Synthesis and Aminomethylation of 2-Amino-4-(2-chlorophenyl)-6-(dicyanomethyl)-1,4-dihydropyridine-3,5-dicarbonitrile N-Methylmorpholinium Salt.

Sequential reaction of 2-chlorobenzaldehyde, cyanothioacetamide, and malononitrile dimer in the presence of an excess of N-methylmorpholine resulted in the formation of N-methylmorphlinium salt of 2-amino-4-(2-chlorophenyl)-6-(dicyanomethyl)-1,4-dihydropyridine-3,5-dicarbonitrile. The resulting salt reacts under Mannich conditions with primary amines and an excess of formaldehyde to form substituted 2-alkylamino-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitriles. Structure of the key compound was confirmed by single crystal X-ray diffraction analysis. © Pleiades Publishing, Ltd. 2022.

2-Aminopropene-1,1,3-tricarbonitrile 1, easily available [1] by dimerization of malononitrile, is a reactive methylene active nitrile and is widely used in various cyclization reactions (see reviews [2, 3]). In reactions with unsaturated nitriles or their precursors, the malononitrile dimer forms partially saturated and/or polyfunctional derivatives of 2-(dicyanomethyl)- and 2-(dicyanomethylene)pyridine 2–9 [4-17] (Scheme 1).

Scheme

Despite the rich synthetic potential, there are scarce data on the preparation of such pyridine derivatives [2, 3]. The potential for the practical use of such compounds has not been fully realized. Thus, anticancer [18], molluscicidal [8], and antibacterial [19, 20] effects of a number of 2-(dicyanomethyl)pyridines have been reported. A series of 3-cyano-2-(dicyanomethylene)pyridines with pronounced fluorescent and photoluminescent properties has been described in [21-23].

Continuing our research in the field of malononitrile dimer chemistry [24-28], we obtained new functional 2-(dicyanomethyl)pyridine derivatives and studied their properties. It has been previously shown that 2-cyanothioacrylamides can react with malononitrile dimer in the presence of bases to eliminate hydrogen sulfide and form dicyanomethanides 5 (Ar = 2-IC6H4) and 7 (Scheme 2) [13, 17]. On the other hand, the three-component reaction of acetaldehyde, dimer 1, and cyanothioacetamide leads to the formation of thioamide 10 [29].

Scheme

We found that the sequential reaction of 2-chlorobenzaldehyde, cyanothioacetamide [30, 31], and malononitrile dimer 1 in EtOH in the presence of an excess of N-methylmorpholine at 25°С proceeds with the formation of 2-amino-4-(2-chlorophenyl)-6-(dicyanomethyl)-1,4-dihydropyridine-3,5-dicarbonitrile N-methylmorpholinium salt 11 in 68% yield (Scheme 3). This reaction includes the intermediate formation of 3-(2-chlorophenyl)-2-cyanoprop-2-enethioamide 12 [32], the Michael addition of the malononitrile dimer anion, and the cyclocondensation of adduct 13 with elimination of H2S to afford the target salt 11.

Scheme

Previously, we found that aminomethylation of isostructural analogs of compound 11, 1,4-dihydropyridine-2-thiolates and -selenolates 14, under the action of an excess of HCHO and primary amines leads to the formation of new tricyclic system derivatives, namely 3,5,7,11-tetraazatricyclo[7.3.1.02.7]tridec-2-ene 15 [33, 34]. Some of compounds 15 showed antiviral activity against tick-borne encephalitis virus [35]. At the same time, the Mannich reaction involving 2-(dicyanomethylene)pyridine 2 under similar conditions [4] yields only 2-(dicyanomethylene)-3,7-diazabicyclonon-3-ene derivatives 16 (Scheme 4).

Scheme

It seemed appropriate to study the behavior of dicyanomethanide 11 in the Mannich reaction. Alkoxymethylation/aminomethylation products, namely substituted 2-(R-amino)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-en-1,5-dicarbonitriles 17 and 18 were obtained in moderate yields (41–69%) upon short-term reflux of compound 11 with a twofold (or equimolar) amount of primary amine and an excess of 37% aqueous HCHO in various alcohols (MeOH, EtOH, PrOH, i-PrOH, BuOH) (Scheme 5).

