3. Experimental
3.1. General
Melting points were determined on an Electrothermal melting point apparatus (Electrothermal 9100) and are uncorrected. IR spectra were recorded for KBr discs on a Pye Unicam SP-1000 spectrophotometer. 1H-NMR & 13C-NMR spectra were measured on a Varian EM-390-200 MHz in CD3SOCD3 as solvent using TMS as internal standard, and chemical shifts are expressed as δ. Analytical data were obtained from the Microanalytical Data Unit at Cairo University, Giza, Egypt. Antitumor evaluation for the newly synthesized products were performed by a research group at the National Research Center & the National Cancer Institute at Cairo University.
4-Methyl-ω-bromoacetophenone cyanoacetylhydrazone (3). To a solution of cyanoacetylhydrazine (1, 2.44 g, 0.02 mol) in 1,4-dioxane (20 mL), ω-bromo-(4-methylacetophenone) (5.24 g, 0.02 mol) was added. The reaction mixture was stirred at room temperature for 1 hr then poured onto a beaker containing an ice/water mixture. The solid product formed was collected by filtration and dried obtaining pale yellow crystals (from ethanol).Yield: 5.02 g (71%), m.p. 148 °C; IR (KBr) υ/cm−1: 3400–3378 (NH), 3105 (CH aromatic), 2956 (CH3), 2259 (CN), 1681 (C=O), 1610 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 4.31, 4.72 (2s, 4H, CH2), 6.50–7.76 (m, 4H, C6H4), 11.46 (s, 1H, NH). MS: (m/z) 293 (M.+) (6%), 200 (28%), 117 (100%), 68 (69.9%); 13C-NMR: 22.6 (CH3), 27.0, 58.7 (2CH2), 118.5 (CN), 126.8, 128.4, 129.5, 138.8 (C6H5), 156.3 (C=N), 173.8 (C=O); Anal. Calcd. for C12H12N3OBr (294.24): C, 48.00; H, 4.11; N, 14.29%. Found: C, 49.27; H, 4.45; N, 14.35%.
3.2. General Procedure for the Synthesis of 4a or 4b
To a solution of 3 (0.54 g, 1.83 × 10−3 mol) in ethanol (25 mL) in a water bath at 60 °C, either potassium cyanide (0.11 g, 1.83 × 10−3 mol) or potassium thiocyanate (0.17 g, 1.83 × 10−3 mol) was added with continuous stirring. The reaction mixture was left in the water bath for 30 min at 60 °C then poured onto a beaker containing ice/water mixture and few drops of hydrochloric acid. The formed solid product was collected by filtration and dried.
4-Methyl-ω-cyanoacetophenonecyanoacetylhydrazone (4a). Pale brown crystals (from ethanol).Yield: 0.20 g (62%), m.p. 160 °C; IR (KBr) υ/cm−1: 3450–3205 (NH), 3031 (CH aromatic), 2260, 2209 (2CN), 1680 (C=O); 1H NMR δ: 2.39 (s, 3H, CH3), 4.46, 5.06 (2s, 4H, 2CH2), 7.18–7.84 (m, 4H, C6H4), 10.82 (s, 1H, NH); 13C NMR: 23.8 (CH3), 27.3, 29.5 (2CH2), 116.9, 117.0 (2CN), 127.3, 128.0, 129.8, 138.9 (C6H4), 155.8 (C=N), 173.8 (C=O); Anal. Calcd. for C13H12N4O (240.26): C, 64.99; H, 5.03; N, 23.32%. Found: C, 64.79; H, 5.11; N, 22.99%.
4-Methyl-ω-thiocyanoacetophenoecyanoacetylhydrazone (4b). Buff crystals (from ethanol). Yield: 0.33 g (67%), m.p. 130 °C; IR (KBr) υ/cm−1: 3445–3225 (NH), 3099 (CH aromatic), 3034 (CH3), 2969, 2925 (2CH2), 2264, 2225 (2CN), 1666 (C=O), 1606 (C=C); 1H-NMR δ: 2.49 (s, 3H, CH3), 4.50, 5.08 (2s, 4H, 2CH2), 7.06–7.93 (m, 4H, C6H4), 11.52 (s, 1H, NH); 13C-NMR: 23.8 (CH3), 27.3, 29.4 (2CH2), 116.7, 117.8 (2CN), 127.0, 128.3, 129.6, 138.6 (C6H4), 155.5 C=N), 173.9 (C=O); Anal. Calcd for C13H12N4OS (272.32): C, 57.33; H, 4.44; N, 20.57; S, 11.77%. Found: C, 57.38; H, 4.64; N, 20.68; S, 11.57%.
