3.6. General Procedure for Preparation of Compounds 8–25
To a solution of 7a–d (1.0 equiv.) and amine (2.0 equiv.) in dioxane was added glacial acetic acid (0.2 equiv.), then the mixture was stirred and heated at 110 °C in a sealed tube for 10–20 h. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel, using petroleum ether/ethyl acetate to afford target products 8–25.
5-(3-Fluorophenyl)-3-isopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (8). Red solid. Yield 83 mg (37%). Mp: 198–199 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.11 (6 H, brs), 3.42–3.50 (1 H, m), 4.04 (3 H, s), 5.29 (1 H, s), 6.47 (1 H, d, J = 8.1 Hz), 6.93 (2 H, brs), 7.10–7.20 (4 H, m), 7.37 (1 H, t, J = 8.1 Hz), 7.69–7.76 (2 H, m), 7.81–7.86 (2 H, m). 13C-NMR (100 MHz, CDCl3) δ: 23.5, 49.4, 53.7, 89.3, 100.1, 113.8, 116.5 (d, J = 22.3 Hz), 116.8, 117.0 (d, J = 20.6 Hz), 122.9, 124.8, 124.9, 127.6, 128.2, 131.4, 132.6, 132.7, 134.6, 135.5, 138.8, 138.9, 142.9, 150.6, 151.3, 155.5, 165.2 (d, J = 249.3 Hz). HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H25FN5O: 454.2038; found: 454.2043.
5-(3-Fluorophenyl)-3-(4-tetrahydropyranyl)imino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydro-phenazine (9). Red solid. Yield 100 mg (41%). Mp: 190–191 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.67 (4 H, brs), 3.41–3.50 (3 H, m), 4.01–4.04 (5 H, m), 5.26 (1 H, s), 6.50 (1 H, d, J = 8.1 Hz), 6.90–6.94 (1 H, m), 6.97 (1 H, s), 7.09–7.22 (4 H, m), 7.38 (1 H, t, J = 8.7 Hz), 7.69–7.76 (2 H, m), 7.81–7.86 (2 H, m), 9.06 (1 H, s). 13C-NMR (100 MHz, CDCl3) δ: 33.3, 33.4, 53.5, 53.7, 65.7, 89.0, 100.3, 113.9, 116.5 (d, J = 22.3 Hz), 116.8, 117.1(d, J = 20.6 Hz), 123.1, 124.4, 124.8, 127.8, 128.3, 131.2, 132.6, 132.7, 134.8, 135.6, 138.7, 138.9, 142.6, 150.9, 151.2, 155.3, 165.2 (d, J = 249.3 Hz). HRMS (ESI-TOF+): m/z [M + H]+ calcd for C29H27FN5O2: 496.2143; found: 496.2152.
5-(3-Chlorophenyl)-3-isopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (10). Red solid. Yield 110 mg (33%). Mp: 215–217 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.11 (6 H, d, J = 6.0 Hz), 3.46 (1 H, m), 4.04 (3 H, s), 5.27 (1 H, s), 6.45 (1 H, m), 6.91 (2 H, m), 7.15 (2 H, m), 7.27 (1 H, m), 7.38 (1 H, s), 7.64 (2 H, m), 7.68 (1 H, m), 7.83 (2 H, m), 8.90 (1 H, brs). 13C-NMR (100 MHz, CDCl3) δ: 23.5, 49.4, 53.7, 89.4, 100.1, 113.8, 116.8, 122.9, 124.8, 124.9, 127.3, 127.6, 128.2, 129.4, 130.1, 131.4, 132.3, 134.6, 135.5, 136.7, 138.7, 138.8, 142.9, 150.6, 151.2, 155.5. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H25ClN5O: 470.1712; found: 470.1696.