Scheme

The reaction tolerates both aliphatic and aromatic amines. Presumably, in each case, the process begins with aminomethylation at the most active nucleophilic positions 3 and 5 of compound 11 to form the 3,7-diazabicyclo[3.3.1]non-2-ene system. The choice of the reaction direction in favor of the formation of products 17 or 18 is apparently determined by the presence or absence of an excess of amine in the reaction medium. Closure of the 1,3,5-triazine ring was not observed in any of the cases. In our opinion, this is due to the low nucleophilicity of the endocyclic nitrogen atom owing to the strong electron-withdrawing effect of the dicyanomethylene fragment. The nature of the amines used and the chosen solvents do not have a fundamental effect on regioselectivity of the aminomethylation process. At the same time, the reaction of the salt 11 with p-toluidine in ethanol resulted in the isolation of the well-known [36] product of its reaction with formaldehyde, 1,3,5-tri(4-methylphenyl)-1,3,5-perhydrotriazine 19. However, it should be noted that compound 19 is also an aminomethylating agent and can successfully act as this agent in the absence of any catalysts (see, for example, recent examples in the review [37]). The absence of reaction with compound 11 can be explained by the relatively low solubility of 1,3,5-perhydrotriazine 19 in aqueous alcohol and removal from the reaction medium.

Structure of compounds 17–19 was determined using mass spectroscopy, 1Н and 13С NMR spectroscopy (DEPTQ), as well as IR spectroscopy method. In addition, structure of compound 17c was studied using single-crystal X-ray diffraction analysis (Fig. 1).

Fig. 1.

General view of the molecule of compound 17c in the crystal.

3,7-Diazabicyclo[3.3.1]nonanes (bispidins) and related compounds are widely used as biologically active compounds [38, 39], complexing agents for metals [40], radionuclides [41], as initial reagents for the synthesis of natural compounds [42], materials for imaging in positron emission tomography [43], platforms for chiral catalysts [44, 45]. Recently, 3,7-diazabicyclononane derivatives have been successfully used as initial templates for constructing complex supramolecular assemblies [46-49]. Recently, submicromolar inhibitors of the main SARS-CoV-2 protease have been found among bispidins [50]. Based on the foregoing, it seemed appropriate to study the profile of the possible biological activity of new compounds by means of molecular docking. Possible protein targets for the obtained compounds were predicted using the GalaxySagittarius protein ligand docking protocol [51] based on the GalaxyWeb web server [52, 53]. The 3D structures of the studied compounds were preliminarily optimized by means of molecular mechanics in the MM2 force field to optimize the geometry and minimize the energy. Docking using the GalaxySagittarius protocol was carried out in the Binding compatability prediction and Re-ranking using docking modes. Table S1 (see Supplementary Materials) shows docking results for each of compounds 17a–17g, 18a–18c for 20 target-ligand complexes with the lowest binding free energy ΔGbind and the best estimate of the protein-ligand interaction. Predicted protein targets are identified by ID in the Protein Data Bank (PDB) and in the UniProt database. As you can see from Table S1, common receptors for compounds 17a–17g, 18a–18c are blood coagulation factor XI (PDB ID 5e2p) and ephrin receptor (ephrin type-A receptor 2, PDB ID 5ia5), which plays an important role in the pathogenesis of some cancer forms (melanoma, Kaposi’s sarcoma). Three-dimensional visualization of the docking results was implemented using the UCSF Chimera software package [54, 55] and is shown in Fig. 2. In general, compounds 17a–17g, 18a–18c can be considered as promising objects for further screening in order to find new agents for the treatment and therapy of oncological diseases and circulatory system diseases.

Fig. 2.

Predicted structure of the protein-ligand complex for compound 17f and blood coagulation factor XI (PDB ID 5e2p).

