Multicomponent synthesis and molecular structure of 3-amino-2-aroyl(alkoxycarbonyl, arylcarbamoyl)-4-aryl(hetaryl)-5-arylcarbamoyl-6-methylthieno[2,3-b]pyridines

Article abstract of DOI:10.1007/s10593-019-02477-7

[Figure not available: see fulltext.] A new, effective method has been developed for the synthesis of functionalized thieno[2,3-b]pyridines by multicomponent condensation reactions of aromatic and heteroaromatic aldehydes, cyanothioacetamide, acetoacetanilides, and alkylating agents containing activated methylene groups. The structures of 3-amino-2-benzoyl-4-(furan-2-yl)-6-methyl-N-phenylthieno[2,3-b]pyridine-5-carboxamide, 3-amino-N²-(4-bromophenyl)-N⁵-(4-chlorophenyl)-6-methyl-4-(3-methylthiophen-2-yl)thieno[2,3-b]pyridine-2,5-dicarboxamide, and 3-amino- 4-(2-chlorophenyl)-N-(4-chlorophenyl)-6-methyl-2-(4-methylbenzoyl)thieno[2,3-b]pyridine-5-carboxamide were studied by X-ray structural analysis.

Full text of DOI:10.1007/s10593-019-02477-7

DOI 10.1007/s10593-019-02477-7
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 442–447
Multicomponent synthesis and molecular structure of
3-amino-2-aroyl(alkoxycarbonyl, arylcarbamoyl)-4-aryl(hetaryl)-
5-arylcarbamoyl-6-methylthieno[2,3-b]pyridines
Ivan V. Dyachenko1, Vladimir D. Dyachenko1, Pavel V. Dorovatovskii2,
Victor N. Khrustalev3, Valentine G. Nenajdenko4*
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: vnkhrustalev@gmail.com
4 Lomonosov Moscow State University,
1-3 Leninskie Gory, Moscow 119991, Russia; e-mail: nenajdenko@gmail.com
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 442–447
Submitted February 13, 2019
Accepted February 20, 2019
O
NMe
, EtOH
1.
O
O
R
N
NH2
CN
Z
2. KOH, DMF
Z
R1HN
Me
R1HN
Me
Hal
+
RCHO +
+
20°C, 5 h
69–85%
O
H2N
S
S
O
O
R, R1 = Ar; Hal = Br, Cl; Z = Ar, NHAr, n-BuO, i-PrO
A new, effective method has been developed for the synthesis of functionalized thieno[2,3-b]pyridines by multicomponent condensation
reactions of aromatic and heteroaromatic aldehydes, cyanothioacetamide, acetoacetanilides, and alkylating agents containing activated
methylene groups. The structures of 3-amino-2-benzoyl-4-(furan-2-yl)-6-methyl-N-phenylthieno[2,3-b]pyridine-5-carboxamide, 3-amino-
N2-(4-bromophenyl)-N5-(4-chlorophenyl)-6-methyl-4-(3-methylthiophen-2-yl)thieno[2,3-b]pyridine-2,5-dicarboxamide, and 3-amino-
4-(2-chlorophenyl)-N-(4-chlorophenyl)-6-methyl-2-(4-methylbenzoyl)thieno[2,3-b]pyridine-5-carboxamide were studied by X-ray
structural analysis.
Keywords: acetoacetanilides, alkylating reagents, aromatic aldehydes, cyanothioacetamide, thieno[2,3-b]pyridines, X-ray structural
analysis.
Functionalized thieno[2,3-b]pyridines have shown
antitumor1,2 and antiviral3,4 activity, some of them have
been identified as kinase inhibitors5,6 and antiderma-
tophytic agents.7 The main methods for the synthesis of
thieno[2,3-b]pyridine derivatives include the thiophene ring
formation in a molecule of pyridine derivative or pyridine
ring formation in a thiophene derivative.8
While continuing the investigation focused on the reacti-
vity of 3-amino-5-arylcarbamoyl-6-methylthieno[2,3-b]-
pyridines that were obtained by the formation of thiophene
ring fused with a pyridine ring,9–13 we developed a new
method for their synthesis on the basis of a multi-
component condensation between aromatic and hetero-
aromatic aldehydes 1а–с, cyanothioacetamide 2,14,15 aceto-
acetanilides 3а–с, and alkylating reagents 4a–g containing
activated methylene groups. The reaction proceeded in
EtOH medium at 20°С in the presence of an equimolar
amount of N-methylmorpholine, with subsequent addition
of DMF and an equimolar amount of aqueous 10% KОН
solution, and resulted in the formation of 3-amino-2-aroyl-
(alkoxycarbonyl, arylcarbamoyl)-4-aryl(hetaryl)-5-arylcar-
bamoyl-6-methylthieno[2,3-b]pyridines 5a–m in up to 85%
yields (Scheme 1).
