4.2. General Method of Synthesis of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-Arylacetamides 1–8
The appropriate N-arylacetamide (1.2 mol) was added dropwise to a solution of 5-nitro-1H-benzoimidazol-2-ylamine (1.0 mol) in acetonitrile (30 mL) and potassium carbonate (2.2 mol) at 90 °C. The mixture was stirred at reflux for between 5 and 18 h. The solvent was removed under vacuum and the residue was suspended in water. The precipitates were filtered and dried. Crude compounds were recrystallized from DMSO:H2O mixture (50:50) or purified by column chromatography.
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-benzylacetamide (1). Yield: 90.1%; m.p. 268–271 °C; Yellow solid, 1H-NMR and 13C-NMR refer to a 75:25 mixture of regioisomers.
75% Regioisomer of (2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-benzylacetamide (1a). 1H-NMR. (400 MHz, DMSO-d6) δ 4.32 (2H, d, JNH-H = 5.6 Hz, NHCH2Ph); 4.83 (2H, s, NHCH2CO); 7.03 (2H, br, NH2); 7.19 (1H, d, Jorto = 8.4 Hz, H-7); 7.23–7.36 (5H, m, Ph); 7.87 (1H, dd, Jmeta = 2.4 Hz, Jorto = 8.4 Hz, H-6); 7.93 (d, Jmeta = 2.0 Hz, 1H, H-4); 8.73 (t, JNH-H = 6.0 Hz, 1H, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.4 (NHCH2Ph); 44.9 (NHCH2CO); 107.1 (C-7); 109.3 (C-6); 114.7 (C-4); 126.8 (C-4′); 127.2 (2C, C-2′, C-6′); 128.2 (2C, C-3′, C-5′); 138.8 (C-1′); 140.1 (C-5); 141.9 (C-7a); 142.8 (C-3a); 158.1(C-2); 165.9 (C=O) ppm.
25% Regioisomer of (2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-benzylacetamide (1b). 1H-NMR (400 MHz, DMSO-d6) δ 4.33 (2H, d, JNH-H =5.6 Hz, NHCH2Ph); 4.87 (2H, s, NHCH2CO); 7.03 (2H, br, NH2); 7.20 (1H, d, Jorto = 8.4 Hz, H-4); 7.23–7.36 (m, 5H, Ph); 7.95 (1H, dd, Jmeta = 2.6 Hz, Jorto = 8.6 Hz, H-5); 7.97 (1H, d, Jmeta = 2.0 Hz, H-7); 8.78 (1H, t, JNH-H = 5.6 Hz, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 42.4 (NHCH2Ph); 44.7 (NHCH2CO); 103.5 (C-7); 113.5 (C-6); 118.5 (C-4); 127.15 (2C, C-2′, C6′); 127.11 (C-4′), 128.2 (2C, C-3′, C-5′); 134.3 (C-1′); 138.7 (C-5); 141.9 (C-7a); 149.7 (C-3a); 159.6 (C-2); 166.1 (C=O) ppm. MS (FAB): m/z 326 (M+H+1).
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-phenylacetamide (2). Yield: 80.1%; m.p. 285–288°C; Yellow solid, 1H-NMR and 13C-NMR indicate a 60:40 mixture of regioisomers.
60% Regioisomer of 2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-phenylacetamide (2a).1H-NMR (400 MHz, DMSO-d6) δ 5.05 (2H, s, NHCH2CO); 7.06 (1H, dd, Jorto = 7.2 Hz, Jorto = 7.2 Hz, H-4′); 7.22 (2H, d, Jorto = 9.2 Hz, H-2′, H-6′); 7.32 (2H, d, Jorto = 8.0 Hz, H-3′, H-5′); 7.61 (2H, br, NH); 7.86 (1H, d, Jorto = 8.0 Hz, H-6); 7.96 (1H, d, Jorto = 8.0 Hz, H-7); 8.11 (1H, s, H-4); 10.52 (1H, br, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.2 (NHCH2CO); 103.9 (C-7); 113.5 (C-6); 118.2 (C-4); 123.5 (C-4′); 127.2 (2C, C-2′, C-6′); 128.2 (2C, C-3′, C-5′); 138.8 (C-1′); 140.1 (C-5); 142.1 (C-7a); 142.8 (C-3a); 158.1 (C-2); 165.9 (C=O) ppm.