In conclusion, we proposed a method for the synthesis of new 2-amino-4-(2-chlorophenyl)-6-(dicyanomethyl)-1,4-dihydropyridine-3,5-dicarbonitrile N-methylmorpholinium salt and studied its aminomethylation. It was found that the reaction proceeds with the participation of solvent molecules and the formation of 4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-en-1,5-dicarbonitrile derivatives. The formation of 1,3,5-triazine fused derivatives was not revealed. Possible protein targets were determined for the synthesized compounds by molecular docking.

EXPERIMENTAL

NMR spectra were recorded on a Bruker DPX-400 NMR spectrometer [400.40 (1Н), 100.63 (13С), 40.55 MHz (15N)] in DMSO-d6 relative to internal TMS or residual solvent signals. IR spectra were recorded on a Bruker Vertex 70 IR Fourier spectrometer with an ATR attachment on a diamond crystal. Mass spectra were obtained on a MX1321 instrument using a direct sample injection system at an ionization chamber temperature of 200°C and an ionizing electron energy of 70 eV. Elemental analysis was carried out on a C,H,N analyzer Carlo Erba 1106, measurement error ±0.4%. Purity of the obtained compounds was monitored by TLC on Silufol UV254 plates, eluting with acetone–hexane (1 : 1) and developing with iodine vapor or UV detector. Melting points were determined on a Kofler instrument and were not corrected.

Commercially available reagents were used; cyanothioacetamide [56] and malononitrile dimer 1 [1] were obtained by known methods.

2-Amino-4-(2-chlorophenyl)-6-(dicyanomethyl)-1,4-dihydropyridine-3,5-dicarbonitrile methylmorpholinium salt (11). A mixture of 0.84 mL (7.5 mmol) of 2-chlorobenzaldehyde, 0.75 g (7.5 mmol) of cyanothioacetamide and 1 drop of N-methylmorpholine in 15–20 mL of ethanol was stirred at 20°С. After 10 min, 1.00 g (7.5 mmol) of malononitrile dimer 1 and 1.5 mL (15 mmol) of N-methylmorpholine were added to the resulting orange suspension of 3-(2-chlorophenyl)-2-cyanothioacrylamide 12. After dissolution of all starting components, the reaction mixture was stirred for 2 h at 20°С and kept for 12 h. The resulting precipitate was filtered off, washed with cold EtOH and dried for 3 h at 60°С. Yield 68%, gray-beige finely crystalline powder, mp 185–187°С. IR spectrum, ν, cm–1: 2217 br, 2193 br (C≡N), 3325 br (N–H, N+–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.78 s (3Н, Ме), 3.17–3.20 m (4Н, СН2NCH2), 3.73–3.76 m (4Н, СН2ОCH2), 4.56 s (1Н, С4Н), 6.03 br. s (2Н, NH2), 7.19–7.22 m, 7.30–7.35 m (each 2Н, Ar), 7.85 s (1H, NH), 8.13 s (1H, N+H, integral intensity of signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 38.4* (С4), 42.6* (Ме), 52.7 (СН2NCH2), 55.1 (С3), 63.4 [C(C≡N)2], 63.5 (СН2OCH2), 65.5 (C5), 114.2 (C3C≡N), 120.8 (C≡N), 121.2 (C≡N), 121.6 (C≡N), 127.8* (CH-Ar), 128.2* (CH-Ar), 129.1* (CH-Ar), 130.0* (CH-Ar), 131.1 (C1-Ar), 144.0, 147.5 (CCl, C2), 151.2 (C6). Here and below, signals in antiphase are marked with an asterisk. Found, %: С 59.61; H 4.67; N 23.03. C21H20ClN7O. Calculated, %: С 59.79; H 4.78; N 23.24. M 421.9.

General procedure for the preparation of compounds 17–19. A mixture of 0.84 g (2 mmol) of salt 11, 4 mmol (for 17 or 19) or 2 mmol (for 18) of the corresponding primary amine, 3.5 mL of 37% aqueous HCHO in 20 mL of alcohol (MeOH, EtOH, PrOH, i-PrOH or BuOH) was brought to a reflux and completely homogenized. The hot solution was filtered through a paper filter and kept for 24–72 h. The resulting precipitate was separated, washed with ethanol and dried for 3 h at 60°С.