3.3. General Procedure for the Synthesis of 6a and 6b
To a solution of compound 3 (1.50 g, 5.09 × 10−3 mol) in ethanol (35 mL) either hydrazine hydrate (0.25 g, 5.09 × 10−3 mol) or phenylhydrazine (0.55 g, 5.09 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The formed solid product was collected by filtration and dried.
4-Methyl-ω-hydrazinoacetophenonecyanoacetylhydrazone (6a). Greenish brown crystals (from ethanol). Yield: 0.65 g (52%), m.p. 120 °C; IR (KBr) υ/cm−1: 3400–3204 (NH2, 2NH), 3027 (CH aromatic), 2918 (CH3), 2203 (CN), 1688 (C=O), 1607 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.39, 4.23 (2s, 4H, 2CH2), 4.82 (s, 2H, NH2), 6.87–8.40 (m, 4H, C6H4), 9.26, 11.41 (2s, 2H, 2NH); 13C-NMR: 23.6 (CH3), 27.0, 29.6 (2CH2), 127.8, 128.3, 129.5, 138.6 (C6H4), 155.6, 164.2 (2C=N), 173.8 (C=O); Anal. Calcd. for C12H15N5O (245.28): C, 58.76; H, 6.16; N, 28.55%. Found: C, 58.55; H, 5.96; N, 28.32%.
4-Methyl-ω-phenylhydrazinoacetophenonecyanoacetylhydrazone (6b). Brown crystals (from ethanol). Yield: 0.95 g (63%), m.p. 72 °C; IR (KBr) υ/cm−1: 3500–3174 (3NH), 3026 (CH aromatic), 2969 (CH3), 2205 (CN), 1687 (C=O), 1600 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.39, 4.35 (2s, 4H, 2CH2), 6.79–8.40 (m, 9H, C6H5, C6H4), 10.82, 11.19, 12.63 (3s, 3H, 3NH); 13C-NMR: 23.6 (CH3), 27.0, 29.9 (2CH2), 120.3, 122.5, 127.3, 128.4, 129.3, 138.5, 140.1 (C6H4, C6H5), 155.6, 164.2 (2C=N), 173.8 (C=O); Anal. Calcd. for C18H19N5O (321.38): C, 67.27; H, 5.96; N, 21.79%. Found: C, 67.37; H, 5.84; N, 22.61%.
α-Benzal-4-methyl-ω-hydrazinoacetophenonecyanoacetylhydrazone (8a): To a solution of compound 6a (0.29 g, 1.18 × 10−3 mol) in ethanol (25 mL) containing piperidine (0.5 mL), benzaldehyde (0.11 g, 1.48 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3hrs then poured onto a beaker containing an ice/water mixture and few drops of hydrochloric acid. The formed solid product was collected by filtration and dried obtaining deep yellowish brown crystals (from ethanol).Yield: 0.26 g (66%), m.p. 90 °C; IR (KBr) υ/cm−1: 3500–3194 (NH2, 2NH), 3027 (CH aromatic), 2919 (CH3), 2218 (CN), 1680 (C=O), 1608 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.36 (s, 2H, CH2), 4.77 (s, 2H, NH2), 5.99 (s, 1H, =CH), 7.27–8.40 (m, 9H, C6H5, C6H4), 8.81, 9.15 (2s, 2H, 2NH); 13C-NMR: 23.2 (CH3), 27.4, 29.2 (2CH2), 122.3, 122.8, 122.5, 126.0 128.3, 129.9, 138.3 (C6H5, C6H4) 155.0, 164.3 (2C=N), 174.3 (C=O); Anal. Calcd. for C19H19N5O (333.39): C, 68.45; H, 5.74; N, 21.01%. Found: C, 68.55; H, 5.54; N, 21.31%.
α-Benzal-4-methyl-ω-phenylhydrazinoacetophenonecyanoacetyl-hydrazone (8b). To a solution of compound 6b (0.36 g, 1.12 × 10−3 mol) in ethanol (25 mL) containing piperidine (0.5 mL), benzaldehyde (0.11 g, 1.12 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The formed solid product was collected by filtration and dried obtaining yellowish brown crystals (from ethanol). Yield: 0.33 g (73%), m.p. 102 °C; IR (KBr) υ/cm−1: 3300-3179 (3NH), 3026 (CH aromatic), 2920 (CH3), 2210 (CN), 1688 (C=O), 1600 (C=C); 1H NMR δ: 2.88 (s, 3H, CH3), 3.37 (s, 2H, CH2), 6.90–8.40 (m, 15H, =CH, 2C6H5, C6H4), 9.20, 10.83, 12.62 (3s, 3H, 3NH); 13C-NMR: 23.2 (CH3), 27.4, 29.2 (2CH2), 120.9, 121.1, 122.3, 122.8, 123.4, 123.9, 122.5, 126.0 128.3, 129.5, 138.6 (2C6H5, C6H4) 155.3, 164.0 (2C=N), 174.6 (C=O); Anal. Calcd. for C25H23N5O (409.48): C, 73.33; H, 5.66; N, 17.10%. Found: C, 73.52; H, 5.97; N, 17.33%.