The mechanism of this synthesis included the formation
of alkene А by Knoevenagel reaction and its Michael
addition to СН acid 3, leading to the adduct B. The next
0009-3122/19/55(4/5)-0442©2019 Springer Science+Business Media, LLC
442

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 442–447
Scheme 1
Scheme 2
steps were intramolecular cyclization of adduct В to the
salt С, which was regioselectively alkylated with
compound 4 to the thioether D. The latter intermediate
underwent thiophene ring closure under the reaction
conditions, forming the final product 5. Despite the
complex sequence of mechanistic steps, the target
heterocycles can be obtained by a one-pot procedure
(Scheme 2).
compounds 5а,i,k and to study their structural features
(Figs. 1–3).
The overall molecular conformation of compounds
5a,i,k was largely determined by the presence of relatively
strong intramolecular N–H···O and N–H···π(С=С)
hydrogen bonds, as well as intermolecular N–H···O and
O–H···O hydrogen bonds. For this reason, the NH2 group
in all compounds assumed a slightly pyramidal confi-
guration (355 and 358, 357, 359°, respectively), while the
carbonyl group at the second position was nearly coplanar
with the central thieno[2,3-b]pyridine ring system. The two
crystallographically independent molecules of compound
5a differed by the type of intramolecular hydrogen bond
involving the NH2 group: there were two N–H···O
hydrogen bonds in one of them, while the other molecule
formed N–H···O and N–H···π(С=С) hydrogen bonds (Fig. 1).
Besides that, the dihedral angle between the planes of
furanyl substituent and the central bicyclic system deviated
from the sterically preferred perpendicular orientation
(45.76(6) and 54.67(7)°, respectively). The dihedral angles
1
A characteristic feature in Н NMR spectra of compounds
5a–m was the presence of singlet signals at 2.52–2.77 ppm
due to the methyl group protons, broadened singlet signals
of amino group at 5.87–7.18 ppm, signals of NH group as
broadened singlets in the range of 7.63–10.60 ppm, as well
as proton signals of aromatic substituents in the appropriate
region of the spectrum. IR spectra contained absorption
bands assigned to the stretching and deformational
vibrations of amino group in the ranges of 3288–3445 and
1614–1648 cm–1, respectively.
We used the method of X-ray structural analysis to
unequivocally confirm the molecular structures of
Figure 1. The molecular structure of compound 5a (two
crystallographically independent molecules forming a hydrogen-
bonded dimer) with atoms represented by thermal vibration
ellipsoids of 50% probability. The thick dotted lines show the
alternative less populated position of the disordered phenyl sub-
stituent. The thin dotted lines show the N–H···O and N–H···π(С=С)
hydrogen bonds.
Figure 2. The molecular structure of compound 5i with atoms
represented by thermal vibration ellipsoids of 40% probability.
The alternative position of the disordered 3-methylthiophene
substituent is not shown. The thin dotted lines show the N–H···O
and N–H···π(С=С) hydrogen bonds.
443

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 442–447
samples were injected into the electrospray ionization
source by syringe pump at 40 µl/min flow rate. The source
gas flow was turned off, capillary voltage 3.5 kV, capillary
temperature 275°С. Orbitrap mass spectra were recorded in
positive and negative ion modes with the resolution of
480000. Internal standards: 2DMSO+Н+ ion (m/z
157.03515) in positive ion mode and dodecyl sulfate anion
(m/z 265.14789) in negative ion mode. Mass spectra for the
rest of the compounds were recorded on an Agilent 1100
Series liquid chromatograph equipped with an Agilent LS/
MSDLS mass selective detector (introduction of samples in
AcOH matrix, EI ionization, 70 eV). Elemental analysis
was performed on a PerkinElmer CHN-analyzer. Melting
points were determined on a Kofler bench. The reaction
progress and purity of the obtained compounds were
controlled by TLC on Silufol UV-254 plates with 3:5
Me2CO–hexane mobile phase, visualization in iodine vapor
and under UV light.
Figure 3. The molecular structure of compound 5k with atoms
represented by thermal vibration ellipsoids of 40% probability.
Thick dotted lines show the alternative positions of disordered
4-methylphenyl and 4-chlorophenyl substituents. Thin dotted
lines show the N–H···O and N–H···π(С=С) hydrogen bonds.
