INTRODUCTION

Nowadays, multicomponent reactions have become increasingly popular for producing complex molecules from simpler ones. This approach permits the rapid assembly of compounds reduced formation of by-products, and is time and energy economical. These features are consistent with most principles of green chemistry [1] and also make the use of multicomponent reactions an ideal synthetic strategy, especially from the perspective of diversity-oriented synthesis [2]. Using this method we have obtained derivatives of cycloalco[b]pyridine [3], pyrano[2,3-d]pyrimidine [4], thieno[2,3-b]pyridine [5] and quinolone [6].

RESULTS AND DISCUSSION

In continuation of our work in this field, we studied multicomponent reactions of cyanothioacetamide [7, 8] leading to 2-alkylthionicotinonitrile derivatives. It was established that condensation of CH-acid 1, furfural 2, o-methoxyacetanilide 3, 1,2-dibromoethane 4 and N-methylmorpholine occurs in ethanol at 20°C to form the corresponding 1,4-dihydropyridine-3-carboxamide derivative 5. Probable reaction mechanism involves the formation of the Knoevenagel alkene— 2-furfurylidenecyanothioacetamide A. Next, Michael addition of CH-acid 3 takes place to form the adduct B. Its subsequent intramolecular cyclization proceeds chemoselectively to give salt C, further alkylation of which with 1,2-dibromoethane leads to 5 (Scheme 1).

Scheme
scheme 1

1.

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Condensation of CH-acid 1, 4-methoxybenzaldehyde 6a, 1-[1-(4-methoxyphenyl)vinyl]pyrrolidine 7a and 2-methylbenzyl bromide 8 was carried out in ethanol in the presence of pyrrolidine at 20°C in air. As a result, nicotinonitrile 9 was isolated in 68% yield. Most probably the reaction involves the formation of a Knoevenagel type alkene A, followed by alkylation of enamine 7a with A [9]. The adduct D formed in this way undergoes intramolecular trans-amination leading to salt E. Further alkylation of the latter with 2-methylbenzyl bromide 8 leads to thioether F, which underwent oxidation at the S atom in an alkaline media with atmospheric oxygen into the final structure 9 (Scheme 2).

Scheme
scheme 2

2.

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Condensation of benzaldehyde 6b, 1-(1-methylvinyl)pyrrolidine 7b, pyrrolidine and N-(thiazol-2-yl)-2-chloroacetamide 10 and cyanothioacetamide 1 occurs under similar conditions to lead to sulfide 11. Use in this condensation of 2-bromo-1-(p-tolyl)ethanone 12 as an alkylating reagent resulted in the formation of thieno[2,3-b]pyridine 13. Note that intermediate G could not be isolated due to its easy intramolecular cyclization into the final structure 13 (Scheme 2).

The reaction can be performed with various aldehydes and enamines. This approach gave thionicotinonitriles 18a–18c (Scheme 3), which are promising intermediates for the creation of anticancer [10–12], antimicrobial [13–15], and antituberculosis [16] drugs. Alkylation of 18a with alkyl halides resulted in sulfide 19 and substituted thieno[2,3-b]pyridines 20a, 20b (Scheme 3) [17–19].

Scheme
scheme 3

3.

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Condensation of CH-acid 1 with sodium 5-methyl-3-oxohexa-1,4-dien-1-olate 23 occurs in boiling ethanol in the presence of an equimolar amount of AcOH to form nitrile 24. The mechanism for the formation of compound 24 involves synthesis of a Knoevenagel alkene, which then cyclizes intramolecularly into the final structure. Alkylation of 24 with 3-(2-bromoacetyl)-2H-chromen-2-one 25 proceeds at 20°C in a DMF solution in the presence of a 10% aqueous KOH solution. As a result, nicotinonitrile 26 was isolated (Scheme 4). Under similar conditions, cyanothioacetamide 1 condenses with 27 and allyl bromide 28 to form 2-allylthio-6-(4-chlorophenyl)nicotinonitrile 29. Due to the high electrophilicity of allyl bromide the reaction proceeds autocatalytically upon short-term boiling of the mixture (Scheme 4).

Scheme
scheme 4

4.

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A three-component condensation of cyanothioacetamide 1, cyclohexanone 30 and 2-bromo-1-(p-tolyl)ethanone 12 proceeds in the presence of triethylamine in refluxing benzene. Nitrile 31 is formed as a result of sequential Knoevenagel and Hantzsch reactions. Alternatively, thiolate 32 can be prepared in 82% yield. Probable scheme of its formation includes the formation of intermediates K (product of the Knoevenagel reaction) and L (adduct of the Michael reaction) (Scheme 5).

Scheme
scheme 5

5.

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The structure of the synthesized compounds was confirmed by IR, mass, 1H and 13C NMR spectroscopy data (see Experimental). To elucidate the mechanisms of the occurring reactions and unambiguously establish the structure of its products, the molecular and crystal structures of compounds 5, 9, 19, 31 and 32 were studied by single crystal X-ray diffraction (Table 1).

Table 1. Crystal structural data for compounds 5, 9, 19, 31 and 32
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The structure of the molecule of compound 5 and the corresponding numbering of atoms are presented in Fig. 1. In the crystal, the molecule of compound 5 is located in a particular position at the inversion center, i.e., it has its own symmetry Ci (\(\bar 1\)).