1-Amino-6-(4-methylphenyl)-3-(α-phenylhydrazoacetonitrilo)-1,2,4-triazine (10a). To a cold solution (0–5 °C) of compound 6a (0.40 g, 1.63 × 10−3 mol) in ethanol (50 mL) containing sodium hydroxide (10 mL, 10%) and a solution of benzenediazonium chloride (1.63 × 10−3 mol) [which was prepared by dissolving sodium nitrite (0.16 g, 2.44 × 10−3 mol) in water, 2 mL was added to a cold solution of aniline (0.15 g, 1.63 × 10−3 mol) containing the appropriate amount of hydrochloric acid and with continuous stirring] was added with continuous stirring. The formed solid product was collected by filtration and dried to give reddish brown crystals (from ethanol and few drops of dimethylformamide). Yield: 0.58 g (63%), m.p. 170 °C; IR (KBr) υ/cm−1: 3400–3307 (NH2, NH), 3027 (CH aromatic), 2919, 2862 (CH3, CH2), 2211 (CN), 1600 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.37 (s, 2H, CH2), 4.22 (s, 2H, NH2), 6.50–8.20 (m, 9H, C6H5, C6H4), 11.64 (s, 1H, NH); 13C-NMR: 23.8 (CH3), 51.9 (triazine CH2), 115.8 (CN), 118.3, 118.9, 119.2, 121.6, 124.8, 133.0, 139.6 (C6H5, C6H4), 156.9, 163.8 164.1 (3 C=N); Anal. Calcd. for C18H17N7 (331.38): C, 65.24; H, 5.17; N, 29.58%. Found: C, 65.42; H, 5.27; N, 29.36%.
3.4. General Procedure for the Synthesis of 10b and 10c
To a cold solution (0–5 °C) of compound 6a (0.49 g, 1.99 × 10−3 mol) in ethanol (50 mL) containing sodium hydroxide solution (10 mL, 10%) was added with continuous stirring a solution of either 3-cyano-4,5,6,7-terahydrobenzo[b]thiophene-2-diazonium chloride (9b) (1.99 × 10−3 mol) or ethyl 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate-2-diazonium chloride (9c) (1.99 × 10−3 mol) [which was prepared by dissolving sodium nitrite (0.20 g, 2.99 × 10−3 mol) in water, 2 mL was added to a cold solution of either the 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (0.35 g, 1.99 × 10−3 mol) or ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.45 g, 1.99 × 10−3 mol) dissolved in acetic acid (50 mL) containing the appropriate amount of hydrochloric acid and with continuous stirring]. The solid product formed was collected by filtration and dried.
1-Amino-6-(4-methylphenyl)-3-(α-(3-cyano-2-hydrazo-4,5,6,7-tetra-hydrobenzo[b]thiophene)aceto-nitrilo)-1,2,4-triazine (10b). Deep brown crystals (from ethanol). Yield: 0.67 g (75%), m.p. 210–214 °C; IR (KBr) υ/cm−1: 3600–3425 (NH2, NH), 3030 (CH aromatic), 2930 (CH3), 2250, 2217 (2CN), 1606 (C=C); 1H-NMR δ: 1.63–2.34 (m, 8H, cyclohexene 4CH2), 2.51 (s, 3H, CH3), 3.60 (s, 2H, CH2), 4.78 (s, 2H, NH2), 6.97–8.32 (m, 4H, C6H4), 9.84 (s, 1H, NH); 13C-NMR: 19.4, 23.0, 25.1, 27.8 (cyclohexene 4CH2), 24.8 (CH3), 51.9 (triazine CH2), 115.8, 116.4 (2CN), 118.3, 118.9, 119.2, 121.6, 124.6, 133.2, 136.5, 136.9 139.6 (thiophene C, C6H5, C6H4), 156.0, 163.5 164.3 (3 C=N); Anal. Calcd. for C21H20N8S (416.50): C, 60.56; H, 4.84; N, 26.90; S, 7.70%. Found: C, 60.28; H, 5.03; N, 26.61; S, 7.88%.