Synthesis of substituted thieno[2,3-b]pyridines 5a–m
(General method). A mixture of aldehyde 1а–с (10 mmol),
cyanothioacetamide 2 (1.0 g, 10 mmol), and DMF (30 ml)
was stirred at 20°С and treated by adding 3 drops of
N-methylmorpholine, followed by stirring for 15 min until
the crystallization of alkene А started. Then acetoacet-
anilide 3а–с (10 mmol) and N-methylmorpholine (1.1 ml,
10 mmol) were added to the mixture, stirring was
continued for 30 min until the solution became homo-
geneous, and the reaction mixture was maintained for 1 day.
The stirred mixture was then diluted with DMF (30 ml) and
treated with alkylating reagent 4a–g (10 mmol), stirred for
1 h, treated with 10% aqueous KОН solution (5.6 ml,
10 mmol), stirred for 2 h, and maintained for 1 day. The
mixture was then diluted with an equal amount of water
and the obtained precipitate was filtered off, washed with
H2O, EtOH, and hexane.
between the planes of thiophene (compound 5i) and
2-chlorophenyl (compound 5k) substituents and the central
bicyclic fragment were equal to 75.4(2) and 79.41(8)°,
respectively.
The conformation of (halo)phenylamino substituents
was directly affected by intermolecular hydrogen bonds.
Thus, the crystal of compound 5a contained two
crystallographically independent molecules that formed
dimers strongly linked by two N–H···O hydrogen bonds.
The dimers were further arranged in alternating chains
along the crystallographic axis b, linked by C–H···O
hydrogen bonds (Fig. S1 in the Supplementary information
file). The molecules in crystals of compounds 5i,k formed
layers that were parallel to the (0 0 1) and (0 1 0) planes,
respectively. Furthermore, in the case of compound 5i, the
layers were linked via N–H···O, O–H···N, and O–H···O
hydrogen bonds through solvated water molecules (Figs.
S2 and S3 in the Supplementary information file).
Thus, a multicomponent condensation of aromatic and
heteroaromatic aldehydes, cyanothioacetamide, acetoacet-
anilides, and alkylating reagents was shown to be a
convenient method for the synthesis of functionalized
thieno[2,3-b]pyridines – potential synthetic intermediates
providing access to promising biologically active
molecules.
3-Amino-2-benzoyl-4-(furan-2-yl)-6-methyl-N-phenylthieno-
[2,3-b]pyridine-5-carboxamide (5а). Yield 3.9 g (85%),
yellow log-like crystals, mp 232–234°С (BuOH). IR spect-
rum, ν, cm–1: 1644 (δNH2), 1667 (CONH), 1703 (C=O),
1
3310–3404 (NH, NH2). H NMR spectrum, δ, ppm (J, Hz):
2.60 (3Н, s, CH3); 6.69 (1Н, br. s, Н-4 Fur); 6.86 (1Н, d,
J = 3.4, Н-3 Fur); 7.07 (1Н, t, J = 7.4, Н Ph); 7.17 (2Н, br. s,
NH2); 7.29 (2Н, t, J = 7.7, Н Ph); 7.49–7.64 (5Н, m, Н Ph);
7.75 (2Н, d, J = 6.8, Н Ph); 7.95 (1Н, d, J = 2.5, Н-5 Fur);
10.48 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 23.2;
104.1; 112.8; 114.3; 119.3 (2C); 120.1; 124.5; 127.8 (2C);
129.0 (2C); 129.3 (2C); 130.8; 131.8; 133.2; 138.8; 141.0;
145.3; 146.2; 150.5; 157.8; 161.7; 165.2; 189.7. Found, m/z:
454.1223 [M+H]+. C26H20N3O3S. Calculated, m/z:
454.1220.