Fig. 1.
figure 1

Molecular structure of compound 5 in the representation of atoms by ellipsoids of anisotropic displacements with 50% probability. Two solvate molecules of butanol are shown. Dashed and dotted lines indicate intra- and intermolecular hydrogen bonds N–H···O and C–H···O.

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The central dihydropyridine ring adopts a flattened bath conformation, with the N1 nitrogen and C4 carbon atoms deviating from the plane through the remaining ring atoms (the standard deviation of the atoms is 0.010 Å) by 0.133(5) and 0.301(6) Å, respectively. The nitrogen atoms N1 and N3 have a trigonal-planar configuration [the sums of bond angles are 357(6)° and 360(6)°, respectively]. The N-(2-methoxyphenyl)-carboxamide fragment has a flattened conformation (the standard deviation of non-hydrogen atoms is 0.078 Å), which is apparently determined by the presence of intramolecular hydrogen bonds N–H···O and C–H···O (Table 2). The angle between the basal plane of the dihydropyridine ring and the plane of the N-(2-methoxyphenyl)carboxamide fragment is 8.1(2)°. It is interesting to note that the bulky furan substituent occupies a sterically less preferred axial position. The molecule of compound 5 contains two asymmetric centers at carbon atoms C4 and C4A and can form four diastereomers. The crystal of compound 5 is a racemate and consists of enantiomeric pairs with the relative configuration of chiral atoms—4RS,4ASR.

Table 2. Hydrogen bonds in molecules 5 and 32b
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In the crystal of compound 5, the molecules form zigzag ribbons parallel to (1 0 \(\bar 1\)), through solvate butanol molecules due to intermolecular hydrogen bonds N–H···O, C–H···O and O–H···N (Table 2, Fig. 2). The tapes are located at van der Waals distances (Fig. 3).

Fig. 2.
figure 2

Zigzag ribbons in the crystal of compound 5. Dashed and dotted lines indicate intra- and intermolecular hydrogen bonds N–H···O, C–H···O and O–H···N.

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Fig. 3.
figure 3

Crystal structure of compound 5 along crystallographic axis b.

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The structure of the molecule of compound 9 and the corresponding numbering of atoms are presented in Fig. 4. Compound 9 crystallizes in the triclinic system, space group P\(\bar 1\), with two crystallographically independent molecules in the unit cell. Two crystallographically independent molecules are conformers and differ in the mutual arrangement of methoxyphenyl fragments relative to the central pyridine ring [twist angles are 37.45(11)/7.68(9)° and 39.99(8)/22.9(2)°, respectively]. Methoxy substituents are almost coplanar with the corresponding phenyl rings [torsion angles are 3.4(4)/1.8(4)° and 5.6(4)/7.1(8)°, respectively].

Fig. 4.
figure 4

Molecular structure of compound 9 in the representation of atoms by ellipsoids of anisotropic displacements with 50% probability (one of two crystallographically independent molecules is represented).

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In a crystal, the molecules are located at van der Waals distances (Fig. 5).

Fig. 5.
figure 5

Crystal structure of compound 9 along crystallographic axis b.

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The structure of the molecule of compound 19 and the corresponding numbering of atoms are presented in Fig. 6. The methoxyphenyl fragment in compound 19 is rotated relative to the central pyridine ring by an angle of 40.75(4)°. The methoxy substituent is almost coplanar with the phenyl ring [torsion angle is 1.1(3)°]. The ethylthio substituent adopts a trans conformation [torsion angle is 175.88(17)°]. In a crystal, the molecules are packed in stacks along the crystallographic axis a and located at van der Waals distances (Fig. 7).

Fig. 6.
figure 6

Molecular structure of compound 19 in the representation of atoms as ellipsoids of anisotropic displacements with 50% probability.

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Fig. 7.
figure 7

Crystal structure of compound 19 along the crystallographic axis a.

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The structure of the molecule of compound 31 and the corresponding numbering of atoms are presented in Fig. 8.

Fig. 8.
figure 8

Molecular structure of compound 31 in the representation of atoms as ellipsoids of anisotropic displacements with 50% probability.

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The thiazole and phenyl rings in the molecule of compound 31 are almost coplanar [dihedral angle is 7.31(9)°]. The ylidene substituent is twisted relative to the central thiazole ring by an angle of 24.48(7)°. The cyclohexane ring has the usual chair conformation; the methyl substituent occupies a sterically more preferable equatorial position. In a crystal, the molecules are packed in stacks along the crystallographic axis b and located at van der Waals distances (Fig. 9).

Fig. 9.
figure 9

Crystal structure of compound 31 along crystallographic axis b.

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The structure of salt 32 and the corresponding numbering of atoms are presented in Fig. 10. The central dihydropyridine ring adopts a flattened bath conformation, with the N1 nitrogen and C4 carbon atoms deviating from the plane through the remaining ring atoms [the standard deviation of the atoms is 0.016 Å) by 0.170(3) and 0.378(3) Å, respectively]. The nitrogen atom N1 takes on a trigonal pyramidal configuration [the sum of the bond angles is 357(5)°], the hydrogen atom is in an equatorial position. The nitrogen atom N6 has a planar configuration [the sum of bond angles is 360(7)°]. The spiro-linked cyclohexane ring has the usual chair conformation.