7-Methyl-2-({[methyl(ethoxymethyl)amino]methyl}amino)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17a). Yield 57%, yellow fine crystalline powder, mp 191–193°С. IR spectrum, ν, cm–1: 2173 m (C≡N), 2205 m (C≡N), 2248 m (C≡N), 3320 br (NH). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.05 t (3Н, СН3CH2O, 3JHH 6.9 Hz), 2.30–2.36 m (6Н, 2МеN), 2.71–2.96 m (2Н, С6Н, С8Н), 3.15–3.26 m (2Н, С6Н, С8Н), 3.43 q (2Н, СН3CH2O, 3JHH 6.9 Hz), 4.31–4.33 m (2Н, NCH2N), 4.51–4.72 m (3Н, NCH2О, С9Н), 7.08–7.15 m (1Н, Ar), 7.36–7.49 m (2H, Ar), 7.58–7.65 m (1H, Ar), 9.95 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 18.6* (СН3CH2O), 40.4, 41.6 (C1, C5), 43.7* (MeN), 46.7* (MeN), 47.9* (C9), 56.0, 59.9 (C6, C8), 60.8 (СН3CH2O), 60.9 [C(C≡N)2], 65.9 (NCH2N), 78.1 (NCH2О), 113.9 (C≡N), 114.6 (C≡N), 115.1 (C≡N), 115.2 (C≡N), 127.8* (CH-Ar), 128.8* (CH-Ar), 130.9* (CH-Ar), 131.1 (C1-Ar), 131.3* (CH-Ar), 135.5 (CCl), 161.9 (C2), 168.5 (C4). Mass spectrum, m/z (Irel, %): 432 (4) [M – EtO]+, 431 (13) [M – EtO – 1]+, 376 (7) [M – EtOCH2N(Me)CH2 + 1]+, 307 (10) [M – EtOCH2N(Me)CH2NH – CH2N(Me)CH2 + 4]+. Found, %: С 60.35; H 2.65; N 23.32. C24H25ClN8O. Calculated, %: C 60.44; H 5.28; N 23.49. M 477.0.

7-Methyl-2-({[methyl(propoxymethyl)amino]methyl}amino)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17b). Yield 48%, bright yellow fine crystalline powder, mp 203–205°С. IR spectrum, ν, cm–1: 2167 m (C≡N), 2195 m (C≡N), 2225 m (C≡N), 3323 br (NH). 1H NMR spectrum (DMSO-d6), δ, ppm: 0.82 t (3Н, СН3СН2СН2O, 3JHH 7.5 Hz), 1.39–1.42 m (2Н, СН3СН2СН2O), 2.30–2.35 m (6Н, МеN), 2.63–2.95 m (2Н, С6Н, С8Н), 3.15–3.33 m (4Н, С6Н, С8Н, СН3СН2СН2O), 4.31–4.36 m (2Н, NCH2N), 4.49–4.77 m (3Н, NCH2О, С9Н), 7.07–7.14 m (1Н, Ar), 7.38–7.50 m (2H, Ar), 7.58–7.67 m (1H, Ar), 9.95 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). Due to the low solubility of the compound in DMSO-d6 an informative 13С DEPTQ NMR spectrum could not be obtained. Found, %: С 60.94; H 5.41; N 22.58. C25H27ClN8O. Calculated, %: C 61.16; H 5.54; N 22.82. M 491.0.

