Functionally substituted pyridines are known for their biological activity, and specifically for neurotropic [1], antimicrobial [2], antibacterial [3], anti-HIV [4], and anticancer [5] properties. Pyrimidines condensed with pyridine and thiophene are suitable as antidermatophytic agents [6], antimicrobials grugs [7], and mGluR1 receptor ligands for positron emission tomography [8]. All this point to the high pharmaceutical potential of such heterocycles, and requires further development of methods for their synthesis and use as medical intermediates.

In continuation of research on the chemistry of nitrogen-containing heterocycles [9-15] involving multicomponent reactions [16, 17] based on cyanothioacetamide as the initial reagent [18, 19], we have studied new versions of production of pyridine and pyrimidine derivatives initiated by the Knoevenagel reaction [20]. It was found that multicomponent condensation of acetylacetones 1a, 1b, cyanothioacetamide 2, and alkylating reagents 3a–3c leads to the formation of substituted thieno[2,3-b]pyridines 4a–4c. The reaction is carried out in ethanol with short-term boiling in the presence of Et3N. The probable reaction scheme includes the formation of the Knoevenagel alkene A at the first stage, which is intramolecularly cyclized into 2-thioxopyridine B. Then, in an alkaline medium, its regioselective alkylation occurs to thioesters C, which intramolecularly close the thiophene cycle to form final 4a–4c structures (Scheme 1).

Scheme
scheme 1

1.

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The introduction of the fourth component, allyl bromide 5, into this condensation led to the N-alkylation of the amide fragment of the hypothetical thienopyridine of type 4. In this way, N-allyl-3-amino-4,5,6-trimethyl-N-(thiazole-2-yl)thieno[2,3-b]pyridine-2-carboxamide 6 was synthesized. The application of α-chloroacetamide 3f as the fourth component in such condensation led to the formation of acetamide 7, as a result of the Williamson reaction at the last stage of the process. Benzimidazolylacetonitrile 8 condenses with acetylacetone 1a in boiling ethanol in the presence of Et3N to form 1,3-dimethylbenzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile 9 (Scheme 1). A possible mechanism of its formation consists in the Knoevenagel condensation and subsequent intramolecular heterocyclization. We note that compound 9 was obtained earlier with a yield of 59% from reagents 1a and 8 in boiling ethanol with catalysis by HClO4 [21].

The three-component condensation of croton aldehyde 10a with CH-acid 2 and α-chloroacetamide 3f proceeds differently through intermediates D and E. It is carried out in boiling ethanol in the presence of an equimolar amount of EtONa. The Michael addition, and not the expected Knoevenagel condensation, turned out to be the first stage of the reaction. Resulting 2-[(4-methyl-3-cyanopyridine-2-yl)thio]acetamide 11 in a DMF solution at 20°C under the action of KOH is intramolecularly cyclized into 3-amino-4-methylthieno[2,3-b]pyridine-2-carboxamide 12, which cyclocondensated with cyclohexanone 13 in boiling glacial acetic acid to form 9′-methyl-1′H-spiro(cyclohexane-1,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine)-4′(3′H)-one 14, which is a promising intermediate for the creation of anticancer drugs [22] (Scheme 2).

Scheme
scheme 2

2.

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Heterocyclic system, 6,11-dihydropyrimido[5,4-b]thieno[3′,2′:2,3]pyrido[2,3-d]pyrimidine 16, was synthesized by multicomponent condensation of benzaldehyde 10b, cyanothioacetamide 2, 4-bromophenacyl bromide 15, and formamide. The Knoevenagel reaction is also initially realized in the course of this process. Resulting benzylidencyanothioacetamide F in ethanol in the presence of Et3N attaches CH-acid 2. Corresponding adduct G, that has arisen in this way, is intramolecularly cyclized into triethylammonium pyridine-2-thiolate H, alkylated by compound 15 to thioester of type 11. Subsequently, under the action of alkali, cyclization into thienopyridine I occurred, which, when boiled in formamide, formed final tetraheterocyclic system 16 (Scheme 2).

1,3-Diphenylbut-2-en-1-one 17 reacts with a twofold excess of malononitrile 18 in boiling ethanol in the presence of Et3N to form 2-(6-methyl-4,6-diphenyl-3-cyano-5,6-dihydropyridine-2(1H)-ylidene)malononitrile 19 (method a). The reaction pathway probably includes the formation of Knoevenagel alkene K, which was later joined by malonitrile 18 according to Thorpe [20] to form intermediate L. The latter is unstable under reaction conditions, which leads to the implementation of the aza-Michael intramolecular reaction and the formation of final structure 19 (Scheme 3).