Experimental
IR spectra were recorded on an IKS-40 instrument for
1
samples in Nujol mulls. H and 13C NMR spectra were
acquired on a Varian VXR-400 spectrometer (400 and
100 MHz, respectively) for samples in CDCl3 solutions
(compounds 5d–f,h) and DMSO-d6 solutions (the rest of
3-Amino-N2-(4-bromophenyl)-N5-(4-chlorophenyl)-
4-(furan-2-yl)-6-methylthieno[2,3-b]pyridine-2,5-dicarb-
oxamide (5b). Yield 4.4 g (76%), yellow powder, mp 147–
149°С (АсOH). IR spectrum, ν, cm–1: 1648 (δNH2), 1665
(CONH), 3296–3387 (NH, NH2). 1H NMR spectrum,
δ, ppm (J, Hz): 2.60 (3Н, s, CH3); 6.24 (2Н, br. s, NH2);
6.64 (1Н, d, J = 3.4, Н-4 Fur); 6.77 (1Н, d, J = 4.1, Н-3
Fur); 7.35 (2Н, d, J = 8.9, Н Ar); 7.47 (2Н, d, J = 9.0,
Н Ar); 7.52 (2Н, d, J = 9.0, Н Ar); 7.63 (2Н, d, J = 8.9,
1
the compounds), using TMS as internal standard. H and
13C NMR spectra of compound 5g were acquired on a
Varian VXR-500 spectrometer (500 and 125 MHz,
respectively) in DMSO-d6. Mass spectra of compounds
5а,b,i,k were recorded on a Thermo Scientific Orbitrap
Elite high-resolution mass spectrometer. Mass spectral
samples were prepared by dissolving in DMSO (1 ml) and
diluting 100-fold with 1% HCOOH solution in MeCN. The
444

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 442–447
Н Ar); 7.91 (1Н, s, Н-5 Fur); 9.73 (1H, br. s, NH); 10.60
(1Н, s, Н-5 Fur); 7.77 (1H, br. s, CONH); 7.88 (2Н, d,
J = 8.7, Н Ar); 8.31 (1Н, d, J = 7.2, Н Ar). Mass spectrum,
m/z (Irel, %): 514 [M+Н]+ (100). Found, %: C 65.42;
H 4.37; N 8.03. C28H23N3О5S. Calculated, %: C 65.51;
H 4.52; N 8.19.
(1H, br. s, NH). 13C NMR spectrum, δ, ppm: 23.0; 112.6
(2C); 114.0 (2C); 115.9; 126.4 (4C); 126.6 (4C); 129.2 (4C);
131.7 (4C); 137.8; 145.9 (2C); 165.6. Found, m/z: 580.9880
[M–H]–. C26H17BrClN4O3S. Calculated, m/z: 580.9906.
Butyl
3-amino-5-(4-chlorophenyl)-4-(furan-2-yl)-
Isopropyl 3-amino-4-(furan-2-yl)-6-methyl-5-phenyl-
carbamoylthieno[2,3-b]pyridine-2-carboxylate (5g). Yield
3.1 g (71%), yellow powder, mp 103–105°С (i-PrOH).
IR spectrum, ν, cm–1: 1639 (δNH2), 1665 (CONH), 1714
(СOО), 3300–3422 (NH, NH2). 1H NMR spectrum, δ, ppm
(J, Hz): 1.32 (6Н, d, J = 6.3, 2CH3); 2.54 (3Н, s, CH3);
5.16–5.24 (1Н, q, J = 6.3, ОСН); 6.04 (2Н, br. s, NH2);
6.69 (1Н, dd, J = 3.3, J = 1.8, Н-4 Fur); 6.83 (1Н, d,
J = 3.3, Н-3 Fur); 7.10 (1Н, t, J = 7.4, Н Ph); 7.32 (2Н, d,
J = 7.9, Н Ph); 7.51 (2Н, d, J = 8.1, Н Ph); 7.95 (1Н, d,
J = 0.8, Н-5 Fur); 10.49 (1H, br. s, СОNH). 13C NMR
spectrum, δ, ppm: 22.3 (2С); 23.0; 68.5; 97.2; 112.7;
114.0; 120.0; 120.2 (2C); 124.5; 129.3 (2C); 130.8; 132.5;
138.9; 145.5; 145.9; 147.9; 156.6; 160.4; 164.5; 165.4.
Mass spectrum, m/z (Irel, %): 436 [M+Н]+ (100). Found, %:
C 63.38; H 4.72; N 9.55. C23H21N3О4S. Calculated, %:
C 63.43; H 4.86; N 9.65.
6-methylcarbamoylthieno[2,3-b]pyridine-2-carboxylate
(5c). Yield 3.6 g (75%), yellow powder, mp 168–170°С
(АсOH). IR spectrum, ν, cm–1: 1641 (δNH2), 1666
1
(CONH), 1712 (СOО), 3292–3407 (NH, NH2). H NMR
spectrum, δ, ppm (J, Hz): 0.94 (3Н, t, J = 7.1, СН3(СН2)3);
1.25–1.46 (2Н, m, СН2); 1.54–1.76 (2Н, m, СН2); 2.63
(3Н, s, CH3); 4.25 (2Н, t, J = 6.6, ОСН2); 6.08 (2Н, br. s,
NH2); 6.69 (1Н, br. s, Н-4 Fur); 6.83 (1Н, d, J = 3.0,
Н-3 Fur); 7.36 (2Н, d, J = 8.7, Н Ar); 7.55 (2Н, d, J = 8.7,
Н Ar); 7.93 (1Н, s, Н-5 Fur); 10.63 (1H, br. s, NH).