7-(2-Furylmethyl)-2-({[2-furylmethyl(ethoxymethyl)amino]methyl}amino)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17c). Yield 68%, orange crystalline powder, mp 161–163°С. IR spectrum, ν, cm–1: 2185 m (C≡N), 2197 m (C≡N), 2220 m (C≡N), 2250 m (C≡N), 3330 br (NH). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.05 t (3Н, СН3CH2O, 3JHH 7.1 Hz), 3.25–3.42 m (4Н, С6Н2, С8Н2), 3.44 q (2Н, СН3CH2O, 3JHH 7.1 Hz), 3.61–3.93 m (4Н, NCH2-furyl), 4.14–4.34 m (2Н, NCH2N), 4.49–5.03 m (3Н, NCH2О, С9Н), 6.25–6.44 m (4H, furyl), 7.04–7.65 m (6Н, Ar, furyl), 9.95 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 18.6* (MeCH2O), 40.7, 45.8 (C1, C5), 46.9* (C9), 51.1 (CH2-furyl), 56.0, 58.2 (C6, C8), 60.9 [C(C≡N)2], 62.4 (МеСН2О), 66.1 (NCH2N), 83.2 (NCH2О), 109.5*, 110.5* (C3, C4-furyl), 113.4 (C≡N), 114.4 (C≡N), 115.0 (C≡N), 115.1 (C≡N), 128.2*, 128.7*, 130.7* (CH-Ar), 130.9 (C1-Ar), 131.3* (CH-Ar), 135.4 (C-Cl), 142.6*, 143.2* (C5-furyl), 149.8 (C2-furyl), 161.8 (C2), 168.5 (C4). Mass spectrum, m/z (Irel, %): 564 (14) [M – EtO]+, 563 (28) [M – EtO – 1]+, 454 (8) [M – EtOCH2NCH2-furyl – 1]+, 442 (9) [M – EtOCH2N(CH2-furyl)CH2 + 1]+. Found, %: С 62.82; H 4.58; N 18.16. C32H29ClN8O3. Calculated, %: C 63.10; H 4.80; N 18.40. M 609.1.

2-({[Methoxymethyl(2-furylmethyl)amino]methyl}amino)-7-(2-furylmethyl)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17d). Yield 59%, orange fine crystalline powder, mp 158–160°С. IR spectrum, ν, cm–1: 2167 m (C≡N), 2200 m (C≡N), 2245 m (C≡N), 3310 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.27–3.44 m (7Н, С6Н2, С8Н2, МеО), 3.62–3.92 m (4Н, NCH2-furyl), 4.13–4.34 m (2Н, NCH2N), 4.39–5.10 m (3Н, NCH2О, С9Н), 6.19–6.45 m (4H, furyl), 7.06–7.64 m (6Н, Ar, furyl), 9.95 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 40.8, 41.7 (C1, C5), 46.9* (МеО), 47.1* (C9), 51.1 (CH2-furyl), 57.8, 58.2 (C6, C8), 60.9 [C(C≡N)2], 66.3 (NCH2N), 81.6 (NCH2О), 109.5*, 110.5* (C3, C4-furyl), 113.8 (C≡N), 114.6 (C≡N), 115.0 (C≡N), 115.1 (C≡N), 127.9* (CH-Ar), 128.8* (CH-Ar), 130.7* (CH-Ar), 131.0 (C1-Ar), 131.3* (CH-Ar), 135.4 (CCl), 143.1*, 143.3* (C5-furyl), 149.8 (C2-furyl), 161.8 (C2), 168.5 (C4). Found, %: С 62.38; H 4.45; N 18.58. C31H27ClN8O3. Calculated, %: C 62.57; H 4.57; N 18.83. M 595.1.

