimethylthieno[2,3-b]pyridin-2-
yl)(4-methoxyphenyl)methanone (1c). Yield 2.6 g
(84%), yellow crystals fluorescing under UV light,
mp 179–181°C (from AcOH). IR spectrum, ν, cm–1:
3402–3298 (NH2), 1700 (C=O). 1H NMR spectrum, δ,
ppm: 2.47 s (3H, Me), 2.73 s (3H, Me), 3.81 s (3H,
MeO), 7.02 s (1H, 5-H), 7.05 d (2H, Harom, J = 8.7 Hz),
7.73 d (2H, Harom, J = 8.7 Hz), 7.93 br.s (2H, NH2).
13C NMR spectrum, δC, ppm: 20.5, 24.4, 55.8, 102.8,
114.1 (2C), 122.1, 122.4, 130.0 (2C), 133.8, 146.3,
158.8, 161.0, 161.8, 161.9, 188.5. Mass spectrum:
m/z 313.1008 [M + H]+. C17H16N2O2S. Calculated:
M + H 313.0932.
Propyl 3-amino-4,6-dimethylthieno[2,3-b]pyri-
dine-2-carboxylate (1g). Yield 1.8 g (69%), yellow
crystals fluorescing under UV light, mp 270–272°C
(from PrOH). IR spectrum, ν, cm–1: 3422–3295 (NH2),
1715 (C=O), 1632 (δNH2). 1H NMR spectrum, δ, ppm:
0.94 t (3H, Me, J = 7.4 Hz), 1.58–1.72 m (2H, CH2),
2.49 s (3H, Me), 2.70 s (3H, Me), 4.17 t (2H, OCH2,
J = 6.6 Hz), 6.75 br.s (2H, NH2), 7.03 s (1H, 5-H).
13C NMR spectrum, δC, ppm: 10.8, 20.3, 22.3, 24.3,
65.8, 94.1, 122.3, 122.7, 145.6, 150.5, 160.1, 160.7,
165.4. Mass spectrum: m/z 265.2 (Irel 100%) [M + 1]+.
Butyl 3-amino-4,6-dimethylthieno[2,3-b]pyri-
dine-2-carboxylate (1d). Yield 2.0 g (72%), colorless
cotton-like material fluorescinf under UV light,
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DYACHENKO et al.
980
Found, %: C 58.96; H 5.96; N 10.48. C13H16N2O2S.
Calculated, %: C 59.07; H 6.10; N 10.60. M 264.4.
(2H, Harom, J = 7.9 Hz), 9.37 br.s (1H, CONH).
13C NMR spectrum, δC, ppm: 14.0, 15.5, 21.6, 23.6,
97.5, 121.8 (2C), 123.9, 124.0, 128.8 (2C), 132.6,
139.3, 142.8, 150.1, 156,6, 158.2, 164.9. Mass spec-
trum: m/z 326.2 (Irel 100%) [M + 1]+. Found, %:
C 66.32; H 5.78; N 12.84. C18H19N3OS. Calculated, %:
C 66.43; H 5.88; N 12.91. M 325.4.
N-(4-Acetylphenyl)-3-amino-4,6-dimethylthieno-
[2,3-b]pyridine-2-carboxamide (1h). Yield 2.8 g
(83%), light yellow powder fluorescing under UV
light, mp 222–224°C (from AcOH). IR spectrum, ν,
cm–1: 3412–3288 (NH2), 1689 (C=O), 1674 (CONH),
1
(3-Amino-4,6-dimethylthieno[2,3-b]pyridin-2-
yl)(4-bromophenyl)methanone (1l). Yield 2.9 g
(75%), yellow crystals, mp 218–220°C (from dioxane).
IR spectrum, ν, cm–1: 3410–3300 (NH2), 1698 (C=O),
1635 (δ NH2). H NMR spectrum (CDCl3), δ, ppm:
2.49 s (3H, Me), 2.51 s (3H, Me), 2.69 s (3H, MeCO),
7.05 s (1H, 5-H), 7.07 br.s (2H, NH2), 7.86 d (2H,
Harom, J = 8.8 Hz), 7.94 d (2H, Harom, J = 8.8 Hz),
9.70 br.s (1H, CONH). 13C NMR spectrum (CDCl3),
δC, ppm: 20.4, 24.3, 26.9, 120.4 (2C), 122.5, 123.9,
129.5 (2C), 132.1, 144.1, 145.3, 150.9, 159.2, 159.8,
166.4, 184.6, 197.1. Mass spectrum: m/z 340.1115
[M + H]+. C18H17N3O2S. Calculated: M + H 340.1041.