13C NMR spectrum, δ, ppm: 14.1; 19.2; 23.0; 30.8; 64.5;
95.9; 112.7; 114.2; 119.9; 121.6 (2C); 128.2; 129.3 (2C);
130.5; 132.6; 137.8; 145.4; 146.2; 148.0; 156.6; 160.6;
164.9; 165.6. Mass spectrum, m/z (Irel, %): 484 [M+Н]+
(100). Found, %: C 59.41; H 4.39; N 8.55. C24H22ClN3О4S.
Calculated, %: C 59.56; H 4.58; N 8.68.
3-Amino-4-(furan-2-yl)-6-methyl-2-(4-methylbenzoyl)-
N-phenylthieno[2,3-b]pyridine-5-carboxamide (5d). Yield
3.7 g (80%), light-yellow powder, mp 246–248°С (dioxane).
IR spectrum, ν, cm–1: 1638 (δNH2), 1666 (CONH), 1714
3-Amino-4-(furan-2-yl)-2-(4-methoxybenzoyl)-6-methyl-
N-phenylthieno[2,3-b]pyridine-5-carboxamide (5h). Yield
3.4 g (70%), bright-yellow powder, mp 120–122°С
(BuOH). IR spectrum, ν, cm–1: 1645 (δNH2), 1667
1
1
(C=O), 3311–3405 (NH, NH2). H NMR spectrum, δ, ppm
(CONH), 1711 (C=O), 3295–3415 (NH, NH2). H NMR
(J, Hz): 2.43 (3Н, s, CH3); 2.59 (3Н, s, CH3); 6.59 (1Н, t,
J = 3.4, Н-4 Fur); 6.83 (1Н, d, J = 3.0, Н-3 Fur); 7.18 (2Н,
br. s, NH2); 7.25 (1Н, t, J = 7.4, Н Ph); 7.30 (2Н, d, J = 7.9,
Н Ar); 7.34 (2Н, t, J = 8.0, Н Ar); 7.47 (2Н, d, J = 7.9,
Н Ar); 7.62 (1Н, s, Н-5 Fur); 7.74 (2Н, d, J = 8.0, Н Ar); 7.88
(1H, br. s, CONH). Mass spectrum, m/z (Irel, %): 468 [M+Н]+
(100). Found, %: C 69.18; H 4.33; N 8.78. C27H21N3О3S.
Calculated, %: C 69.36; H 4.53; N 8.99.
spectrum, δ, ppm (J, Hz): 2.52 (3Н, s, CH3); 3.86 (3Н, s,
CH3О); 6.58 (1Н, br. s, Н-4 Fur); 6.97 (1Н, br. s, Н-3 Fur);
6.98 (2Н, d, J = 8.4, Н Ar); 7.15 (2Н, br. s, NH2); 7.25 (1Н,
t, J = 7.2, Н Ph); 7.34 (2Н, t, J = 7.2, Н Ph); 7.52 (2Н, d,
J = 7.5, Н Ph); 7.60 (1Н, br. s, Н-5 Fur); 7.84 (2Н, d,
J = 8.4, Н Ar); 8.17 (1H, br. s, CONH). Mass spectrum, m/z
(Irel, %): 484 [M+Н]+ (100). Found, %: C 66.87; H 4.22;
N 8.58. C27H21N3О4S. Calculated, %: C 67.07; H 4.38;
N 8.69.
Butyl 3-amino-4-(furan-2-yl)-6-methyl-5-phenylcarba-
moylthieno[2,3-b]pyridine-2-carboxylate (5e). Yield
3.3 g (74%), yellow powder, fluorescence observed under
UV light, mp 80–82°С (BuOH). IR spectrum, ν, cm–1: 1640
(δNH2), 1668 (CONH), 1718 (СOО), 3310–3422 (NH,
3-Amino-N2-(4-bromophenyl)-N5-(4-chlorophenyl)-
6-methyl-4-(3-methylthiophen-2-yl)thieno[2,3-b]-
pyridine-2,5-dicarboxamide (5i). Yield 5.0 g (81%),
yellow crystals, fluorescence observed under UV light,
mp 274–276°С (BuOH). IR spectrum, ν, cm–1: 1647
1
NH2). H NMR spectrum, δ, ppm (J, Hz): 0.97 (3Н, t,
1
J = 7.4, СН3(СН2)3); 1.38–1.51 (2Н, m, СН2); 1.66–1.73
(2Н, m, СН2); 2.77 (3Н, s, CH3); 4.28 (2Н, t, J = 6.6,
ОСН2); 5.87 (2Н, br. s, NH2); 6.57 (1Н, s, Н-4 Fur); 6.80
(1Н, d, J = 3.1, Н-3 Fur); 7.21 (1Н, t, J = 8.0, Н Ph); 7.26–
7.31 (3Н, m, Н-5 Fur, H Ph); 7.39 (2Н, d, J = 7.7, Н Ph);
7.63 (1H, br. s, СОNH). Mass spectrum, m/z (Irel, %): 450
[M+Н]+ (100). Found, %: C 63.98; H 5.03; N 9.14.