Fig. 10.
figure 10

The molecular structure of salt 32 in the representation of atoms by ellipsoids of anisotropic displacements with 40% probability. The dashed line shows the intermolecular hydrogen bond N–H···S.

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In the crystal, triethylammonium cations and thiolate anions form flat ribbons due to intermolecular hydrogen bonds N–H···S and N–H···N (Table 1, Fig. 11). The tapes are packed in a parquet manner and located at van der Waals distances.

Fig. 11.
figure 11

Flat ribbons in salt crystal 32. Dashed lines indicate intermolecular hydrogen bonds N–H···S and N–H···N.

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CONCLUSIONS

Multicomponent condensations of cyanothioacetamide, initiated by the Knoevenagel reaction and consisting of carbonyl compounds, CH acids, enamines and alkylating reagents, are carried out under mild conditions and lead to the production of new promising intermediates for the creation of pharmaceuticals—substituted 2-thioxonicotinonitriles, thieno[2,3-b]pyridines, 1,4-dihydronicotinamide and thiazole.

EXPERIMENTAL

The unit cell parameters and reflection intensities for crystals of compounds 5 and 9 were measured on a Bruker D8 QUEST PHOTON-III diffractometer (graphite monochromator, φ- and ω-scanning). The unit cell parameters and reflection intensities for crystals of compounds 19, 31 and 32 were measured on a Bruker SMART APEX-II diffractometer (graphite monochromator, φ- and ω-scanning). The experimental data were processed using the SAINT program [20]. For the data obtained, X-ray absorption was taken into account using the SADABS program [21]. The main crystal structural data and refinement parameters are presented in Table 2.

The structures were determined by direct methods and refined by the full-matrix least squares method for F2 in the anisotropic approximation for non-hydrogen atoms. In the crystal of compound 9, one of the four methoxyphenyl fragments was found to be disordered at two positions with occupancies of 0.630(7) : 0.370(7). In addition, refining the positions of disordered solvate ethanol molecules in the crystal of compound 9 was unsuccessful, so their contribution to X-ray scattering was removed using the SQUEEZE program, part of the PLATON15 software package [22]. The hydrogen atoms of the amino groups in compounds 5 and 32 and the hydroxy group of the solvate butanol molecule in compound 5 were identified objectively in difference Fourier syntheses and refined isotropically with fixed displacement parameters [Uiso(H) = 1.2Ueq(N) and 1.5Ueq(O)]. The positions of the remaining hydrogen atoms in all compounds were calculated geometrically and included in the refinement with fixed positional parameters (rider model) and isotropic displacement parameters [Uiso(H) = 1.5Ueq(C) for CH3 groups and 1.2Ueq(C) for the rest groups]. All calculations were carried out using the SHELXTL software package [23]. Tables of atomic coordinates, bond lengths, bond and torsion angles and anisotropic displacement parameters have been deposited in the Cambridge Structural Data Bank [CCDC 2358319 (5·2BuOH), 2358320 (9·5/8EtOH), 2358321 (19), 2358322 (31) and 2358323 (32)].

IR spectra were obtained on an IKS-40 instrument in mineral oil. 1H NMR spectra and 13C were recorded on a Varian VXR-400 spectrophotometer (399.97 and 100 MHz, respectively) in DMSO-d6 solutions, internal standard – TMS. Mass spectra were registered on a MS-890 instrument (70 eV) using direct injection into the ion source (compounds 24c and 26) and an Orbitrap Elite high-resolution mass spectrometer (9, 11, 18b, 19). The sample for HRMS was dissolved in 1 mL DMSO, diluted 100 times with 1% HCOOH in CH3CN, and injected with a syringe pump at a rate of 40 μL/min into an electrospray ionization source. The source gas flows were turned off, the voltage on the needle was 3.5 kV, the capillary temperature was 275°C. Mass spectra were recorded in positive and negative ion modes in an orbital trap with a resolution of 480000. Internal calibrants were 2DMSO + H+ ion (m/z = 157.03515) in positive ions and dodecyl sulfate anion (m/z = 265.14789) in negative ions. Melting points were determined using a Kofler block. The progress of the reaction and the purity of the resulting compounds were monitored by TLC on Silufol UV-254 plates in the acetone-hexane system (3:5), development with iodine vapor and UV irradiation.