1
1641 (δNH2). H NMR spectrum, δ, ppm: 1.19 t (3H,
Me, J = 7.5 Hz), 2.68 s (3H, Me), 2.81 br.s (5H, Me,
CH2), 7.51 br.s (2H, NH2), 7.61 d (2H, Harom, J =
8.3 Hz), 7.73 d (2H, Harom, J = 8.3 Hz). Mass spectrum:
m/z 390.1 (Irel 100%) [M + 1]+. Found, %: C 55.39;
H 4.36; N 7.05. C18H17BrN2OS. Calculated, %:
C 55.53; H 4.40; N 7.20. M 389.3.
Octyl 3-amino-4,6-dimethylthieno[2,3-b]pyri-
dine-2-carboxylate (1i). Yield 2.6 g (79%), colorless
cotton-like material, mp 152–154°C (from EtOH). IR
spectrum, ν, cm–1: 3405–2284 (NH2), 1698 (C=O),
7,8,9-Trimethylpyrido[3′,2′:4,5]thieno[3,2-d]py-
rimidin-4-amine (6) was synthesized according to
the procedure described above for compounds 1 using
1.2 mL (10 mmol) of 3-methylpentane-2,4-dione (2b)
and 0.63 mL (10 mmol) of chloroacetonitrile (5). The
precipitate was filtered off and mixed with 25 mL of
formamide, and the mixture was refluxed for 2 h.
After cooling to room temperature, the precipitate was
filtered off and washed with ethanol and hexane. Yield
1.7 g (68%), colorless powder, mp 332–334°C (from
AcOH). IR spectrum, ν, cm–1: 3415–3307 (NH2), 1642
1
1637 (δ NH2). H NMR spectrum (CDCl3), δ, ppm:
0.83 t (3H, Me, J = 7.4 Hz), 1.19–1.46 m (10H, CH2),
1.53–1.74 m (2H, CH2), 2.48 s (3H, Me), 2.70 s (3H,
Me), 4.19 t (2H, OCH2, J = 6.3 Hz), 6.75 br.s (2H,
NH2), 7.02 s (1H, 5-H). 13C NMR spectrum (CDCl3),
δC, ppm: 14.4, 20.2, 22.5, 24.3, 25.9, 28.7, 28.9, 29.1,
31.6, 64.3, 119.2, 122.2, 123.0, 146.5, 151.4, 160.0,
160.6, 165.7. Mass spectrum: m/z 335.1785 [M + H]+.
C18H26N2O2S. Calculated: M + H 335.1715.
1
(δNH2). H NMR spectrum, δ, ppm: 2.53 s (3H, Me),
3-Amino-4,5,6-trimethyl-N-(2-methylphenyl)-
thieno[2,3-b]pyridine-2-carboxamide (1j). Yield
2.3 g (70%), yellow crystals, mp 228–230°C (from
BuOH), sublimes at 185°C. IR spectrum, ν, cm–1:
3418–3305 (NH, NH2), 1674 (CONH), 1633 (δNH2).
1H NMR spectrum, δ, ppm: 2.23 s (3H, Me), 2.24 s
(3H, Me), 2.53 s (3H, Me), 2.66 s (3H, Me), 6.92 br.s
(2H, NH2), 7.15 t (1H, Harom, J = 8.1 Hz), 7.20 t (1H,
Harom, J = 8.1 Hz), 7.26 d (1H, Harom, J = 8.4 Hz),
7.29 d (1H, Harom, J = 8.2 Hz), 9.13 br.s (1H, CONH).
Mass spectrum: m/z 326.2 (Irel 100%) [M + 1]+. Found,
%: C 66.29; H 5.74; N 12.85. C18H19N3OS. Calculat-
ed, %: C 66.43; H 5.88; N 12.91. M 325.4.
2.56 s (3H, Me), 2.97 s (3H, Me), 7.44 br.s (2H, NH2),
8.49 s (1H, 2-H). 13C NMR spectrum, δC, ppm: 14.6,
15.1, 24.2, 112.0, 116.6, 124.1, 124.4, 145.0, 155.0,
155.6, 158.5, 158.8. Mass spectrum: m/z 245.0856
[M + H]+. C12H12N4S. Calculated: M + H 245.0783.