C24H23N3О4S. Calculated, %: C 64.13; H 5.16; N 9.35.
3-Amino-4-(furan-2-yl)-2-(4-methoxybenzoyl)-N-(2-
methoxyphenyl)-6-methylthieno[2,3-b]pyridine-5-carb-
oxamide (5f). Yield 4.0 g (78%), light-yellow fibrous solid,
fluorescence observed under UV light, mp 217–219°С
(АсОН). IR spectrum, ν, cm–1: 1635 (δNH2), 1669
(δNH2), 1671 (CONH), 3280–3422 (NH, NH2). H NMR
spectrum, δ, ppm (J, Hz): 1.97 (3Н, s, CH3); 2.61 (3Н, s,
CH3); 5.92 (2Н, br. s, NH2); 6.99 (1Н, d, J = 5.1, Н-4 Th);
7.31 (2Н, d, J = 6.8, Н Ar); 7.44 (2Н, d, J = 7.4, Н Ar);
7.46 (2Н, d, J = 7.4, Н Ar); 7.62 (2Н, d, J = 6.8, Н Ar);
7.65 (1Н, d, J = 5.1, Н-5 Th); 9.66 (1H, br. s, СОNH);
10.58 (1H, br. s, СОNH). 13C NMR spectrum, δ, ppm:
14.6; 22.9; 97.9; 115.8; 118.3; 121.5 (2C); 123.5 (2C);
126.8; 128.0; 128.4 (2C); 129.2; 130.1; 131.7 (2С); 132.4;
136.6; 137.7; 138.5; 138.6; 147.3; 155.7; 159.1; 164.1;
165.0. Found, m/z: 610.9809 [M–H]–. C27H19BrClN4O2S2.
Calculated, m/z: 610.9785.
3-Amino-N5-(4-chlorophenyl)-6-methyl-4-(3-methyl-
thiophen-2-yl)thieno[2,3-b]pyridine-2,5-dicarboxamide
1
(CONH), 1713 (C=O), 3296–3417 (NH, NH2). H NMR
spectrum, δ, ppm (J, Hz): 2.77 (3Н, s, CH3); 3.80 (3Н, s,
CH3О); 3.89 (3Н, s, CH3О); 6.55 (1Н, s, Н-4 Fur); 6.80
(1Н, d, J = 3.0, Н-3 Fur); 6.85 (2Н, d, J = 7.9, Н Ar); 6.88–
7.02 (3Н, m, H Ar, NH2); 7.07 (2Н, t, J = 7.3, Н Ar); 7.62
(5j). Yield 3.6
g
(79%), bright-yellow powder,
fluorescence observed under UV light, mp 293–295°С
(BuOH). IR spectrum, ν, cm–1: 1638 (δNH2), 1672
(CONH), 3311–3418 (NH, NH2). 1H NMR spectrum, δ, ppm
445

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 442–447
(J, Hz): 2.49 (3Н, s, CH3); 2.62 (3Н, s, CH3); 5.78 (2Н, br.
Compound 5a. Yellow prismatic crystals, C26H19N3O3S
(Mr 453.50), monoclinic, space group P21/c; a 10.184(2),
b 30.374(6), c 14.527(3) Å; β 104.00(3)°; V 4360.1(16) Å3;
Z 8; dcalc 1.382 g/cm3; F(000) 1888; μ 0.416 mm–1. A total
of 56256 reflections were collected (8957 independent
reflections, Rint 0.084, 2θ 76.96°). The structure was solved
by direct method and refined by full-matrix method of least
squares F2 in anisotropic approximation for non-hydrogen
atoms. The (amino)phenyl substituent in one of the two
crystallographically independent molecules was disordered
across two positions with population ratio of 0.9:0.1. The
hydrogen atoms of amino groups were localized
objectively from Fourier difference syntheses of electron
density and refined isotropically with fixed shift parameters
(Uiso(H) = 1.2Ueq(N)). The rest of the hydrogen atoms, the
positions of which were calculated geometrically, were
included in the refinement with fixed positional parameters
according to the riding model and isotropic shift parameters
(Uiso(H) = 1.5Ueq(C) for CH3 groups and Uiso(H) = 1.2Ueq
(C) for the rest of the groups). The final probability factors
were R1 0.050 for 7552 independent reflections with I ≥ 2σ(I)
and wR2 0.136 for all independent reflections. The
maximum and minimum values of residual electron density
peaks were 0.66 and –0.90 e/Å3. The complete X-ray
structural dataset for compound 5a was deposited at the
Cambridge Crystallographic Data Center (deposit CCDC
1896354).