6,6′-[Ethane-1,2-diylbis(sulfanediyl)]bis[5-cyano-4-(furan-2-yl)-N-(2-methoxyphenyl)-2-methyl-1,4-dihydropyridine-3-carboxamide] (5). To a stirred solution of 1.0 g (10 mmol) of cyanothioacetamide 1 in 25 mL of ethanol at 20°C were added 0.83 mL (10 mmol) of furfural 2 and 1 drop of N-methylmorpholine. The resulting mixture was stirred for 15 min until crystallization of 2-furfurylidenecyanothioacetamide A began, and 2.1 g (10 mmol) of o-methoxyacetoacetanilide 3 and 1.1 mL (10 mmol) of N-methylmorpholine were added. After stirring for 2 h, 0.45 mL (5 mmol) of 1,2-dibromoethane 4 was added to the reaction mixture. After 24 h, the mixture was diluted with an equal volume of water and the resulting precipitate was filtered off, which was washed successively with water, ethanol and hexane. Yield 2.8 g (74%), yellow crystals, mp 230–232°С (BuOH). IR spectrum, ν, cm–1: 3188 (NН), 2203 (C≡N), 1660 (NHCO). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.14 s (6H, Me), 3.36 s (4H, SCH2), 3.73 s (6H, MeO), 4.77 s (2H, H4), 6.21 d (2H, 2H4furyl, J 4.5 Hz), 6.38 d (2H, 2H3furyl, J 5.0 Hz), 6.83 t (2H, HAr, J 7.5 Hz), 6.92–7.05 m (4H, HAr), 7.56 s (2H, 2Н5furyl), 7.80 d (2Н, HAr, J 7.8 Hz), 8.53 br. s (2H, 2NH), 9.38 br. s (2H, NHCO). 13C NMR spectrum (DMSO-d6), δC, ppm: 17.8 (2C), 39.3 (2C), 56.1 (2C), 60.8 (2C), 85.9 (2C), 103.8 (2C), 103.8 (2C), 106.8 (2С), 111.4 (2С), 119.6 (2С), 120.6 (2С), 122.2 (2С), 124.8 (2С), 127.7 (2С), 140.4 (2С), 143.4 (2С), 143.8 (2С), 150.1 (2С), 155.8 (2С), 165.7 (2С). Mass spectrum, m/z (Irel, %): 759.2 (100) [M – 1]+. Found, %: C 63.00; H 4.68; N 10.97. C40H36N6O6S2. Calculated, %: C 63.14; H 4.77; N 11.05. M 760.9.

4,6-Bis(4-methoxyphenyl)-2-[(2-methylbenzyl)sulfonyl]nicotinonitrile (9). To a stirred solution of 1.0 g (10 mmol) of CH-acid 1 in 20 mL of ethanol were added 1.2 mL (10 mmol) of obepine 6a and 1 drop of pyrrolidine at 20°C. the resulting mixture was stirred for 20 min until crystallization of 4-methoxybenzylidenecyanothioacetamide A began, and then 2.0 g (10 mmol) of enamine 7a was added. The reaction mixture was stirred for 4 h, then 1.2 g (10 mmol) of 2-methylbenzyl bromide 8 was added. After 24 h, 5.6 mL (10 mmol) of a 10% aqueous solution of KOH was added to the mixture, stirred for 1 h and left in air for 48 h, after which it was diluted with an equal volume of water. The resulting precipitate was filtered off and washed successively with water, ethanol, and hexane. Yield 3.3 g (68%), light yellow crystals, mp 162–164°C (dioxane). IR spectrum, ν, cm–1: 2218 (C≡N). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.40 s (3H, Me), 3.83 s (3H, MeO), 3.84 s (3H, MeO), 5.12 s (2H, CH2), 7.11–7.32 m (5H, HAr), 7.25 br. s (3H, HAr), 7.69 d (2H, HAr, J 8.9 Hz), 8.26–8.33 m (3H, HAr). 13C NMR spectrum (DMSO-d6), δC, ppm: 19.9, 55.5, 55.9, 56.0, 102.3, 114.2, 114.7 (2C), 115.0 (2C), 122.7, 125.9, 126.3, 127.7 (2C), 129.4, 130.3 (2C), 131.0, 131.3 (2C), 133.2, 139.6, 156.2, 158.0, 159.6, 161.4, 162.6. Mass spectrum (HRMS ESI), m/z: 485.1546 [M + 1]+ (calcd for C28H24N2O4S: 485.1457).

2-[(3-Cyano-6-methyl-4-phenylpyridin-2-yl)thio]-N-(thiazol-2-yl)acetamide (11). To a stirred solution of 1.0 g (10 mmol) of CH-acid 1 in 20 mL of ethanol at 20°C were added 1.0 mL (10 mmol) of benzaldehyde 6b and 1 drop of pyrrolidine. The resulting mixture was stirred for 15 min until the crystallization of benzalcyanothioacetamide A began, and then 1.1 g (10 mmol) of enamine 7b was added. The reaction mixture was stirred for 4 h, then 1.7 g (10 mmol) of N-(thiazol-2-yl)chloroacetamide 10 was added, stirred for 2 h and left. After 24 h, the mixture was diluted with an equal volume of water and the resulting precipitate was filtered off and washed successively with water, ethanol and hexane. Yield 3.2 g (86%), light yellow crystals, mp 236–238°С (BuOH). IR spectrum, ν, cm–1: 3334 (NН), 2221 (C≡N), 1665 (CONH). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.38 s (3H, Me), 4.27 s (2H, SCH2), 7.18 d (1H4thiazole, J 3.6 Hz), 7.23 s (1H5Py), 7.45 d (1Н5thiazole, J 3.6 Hz), 7.52–7.66 m (5H, Ph), 12.45 br. s (1H, NH). 13C NMR spectrum (DMSO-d6), δC, ppm: 24.6, 34.2, 101.9, 113.9, 116.0, 116.6, 120.2, 128.9 (2C), 129.4 (2C), 130.5, 135.9, 138.2, 153.7, 161.6, 162.3, 166.9. Mass spectrum (HRMS ESI), m/z: 367.0687 [M + H]+ (calcd for C18H14N4OS2: 367.0609).