Ethyl 1-amino-6-(4-methylphenyl)-3-(α(2-hydrazo-4,5,6,7-tetra-hydrobenzo[b]thiophene-3-carboxyl-ate)acetonitrilo)-1,2,4-triazine (10c). Brown crystals (from ethanol) Yield: 0.53 g (57%), m.p. 90 °C; IR (KBr) υ/cm−1: 3400–3287 (NH2, NH), 2976, 2934, 2860 (2CH3, CH2), 2213 (CN), 1711 (C=O); 1H- NMR δ: 1.07–1.92 (m, 8H, cyclohexene 4CH2), 2.51 (s, 3H, CH3), 2.77 (t, 3H, J = 7.04 Hz, CH3), 3.36 (s, 2H, CH2), 4.24 (q, 2H, J = 7.04 Hz, CH2), 4.99 (s, 2H, NH2), 6.50–8.08 (m, 4H, C6H4), 9.88(s, 1H, NH); 13C-NMR: 14.5, 24.6 (2 CH3), 23.2, 23.6, 25.1, 27.6 (cyclohexene 4CH2), 55.4 (triazine CH2), 60.8 (ester CH2), 128.7, 129.0, 129.7, 132.1, 136.5, 138.9, 140.8 (C6H5, thiophene C), 115.9, 116.7 (2CN), 155.2, 158.0, 163.1 (3 C=N), 165.6 (CO); Anal. Calcd. for C23H25N7O2S (463.56): C, 59.59; H, 5.44; N, 21.15; S, 6.93%. Found: C, 59.83; H, 5.46; N, 20.91; S, 7.05%.
1-Phenylamino-6-(4-methylphenyl)-3-(α-phenylhydrazoacetonitrilo)-1,2,4-triazine (10d). To a cold solution (0–5 °C) of compound 6b (0.53 g, 1.64 × 10−3 mol) in ethanol (50 mL) containing sodium hydroxide (10 mL, 10%) was added with continuous stirring a solution of benzenediazonium chloride (1.64 × 10−3 mol) [which was prepared by dissolving sodium nitrite (0.17 g, 2.47 × 10−3 mol) in water, 2 mL was added to a cold solution of aniline (0.15 g, 1.64 × 10−3 mol) containing the appropriate amount of hydrochloric acid and with continuous stirring]. The formed solid product was collected by filtration to give reddish brown crystals (from ethanol and few drops of dimethylformamide). Yield: 0.58 g (86%), m.p. 120 °C; IR (KBr) υ/cm−1: 3500–3422 (2NH), 3057 (CH aromatic), 3028, 2921(CH3, CH2), 2211 (CN), 1600 (C=C); 1H-NMR δ: 2.50 (s, 3H, CH3), 3.31 (s, 2H, CH2), 6.60–7.65 (m, 14H, 2C6H5, C6H4), 8.16, 9.05 (s, 2H, 2NH); 13C-NMR: 23.6 (CH3), 51.9 (triazine CH2), 115.6 (CN), 118.6, 118.7, 119.2, 120.1, 121.6, 124.8, 133.6, 134.8, 139.9 (2C6H5, C6H4), 156.6, 163.7, 164.0 (3 C=N); Anal. Calcd. for C24H21N7 (407.47): C, 70.74; H, 5.19; N, 24.06%. Found: C, 71.05; H, 5.38; N, 23.87%.
3.5. General Procedure for the Synthesis of 10e and 10f
To a cold solution (0–5 °C) of compound 6b (0.40 g, 1.24 × 10−3 mol) in ethanol (50 mL) containing sodium hydroxide solution (10 mL, 10%) was added with continuous stirring a solution of either 3-cyano-4,5,6,7-terahydrobenzo[b]thiophene-2-diazonium chloride (9b) (1.24 × 10−3 mol) or ethyl 4,5,6,7-tetrahydrobenzo[b]thiophen-3-carboxylate-2-diazonium chloride (9c) (1.24 × 10−3 mol) [which was prepared by dissolving sodium nitrite (0.12 g, 1.86 × 10−3 mol) in water, 2 mL was added to a cold solution of either the 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (0.22 g, 1.99 × 10−3 mol) or ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.28 g, 1.99 × 10−3 mol) dissolved in acetic acid (50 mL) containing the appropriate amount of hydrochloric acid and with continuous stirring]. The solid product formed was collected by filtration and dried.