Compound 5i. Yellow platelets, C27H20N4O2S2ClBr·H2O
(Mr 629.96), triclinic, space group P-1; a 9.5200(19),
b 9.766(2), c 17.160(3) Å; α 74.91(3)°; β 83.54(3)°;
γ 64.03(3)°; V 1384.9(6) Å3; Z 2; dcalc 1.511 g/cm3; F(000) 640;
μ 1.230 mm–1. A total of 18895 reflections were collected
(5547 independent reflections, Rint 0.053, 2θ 76.82°). The
structure was solved by direct method and refined by full
matrix method of least squares F2 in anisotropic approxi-
mation for non-hydrogen atoms. The 3-methylthiophene sub-
stituent was disordered across two positions with equal popu-
lations. The hydrogen atoms of amino groups and solvated
water molecule were objectively localized from Fourier
difference syntheses of electron density and refined iso-
tropically with fixed shift parameters (Uiso(H) = 1.2Ueq(N)
and 1.5Ueq(O)). The rest of the hydrogen atoms, the
positions of which were calculated geometrically, were
included in the refinement with fixed positional para-
meters according to the riding model and isotropic shift
parameters (Uiso(H) = 1.5Ueq(C) for the CH3 group and
Uiso(H) = 1.2Ueq(C) for the rest of the groups). The final
probability factors were R1 0.050 for 4916 independent
reflections with I ≥ 2σ(I) and wR2 0.123 for all independent
reflections. The maximum and minimum values of residual
electron density peaks were 0.48 and –0.62 e/Å3. The
complete X-ray structural dataset for compound 5i was
deposited at the Cambridge Crystallographic Data Center
(deposit CCDC 1896355).
s, NH2); 6.99 (1Н, d, J = 4.8, Н-4 Th); 7.27 (2Н, br. s,
СОNH2); 7.33 (2Н, d, J = 8.6, Н Ar); 7.47 (2Н, d, J = 8.6,
Н Ar); 7.64 (1Н, d, J = 4.8, Н-5 Th); 10.58 (1H, br. s,
СОNH). Mass spectrum, m/z (Irel, %): 457 [M+Н]+ (100).
Found, %: C 55.08; H 3.66; N 12.07. C21H17ClN4О2S2.
Calculated, %: C 55.20; H 3.75; N 12.26.
3-Amino-4-(2-chlorophenyl)-N-(4-chlorophenyl)-6-methyl-
2-(4-methylbenzoyl)thieno[2,3-b]pyridine-5-carboxamide
(5k). Yield 3.8 g (69%), yellow crystals, mp 262–264°С
(dioxane). IR spectrum, ν, cm–1: 1647 (δNH2), 1668
1
(CONH), 1709 (C=O), 3315–3445 (NH, NH2). H NMR
spectrum, δ, ppm (J, Hz): 2.37 (3Н, s, CH3); 2.63 (3Н, s,
CH3); 6.52 (2Н, br. s, NH2); 7.28 (2Н, d, J = 8.9, Н Ar);
7.32 (2Н, d, J = 8.1, Н Ar); 7.38 (2Н, d, J = 8.9, Н Ar);
7.47 (1Н, t, J = 8.9, Н Ar); 7.51 (1Н, t, J = 8.1, Н Ar); 7.61
(1Н, t, J = 6.2, Н Ar); 7.63 (1Н, d, J = 6.2, Н Ar); 7.66
(2Н, d, J = 8.1, Н Ar); 10.53 (1H, br. s, CONH). 13C NMR
spectrum, δ, ppm: 21.5; 23.2; 104.0; 119.6; 121.5 (4C);
127.9 (4C); 129.2 (4С); 129.5; 132.1 (2С); 133.2; 137.5;
138.3; 141.9 (2С); 150.1; 157.4; 161.1; 164.6; 189.4.
Found, m/z: 546.0806 [M–H]–. C29H20Cl2N3O2S.
Calculated, m/z: 546.0729.