40% Regioisomer of 2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-phenylacetamide (2b). 1H-NMR (400 MHz, DMSO-d6) δ 5.01 (2H, s, NHCH2CO); 7.06 (1H, dd, Jorto = 7.2 Hz, Jorto = 7.2 Hz, H-4′); 7.22 (2H, d, Jorto = 9.2 Hz, H-2′, H-6′); 7.32 (2H, d, Jorto = 8.0 Hz, H-3′, H-5′); 7.63 (br, 2H, NH); 7.86 (d, Jorto = 8.8 Hz, 1H, H-4); 7.96 (1H, d, Jorto = 8.0 Hz, H-5); 8.32 (s, 1H, H-7); 10.52 (1H, br, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.6 (NHCH2CO); 107.4 (C-7); 109.4 (C-6); 114.9 (C-4); 119.1 (2C, C-2′, C-6′); 123.5 (C-4′). 128.9 (2C, C-3′, C-5′); 138.8 (C-1′); 140.5 (C-5); 142.1 (C-7a); 142.9 (C-3a); 158.4 (C-2); 164.9 (C=O) ppm. MS (FAB): m/z 312 (M+H+1).
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-(4-fluorophenyl) acetamide (3). Yield: 72.0%; m.p. 313.0–315.0 °C; Yellow solid, 1H-NMR and 13C-NMR indicate a 70:30 mixture of regioisomers.
70% Regioisomer of 2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-(4-fluorophenyl) acetamide (3a). 1H-NMR (400 MHz, DMSO-d6) δ 4.98 (2H, s, NHCH2CO); 7.08 (2H, br, NH); 7.17 (2H, dd, Jorto = 8.8 Hz, Jorto = 8.8 Hz, H-3′, H5′); 7.30 (1H, d, Jorto = 8.8 Hz, H-7); 7.62 (2H, dd, Jorto = 5.2 Hz, Jorto = 8.8 Hz, H-2′, H6′); 7.87 (1H, dd, Jmeta = 2.4 Hz, Jorto = 8.8 Hz, H-6); 7.95 (1H, d, Jmeta = 2.8 Hz, H-4); 10.47 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.3 (NHCH2CO); 107.2 (C-7); 109.3 (C-6); 114.7 (C-4); 115.3 (d, JC-F = 56.2 Hz, 2C, C-3′, C-5′); 120.7 (d, JC-F = 7.6 Hz, 2C, C-2′, C-6′); 135.0 (C-1′); 140.3 (C-5); 141.9 (C-7a); 142.8 (C-3a); 158.1 (C-2); 159.3 (d, JC-F = 56.2 Hz, C-4′); 164.6 (C=O) ppm.
30% Regioisomer of 2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-(4-fluorophenyl) acetamide (3b). 1H-NMR (400 MHz, DMSO-d6) δ 5.02 (2H, s, NHCH2CO); 7.33 (2H, br, NH); 7.17 (2H, dd, Jorto = 8.8 Hz, Jorto = 8.8 Hz, H-3′, H5′); 7.21 (1H, d, Jorto = 8.8 Hz, H-4); 7.62 (2H, dd, Jmeta = 5.2 Hz, Jorto = 8.8 Hz, H-2′, H6′); 7.87 (1H, dd, Jmeta = 2.4 Hz, Jorto = 8.8 Hz, H-5); 8.12 (1H, d, Jmeta = 2.4 Hz, H-7); 10.47 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.1 (NHCH2CO); 103.7 (C-7); 113.3 (C-6); 118.0 (C-4); 120.7 (d, JC-F = 7.6 Hz, 2C, C-2′, C-6′); 159.3 (d, JC-F = 56.2 Hz, C-4′); 115.3 (d, JC-F = 56.2 Hz, 2C, C-3′, C-5′); 134.6 (C-1′); 138.8 (C-5); 141.9 (C-7a); 149.6 (C-3a); 156.7 (C-2); 164.7 (C=O) ppm. MS (FAB): m/z 330 (M+H+1).