2-({[Butoxymethyl(2-furylmethyl)amino]methyl}amino)-7-(2-furylmethyl)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17e). Yield 63%, yellow fine crystalline powder, mp 145–147°С. IR spectrum, ν, cm–1: 2165 m (C≡N), 2193 m (C≡N), 2225 m (C≡N), 3375 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 0.85 t (3Н, СН3СН2СН2СН2О, 3JHH 7.2 Hz), 1.25–1.29 m (2Н, СН3СН2СН2СН2О), 1.35–1.38 m (2Н, СН3СН2СН2СН2О), 3.24–3.42 m (6Н, С6Н2, С8Н2, СН3СН2СН2СН2О), 3.74–3.91 m (4Н, NCH2-furyl), 4.35 br. s, 4.49 br. s (2Н, NCH2N), 4.58 s (1Н, С9Н), 4.67–4.90 m (2Н, NCH2О), 6.23–6.45 m (4H, furyl), 7.05–7.64 m (6Н, Ar, furyl), 9.95 br. s (1H, NH, integral intensity of signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 13.9* (СН3СН2СН2СН2О), 18.7 (СН3СН2СН2СН2О), 34.7 (СН3СН2СН2СН2О), 40.9, 41.9 (C1, C5), 46.9* (СН3СН2СН2СН2О), 47.1* (C9), 51.1 (CH2-furyl), 58.2, 60.4 (C6, C8), 61.1 (C(C≡N)2), 68.4 (NCH2N), 81.6 (NCH2О), 109.4*, 110.4* (C3, C4-furyl), 113.8 (C≡N), 114.6 (C≡N), 115.0 (C≡N), 115.1 (C≡N), 127.9* (CH-Ar), 128.8* (CH-Ar), 130.7* (CH-Ar), 130.9 (C1-Ar), 131.3* (CH-Ar), 135.4 (C-Cl), 143.2* (C5-furyl), 149.8 (C2-furyl), 161.8 (C2), 168.5 (C4). Found, %: С 63.94; H 5.08; N 17.34. C34H33ClN8O3. Calculated, %: C 64.09; H 5.22; N 17.59. M 637.1.

7-Phenyl-2-({[phenyl(ethoxymethyl)amino]methyl}amino)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17f). Yield 74%, brown fine crystalline powder, mp 155–157°С. IR spectrum, ν, cm–1: 2175 m (C≡N), 2195 m (C≡N), 2247 m (C≡N), 3390 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.06 t (3Н, СН3CH2O, 3JHH 6.9 Hz), 3.43 q (2Н, СН3CH2O, 3JHH 6.9 Hz), 4.02–4.11 m (2Н, С6Н, С8Н), 4.24–4.36 m (2Н, С6Н, С8Н), 4.55–4.93 m (5Н, NCH2N, С9Н, NCH2О), 6.77–7.67 m (14Н, 3Ar), 10.19 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). Due to the low solubility of the compound in DMSO-d6 an informative 13С DEPTQ NMR spectrum could not be registered. Mass spectrum, m/z (Irel, %): 557 (6) [M – EtO + 1]+, 556 (6) [M – EtO]+, 555 (7) [M – EtO – 1]+, 495 (20) [M – Ph – Et]+, 452 (12) [M – EtOCH2NPh]+, 451 (13) [M – EtOCH2NPh – 1]+, 450 (25) [M – EtOCH2NPh – 2]+. Found, %: С 67.71; H 4.69; N 18.45. C34H29ClN8O3. Calculated, %: C 67.94; H 4.86; N 18.64. M 601.1.

7-Isopropyl-2-({[isopropyl(ethoxymethyl)amino]methyl}amino)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (17g). Yield 69%, yellow fine crystalline powder, mp 189–192°С. IR spectrum, ν, cm–1: 2177 m (C≡N), 2200 m (C≡N), 2197 m (C≡N), 2250 m (C≡N), 3330 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 0.94–0.95 m (12Н, Ме-i-Pr), 1.05 t (3Н, СН3CH2O, 3JHH 6.9 Hz), 1.10 m, 1.16 m (2Н, NCH, i-Pr), 2.73–3.07 m (2Н, С6Н, С8Н), 3.16–3.32 m (2Н, С6Н, С8Н), 3.43 q (2Н, СН3CH2O, 3JHH 6.9 Hz), 4.29–4.34 m (2Н, NCH2N), 4.51 br. s (1Н, С9Н), 4.71 m, 4.80 m (2Н, NCH2О), 7.08–7.14 m (1Н, Ar), 7.39–7.47 m (2H, Ar), 7.58–7.64 m (1H, Ar), 9.78 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). Due to the low solubility of the compound in DMSO-d6 an informative 13С DEPTQ NMR spectrum could not be registered. Mass spectrum, m/z (Irel, %): 488 (12) [M – EtO]+, 487 (28) [M – EtO – 1]+, 404 (14) [M – EtOCH2N(i-Pr)CH2 + 1]+. Found, %: С 63.00; H 6.14; N 20.89. C28H33ClN8O. Calculated, %: C 63.09; H 6.24; N 21.02. M 533.1.