1-Phenylamino-6-(4-methylphenyl)-3-(α-(3-cyano-2-hydrazo-4,5,6,7-tetrahydrobenzo[b]thiophene)-acetonitrilo)-1,2,4-triazine (10e). Reddish brown crystals (from ethanol), yield: 0.34 g (55%), m.p. 190 °C; IR (KBr) υ/cm−1: 3500–3425 (2NH), 3030 (CH aromatic), 2930 (CH3), 2250, 2217 (2CN), 1606 (C=C); 1H-NMR δ: 1.63–2.34 (m, 8H, cyclohexene), 2.51 (s, 3H, CH3), 3.60 (s, 2H, CH2), 6.97–8.32 (m, 9H, C6H5, C6H4), 9.84, 10.00 (s, 2H, 2NH); 13C-NMR: 19.1, 23.3, 25.4, 27.4 (cyclohexene 4CH2), 24.9 (CH3), 51.7 (triazine CH2), 115.6, 116.3 (2CN), 118.3, 118.9, 119.2, 121.6, 124.6, 133.2, 136.5, 136.9 139.4 (thiophene C, C6H5, C6H4), 156.1, 163. 3, 164.6 (3 C=N). Anal. Calcd. for C27H24N8S (492.60): C, 65.83; H, 4.91; N, 22.75; S, 6.51%. Found: C, 65.96; H, 5.24; N, 22.55; S, 6.79%.
Ethyl 1-phenylamino-6-(4-methylphenyl)-3-(α(2-hydrazo-4,5,6,7-tetrahydrobenzo-[b]thiophen-3-carboxylate)acetonitrilo)-1,2,4-triazine (10f). Pale reddish brown crystals (from ethanol). Yield: 0.40 g (59%), m.p. 150–160 °C; IR (KBr) υ/cm−1: 3400–3287 (2NH), 2976, 2934, 2860 (2CH3, CH2), 2213 (CN), 1711 (C=O); 1H-NMR δ: 1.07–1.92 (m, 8H, cyclohexene), 2.51 (s, 3H, CH3), 2.77 (t, 3H, J = 6.89 Hz, CH3), 3.36 (s, 2H, CH2), 4.24 (q, 2H, J = 6.89 Hz, CH2), 6.50–8.08 (m, 9H, C6H5, C6H4), 9.88, 10.30 (2s, 2H, 2NH); 13C-NMR: 14.3, 24.8 (2 CH3), 23.0, 23.3, 25.1, 27.8 (cyclohexene 4CH2), 55.54 (triazine CH2), 60.8 (ester CH2), 128.7, 129.2, 129.7, 132.0, 136.5, 138.9, 140.8 (C6H5, thiophene C), 115.8, 116.5 (2CN), 155.2, 158.0, 163.3 (3 C=N), 165.6 (CO); Anal. Calcd. for C29H29N7O2S (539.65): C, 64.54; H, 5.42; N, 18.17; S, 5.94%. Found: C, 64.68; H, 5.23; N, 17.97; S, 6.20%.
3.6. General Procedure for the Synthesis of 12a and 12b
To a solution of compound 6a (0.47 g, 1.91 × 10−3 mol) in ethanol (20 mL) containing triethylamine (0.5 mL), either malononitrile (0.12 g, 1.91 × 10−3 mol) or ethyl cyanoacetate (0.21 g, 1.91 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The solid product formed was collected by filtration and dried.
3-Cyano-4,6-diamino-2-oxo-1-imino-(4-methyl-ω-hydrazinoaceto-phenonylidieno)pyridine (12a). Brown crystals (from ethanol). Yield: 0.38 g (64%), m.p. 158 °C; IR (KBr) υ/cm−1: 3500–3227 (3NH2, NH), 3028 (CH aromatic), 2974 (CH3), 2919 (CH2), 2201 (CN), 1685 (C=O), 1600 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.38 (s, 2H, CH2), 4.38, 4.79, 5.30 (3s, 6H, 3NH2), 7.05–8.19 (m, 5H, pyridine H-3, C6H4), 10.82 (s, 1H, NH); 13C-NMR: 23.8 (CH3), 51.7 (CH2), 80.9, 89.5, 114.8, 125.6 (pyridine C), 117.9 (CN), 126.2, 128.0, 129.3, 129.6 (C6H5), 163.5 (C=O), 170.9 (C=N); Anal. Calcd. for C15H17N7O (311.34): C, 57.87; H, 5.50; N, 31.49%. Found: C, 57.96; H, 5.48; N, 31.68%.