8′-Ethyl-7′,9′-dimethyl-1′H-spiro[cyclohexane-
1,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]-
4′(3′H)-one (8) was synthesized according to the
procedure described above for compounds 1 using
1.35 mL (10 mmol) of 3-ethylpentane-2,4-dione (2c)
and 0.94 g (10 mmol) of chloroacetamide (7). The
precipitate was filtered off and added to 25 mL of
acetic acid, 1.0 mL (10 mmol) of cyclohexanone was
added, and the mixture was refluxed for 3 h. After
cooling to room temperature, the precipitate was
filtered off and washed with ethanol and hexane. Yield
2.4 g (74%), colorless powder, mp 229–231°C (from
AcOH). IR spectrum, ν, cm–1: 3300 (NH), 1666
3-Amino-5-ethyl-4,6-dimethyl-N-phenylthieno-
[2,3-b]pyridine-2-carboxamide (1k). Yield 2.5 g
(78%), yellow crystals, mp 236–238°C (from BuOH),
sublimes at 170°C. IR spectrum, ν, cm–1: 3440–3289
1
(NH, NH2), 1688 (CONH), 1639 (δ NH2). H NMR
1
spectrum, δ, ppm: 1.10 t (3H, MeCH2, J = 7.2 Hz),
2.58 s (3H, Me), 2.73 br.s (5H, Me, CH2), 7.07 br.s
(3H, Harom, NH2), 7.31 t (2H, Harom, J = 7.6 Hz), 7.67 d
(CONH). H NMR spectrum, δ, ppm: 1.09 t (3H,
MeCH2, J = 7.1 Hz), 1.22 br.s (2H, CH2), 1.56 br.s
(6H, CH2), 2.03 br.s (2H, CH2), 2.54 s (3H, Me), 2.57 s
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ONE-POT SYNTHESIS OF THIENO[2,3-b]PYRIDINE
981
Petrov, M.L., Solod, O.V., Trishin, Yu.G., Yakovlev, I.P.,
Nenaidenko, V.G., Beloglazkina, E.K., Beletskaya, I.P.,
Ustynyuk, Yu.A., Solov’ev, P.A., Ivanov, I.V.,
Malina, E.V., Sivova, N.V., Negrebetskii, V.V.,
Baukov, Yu.I., Pozharskaya, N.A., Traven’, V.F.,
Shchekotikhin, A.E., Varlamov, A.V., Borisova, T.N.,
Lesina, Yu.A., Krasnokutskaya, E.A., Rogozhnikov, S.I.,
Shurov, S.N., Kustova, T.P., Klyuev, M.V., Khelevi-
na, O.G., Stuzhin, P.A., Fedorov, A.Yu., Gushchin, A.V.,
Dodonov, V.A., Kolobov, A.V., Plakhtinskii, V.V.,
Orlov, V.Yu., Kriven’ko, A.P., Fedotova, O.V., Pchelin-
tseva, N.V., Charushin, V.N., Chupakhin, O.N., Klimoch-
kin, Yu.N., Klimochkina, A.Yu., Kuryatnikov, V.N.,
Malinovskaya, Yu.A., Levina, A.S., Zhuravlev, O.E.,
Voronchikhina, L.I., Fisyuk, A.S., Aksenov, A.V.,
Aksenov, N.A., and Aksenova, I.V., Russ. J. Org. Chem.,
2017, vol. 53, p. 1275.
(3H, Me), 2.73 q (2H, MeCH2, J = 7.1 Hz), 5.87 br.s
(1H, NH), 7.87 br.s (1H, CONH). Mass spectrum:
m/z 330.2 (Irel 100%) [M + 1]+. Found, %: C 65.53;
H 6.94; N 12.68. C18H23N3OS. Calculated, %: C 65.62;
H 7.04; N 12.75. M 329.5.
FUNDING
This study was performed under financial support by the
program “5–100” for increasing the rating of the Peoples’
Friendship University of Russia. The X-ray diffraction
studies were carried out using the unique research equipment
“Kurchatov Source of Synchrotron Radiation” under financial
support by the Ministry of Science and Higher Education of
the Russian Federation (project ID RFMEFI61917X0007).
https://doi.org/10.1134/S1070428017090019
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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