7-Methyl-9-(2-chlorophenyl)-4-(dicyanomethylene)-2-(ethoxymethylamino)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (18a). Yield 44%, orange fine crystalline powder, mp 193–195°С. IR spectrum, ν, cm–1: 2160 m (C≡N), 2193 m (C≡N), 2215 m (C≡N), 3337 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.11 t (3Н, СН3CH2O, 3JHH 7.0 Hz), 2.34 br. s (3Н, МеN), 3.18–3.38 m (4Н, С6Н2, С8Н2), 3.51 q (2Н, СН3CH2O, 3JHH 7.0 Hz), 4.54 s (1Н, С9Н), 4.85 d, 5.08 d (2Н, NCH2О, 3JHH 9.9 Hz), 7.05 d. d (1Н, Ar, 3JHH 7.6, 4JHH 1.8 Hz), 7.42­–7.50 m (2H, Ar), 7.66 d. d (1Н, Ar, 3JHH 7.7, 4JHH 1.6 Hz), 10.32 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 14.9* (СН3CH2O), 40.6, 42.2 (C1, C5), 43.3* (MeN), 46.8* (C9), 59.8, 60.8 [C6, C8, signal overlay with C(C≡N)2], 64.3 (СН3CH2O), 71.8 (NCH2О), 113.3 (C≡N), 114.1 (C≡N), 114.9 (C≡N), 115.0 (C≡N), 127.8* (CH-Ar), 128.7* (CH-Ar), 130.8* (CH-Ar), 130.9 (C1-Ar), 131.5* (CH-Ar), 135.5 (CCl), 159.6 (C2), 167.3 (C4). Found, %: С 60.85; H 4.57; N 22.58. C22H20ClN7O. Calculated, %: C 60.90; H 4.65; N 22.60. M 433.9.

2-(Isopropoxymethylamino)-7-methyl-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (18b). Yield 49%, yellow fine crystalline powder, mp 172–174 °С. IR spectrum, ν, cm–1: 2195 m (C≡N), 2220 m (C≡N), 3330 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.03 d (6Н, Ме2СН, 3JHH 6.1 Hz), 2.48 s (3Н, МеN), 2.66–2.92 m (2Н, С6Н, С8Н), 3.08–3.28 m (2Н, С6Н, С8Н), 3.76–3.78 m (1Н, СН i-Pr), 4.31 br. s (1Н, С9Н), 4.47–4.76 m (2Н, NCH2О), 7.06–7.17 m (1Н, Ar), 7.37–7.47 m (2H, Ar), 7.58–7.65 m (1Н, Ar), 9.03 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 25.5 (2Ме, i-Pr), 40.6, 40.8 (C1, C5), 43.3 (MeN), 47.9 (C9), 60.0*, 60.8* (C6, C8), 60.9* [C(C≡N)2], 62.0 (СН, i-Pr), 85.9 (NCH2О), 113.5* (C≡N), 114.9* (C≡N), 116.3* (C≡N), 117.7* (C≡N), 127.9 (CH-Ar), 128.7 (CH-Ar), 130.8 (CH-Ar), 131.3 (CH-Ar), 131.7* (C1-Ar), 135.4* (CCl), 159.6* (C2), 167.4* (C4). Found, %: С 61.54; H 4.94; N 21.81. C23H22ClN7O. Calculated, %: C 61.67; H 4.95; N 21.89. M 447.9.