4-Amino-3-cyano-6-hydroxy-2-oxo-1-imino(4-methyl-ω-hydrazino-acetophenonylidieno)pyridine (12b). Pale brown crystals (from ethanol).Yield: 0.66 g (111%), m.p. 140 °C; IR (KBr) υ/cm−1: 3600–3227 (OH, 2NH2, NH), 3028 (CH aromatic), 2974 (CH3), 2919 (CH2), 2201 (CN), 1685 (C=O), 1600 (C=C); 1H-NMR δ: 2.50 (s, 3H, CH3), 3.39 (s, 2H, CH2), 4.34, 4.77, (2s, 4H, 2NH2), 7.05–8.19 (m, 5H, pyridine H-3, C6H4), 10.84 (s, 1H, NH), 12.64 (s, 1H, OH); 13C-NMR: 23.6 (CH3), 51.4 (CH2), 82.9, 89.5, 116.8, 125.9 (pyridine C), 117.9 (CN), 126.4, 128.0, 129.3, 129.6 (C6H5), 170.9, 176.5 (2C=N), 164.3 (2C=O); Anal. Calcd. for C15H16N6O2 (312.33): C, 57.68; H, 5.16; N, 26.90%. Found: C, 57.42; H, 5.09; N, 26.76%.
3.7. General Procedure for the Synthesis of 12c and 12d
To a solution of compound 6b (0.60 g, 1.86 × 10−3 mol) in ethanol (20 mL) containing triethylamine (0.5 mL), either malononitrile (0.12 g, 1.86 × 10−3 mol) or ethyl cyanoacetate (0.21 g, 1.86 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The solid product formed was collected by filtration and dried.
3-Cyano-4,6-diamino-2-oxo-1-imino-(4-methyl-ω-phenylhydrazino-acetophenonylidieno)pyridine (12c) Green crystals (from ethanol). Yield: 0.51 g (70%), m.p. 80 °C; IR (KBr) υ/cm−1: 3480–3227 (2NH2, 2NH), 3028 (CH aromatic), 2974 (CH3), 2919 (CH2), 2201 (CN), 1685 (C=O), 1600 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.38 (s, 2H, CH2), 4.38, 4.79, (2s, 4H, 2NH2), 6.48–8.19 (m, 10H, pyridine H-3, C6H5, C6H4), 10.82, 11.20 (2s, 2H, 2NH); 13C-NMR: 23.7 (CH3), 51.9 (CH2), 80.7, 89.3, 114.9, 125.3 (pyridine C), 118.3 (CN), 126.4, 128.0, 129.3, 129.6 (C6H5), 170.9 (C=N), 162.5 (C=O); Anal. Calcd. for C21H21N7O (387.44): C, 65.10; H, 5.46; N, 25.30%. Found: C, 64.21; H, 5.36; N, 25.38%.
4-Amino-3-cyano-6-hydroxy-2-oxo-1-imino(4-methyl-ω-phenyl-hydrazinoacetophenonylidieno) pyridine (12d). Yellowish green crystals (from ethanol). Yield: 0.58 g (80%). Mp 84–100 °C; IR (KBr) υ/cm−1: 3600–3185 (OH, NH2, 2NH), 3027 (CH aromatic), 2975 (CH3), 2919 (CH2), 2206 (CN), 1684 (C=O), 1600 (C=C); 1H-NMR δ: 2.50 (s, 3H, CH3), 3.39 (s, 2H, CH2), 4.34 (s, 2H, NH2), 6.21 (s, 1H, pyridine H-3), 7.33–8.70 (m, 9H, C6H5, C6H4), 10.84, 11.22 (2s, 2H, 2NH), 12.64 (s, 1H, OH); 13C-NMR: 23.6 (CH3), 51.6 (CH2), 80.2, 89.5, 114.5, 125.0 (pyridine C), 118.1 (CN), 126.2, 128.2, 129.5, 129.6 (C6H5), 164.8 (C=O), 170.9 (C=N); Anal. Calcd. for C21H20N6O2 (388.43): C, 64.93; H, 5.19; N, 21.63%. Found: C, 65.42; H, 5.69; N, 21.13%.
3.8. General Procedure for the Synthesis of 14a and 14b
To a solution of compound 6a (0.52 g, 2.12 × 10−3 mol) in ethanol (20 mL) containing piperidine (0.5 mL), either acetylacetone (0.21 g, 2.21 × 10−3 mol) or ethyl acetoacetate (0.27 g, 2.21 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The solid product formed was collected by filtration and dried.