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-(4-chlorophenyl) acetamide (4). Yield: 92.1%; m.p. 294.0–296.0 °C; Yellow solid, 1H-NMR and 13C-NMR indicate 69:31 mixture of regioisomers.
69% Regioisomer of 2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-(4-chlorophenyl) acetamide (4a). 1H-NMR (400 MHz, DMSO-d6) δ 5.04 (2H, s, NHCH2CO); 7.32 (2H, br, NH); 7.37 (1H, d, Jorto = 8.8 Hz, H-7); 7.63 (2H, d, Jmeta = 2.4 Hz, Jorto = 5.2 Hz, H-3′, H-5′); 7.65 (2H, d, Jmeta = 2.0 Hz, Jorto = 5.2 Hz, H-2′, H-6′); 7.96 (1H, d, Jmeta = 2.8 Hz, Jorto = 8.8 Hz, H-6); 8.12 (1H, d, Jmeta = 2.0 Hz, H-4); 10.56 (s, 1H, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.2 (NHCH2CO); 103.9 (C-7); 113.4 (C-6); 118.1 (C-4); 120.5 (2C, C-2′,C-6′); 126.9 (C-4′); 128.7 (2C, C-3′,C-5′); 137.6 (C-1′); 138.8 (C-5); 141.9 (C-7a); 149.6 (C-3a); 159.7 (C-2); 165.1 (C=O) ppm.
31% Regiisomer of 2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-(4-chlorophenyl) acetamide (4b). 1H-NMR (400 MHz, DMSO-d6) δ 4.99 (2H, s, NHCH2CO); 7.06 (2H, br, NH); 7.21 (1H, d, Jorto = 8.8 Hz, H-4); 7.63 (2H, d, Jmeta = 2.4 Hz, Jorto = 5.2 Hz, H-3′, H-5′); 7.65 (2H, d, Jmeta = 2.0 Hz, Jorto = 5.2 Hz, H-2′, H-6′); 7.86 (1H, d, Jmeta = 2.0 Hz, Jorto = 8.8 Hz, H-5); 7.96 (1H, d, Jmeta = 2.0 Hz, H-7); 10.59 (s, 1H, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.3 (NHCH2CO); 107.3 (C-7); 109.3 (C-6); 114.8 (C-4); 120.5 (2C, C-2′, C-6′); 126.9 (C-4′); 128.7 (2C, C-3′, C-5′); 134.6 (C-1′); 140.3 (C-5); 141.9 (C-7a); 142.7 (C-3a); 158.6 (C-2); 164.9 (C=O) ppm. MS (FAB): m/z 346 (M+H+1).
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-(4-cyanophenyl) acetamide (5). Yield: 81.5%; m.p. 254.0–256.7 °C; Yellow solid, 1H-NMR and 13C-NMR indicate 57:43 mixture of regioisomers.
57% Regioisomer of 2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-(4-cyanophenyl) acetamide (5a). 1H-NMR (400 MHz, DMSO-d6) δ 5.08 (2H, s, NHCH2CO); 7.07 (2H, br, NH); 7.22 (1H, d, Jorto = 8.8 Hz, H-7); 7.79 (4H, s, H-2′, H-3′, H-5′, H-6′); 7.85 (1H, d, Jorto = 8.8 Hz, H-6); 7.94 (1H, d, Jmeta = 2.0 Hz, H-4); 10.84 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.3 (NHCH2CO); 103.9 (C-7); 105.2 (C-4′); 113.4 (C-6); 118.1 (C-4); 118.9 (CN); 119.2 (2C, C-2′,C-6′); 133.4 (2C, C-3′, C-5′); 134.6 (C-1′); 138.9 (C-5); 142.8 (C-7a); 149.6 (C-3a); 159.6 (C-2); 165.8 (C=O) ppm.