Scheme
scheme 3

3.

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The same result was obtained by self-condensation of 2-(1-phenylethylidene)malonitrile 20 in ethanol at 20°C, catalyzed by Et3N (method b). The probable reaction scheme involves the formation of Michael adduct M, which eliminates malonitrile 18 and forms new alkene K. Then released malononitrile 18 attaches to alkene K to form corresponding enaminonitrile L. The aza-Michael reaction, which is then realized, stops the formation of final structure 19 (Scheme 3). The process of alkene 20 conversion into intermediate K through adduct M refers to a variant of the Michael reaction, which proceeds as the exchange by methylene components [23, 24].

The spectral characteristics confirm the structure of the synthesized compounds (see the Experimental). Compounds 4b, 4c, 11, and 19 were studied by the XRD method in order to clarify the mechanism of the above transformations and to determine unambiguously the structure of their products.

The structure of compound 4b molecule and the corresponding numbering of atoms are shown in Fig. 1. The amino and carbonyl groups in compound 4b are practically coplanar to the central bicyclic thieno[2,3-b]pyridine fragment (the standard deviation of atoms is 0.029 Å), which is defined by the presence of both a long chain of conjugated bonds and a strong intramolecular hydrogen bond N–H···O (Table 1 and Fig. 1). The phenyl cycle is turned relative to the plane of the central bicyclic fragment by 33.9(1)°. The n-butyl substituent takes a typical conformation (“all-trans”) and is located perpendicular to the phenyl cycle.

Fig. 1.
figure 1

Molecular structure of compound 4b in the representation of atoms by ellipsoids of anisotropic displacements with a 50% probability. The dashed line shows the intramolecular hydrogen bond N–H···O.

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Table 1. Hydrogen bonds in structures 4b, 4c, 11, and 19
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Crystallographic operations for generating symmetrically equivalent atoms: a –x+11/2, y–1/2, –z+1/2; b –x+1, –y+1, –z+1; c –x+11/2, y+1/2, –z+11/2; d x, y+1, z; e –x+2, –y+1, –z+1.

In the crystal, the molecules of compound 4b are located at van der Waals distances (Fig. 2). The structure of the molecule of compound 4c and the corresponding numbering of atoms are shown in Fig. 3. Unlike compound 4b, the NH2 amino group in compound 4c has a pyramidal configuration (the sum of the valence angles at the nitrogen atom is 350(7)°), and the amide group is slightly twisted with respect to the central bicyclic thieno[2,3-b]pyridine fragment (the corresponding interplane angle is 11.81(17)°). The observed structure of compound 4c molecule is probably determined by the presence in the crystal structure of a branched system of strong hydrogen bonds of intramolecular N–H···O and intermolecular N–H···N types, and also weak intermolecular bonds of N–H···O type (Table 1, Fig. 4, frame structure).

Fig. 2.
figure 2

Сrystal structure of compound 4b along the crystallographic axis a. The dashed lines show intramolecular hydrogen bonds.

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Fig. 3.
figure 3

Molecular structure of compound 4c in the representation of atoms by ellipsoids of anisotropic displacements with a 50% probability. The dashed line shows the intramolecular hydrogen bond N–H···O.

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Fig. 4.
figure 4

Crystal structure of compound 4c along the crystallographic axis c. Dashed lines show intra- and intermolecular hydrogen bonds.

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The phenyl substituent is turned by 52.86(6)° relative to the plane of the central bicyclic fragment, and the methoxy group is practically coplanar to the phenyl cycle (the torsion angle C10–C11–O11–C14 is –9.7(4)°).

The structure of the compound 11 molecule and the corresponding numbering of atoms are shown in Fig. 5. Excluding the hydrogen atoms of the methyl and methylene groups, the molecule of compound 11 consists of two almost flat fragments, (4-methyl-3-cyanopyridine-2-yl)thiol (the standard deviation of the atoms is 0.064 Å) and acetamide (the standard deviation of the atoms is 0.060 Å), having a common fragment –S–CH2– and located almost perpendicular to each other (the angle between these planes is equal to 84.16(4)°). In the crystal, the molecules of compound 11 form H-linked tapes along the crystallographic axis b (Table 1, Fig. 6). The tapes are located at van der Waals distances (Fig. 7).