5-(3-Chlorophenyl)-3-cyclopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (11). Red solid. Yield 149 mg (46%). Mp: 211–214 °C. 1H-NMR (300 MHz, CDCl3) δ: 0.84 (4 H, m), 2.72 (1 H, m), 4.03 (3 H, s), 5.54 (1 H, s),6.44 (1 H, m), 6.90 (2 H, m), 7.17 (3 H, m), 7.38 (1 H, s), 7.66 (2 H, m), 7.74 (1 H, m), 7.80 (2 H, m). 13C-NMR (100 MHz, CDCl3) δ: 10.1, 32.9, 53.7, 89.8, 100.2, 113.9, 116.8, 124.4, 124.7, 127.1, 127.2, 127.8, 128.3, 129.3, 130.1, 132.3, 134.6, 136.7, 138.6, 138.9, 142.2, 142.7, 150.9, 153.5, 155.4, 161.0. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H23ClN5O: 468.1586; found: 468.1573.
5-(3-Chlorophenyl)-3-cyclobutylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (12). Red solid. Yield 142 mg (42%). Mp: 205–208 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.75 (2 H, m), 2.07 (2 H, m), 2.20 (2 H, m), 3.93 (1 H, m), 4.04 (3 H, s), 5.08 (1 H, s), 6.50 (1 H, m), 6.93 (2 H, m), 7.17 (3 H, m), 7.38 (1 H, s), 7.69 (3 H, m), 7.84 (2 H, m). 13C-NMR (100 MHz, CDCl3) δ: 16.1, 32.0, 53.7, 54.9, 90.9, 100.3, 113.9, 116.8, 123.1, 124.8, 127.4, 127.8, 128.3, 129.4, 130.1, 131.2, 132.2, 134.2, 135.6, 136.7, 138.7, 138.9, 142.6, 142.8, 151.2, 151.4, 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C28H25ClN5O: 482.1742; found: 482.1703.
5-(3-Chlorophenyl)-3-cyclohexylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (13). Red solid. Yield 62 mg (49%). Mp: 197–201 °C.1H-NMR (300 MHz, CDCl3) δ: 1.10 (3 H, m), 1.28 (2 H, m), 1.53 (3 H, m), 1.68 (2 H, m), 2.98 (1 H, m), 3.94 (3 H, s), 5.12 (1 H, s), 6.55 (2 H, m), 6.81 (1 H, s), 7.11 (3 H, m), 7.55 (2 H, m), 7.81 (5 H, m), 9.00 (1 H, s). 13C-NMR (100 MHz, CDCl3) δ: 23.8, 25.4, 33.0, 53.6, 56.9, 88.7, 100.1, 113.9, 117.4, 122.8, 124.0, 124.1, 127.8, 127.9, 128.0, 128.2, 129.0, 130.0, 131.0, 132.9, 134.2, 135.1, 135.3, 138.2, 138.5, 141.5, 150.1, 150.3. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C30H29ClN5O: 510.2061; found: 510.2059.
5-(3-Chlorophenyl)-3-(4-tetrahydropyranyl)imino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (14). Red solid. Yield 308 mg (86%). Mp: 203–206 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.75 (4 H, m), 2.85 (1 H, m), 3.43 (2 H, m), 3.96 (2 H, m), 4.04 (3 H, s), 5.27 (1 H, s), 6.53 (1 H, m), 6.90 (2 H, m), 7.17 (3 H, m), 7.38 (1 H, s), 7.64 (2 H, m), 7.74 (1 H, m), 7.84 (2 H, m), 9.08 (1 H, s). 13C-NMR (100 MHz, CDCl3) δ: 34.2, 53.5, 53.8, 66.9, 89.1, 100.4, 113.9, 116.7, 124.4, 124.7, 127.1, 127.2, 127.8, 128.3, 129.3, 130.1, 132.3, 134.6, 136.7, 138.6, 138.9, 142.2, 142.7, 150.9, 153.5, 155.4, 161.0. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C29H27ClN5O2: 512.1848; found: 512.1838.
5-(3,4-Difluorophenyl)-3-isopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (15). Red solid. Yield 270 mg (80%). Mp: 229–231 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.13 (6 H, d, J = 6.9 Hz), 3.45–3.53 (1 H, m, J = 6.3 Hz), 4.04 (3 H, s), 5.28 (1 H, s), 6.43 (1 H, d, J = 7.5 Hz), 6.89–6.93 (2 H, m), 7.13–7.25 (4 H, m), 7.49–7.59 (1 H, m), 7.68 (1 H, d, J = 7.2 Hz), 7.81–7.84 (2 H, m), 8.92 (1 H, s). 13C-NMR (100 MHz, CDCl3) δ: 23.5, 23.6, 49.5, 53.7, 89.2, 100.1, 113.5, 116.8, 118.8 (d, J = 17.8 Hz), 120.0 (d, J = 18.5 Hz), 123.1, 124.8, 124.9, 125.8, 127.7, 128.3, 131.4, 133.7, 134.7, 135.5, 138.9, 142.9, 151.0 (dd, J = 251.8, 12.0 Hz), 151.2, 152.0 (dd, J = 252.6, 13.2 Hz), 155.5. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H24F2N5O: 472.1943; found: 472.1937.