43% Regioisomer of 2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-(4-cyanophenyl) acetamide (5b). 1H-NMR (400 MHz, DMSO-d6) δ 5.03 (2H, s, NHCH2CO); 7.32 (2H, br, NH); 7.33 (1H, d, Jorto = 8.8 Hz, H-4); 7.79 (4H, s, H-2′, H-3′, H-5′, H-6′); 7.85 (1H, d, Jorto = 8.8 Hz, H-5); 7.97 (1H, d, Jmeta = 2.0 Hz, H-7); 10.87 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.5 (NHCH2CO); 103.3 (C-7); 105.2 (C-4′); 109.4 (C-6); 114.8 (C-4); 118.9 (CN); 119.2 (2C, C-2′, C-6′); 133.4 (2C, C-3′, C-5′); 134.6 (C-1′); 140.3 (C-5); 142.7 (C-7a); 142.0 (C-3a); 158.1 (C-2); 165.7 (C=O) ppm. MS (FAB): m/z 337 (M+H+1).
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-(4-nitrophenyl) acetamide (6). Yield: 79.8%; m.p. 309.0–312.0 °C; Yellow solid, 1H-NMR and 13C-NMR indicates a 59:41mixture of reigoisomers.
59% Regioisomer of 2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-(4-nitrophenyl) acetamide (6a). 1H-NMR (400 MHz, DMSO-d6) δ 5.11 (2H, s, NHCH2CO); 7.34 (2H, br, NH); 7.36 (1H, d, Jorto = 8.8 Hz, H-7); 7.85 (2H, dd, Jmeta = 2.8 Hz, Jorto = 5.2 Hz, H-2′, H-6′); 7.86 (2H, dd, Jmeta = 2.4 Hz, Jorto = 8.0 Hz, H-3′, H-5′); 8.19 (1H, d, Jmeta = 2.0 Hz, H-4); 8.25 (1H, d, Jorto = 8.4 Hz, H-6); 11.04 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.4 (NHCH2CO); 104.0 (C-7); 144.9 (C-4′); 113.4 (C-6); 118.1 (C-4); 118.7 (2C, C-2′, C-6′); 125.1 (2C, C-3′, C-5′); 134.6 (C-1′); 138.9 (C-5); 142.2 (C-7a); 149.6 (C-3a); 159.6 (C-2); 166.0 (C=O) ppm.
41% Regioisomer compound 2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-(4-nitrophenyl) acetamide (6b). 1H-NMR (400 MHz, DMSO-d6) δ 5.06 (2H, s, NHCH2CO); 7.09 (2H, br, NH); 7.22 (d, Jorto = 8.8 Hz, 1H, H-4); 7.83 (1H, d, Jmeta = 2.4 Hz, H-7); 7.95 (2H, dd, Jmeta = 2.8 Hz, Jorto = 5.2 Hz, H-2′, H-6′); 7.96 (2H, dd, Jmeta = 2.4 Hz, Jorto = 8.0 Hz, H-3′, H-5′); 8.25 (1H, d, Jorto = 8.4 Hz, H-5); 11.01 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.6 (NHCH2CO); 107.4 (C-7); 144.7 (C-4′); 109.4 (C-6); 114.8 (C-4); 118.7 (2C, C-2′, C-6′); 125.1 (2C, C-3′, C-5′); 134.6 (C-1′); 140.3 (C-5); 142.0 (C-7a); 142.7 (C-3a); 158.1 (C-2); 165.8 (C=O) ppm. MS (FAB): m/z 357 (M+H+1).
2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-(2,6-dichlorophenyl) acetamide (7). Yield: 61.4%; m.p. 303.0–306.0 °C; Yellow solid, 1H-NMR and 13C-NMR indicate a 55:45 mixture of reigoisomers.