(3-Amino-6-methyl-4-phenylthieno[2,3-b]pyridin-2-yl)(p-tolyl)methanone (13) was obtained similarly to compound 11 with use of 1.0 g (10 mmol) of CH-acid 1, 1.0 mL (10 mmol) of benzaldehyde 6b, 1.1 g (10 mmol) of enamine 7b and 2.1 g (10 mmol) of alkylating reagent 12. Yield 2.8 g (77%), yellow powder, mp 82–84°C (AcOH). IR spectrum, ν, cm–1: 3398, 3342, 3305 (NH2), 1711 (C=O), 1642 [δ(NH2)]. 1H NMR spectrum (DMSO-d6), δ, ppm: 2.38 s (3H, Me), 2.59 s (3H, Me), 6.87 br. s (2H, NH2), 7.13 s (1H6), 7.31 d (2HAr, J 6.2 Hz), 7.51 br. s (2HAr, Ph), 7.58 br. s (3HAr, Ph), 7.66 d (2HAr, J 6.2 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm: 21.5, 24.6, 103.2, 119.2, 122.2, 127.9 (3С), 128.7 (2С), 129.4 (3С), 129.5, 136.6, 138.6, 141.7, 148.2, 150.6, 161.0, 162.1, 189.3. Mass spectrum, m/z (Irel, %): 359.2 (100) [M + 1]+. Found, %: C 73.60; H 5.01; N 7.77. C22H18N2OS. Calculated, %: C 73.71; H 5.06; N 7.82. M 358.5.

Azepan-1-ium 3-cyano-4-(3-ethoxy-4-hydroxyphenyl)-6-methylpyridine-2-thiolate (15). To a stirred mixture of 1.0 g (10 mmol) of cyanothioacetamide 1 and 1.7 g (10 mmol) of 4-hydroxy-3-ethoxybenzaldehyde 6c in 20 mL of ethanol at 20°C was added 1 drop of azepane and stirred for 20 min until crystals of alkene A appeared, then 1.4 g (10 mmol) of enamine 14 was added and left. After 24 h, the resulting precipitate was filtered off and washed with ethanol and hexane. Yield 2.7 g (70%), yellow crystals, sublimated into cubic crystals at 210°C, mp 290–292°С (EtOH). IR spectrum, ν, cm–1: 3507 (OH), 3281 (NH2+), 2221 (C≡N). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.35 t (3H, MeCH2, J 6.7 Hz), 1.58 br. s [4H, (CH2)2], 1.72 br. s [4H, (CH2)2], 2.28 s (3H, Me), 3.05 t (4H, CH2N+CH2, J 5.3 Hz), 4.06 q (2H, OCH2, J 6.7 Hz), 6.52 s (1H5Py), 6.85 d (1HAr, J 8.1 Hz), 6.97 d (1HAr, J 8.1 Hz), 7.08 s (1HAr). Signals from the protons of the +NH2 and OH groups do not appear, apparently due to rapid deuterium exchange. 13C NMR spectrum (DMSO-d6), δC, ppm: 15.2, 23.6, 26.2, 26.8 (2С), 33.4, 46.2 (2С), 64.4, 107.5, 113.4, 114.2, 116.0, 120.3, 121.7, 128.5, 146.9, 148.9, 153.3, 157.4, 182.6. Mass spectrum, m/z (Irel, %): 287.0 (100) [Manion + 1]+, 100.2 (100) [Mcation + 1]+. Found, %: C 65.34; H 6.96; N 10.78. C21H27N3O2S. Calculated, %: C 65.42; H 7.06; N 10.90. M 385.5.

2-{[2-(4-Bromophenyl)-2-oxoethyl]thio}-4-(3-ethoxy-4-hydroxyphenyl)-6-methylnicotinonitrile (17). To a stirred solution of 3.9 g (10 mmol) of salt 15 in 15 mL of DMF at 20°C was added 2.8 g (10 mmol) of 4-bromophenacyl bromide 16, stirred for 2 h, diluted with an equal volume of water, and the resulting precipitate was filtered off. They were washed successively with water, ethanol and hexane. Yield 4.0 g (82%), light yellow crystals, mp 178–180°С (AcOH). IR spectrum, ν, cm–1: 3405 (OH), 2222 (C≡N), 1713 (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.36 t (3H, Me, J 6.9 Hz), 2.11 s (3H, Me), 4.09 q (2H, OCH2, J 6.9 Hz), 4.81 s (2H, SCH2), 6.93 d (1HAr, J 8.2 Hz), 7.07 d (1HAr, J 8.2 Hz), 7.18 s (1HAr), 7.21 s (1H5Py), 7.79 d (2HAr, J 8.4 Hz), 8.02 d (2HAr, J 8.4 Hz), 9.58 br. s (1H, OH). 13C NMR spectrum (DMSO-d6), δC, ppm: 15.1, 24.4, 37.6, 64.5, 101.4, 114.2, 116.3, 116.6, 119.6, 122.1, 126.5, 127.9, 130.7 (2C), 132.3 (2C), 136.0, 147.3, 149.4, 153.7, 161.5, 161.7, 193.7. Mass spectrum, m/z (Irel, %): 484.0 (100) [M + 1]+. Found, %: C 57.07; H 3.88; N 5.71. C23H19BrN2O3S. Calculated, %: C 57.15; H 3.96; N 5.80. M 483.4.