5-(3,4-Difluorophenyl)-3-cyclopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (16). Red solid. Yield 233 mg (yield 71%). Mp: 213–214 °C. 1H-NMR (300 MHz, CDCl3) δ: 0.86 (2 H, d, J = 2.7 Hz), 0.93 (2 H, d, J = 6.0 Hz), 2.77 (1 H, m), 4.01 (3 H, s), 5.54 (1 H, s), 6.42 (1 H, d, J = 8.4 Hz), 6.86 (1 H, s), 6.99 (1 H, m), 7.12 (4 H, m), 7.52 (1 H, m), 7.66 (1 H, d, J = 8.1 Hz), 7.82 (2 H, m), 8.58 (1 H, s). 13C-NMR (100 MHz, CDCl3): δ: 10.2, 33.0, 53.7, 89.7, 100.1, 113.5, 116.8, 118.9 (d, J = 17.9 Hz), 120.0 (d, J = 18.3 Hz), 123.1, 124.7, 125.1, 125.9, 127.7, 128.2, 131.6, 133.7, 134.5, 135.7, 139.0, 142.7, 151.0 (dd, J = 254.5, 13.1 Hz), 151.4, 151.9 (dd, J = 252.9, 13.5 Hz), 155.5. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H22F2N5O: 470.1787; found: 470.1762.
5-(3,4-Difluorophenyl)-3-cyclobutylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (17). Red solid. Yield 300 mg (78%). Mp: 200–201 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.70–1.82 (2 H, m), 2.03–2.20 (4 H, m), 3.81–4.04 (1 H, m), 4.04 (3 H, s), 5.08 (1 H, s), 6.46 (1 H, d, J = 7.5 Hz), 6.89–6.93 (2 H, m), 7.12–7.23 (4 H, m), 7.50–7.59 (1 H, m), 7.69 (1 H, d, J = 7.5 Hz), 7.82–7.84 (2 H, m). 13C-NMR (100 MHz, CDCl3) δ: 16.1, 32.0, 53.7, 54.9, 90.7, 100.3, 113.6, 116.8, 118.8 (d, J = 17.7 Hz), 119.9 (d, J = 18.1 Hz), 123.2, 124.7, 124.9, 125.8, 127.8, 128.4, 131.3, 133.6, 134.2, 135.6, 138.9, 142.7, 151.0 (dd, J = 251.1, 11.8 Hz), 151.1, 151.3, 151.9 (dd, J = 253.4, 13.7 Hz), 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C28H24F2N5O: 484.1943; found: 484.1933.
5-(3,4-Difluorophenyl)-3-cyclohexylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (18). Red solid. Yield 330 mg (81%). Mp: 218–219 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.23–1.79 (10 H, m), 3.14–3.20 (1 H, m), 4.03 (3 H, s), 5.26 (1 H, s), 6.45 (1 H, d, J = 7.5 Hz), 6.88–6.93 (2 H, m), 7.11–7.25 (4 H, m), 7.49–7.58 (1 H, m), 7.69 (1 H, d, J = 7.5 Hz), 7.80–7.84 (2 H, m). 13C-NMR (100 MHz, CDCl3) δ: 24.2, 25.9, 33.5, 33.6, 53.7, 57.4, 89.4, 100.1, 113.5, 116.8, 118.8 (d, J = 17.8 Hz), 119.8 (d, J = 18.1 Hz), 123.0, 124.5, 124.9, 125.8, 127.7, 128.3, 131.4, 133.7, 134.6, 135.6, 138.7, 142.8, 150.4, 151.0 (dd, J = 251.5, 11.9 Hz), 151.3, 151.9 (dd, J = 252.6, 13.5 Hz), 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C30H28F2N5O: 512.2256; found: 512.2263.