3-Cyano-4,6-diamethyl-2-oxo-1-imino-(4-methyl-ω-hydrazinoaceto-phenonylidieno)pyridine (14a) Brown crystals (from ethanol). Yield: 0.37 g (56%), m.p. 144 °C; IR (KBr) υ/cm−1: 3433–3229 (NH2, NH,), 3027 (CH aromatic), 2221 (CN), 1685 (C=O), 1600 (C=C); 1H-NMR δ: 2.34, 2.54, 3.04 (3s, 9H, 3CH3), 3.39 (s, 2H, CH2), 6.21 (s, 1H, pyridine H-3), 6.72–7.45 (m, 4H, C6H4), 10.84, 11.63 (s, 2H, 2NH); 13C-NMR: 16.0, 19.2, 24.3 (3CH3), 51.2 (CH2), 80.0, 88.3, 115.3, 123.9 (pyridine C), 116.8 (CN), 126.0, 127.9, 128.3, 129.1 (C6H5), 164.9 (C=O), 173.6 (C=N); Anal. Calcd. for C17H19N5O (309.37): C, 66.00; H, 6.19; N, 22.63%; found: C, 66.29; H, 6.23; N, 23.53%.
3-Cyano-6-hydroxy-4-methyl-2-oxo-1-imino(4-methyl-ω-hydrazino-acetophenonylidieno)pyridine (14b). Brown crystals (from ethanol). Yield: 0.38 g (57%), m.p. 136 °C; IR (KBr) υ/cm−1: 3549–3321 (OH, NH2, NH), 3027 (CH aromatic), 2213 (CN), 1680 (C=O), 1600 (C=C); 1H-NMR δ: 2.53, 3.13 (3s, 9H, 3CH3), 3.39 (s, 2H, CH2), 6.22 (s, 1H, pyridine H-3), 6.73–7.39 (m, 4H, C6H4), 10.85, 11.33 (s, 2H, 2NH), 12.21 (s, 1H, OH); 13C-NMR: 16.1, 19.0, 24.3 (3CH3), 51.3 (CH2), 80.2, 88.3, 115.3, 152.1 (pyridine C), 116.6 (CN), 126.3, 127.6, 128.3, 129.1 (C6H5), 165.3 (C=O), 173.8 (C=N); Anal. Calcd. for C16H17N5O2 (311.34): C, 61.44; H, 5.50; N, 22.49%; found: C, 61.23; H, 5.67; N, 22.30%.
3.9. General Procedure for the Synthesis of 14c and 14d
To a solution of compound 6b (0.60 g, 1.86 × 10−3 mol) in ethanol (20 mL) containing piperidine (0.5 mL), either acetylacetone (0.18 g, 1.86 × 10−3 mol) or ethyl acetoacetate (0.24 g, 1.86 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The solid product formed was collected by filtration and dried.
3-Cyano-4,6-diamethyl-2-oxo-1-imino-(4-methyl-ω-phenylhydrazino-acetophenonylidieno)pyridine (14c) Yellowish brown crystals (from ethanol). Yield: 0.61 g (85%), m.p. 100 °C; IR (KBr) υ/cm−1: 3450–3229 (2NH), 3027 (CH aromatic), 2213 (CN), 1680 (C=O), 1600 (C=C); 1H-NMR δ: 2.34, 2.51, 3.01 (3s, 9H, 3CH3), 3.37 (s, 2H, CH2), 6.21 (s, 1H, pyridine H-3), 6.50–8.41 (m, 9H, C6H5, C6H4), 10.82, 12.63 (s, 2H, 2NH); 13C-NMR: 16.3, 19.1, 24.3 (3CH3), 51.5 (CH2), 80.3, 88.6, 115.0, 127.7, 155.8 (pyridine C), 116.5 (CN), 118.7, 119.0, 120.8, 122.5, 126.0, 127.8, 128.7, 129.8 (C6H5, C6H4), , 166.2 (C=O), 173.6 (C=N); Anal. Calcd. for C23H23N5O (385.47): C, 71.66; H, 6.01; N, 18.16%; found: C, 71.86; H, 5.98; N, 17.99%.
3-Cyano-6-hydroxy-4-methyl-2-oxo-1-imino(4-methyl-ω-phenyl-hydrazinoacetophenonylidieno)-pyridine (14d). Yellowish brown crystals (from ethanol). Yield: 0.48 g (66%). m.p. 96 °C; IR (KBr) υ/cm−1: 3600–3220 (OH, 2NH), 3027 (CH aromatic), 2211 (CN), 1682 (C=O), 1600 (C=C); 1H-NMR δ: 2.51, 3.00 (2s, 6H, 2CH3), 3.40 (s, 2H, CH2), 6.54 (s, 1H, pyridine H-3), 7.34–8.40 (m, 9H, C6H5, C6H4), 9.62, 10.82 (2s, 2H, 2NH), 12.65 (s, 1H, OH); 13C-NMR: 16.3, 19.4, 24.6 (3CH3), 51.5 (CH2), 80.8, 88.4, 116.5, 155.4 (pyridine C), 116.5 (CN), 118.8, 119.0, 120.3, 121.7, 126.0, 127.8, 128.9, 129.0 (C6H5, C6H4), , 166.4 (C=O), 173.9 (C=N); Anal. Calcd. for C22H21N5O2 (387.44): C, 68.20; H, 5.46; N, 18.07%; Found: C, 68.49; H, 5.84; N, 17.79%.