Fig. 5.
figure 5

Molecular structure of compound 11 in the representation of atoms by ellipsoids of anisotropic displacements with a 50% probability.

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Fig. 6.
figure 6

H-linked bands of compound 11 molecules along the crystallographic axis b. The dashed lines show intermolecular hydrogen bonds N–H···O.

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Fig. 7.
figure 7

Crystal structure of compound 11 along the crystallographic axis b. Dashed lines show intermolecular hydrogen bonds.

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The structure of the compound 19 molecule and the corresponding numbering of atoms are shown in Fig. 8. The central tetrahydropyridine cycle in the molecule of compound 19 takes the conformation of an asymmetric bath with the deviation of nitrogen N1 and carbon C6 atoms from the middle plane drawn through the remaining atoms of the cycle by 0.421(2) and 0.908(2) Å, respectively. The phenyl substituent at the carbon atom C4 is turned relative to the basal plane of the tetrahydropyridine cycle by 44.06(7)°. It is important to note that the more voluminous phenyl substituent at the carbon atom C6 occupies a less sterically preferred axial position, which is determined, apparently, by the direction of the chemical reaction. The molecule of compound 19 contains the asymmetric carbon atom C6. The crystal of compound 19 represents a racemate.

Fig. 8.
figure 8

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

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In the crystal, molecules of compound 19 form centrosymmetric H-linked dimers by means of intermolecular hydrogen bonds N–H···N (Table 1, Fig. 9). Dimers are located at van der Waals distances (Fig. 10).

Fig. 9.
figure 9

Centrosymmetric H-linked dimers of compound 19 molecules. Dashed lines show intermolecular hydrogen bonds N–H···N.

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Fig. 10.
figure 10

Crystal structure of compound 19 along the crystallographic axis a. Dashed lines show intermolecular hydrogen bonds N–H···N.

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EXPERIMENTAL

Unit cell parameters and reflection intensities for crystals of compounds 4b, 4c, 11, and 19 were measured at the “XRD” synchrotron station of the “Kurchatov Institute” National Research Center, using a Rayonix SX-165 two-coordinate detector (φ-scanning in steps of 1.0°). The experimental data were processed using the iMOSFLM program, which is part of the CCP4 software package [25]. For the obtained data, the absorption of X-ray radiation was considered according to the Scala program [26]. The main structural data and refinement parameters are presented in Table 2. The structures are determined by direct methods and refined by the full-matrix least squares method by F2 in the anisotropic approximation for noN–Hydrogen atoms. The hydrogen atoms of amino groups were revealed objectively in difference Fourier syntheses and refined isotropically with fixed displacement parameters (Uiso(H) = 1.2Ueq(N)). The positions of the remaining hydrogen atoms in all compounds were calculated geometrically and included in the refinement with fixed positional parameters (the “rider” model) and isotropic displacement parameters (Uiso(H) = 1.5Ueq(C) for CH3 groups and 1.2Ueq(C) for the remaining groups). All calculations were carried out using the SHELXTL software package [27]. Tables of atomic coordinates, bond lengths, valence and torsion angles, and anisotropic displacement parameters for compounds 4b, 4c, 11, and 19 are deposited in the Cambridge Structural Data Bank, the deposit numbers CCDC 2269289 (4b), CCDC 2269290 (4c), CCDC 2269291 (11) and CCDC 2269292 (19).

Table 2. Crystal structure data for compounds 4b, 4c, 11, and 19
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IR spectra were obtained on an IKS-40 device in vaseline oil. The 1H and 13C NMR spectra were recorded on a Varian VXR–400 spectrophotometer (399.97 and 100 MHz, respectively) in DMSO-d6 solutions with TMS as the internal standard. Mass spectra were taken on an Agilent 1100 Series spectrometers with a selective detector: Agilent LS/MSDLS (samples of compounds 4b, 7, 11, 12, 14, 16, and 19 were injected in a CH3COOH matrix, EI ionization, 70 eV), KRATOS MS-890 (70 eV) with direct injection of compounds 4c and 6 into an ion source, and a high-resolution Orbitrap Elite mass spectrometer (4a and 9). The HRMS sample was dissolved in 1 mL of DMSO, diluted 100 times with 1% HCOOH in CH3CN, and injected into an ionization source by electrospraying with a syringe pump at a rate 40 µL/min. The gas flows of the source were switched off, the voltage on the needle was 3.5 kV, and the capillary temperature was 275°C. The mass spectra were recorded in the modes of positive and negative ions in an orbital trap with a resolution of 480000. Internal calibrants were 2DMSO + H+ ion (m/z 157.03515) for positive ions and dodecyl sulfate anion (m/z 265.14789) for negative ions. Melting points were determined on a Kofler block. The course of the reaction and the purity of the obtained compounds were controlled by TLC on Silufol UV-254 plates in the acetone-hexane system (3 : 5), with development by iodine vapor and UV irradiation.