5-(3,4-Difluorophenyl)-3-(4-tetrahydropyranyl)imino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydro-phenazine (19). Red solid. Yield 240 mg (59%). Mp: 255–256 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.65–1.68 (4 H, m), 3.46–3.55 (3 H, m), 4.05 (5 H, m), 5.25 (1 H, s), 6.46 (1 H, d, J = 9.0 Hz), 6.90–6.95 (2 H, m), 7.13–7.24 (4 H, m), 7.51–7.60 (1 H, m), 7.71 (1 H, d, J = 7.5 Hz), 7.81–7.85 (2 H, m), 9.08 (1 H, s).13C-NMR (100 MHz, CDCl3) δ: 33.2, 33.4, 53.3, 53.8, 65.5, 88.9, 100.3, 113.7, 116.8, 118.7 (d, J = 19.7 Hz), 119.9 (d, J = 18.1 Hz), 123.3, 124.3, 124.8, 125.7, 127.9, 128.4, 131.2, 133.5, 134.9, 135.6, 138.8, 142.8, 150.9, 151.0 (dd, J = 251.4, 13.6 Hz), 151.9 (dd, J = 252.8, 13.4 Hz), 155.3. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C29H26F2N5O2: 514.2049; found: 514.2042.
5-(3,4-Difluorophenyl)-3-(4-methoxycyclohexyl)imino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydro-phenazine (20). Red solid. Yield 432 mg (84%). Mp: 214–215 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.26 (2 H, m), 1.40 (2 H, m), 1.73 (2 H, m), 2.05 (2 H, m), 3.16 (1 H, m), 3.27 (1 H, m), 3.36 (3 H, s), 4.03 (3 H, s), 5.26 (1 H, s), 6.46 (1 H, d, J = 7.5 Hz), 6.92 (2 H, m), 7.15 (3 H, m), 7.22 (1 H, m), 7.53 (1 H, m), 7.69 (1 H, d, J = 8.1 Hz), 7.82 (2 H, m), 8.94 (1 H, brs). 13C-NMR (100 MHz, CDCl3) δ: 29.3, 29.5, 30.8, 53.7, 55.8, 56.9, 78.2, 89.2, 100.2, 113.6, 116.8, 118.7 (d, J = 18.0 Hz), 119.9 (d, J = 18.9 Hz), 123.2, 124.7, 125.7, 127.8, 128.4, 131.4, 133.5, 134.7, 135.6, 138.8, 142.7, 151.0 (dd, J = 252.5, 13.7 Hz), 151.1, 151.9 (dd, J = 252.2, 13.5 Hz), 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C31H30F2N5O2: 542.2362; found: 542.2338.
5-(3,4-Dichlorophenyl)-3-isopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (21). Red solid. Yield 130 mg (68%). Mp: 245–247 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.13 (6 H, d, J = 6.3 Hz), 3.50 (1 H, m), 4.03 (3 H, s), 5.29 (1 H, s), 6.43 (1 H, d, J = 6.3 Hz), 6.89 (1 H, s), 6.93 (1 H, m), 7.10–7.23 (3 H, m), 7.49 (1 H, d, J = 2.4 Hz), 7.68 (1 H, m), 7.80–7.84 (3 H, m). 13C-NMR (100 MHz, CDCl3) δ: 23.6, 49.5, 53.7, 89.3, 100.1, 113.6, 116.8, 123.1, 124.8, 125.0, 127.7, 128.3, 128.6, 131.3, 133.1, 134.3, 134.5, 135.3, 135.5, 136.8, 138.9, 142.9, 150.4, 151.2, 155.5. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H24Cl2N5O: 504.1853; found: 504.1852.