3-Amino-N2-(4-bromophenyl)-4-(2-chlorophenyl)-
N5-(4-chlorophenyl)-6-methylthieno[2,3-b]pyridine-2,5-di-
carboxamide (5l). Yield 4.6 g (73%), dark-red crystals,
fluorescence observed under UV light, mp 312–314°С
(BuOH). IR spectrum, ν, cm–1: 1640 (δNH2), 1665 (CONH),
1
3288–3430 (NH, NH2). H NMR spectrum, δ, ppm (J, Hz):
2.67 (3Н, s, CH3); 5.70 (2Н, br. s, NH2); 7.32 (2Н, d, J = 8.7,
Н Ar); 7.38–7.52 (6Н, m, Н Ar); 7.57–7.68 (4Н, m, Н Ar);
10.63 (2H, br. s, 2СОNH). Mass spectrum, m/z (Irel, %):
627 [M+Н]+ (100). Found, %: C 53.55; H 2.94; N 8.81.
C28H19BrCl2N4О2S. Calculated, %: C 53.69; H 3.06; N 8.95.
3-Amino-N2-(4-bromophenyl)-4-(2-chlorophenyl)-
N5-(2-methoxyphenyl)-6-methylthieno[2,3-b]pyridine-
2,5-dicarboxamide (5m). Yield 5.3 g (85%), yellow
powder, mp 277–279°С (BuOH). IR spectrum, ν, cm–1:
1614 (δNH2), 1655 (CONH), 3318, 3396, 3476 (NH, NH2).
1H NMR spectrum, δ, ppm (J, Hz): 2.72 (3Н, s, CH3); 3.78
(3Н, s, CH3О); 5.73 (2Н, br. s, NH2); 6.83 (1Н, t, J = 7.5,
Н Ar); 7.00 (1Н, d, J = 8.1, Н Ar); 7.10 (1Н, t, J = 7.6, Н Ar);
7.32 (1Н, d, J = 7.6, Н Ar); 7.44–7.58 (4Н, m, Н Ar); 7.64
(4Н, t, J = 8.7, Н Ar); 9.65 (1H, br. s, СОNH); 9.68 (1H,
br. s, СОNH). 13C NMR spectrum, δ, ppm: 23.1; 56.2; 98.0;
112.0; 115.8; 120.5; 120.6; 123.6; 123.9 (4С); 126.5; 129.9;
131.4; 131.7 (4С); 131.8; 133.1; 138.7; 140.6; 147.5; 151.6;
156.4; 158.8; 164.2; 165.0. Mass spectrum, m/z (Irel, %):
622 [M+Н]+ (100). Found, %: C 55.88; H 3.44; N 8.95.
C29H22BrClN4О3S. Calculated, %: C 56.01; H 3.57; N 9.01.
X-ray structural analysis of compounds 5a,i,k was
performed at the "Belok" synchrotron beamline at the
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 step of 1.0°). Processing of
experimental data was performed with the iMOSFLM
program, obtained as a part of the CCP4 software suite.16
Absorption of X-ray radiation was taken into account by
processing the obtained data with the Scala program.17
Compound 5k. Yellow platelets, C29H21N3O2SCl2
(Mr 546.45), monoclinic, space group P21/n; a 8.9393(18),
b 31.024(6), c 9.901(2) Å; β 108.76(3)°; V 2600.0(10) Å3;
Z 4; dcalc 1.396 g/cm3; F(000) 1128; μ 0.854 mm–1. A total
of 36328 reflections were collected (5519 independent
446

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 442–447
2. Eggenweiler, H.-M.; Wolf, M. DE Patent 102005024245; Ref.
reflections, Rint 0.086, 2θ 76.95°). The structure was solved
by direct method and refined by full-matrix method of least
squares F2 in anisotropic approximation for non-hydrogen
atoms. The 4-methylphenyl and 4-chlorophenyl
substituents were disordered each across two positions with
equal populations. The hydrogen atoms of amino groups
were objectively localized from Fourier difference syntheses
of electron density and included in the refinement with
fixed positional parameters according to the riding model
and isotropic shift parameters (Uiso(H) = 1.2Ueq(N)). The
rest of the hydrogen atoms, the positions of which were
calculated geometrically, were included in the refinement
with fixed positional parameters according to the riding
model and isotropic shift parameters (Uiso(H) = 1.5Ueq(C)
for CH3 groups and Uiso(H) = 1.2Ueq(C) for the rest of the
groups). The final probability parameters were R1 0.088 for
3927 independent reflections with I ≥ 2σ(I) and wR2 0.229
for all independent reflections. The maximal and minimal
values of residual electron density peak values were 1.09
and −0.77 e/Å3. The complete X-ray structural dataset for
compound 5k was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1896356).
All calculations were performed using the SHELXTL
software suite.18
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Supplementary information file containing X-ray
structural analysis results for compound 5a is available at
the journal website at http://link.springer.com/journal/10593.
This work received financial support from the Ministry
of Education and Science of the Russian Federation
(Project No. 4.1154.2017/4.6).
References
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