3-Amino-4,6-dimethyl-5-R-2-Z-carbonylthieno[2,3-b]pyridines (4a–4c). General procedure. To a mixture of 10 mmol of the corresponding 1,3-diketone 1a, 1b and 1.0 g (10 mmol) of cyanothioacetamide 2 in 20 mL of absolute ethanol, three drops of Et3N were added and refluxed for 15 min. After cooling, 5.6 mL (10 mmol) of 10% KOH aqueous solution and 10 mmol of alkylating reagent 3a-3c were successively added to the stirred mixture, stirred for 2 h, the same amount of alkali was added again, stirred for 1 h, and diluted with an equal volume of water. The resulting precipitate was filtered off and washed with water, ethanol, and hexane.

3-Amino-4,6-dimethyl-N-(quinoline-8-yl)thieno[2,3-b]pyridine-2-carboxamide (4a). Yield 2.6 g (75%), colorless powder, mp 275–277°C (BuOH), fluoresces under UV irradiation. IR spectrum, ν, cm–1: 3411, 3332, 3300, 3288 (NН, NH2), 1686 (CONH), 1645 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 2.49 s (3H, Me), 2.74 s (3H, Me), 7.07 br. s (3H, NH2+Harom), 7.59–7.70 m (3Нarom.), 8.42 d (1Нarom., J 8.0 Hz), 8.67 d (1Нarom., J 7.4 Hz), 8.96 s (1H5Py), 9.98 br. s (1H, NH). 13С NMR spectrum, δC, ppm: 19.9, 23.9, 96.7, 99.5, 105.0, 109.8, 121.8, 122.3, 124.1 (2С), 125.2, 127.4 (2С), 128.5, 133.2, 136.7, 137.5, 146.4, 164.9. HRMS (ESI), m/z: found 349.1126 [M + H]+. C19H16N4OS. Calculated 349.1045.

(3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-yl)(4-butylphenyl)methanon (4b). Yield 2.4 g (76%), colorless crystals, mp 113–114°С (MeOH). IR spectrum, ν, cm–1: 3316, 3284, 3202 (NH2), 1699 (C=O), 1645 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 0.91 t (3H, Me, J 6.4 Hz), 1.12–1.81 m (4H, 2CH2), 2.52 s (3H, Me), 2.76 s (3H, Me), 7.09 s (1H5Py), 7.34 d (2Нarom., J 8.3 Hz), 7.69 d (2Нarom., J 8.3 Hz), 8.00 br. s (2H, NH2). Mass spectrum, m/z (Irel, %): 339.1 (100) [M + 1]+. C20H22N2OS. М 338.5.

3-Amino-N-(4-methoxyphenyl)-4,5,6-trimethylthieno[2,3-b]pyridine-2-carboxamide (4c). Yield 2.7 g (80%), colorless powder, mp 271–273°С (BuOH). IR spectrum, ν, cm–1: 3330, 3300, 3244 (NH2), 1670 (CONH), 1638 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 2.29 s (3H, Me), 2.56 s (3H, Me), 2.70 s (3H, Me), 3.75 s (3H, Me), 6.79 br. s (2H, NH2), 6.85 d (2Нarom, J 7.9 Hz), 7.57 d (2Нarom., J 7.9 Hz), 9.10 br. s (2H, NH). Mass spectrum , m/z (Irel, %): 343 (2) [M + 2]+, 342 (6) [M + 1]+, 341 (39) [M]+, 219 (52) [M – MeOC6H4NH]+, 191 (10), 123 (100) [MeOC6H4NH2]+, 108 (17), 44 (7) [C=S]+, 41 (4). C18H19N3O2S. М 341.4.