5-(3,4-Dichlorophenyl)-3-cyclopropylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (22). Red solid. Yield 120 mg (65%). Mp: 215–217 °C. 1H-NMR (300 MHz, CDCl3) δ: 0.86–0.96 (4 H, m), 2.80 (1 H, m), 4.00 (3 H, s), 5.54 (1 H, s), 6.41 (1 H, d, J = 8.7 Hz), 6.86 (1 H, s), 6.91 (1 H, m), 7.10–7.28 (3 H, m), 7.51 (1 H, d, J = 2.1 Hz), 7.65 (1 H, m), 7.80–7.83 (3 H, m). 13C-NMR (100 MHz, CDCl3) δ: 10.3, 33.1, 53.7, 89.8, 100.0, 113.6, 116.8, 123.1, 124.6, 125.2, 127.7, 128.2, 128.8, 131.4, 133.2, 134.3, 135.4, 135.7, 136.8, 139.0, 142.7, 151.4, 152.2, 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C27H22Cl2N5O: 502.1317; found: 502.1316.
5-(3,4-Dichlorophenyl)-3-cyclobutylimino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydrophenazine (23). Red solid. Yield 167 mg (65%). Mp: 216–219 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.81 (2 H, m), 2.08 (2 H, m), 2.22 (2 H, m), 3.95 (1 H, m), 4.05 (3 H, s), 5.11 (1 H, s), 6.47 (1 H, d, J = 7.5 Hz), 6.91 (2 H, m), 7.17 (2 H, m), 7.23 (1 H, m), 7.50 (1 H, d, J = 2.1 Hz), 7.69 (1 H, d, J = 7.5 Hz), 7.84 (3 H, m), 8.79 (1 H, brs). 13C-NMR (100 MHz, CDCl3) δ: 16.1, 32.0, 53.7, 54.8, 90.8, 100.3, 113.7, 116.8, 123.2, 124.7, 124.9, 127.8, 128.4, 128.6, 131.1, 131.3, 133.0, 134.0, 134.3, 135.3, 135.6, 136.7, 139.0, 142.8, 151.1, 151.2, 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C28H24Cl2N5O: 516.1352; found: 516.1322.
5-(3,4-Dichlorophenyl)-3-(4-tetrahydropyranyl)imino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydro-phenazine (24). Red solid. Yield 140 mg (67%). Mp: 232–233 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.61–1.72 (4 H, m), 3.48–3.52 (3 H, m), 4.04 (5 H, m), 5.26 (1 H, s), 6.47 (1 H, d, J = 7.8 Hz), 6.90–6.94 (1 H, m), 6.95 (1 H, s), 7.13–7.23 (3 H, m), 7.49 (1 H, s), 7.70 (1 H, d, J = 7.2 Hz), 7.81–7.85 (3 H, m). 13C-NMR (100 MHz, CDCl3) δ: 33.3, 53.3, 53.8, 65.5, 89.1, 100.3, 113.7, 116.8, 123.3, 124.4, 124.8, 127.9, 128.4, 128.5, 131.0, 131.2, 133.1, 134.4, 134.7, 135.4, 135.6, 136.7, 138.8, 142.6, 150.9, 155.3. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C29H26Cl2N5O2: 546.1875; found: 546.1874.
5-(3,4-Dichlorophenyl)-3-(4-methoxycyclohexyl)imino-2-(2-methoxy-3-pyridyl)amino-3,5-dihydro-phenazine (25). Red solid. Yield 100 mg (45%). Mp: 215–217 °C. 1H-NMR (300 MHz, CDCl3) δ: 1.23–1.51 (4 H, m), 1.73–2.10 (4 H, m), 3.15–3.29 (2 H, m), 3.37 (3 H, s), 3.78 (3 H, s), 5.27 (1 H, s), 6.48 (1 H, d, J = 8.4 Hz), 6.90–6.93 (2 H, m), 7.12–7.24 (3 H, m), 7.49 (1 H, d, J = 2.1 Hz), 7.70 (1 H, d, J = 7.2 Hz), 7.79–7.84 (3 H, m). 13C-NMR (100 MHz, CDCl3) δ: 29.3, 29.4, 30.7, 53.7, 55.8, 56.8, 89.3, 100.2, 113.7, 116.8, 123.2, 124.7, 124.8, 127.8, 128.4, 128.5, 131.1, 131.2, 133.0, 134.4, 134.5, 135.3, 135.6, 136.7, 138.8, 142.7, 151.0, 151.1, 155.4. HRMS (ESI-TOF+): m/z [M + H]+ calcd for C31H30Cl2N5O2: 574.2129; found: 574.2128.