7-Isopropyl-2-(isopropoxymethylamino)-9-(2-chlorophenyl)-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitrile (18c). Yield 41%, orange fine crystalline powder, mp 241–243°С. IR spectrum, ν, cm–1: 2170 m (C≡N), 2195 m (C≡N), 3303 br (N–H). 1H NMR spectrum (DMSO-d6), δ, ppm: 0.95 m (6Н, Ме2СНN), 1.03 d (6Н, Ме2СНO, 3JHH = 6.1 Hz), 2.61-2.92 m (2Н, С6Н, С8Н), 3.08-3.27 m (2Н, С6Н, С8Н), 3.34-3.36 m (1Н, Ме2СНN), 3.75-3.78 m (1Н, Ме2СНO), 4.33 br. s (1Н, С9Н), 4.51–4.54 m, 4.76–4.80 m (2Н, NCH2О), 7.07–7.18 m (1Н, Ar), 7.38–7.48 m (2H, Ar), 7.57–7.64 m (1Н, Ar), 9.88 br. s (1H, NH, integral intensity of the signal is underestimated, probably due to deuterium exchange). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 17.4*, 18.4* (Ме2СНN), 25.5* (Ме2СНО), 41.1, 41.9 (C1, C5), 47.7* (C9), 53.3* (Ме2СНN), 55.3, 55.7 (C6, C8), 62.0* (Ме2СНО), 63.3 [C(C≡N)2], 81.9 (NCH2О), 113.9 (C≡N), 114.6 (C≡N), 115.3 (C≡N), 116.5 (C≡N), 128.0* (CH-Ar), 128.8* (CH-Ar), 130.8* (CH-Ar), 131.2* (CH-Ar), 131.3 (C1-Ar), 135.4 (CCl), 162.2 (C2), 169.2 (C4). Found, %: С 63.00; H 5.21; N 20.49. C25H26ClN7O. Calculated, %: C 63.08; H 5.51; N 20.60. M 476.0.

1,3,5-Tri(4-methylphenyl)-1,3,5-triazinane (19). Yield 34%, colorless crystals, mp 125–127°С (mp 125°С [43]).1H NMR spectrum (DMSO-d6), δ, ppm: 2.17 br. s (9Н, 3Ме), 4.74 br. s (6Н, 3СН2), 6.94 d (6Н, 3Ar, 3JHH 8.7 Hz), 6.99 d (6Н, 3Ar, 3JHH 8.7 Hz). 13С NMR spectrum DEPTQ (DMSO-d6), δС, ppm: 20.1 (Me), 67.7* (CH2), 117.0 (CH-Ar), 128.6* (C4-Ar), 129.4 (CH-Ar), 146.0* (C1-Ar). Found, %: С 80.57; H 7.59; N 11.59. C24H27N3. Calculated, %: C 80.63; H 7.61; N 11.75. M 357.5.

Single crystal X-ray diffraction analysis. Experimental material for a crystal of compound 17c (C32H29ClN8O3) was obtained on a Bruker APEX-II CCD diffractometer at 296.15 K. The structure was solved by a direct method using the Olex2 [57] and ShelXD [58] software package and refined using the SHELXL package [59]. The structure was refined by full-matrix least squares in the anisotropic approximation for non-hydrogen atoms by F. The main characteristics and unit cell parameters of 17c: crystal size 0.32 × 0.3 × 0.29 mm, triclinic crystal system, space group P-1, M 609.08; unit cell parameters: а 11.6884(7), b 12.1570(7), с 12.2224(7) Å, α 99.2520(10)°, β 113.6070(10)°, γ 93.6220(10)°, V 1555.00(16) Å3, Z 2, dcalc 1.301 g/cm3; μ(CuKα) 0.170 mm–1, F(000) 636.0, θ 3.42°–56.64°; reflection index intervals: –15 ≤ h ≤ 15, –16 ≤ k ≤ 16, –16 ≤ l ≤ 16; 18091 reflections were measured, 7738 were independent [Rint 0.0166], 7738 reflections show I > 2σ(I). Number of refined parameters was 355. Final divergence factors were R1 0.0838 and wR2 0.2590, R1 0.1018 and wR2 0.2840 for all reflections, GOOF by F was 1.072; Δρmax and Δρmin 0.95 and –0.87 e/Å3. Crystal data for compound 17c were deposited in the Cambridge Crystallographic Data Center (CCDC 2081885).

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