N-Allyl-3-amino-4,5,6-trimethyl-N-(thiazole-2-yl)thieno[2,3-b]pyridine-2-carboxamide (6) was obtained similarly to compounds 4, starting from 1.16 mL (10 mmol) of 1,3-diketone 1b, 1.0 g (10 mmol) of CH-acid 2, and 1.44 g (10 mmol) of α-chloro-N-(thiazol-2-yl) acetamide 3d. The resulting precipitate was dissolved in 15 mL of DMF, and 5.6 mL (10 mmol) of a 10% aqueous solution of KOH and 0.85 mL (10 mmol) of allyl bromide 5 were successively added, stirred for 1 h, and left. After 24 h, the mixture was diluted with an equal volume of water, the resulting precipitate was filtered off, and washed with water, ethanol, and hexane. Yield 2.8 g (79%), yellow powder, mp 213–215°С (BuOH), fluoresces under UV irradiation. IR spectrum, ν, cm–1: 3402, 3311, 3205 (NH2), 1666 (CONH), 1642 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 2.20 s (3H, Me), 2.49 s (3H, Me), 2.64 s (3H, Me), 4.80 d (2Н, NСН2, J 4.0 Hz), 5.21 d (1Н, СН2=, 2Jtrans 17.0 Hz), 5.25 d (1Н, СН2=, 2Jcis 10.3 Hz), 5.92–6.08 m (1H, =CH), 6.88 br. s (2H, NH2), 6.99 d (1H5thiazole, J 3.8 Hz), 7.48 d (1H4thiazole, J 3.8 Hz). 13С NMR spectrum, δC, ppm: 14.4, 15.6, 24.0, 50.3, 105.9, 108.9, 118.6, 124.0, 125.9, 127.3, 132.0, 142.3, 147.1, 157.2, 157.3, 164.8, 172.0. HRMS (ESI), m/z: found 359.0998 [M + H]+. C17H18N4OS2. Calculated 359.0922.

2-[2-(3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxy)phenoxy]acetamide (7) was obtained similarly to compounds 4, starting from 1.0 mL (10 mmol) of acetylacetone 1a, 1.0 g (10 mmol) of CH-acid 2, and 2.15 g (10 mmol) of o-hydroxyphenacyl bromide 3e. The resulting precipitate was dissolved in 15 mL of DMF and 5.6 mL (10 mmol) of a 10% aqueous solution of KOH, and 0.94 g (10 mmol) of α-chloroacetamide 3f were successively added, stirred for 1 h, and left. After 24 h, the mixture was diluted with an equal volume of water, the resulting precipitate was filtered off, and washed with water, ethanol, and hexane. Yield 2.9 g (81%), bright yellow powder, mp 205–207°С (BuOH). IR spectrum, ν, cm–1: 3410, 3335, 3300, 3245 (NH2), 1676 (CONH), 1644 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 2.47 s (3H, Me), 2.72 s (3H, Me), 4.50 s (2Н, СН2), 7.05 t (1Harom, J 8.1 Hz), 7.11 d (1Harom, J 8.4 Hz), 7.13 br. s (2H, NH2), 7.36 d (1Harom, J 7.5 Hz), 7.42 t (1Harom, J 6.2 Hz), 7.46 s (1H5arom.), 7.94 br. s (2Н, СONН2). 13С NMR spectrum, δC, ppm: 20.5, 24.4, 67.7, 105.2, 114.0, 121.6, 122.1, 122.4, 128.4, 131.0, 131.9, 146.6, 152.5, 154.7, 161.3, 162.2, 170.4, 188.9. HRMS (ESI), m/z: found 356.1066 [M + H]+. C18H17N3O3S. Calculated 356.0991.

1,3-Dimethylbenzene[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (9). To a solution of 1.0 mL (10 mmol) of acetylacetone 1a in 25 mL of ethanol, 1.6 g (10 mmol) of benzimidazolylacetonitrile 8 and 1.4 mL (10 mmol) of triethylamine was added and refluxed for 2 h. After cooling the reaction mixture to room temperature, the resulting precipitate was filtered off and washed with ethanol and hexane. Yield 1.64 g (74%), light yellow cotton wool-like product, mp 235–237°С (AcOH), fluoresces under UV irradiation. IR spectrum, ν, cm–1: 2214 (C≡N). 1Н NMR spectrum, δ, ppm: 2.58 s (3H, Me), 3.04 s (3H, Me), 6.83 s (1H2Py), 7.37 t (1Harom, J 7.2 Hz), 7.56 t (1Harom, J 7.5 Hz), 7.87 d (1Harom, J 8.0 Hz), 8.22 d (1Harom, J 8.2 Hz). 13С NMR spectrum, δC, ppm: 20.6, 21.1, 113.4, 115.5, 115.9, 119.5, 121.7, 126.1 (2С), 130.1, 144.6, 145.0, 147.2, 149.7. Mass spectrum, m/z (Irel, %): 222.2 (100) [M + 1]+. Found, %: С 75.92; H .13; N 8.95. C14H11N3. Calculated, %: C 76.00; H 5.01; N 18.99. М 221.3.