6-Methyl-4-(4-methoxyphenyl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (18a) was prepared similarly to compound 15, starting from 1.0 g (10 mmol) of cyanothioacetamide 1, 1.2 mL (10 mmol) of obepine 6a and 1.4 g (10 mmol) of enamine 14 before the stage of sediment separation. The reaction mixture was then diluted with 10% hydrochloric acid to pH = 5 and left. After 24 h, the mixture was diluted with an equal volume of water, the resulting precipitate was filtered off, and washed successively with water, ethanol, and hexane. Yield 1.8 g (70%), yellow powder, sublimated at 200°C, mp 253–255°С (AcOH). IR spectrum, ν, cm–1: 3312 (NН), 2218 (C≡N), 1211 (C=S). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.40 s (3H, Me), 3.84 s (3H, MeO), 6.80 s (1H5Py), 7.10 d (2HAr, J 8.7 Hz), 7.61 d (2HAr, J 8.7 Hz), 13.97 br. s (1H, NH). Mass spectrum, m/z (Irel, %): 257.0 (100) [M + 1]+. Found, %: C 65.52; H 4.66; N 10.88. C14H12N2OS. Calculated, %: C 65.60; H 4.72; N 10.93. M 256.1.

4-(4-Hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (18b) was prepared similarly to compound 18a starting from 1.0 g (10 mmol) of CH-acid 1, 1.5 g (10 mmol) of 4-hydroxy-3-methoxybenzaldehyde 6d and 1.4 g (10 mmol) of enamine 14. Yield 2.3 g (85%), yellow powder, mp 180–182°С (AcOH). IR spectrum, ν, cm–1: 3485 (OH), 2981 (NH), 2214 (C≡N), 1213 (C=S). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.38 s (3H, Me), 3.82 s (3H, MeO), 6.83 s (1H5Py), 6.90 d (1HAr, J 8.2 Hz), 7.11 d (1HAr, J 8.2 Hz), 7.22 s (1HAr), 9.77 br. s (1H, ОH), 13.91 br. s (1H, NH). 13C NMR spectrum (DMSO-d6), δC, ppm: 19.0, 55.8, 110.3, 112.5, 113.8, 115.6, 117.5, 122.0, 126.0, 147.5, 149.3, 152.7, 156.4, 177. 9. Mass spectrum (HRMS ESI), m/z: 273.0701 [M + H]+ (calcd for C14H12N2O2S: 273.0609).

4-(4-Hydroxyphenyl)-6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (18c) was prepared similarly to compound 18a starting from 1.0 g (10 mmol) of CH-acid 1, 1.22 g (10 mmol) of 4-hydroxybenzaldehyde 6e and 1.4 g (10 mmol) of enamine 14. Yield 1.9 g (79%), yellow powder, mp 285–287°С (AcOH). IR spectrum, ν, cm–1: 3268 (OH), 3081 (NH), 2220 (C≡N), 1211 (C=S). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.39 s (3H, Me), 6.78 s (1H5Py), 6.90 d (2HAr, J 8.3 Hz), 7.51 d (2HAr, J 8.3 Hz), 10.17 br. s (1H, OH), 13.92 br. s (1H, NH). 13C NMR spectrum (DMSO-d6), δC, ppm: 19.5, 110.7, 114.1, 116.0 (2C), 117.8, 126.2, 130.6 (2C), 153.2, 156.8, 160.4, 179.0. Mass spectrum, m/z (Irel, %): 243.0 (100) [M + 1]+. Found, %: C 64.38; H 4.05; N 11.45. C13H10N2OS. Calculated, %: C 64.44; H 4.16; N 11.56. M 242.3.

2-(Ethylthio)-4-(4-methoxyphenyl)-6-methylnicotinonitrile (19). To a stirred mixture of 2.6 g (10 mmol) of compound 18a in 15 mL of DMF at 20°C were successively added 5.6 mL (10 mmol) of a 10% aqueous solution of KOH and 0.8 mL (10 mmol) of ethyl iodide 21. The resulting mixture was stirred for 2 h and diluted equal to volume of water. The resulting precipitate was filtered off and washed successively with water, ethanol, and hexane. Yield 2.1 g (73%), colorless needle crystals, mp 92–94°C (AcOH). IR spectrum, ν, cm–1: 2219 (C≡N). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.30 t (3H, MeCH2, J 7.3 Hz), 2.52 s (3H, Me), 3.21 q (2H, SCH2, J 7.3 Hz), 3.80 s (3H, MeO), 7.07 d (2HAr, J 8.8 Hz), 7.19 s (1H5Py), 7.56 d (2HAr, J 8.8 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm: 19.6, 29.3, 29.8, 60.6, 106.7, 119.5 (2С), 121.2, 124.2, 132.8, 135.2 (2С), 158.0, 165.9, 167.0, 167.5. Mass spectrum (HRMS ESI), m/z: 285.1047 [M + H]+ (calcd for C16H16N2OS: 285.0983).