2-Acetonitrilo-5-(4-methylphenyl)-1,3,4-oxadiazine (15). A solution of compound 3 (1.00 g, 3.39 × 10−3 mol) in sodium ethoxide (50 mL) was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture and a few drops of hydrochloric acid. The formed solid product was collected by filtration and dried to give pale brown crystals (from ethanol). Yield 0.39 g (54%), m.p. 190–193 °C; IR (KBr) υ/cm−1: 3028 (CH aromatic), 2998 (CH3), 2922, 2854 (2CH2), 2210 (CN), 1673 (C=N), 1609 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 3.35, 4.42 (2s, 4H, 2CH2), 7.00–8.40 (m, 4H, C6H4); 13C-NMR: 24.4 (CH3), 20.3 (CH2), 64.3 (oxadiazine CH2), 116.9 (CN), 126.0, 127.8, 128.9, 129.0, 133.1 (C6H5), 170.5 (C=N); Anal. Calcd. for C12H11N3O (213.24): C, 67.59; H, 5.19; N, 19.70%; found: C, 67.70; H, 5.38; N, 19.88%.
2-(α-Benzalacetonitrilo)-5-(4-methylphenyl)-1,3,4-oxadiazine hydrochloride (16). To a solution of compound 3 (2.00 g, 6.79 × 10−3 mol) in ethanol (30 mL) containing piperidine (0.5 mL), benzaldehyde (0.72 g, 6.79 × 10−3 mol) was added. The reaction mixture was heated under reflux for 3 hrs then poured onto a beaker containing an ice/water mixture with a few drops of hydrochloric acid. The formed solid product was collected by filtration and dried to afford brown crystals (from ethanol). Yield: 1.35 g (58%), m.p. 100 °C; IR (KBr) υ/cm−1: 3050 (CH aromatic), 3029 (CH3), 2921 (CH2), 2830 (CH), 2216 (CN), 1604 (C=C); 1H-NMR δ: 2.51 (s, 3H, CH3), 4.22 (s, 2H, CH2), 5.16 (s, 1H, =CH), 7.35–8.02 (m, 9H, C6H5, C6H4); 13C-NMR: 24.6 (CH3), 63.8 (oxadiazine CH2), 116.7 (CN), 118.2 (CH=C), 120.4, 121.9, 124.5, 126.2, 127.4, 127.9, 129.2, 133.9 (C6H4, C6H5), 144.2 (CH=C), 171.5, 173.9 (2C=N); Anal. Calcd. for C19H15N3O (301.34): C, 75.73; H, 5.02; N, 13.94%; found: C, 75.52; H, 4.91; N, 14.31%.
2-(α-Phenylhydrazoacetonitrilo)-5-(4-methylphenyl)1,3,4-oxadiazine (17). To a cold solution (0–5 °C) of compound 15 (1.00 g, 3.39 × 10−3 mol), in ethanol (50 mL) was added with continuous stirring benzenediazonium chloride (3.39 × 10−3 mol) [which was prepared by dissolving sodium nitrite (0.35 g, 5.09 × 10−3 mol) in water, 2 mL was added to a cold solution of aniline (0.31 g, 3.39 × 10−3 mol) containing the appropriate amount of hydrochloric acid and with continuous stirring]. The solid product formed after adjusting the pH 6 and stirring was collected by filtration and dried to give reddish brown crystals (from ethanol and dimethylformamide). Yield: 0.96 g (89%), m.p. 130 °C; IR (KBr) υ/cm−1: 3300–3215 (NH), 3057 (CH aromatic), 3030 (CH3), 2920 (CH2), 2219 (CN), 1679 (C=N), 1603 (C=C); 1H-NMR δ: 2.52 (s, 3H, CH3), 3.38 (s, 2H, CH2), 7.21–8.82 (m, 9H, C6H5, C6H4), 10.22 (s, 1H, NH). ). 13C-NMR: 24.3 (CH3), 63.0 (oxadiazine CH2), 116.5 (CN), 121.5, 121.9, 124.0, 123.5, 126.7, 127.0, 127.6, 129.2, 133.0 (C6H4, C6H5), 166.9, 170.5, 173.9 (3C=N). Anal. Calcd. for C18H15N5O (317.35): C, 68.12; H, 4.76; N, 22.06%; found: C, 67.92; H, 4.91; N, 21.25%.