2-[(4-Methyl-3-cyanopyridine-2-yl)thio]acetamide (11). To a stirred solution of 0.83 mL (10 mmol) of crotonal 10a in 10 mL of absolute ethanol, 1.0 g (10 mmol) of CH acid 2 and a solution prepared from 0.23 g of Na and 15 mL of absolute ethanol was added. After stirring for 10 min, the mixture was refluxed for 2 h and left. After 2 h, 0.94 g (10 mmol) of α-chloroacetamide 3f was added to the stirred mixture, stirred for 3 h, and diluted with an equal volume of water. The resulting precipitate was filtered off and washed successively with water, ethanol, and hexane. Yield 1.4 g (67%), yellow crystals, mp 208–210°С (AcOH), sublimates into needle-shaped crystals at 175°С. IR spectrum, ν, cm–1: 3398, 3325, 2990 (NH2), 1666 (CONH), 2218 (C≡N). 1Н NMR spectrum, δ, ppm: 2.42 s (3H, Me), 3.89 s (2Н, СН2), 6.99 br. s (1Н, NH2), 7.13 d (1H5Py, J 5.1 Hz), 7.37 br. s (1Н, NH2), 8.45 d (1H6Py, J 5.1 Hz). Mass spectrum, m/z (Irel, %): 208.1 (100) [M + 1]+. Found, %: C 52.02; H 4.32; N 20.20. C9H9N3OS. Calculated, %: C 52.16; H 4.38; N 20.28. М 207.3.

3-Amino-4-methylthieno[2,3-b]pyridine-2-carboxamide (12). To a stirred solution of 2.1 g (10 mmol) of compound 11 in 15 mL of DMF, 5.6 mL (10 mmol) of a 10% aqueous solution of KOH was added at 20°C, stirred for 2 h, and diluted with an equal volume of water. The resulting precipitate was filtered off and washed successively with water, ethanol, and hexane. Yield 1.74 g (84%), light yellow crystals, mp 225–227°С (BuOH), sublimates into needle-shaped crystals at 200°С. IR spectrum, ν, cm–1: 3402, 3385, 3330, 2296 (NH2), 1672 (CONH), 1641 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 2.80 s (3H, Me), 6.69 br. s (2Н, NН2), 6.85 br. s (2Н, NH2), 6.99 d (1H5Py, J 4.3 Hz), 8.33 d (1H6Py, J 4.3 Hz). Mass spectrum , m/z (Irel, %): 209 (5) [M + 2]+, 208 (13) [M + 1]+, 207 (100) [M]+, 190 [M – NH3]+, 162 (33), 135 (42), 118 (40), 91 (17), 65 (18), 45 (19), 39 (15). C9H9N3OS. М 207.3.

9′-Methyl-1′H-spiro(cyclohexane-1,2′-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidine)-4′(3′H)-one (14). A mixture of 2.07 g (10 mmol) of compound 12 and 1.03 mL (10 mmol) of cyclohexanone 13 was refluxed for 2 h in 20 mL of glacial acetic acid. After the reaction mixture cooled, the resulting crystals were filtered off and washed with diethyl ether. Yield 2.3 g (79%), colorless fine-crystalline powder, mp 235–237°С (AcOH), fluoresces under UV irradiation. IR spectrum, ν, cm–1: 3335 (NH), 1668 (CONH). 1Н NMR spectrum, δ, ppm: 1.02–2.14 m (1Hcyclohexane), 1.43–1.59 m (7Hcyclohexane), 1.83–2.15 m (2Hcyclohexane), 2.78 s (3H, Me), 5.94 br. s (Н1, NH), 7.19 d (H8, J 4.5 Hz), 7.93 br. s (1H, CONH), 8.43 d (H7, J 4.5 Hz). Mass spectrum, m/z (Irel, %): 288.1 (100) [M + 1]+. Found, %: С 62.51; H 5.88; N 14.50. C15H17N3OS. Calculated, %: C 62.69; H 5.96; N 14.62. М 287.1.