3-Amino-6-methyl-4-(4-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide (20a) was prepared similarly to compound 19 starting from 2.6 g (10 mmol) of pyridinethione 18a and 0.94 g (10 mmol) of α-chloroacetamide 22a. Yield 2.5 g (80%), bright yellow powder, at 180°C sublimes into lamellar crystals, mp 225–227°С (BuOH). IR spectrum, ν, cm–1: 3410, 3331, 3300, 3290 (NH2), 1665 (CONH), 1637 [δ(NH2)]. 1H NMR spectrum (DMSO-d6), δ, ppm: 2.56 s (3H, Me), 3.82 s (3H, MeO), 5.94 br. s (2H, NH2), 7.03 s (1H5Py), 7.07 d (2HAr, J 8.6 Hz), 7.16 br. s (2H, CONH2), 7.38 d (2HAr, J 8.6 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm: 24.4, 55.8, 97.4, 114.6 (2С), 120.6, 122.1, 129.0, 130.4 (2С), 146.3, 146.9, 158.7, 159.6, 160.2, 167.5. Mass spectrum, m/z (Irel, %): 314.2 (100) [M + 1]+. Found, %: C 61.19; H 4.74; N 13.35. C16H15N3O2S. Calculated, %: C 61.32; H 4.82; N 13.41. M 313.4.

3-Amino-6-methyl-4-(4-methoxyphenyl)-N-(quinolin-8-yl)thieno[2,3-b]pyridine-2-carboxamide (20b) was prepared analogously to compound 19 with use of 2.6 g (10 mmol) of pyridinethione 18a and 2.2 g (10 mmol) of 2-chloro-N-(quinolin-8-yl)acetamide 22b. Yield 3.4 g (77%), brown powder, mp 162–164°С (BuOH). IR spectrum, ν, cm–1: 3415, 3346, 3300, 3295 (NH, NH2), 1668 (CONH), 1635 [δ(NH2)]. 1H NMR spectrum (DMSO-d6), δ, ppm: 2.69 s (3H, Me), 3.90 s (3H, MeO), 6.06 br. s (2H, NH2), 6.97 s (1H5Py), 7.04 d (2HAr, J 8.4 Hz), 7.39 d (2HAr, J 8.4 Hz), 7.45–7.78 m (3HAr), 8.15 d (1HAr, J 8.1 Hz), 8.74 d (1HAr, J 7.1 Hz), 8.88 br. s (1HAr), 10.17 br. s (1H, NH). Mass spectrum, m/z (Irel, %): 441.2 (100) [M + 1]+. Found, %: C 68.02; H 4.46; N 12.65. C25H20N4O2S. Calculated, %: C 68.16; H 4.58; N 12.72. M 440.5.

6-(2-Methylprop-1-en-1-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (24). To a stirred suspension of 1.0 g (10 mmol) of cyanothioacetamide 1 and 0.5 g (10 mmol) of salt 23 in 20 mL of absolute ethanol at 20°C was added 0.6 mL (10 mmol) of glacial acetic acid, after which the reaction mixture was heated to boiling and filtered through a pleated filter. After the filtrate cooled to 20°C, it was diluted with 10% hydrochloric acid to pH = 5 and left. After 24 h, the mixture was diluted with an equal volume of water, and the resulting precipitate was filtered off and washed successively with water, ethanol, and hexane. Yield 1.3 g (70%), yellow powder, mp 188–190°С (AcOH). IR spectrum, ν, cm–1: 3334 (NH), 2216 (C≡N). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.98 s [6H, (Me)2], 6.12 s (1H, =CH), 6.33 d (1H5Py, J 7.4 Hz), 7.95 d (1H5Py, J 7.4 Hz), 13.69 br. s (1H, NH). Mass spectrum, m/z (Irel, %): 192 (3) [M + 2]+, 191 (58) [M + 1]+, 189 (100) [M – 1]+, 175 (15) , 162 (12), 148 (14), 142 (23), 114 (11), 77 (13), 64 (14), 45 (9), 39 (31). Found, %: C 63.02; H 5.25; N 14.66. C10H10N2S. Calculated, %: C 63.13; H 5.30; N 14.72. M 190.3.

6-(2-Methylprop-1-en-1-yl)-2-{[2-oxo-2-(2-oxo-2H-chromen-3-yl)ethyl]thio}nicotinonitrile (26) was obtained analogously to compound 19 with use of 1.9 g (10 mmol) of pyridinethione 24 and 2.7 g (10 mmol) of 3-(2-bromoacetyl)-2H-chromen-2-one 25. Yield 2.6 g (70%), yellow powder, mp 164–166°С (BuOH). IR spectrum, ν, cm–1: 2219 (C≡N), 1714, 1695 (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.81 s [6H, (Me)2], 4.68 s (2H, CH2), 6.19 s (1H, =CH), 7.09 d (1H5Py, J 7.5 Hz), 7.32–7.51 m (2HAr), 7.63 t (1HAr, J 8.0 Hz), 7.96 d (1HAr, J 8.0 Hz), 8.01 d (1H4Py, J 7.5 Hz), 8.60 s (1H4coumarin). Mass spectrum, m/z (Irel, %): 376 (5) [M]+, 348 (4), 204 (89), 187 (55), 173 (90), 142 (25), 101 (62), 89 (100), 77 (44), 63 (65), 44 (31), 39 (65). Found, %: C 66.92; H 4.19; N 7.36. C21H16N2O3S. Calculated, %: C 67.01; H 4.28; N 7.44. M 376.4.