10-Amino-4-(4-bromophenyl)-11-phenyl-6,11-dihydropyrimido[5,4-b]thieno[3′,2′:2,3]pyrido[2,3-d]pyrimidine (16). To a stirred solution of 1.0 mL (10 mmol) of benzaldehyde 10b in 20 mL of ethanol at 20°C, 1.0 g (10 mmol) of CH acid 2 and 1 drop of Et3N, stirred for 15 min until the crystallization of benzylidenecyanothioacetamide F began, was added. Then the same amount of cyanothioacetamide 2 and 1.4 mL (10 mmol) of Et3N was added again, stirred for 1 h, and left. After 24 h, 2.8 g (10 mmol) of p-bromophenacyl bromide 15 was added, stirred for 4 h, 10 mL of DMF and 5.6 mL (10 mmol) of a 10% aqueous solution of KOH were added, stirred for 1 h, and diluted with an equal volume of water. The resulting precipitate was filtered off and refluxed in 20 mL of formamide for 2 h. After the reaction mixture cooled, the resulting precipitate was filtered off and washed with diethyl ether. Yield 4.2 g (86%), yellow powder, mp 338–340°С (dioxane), fluoresces under UV irradiation. IR spectrum, ν, cm–1: 3404, 3381, 3300 (NH2), 1644 (δ(NH2)). 1Н NMR spectrum, δ, ppm: 5.70 s (H11), 6.66 br. s (2H, NH2), 7.10 t (1Harom, J 5.8 Hz), 7.20 t (2Harom, J 6.0 Hz), 7.45 d (2Harom, J 6.0 Hz), 7.82 d (2Harom, J 6.6 Hz), 7.95 d (2Harom, J 6.6 Hz), 9.02 s (1Harom), 11.02 br. s (1H, NH6). 13С NMR spectrum, δ, ppm: 36.3, 66.8, 95.2, 111.4, 122.1, 124.8, 127.0, 128.2 (2С), 128.6 (2С), 130.3 (2С), 132.6 (2С), 136.6, 144.7, 149.5, 155.3, 155.5, 156.9, 160.0, 162.2. Mass spectrum, m/z (Irel, %): 486 (100) [M – 1]+. C23H15BrN6S. М 487.4.

2-(6-Methyl-4,6-diphenyl-3-cyano-5,6-dihydropyridine-2(1H)-ylidenmalononitrile (19). Method a. A mixture of 2.2 g (10 mmol) of compound 17, 1.32 g (20 mmol) of malononitrile 18, and 3 drops of Et3N in 20 mL of ethanol was refluxed for 1 h. After cooling the reaction mixture, the resulting precipitate was filtered off and washed with ethanol and hexane. Yield 2.7 g (79%).

Method b. A solution of 1.7 g (10 mmol) of substituted crotononitrile 20 and 3 drops of Et3N in 20 mL of ethanol at 20°C was stirred for 2 h and left. After 24 h, the resulting precipitate was filtered off and washed with ethanol and hexane. Yield 2.8 g (84%), yellow crystals, mp 110–112°С (EtOH). IR spectrum, ν, cm–1: 3538, 3474 (NH), 2219 sh. (C≡N). 1Н NMR spectrum, δ, ppm: 1.73 s (3H, Me), 3.32 d (1H5Py, 2J 8.5 Hz), 3.77 d (1H5Py, 2J 18.5 Hz), 7.11–7.32 m (10Harom), 9.75 br. s (1H, NH). 13С NMR spectrum, δ, ppm: 28.5, 44.2, 49.6, 57.1, 101.2, 113.8, 115.0, 115.6, 125.0 (2C), 127.6, 127.8 (2С), 128.3, 128.8, 129.0, 132.2, 135.6, 142.9, 157.9, 169.0, 186.5. Mass spectrum, m/z (Irel, %): 335 (100) [M – 1]+. C22H16N4. М 336.4.

CONCLUSION

Multicomponent condensation of carbonyl compounds, CH-acids, and alkylating reagents is initiated by the Knoevenagel reaction under mild conditions, and results in pyridines, tetrahydropyridines, thienopyridines, pyridothienopyrimidines, and pyrimidothienopyridopyrimidines.