2-Allylthio-6-(4-chlorophenyl)nicotinonitrile (29). Glacial AcOH 0.6 mL (10 mmol) was added to a stirred suspension of 1.0 g (10 mmol) of CH-acid 1 and 2.0 g (10 mmol) of salt 27 in 20 mL of absolute ethanol at 20°C, after which the reaction mixture was heated to boiling and filtered through a pleated filter. After cooling to 20°C, 0.85 mL (10 mmol) of allyl bromide 28 was added to the filtrate, stirred for 1 h, and left. After 2 h, the mixture was diluted with an equal volume of water and left for 24 h. The resulting precipitate was filtered off and washed successively with water, ethanol and hexane. Yield 2.2 g (78%), yellow plate-like crystals, fluoresce under UV irradiation, mp 117–119°С (EtOH). IR spectrum, ν, cm–1: 2221 (C≡N). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.99 d (2H, SCH2, J 6.8 Hz), 5.09 d (1H, =CH2, Jcis 10.0 Hz), 5.32 d (1H, =CH2, Jtrans 17.0 Hz), 5.82–6.01 m (1H, CH=), 7.53 d (2HAr, J 8.6 Hz), 7.83 d (1H4Py, J 8.2 Hz), 8.13 d (2HAr, J 8.6 Hz), 8.21 d (1H5Py, J 8.2 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm: 32.7, 105.3, 116.1, 116.2, 118.9, 129.4 (2C), 129.5 (2C), 133.6, 135.8, 136.1, 143.1, 157.4, 161.1. Mass spectrum, m/z (Irel, %): 287.4 (100) [M + 1]+. Found, %: C 62.70; H 3.84; N 9.75. C15H11ClN2S. Calculated, %: C 62.82; H 3.87; N 9.77. M 286.8.

2-Cyclohexylidene-2-[4-(p-tolyl)thiazol-2-yl]acetonitrile (31). A mixture of 1.0 g (10 mmol) of cyanothioacetamide 1, 1.0 mL (10 mmol) of freshly distilled cyclohexanone 30 and 1 drop of Et3N was boiled in 50 mL of dry benzene with a water separator (Dean–Stark nozzle) for 1 h, after which 2.1 g (10 mmol) of 4-methylphenacyl bromide 12 was added and refluxing was continued for another 1 h. After the reaction mixture cooled, the resulting crystals were filtered off and washed with benzene, ethanol and hexane. Yield 2.2 g (75%), yellow crystals, mp 105–107°С (EtOH). IR spectrum, ν, cm–1: 2212 (C≡N). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.82–1.99 m [6H, (CH2)3], 2.83 s (3H, Me), 2.73 t (2H, CH2, J 8.0 Hz), 3.05 t (2H, CH2, J 6.0 Hz), 7.19 d (2H, HAr, J 8.0 Hz), 7.78 d (2H, HAr, J 8.0 Hz), 7.90 s (1H, H5thiazole). Found, %: C 73.24; H 6.27; N 9.68. C18H12N2S. Calculated, %: C 73.43; H 6.16; N 9.51. M 294.4.

Triethylammonium 4-amino-1,5-dicyano-3-azaspiro[5.5]undeca-1,4-dien-2-thiolate (32). A mixture of 1.0 mL (10 mmol) of freshly distilled cyclohexanone 30, 2.0 g (20 mmol) of cyanothioacetamide 1 and 1.4 mL (10 mmol) of Et3N was boiled in 30 ml of dry benzene with a water separator for 2 h. After the reaction mass cooled to room temperature, the resulting precipitate was filtered off and washed benzene and hexane. Yield 2.9 g (82%), brown crystals, mp 142–144°С (benzene). IR spectrum, ν, cm–1: 3415, 3340, 3286 (NH2), 2166 (C≡N), 1642 [δ(NH2)]. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.21 t [9H, (Me)3, J 7.1 Hz), 1.26–1.73 m [10H, (CH2)5], 3.07 q [6H, (CH2Me)3, J 7.1 Hz], 5.12 br. s (2H, NH2), 7.98 br. s (1H, H1Py). The signal of the +NH proton does not appear, apparently due to rapid deuterium exchange. 13C NMR spectrum (DMSO-d6), δC, ppm: 9.2 (3С), 22.2 (2С), 25.8, 35.5, 46.3 (3С), 59.1, 85.1, 107.3, 124.6, 152.6, 155.5, 165.3, 194.6. Mass spectrum, m/z (Irel, %): 245.1 [Manion – 1]+ (100), 102.2 [Mcation + 1]+ (100). Found, %: C 62.12; H 8.33; N 20.04. C18H29N5S. Calculated, %: C 62.21; H 8.41; N 20.15. M 347.5.