55% Regioisomer of 2-(2-amino-6-nitro-1H-benzimidazol-1-yl)-N-(2,6-dichlorophenyl) acetamide (7a). 1H-NMR (400 MHz, DMSO-d6) δ 5.11 (2H, s, NHCH2CO); 7.21 (1H, d, Jorto = 8.4 Hz, H-7); 7.36 (2H, dd, Jmeta = 3.8 Hz, Jorto = 8.4 Hz, H-3′, H-5′); 7.41 (2H, br, NH); 7.54 (1H, d, Jorto = 8.0 Hz, H-4′); 7.97 (1H, d, Jmeta = 2.6 Hz, Jorto = 8.6 Hz, H-6); 8.02 (1H, d, Jmeta = 2.4 Hz, H-4); 10.45 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 44.6 (NHCH2CO); 103.7 (C-7); 109.4 (C-6); 114.8 (C-4); 128.5 (2C, C-3′, C-5′); 129.5 (2C, C-2′, C-6′); 132.2 (C-1′); 133.4 (C-4′); 138.7 (C-5); 142.0 (C-7a); 142.9 (C-3a); 158.0 (C-2); 165.2 (C=O) ppm.
45% Regioisomer of 2-(2-amino-5-nitro-1H-benzimidazol-1-yl)-N-(2,6-dichlorophenyl)acetamide (7b). 1H-NMR (400 MHz, DMSO-d6) δ 5.08 (2H, s, NHCH2CO); 7.12 (2H, br, NH); 7.21 (1H, d, Jorto = 8.8 Hz, H-4); 7.34 (2H, dd, Jmeta = 3.6 Hz, Jorto = 8.4 Hz, H-3′, H-5′); 7.55 (1H, d, Jorto = 8.0 Hz, H-4′); 7.91 (1H, d, Jmeta = 2.0 Hz, Jorto = 8.8 Hz, H-5); 7.94 (1H, d, Jmeta = 2.4 Hz, H-7); 10.45 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 44.8 (NHCH2CO); 107.1 (C-7); 113.4 (C-6); 118.24 (C-4); 128.5 (2C, C-3′, C-5′); 129.5 (2C, C-2′, C-6′); 134.1 (C-1′); 133.4 (C-4′); 140.0 (C-5); 142.0 (C-7a); 149.8 (C-3a); 159.6 (C-2); 165.3 (C=O) ppm. MS (FAB): m/z 381 (M+H+1).
2-(2-Amino-5(6)-nitro-2,3-dihydro-1H-benzimidazol-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide (8). Yield: 60.7%; m.p. 282.0–284.0 °C; Yellow solid, 1H-NMR and 13C-NMR indicate 61:39 mixture of regioisomers.
61% Regioisomer of 2-(2-amino-6-nitro-2,3-dihydro-1H-benzimidazol-1-yl)-N-[3-(trifluoromethyl)phenyl] acetamide (8a). 1H-NMR (400 MHz, DMSO-d6) δ 5.07 (2H, s, NHCH2CO); 7.32 (2H, br, NH); 7.22 (1H, d, Jorto = 8.4 Hz, H-7); 8.10 (1H, d, Jmeta = 2.8 Hz, H-2′); 7.85 (2H, dd, Jmeta = 2.8 Hz, Jorto = 5.2 Hz, H-6′); 7.86 (2H, dd, Jmeta = 2.4 Hz, Jorto = 8.0 Hz, H-4′, H-5′); 8.15 (1H, d, Jmeta = 2.4 Hz, H-4); 7.96 (1H, dd, Jmeta = 2.2 Hz, Jorto = 8.6 Hz, H-6); 10.73 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.2 (NHCH2CO); 103.9 (C-7); 109.4 (C-6); 115.0 (C-2′); 119.8 (C-4′); 118.1 (C-4); 118.1 (C-6′); 122.5 (q, JC-F = 277.8 Hz, CF3); 129.5 (q, JC-F = 33.4 Hz, C-3′); 130.1 (C-5′); 134.6 (C-1′); 138.9 (C-5); 141.9 (C-7a); 149.7 (C-3a); 159.7 (C-2); 165.6 (C=O) ppm.
39% Regiosiomer of 2-(2-amino-5-nitro-2,3-dihydro-1H-benzimidazol-1-yl)-N-[3-(trifluoromethyl)phenyl] acetamide (8b). 1H-NMR (400 MHz, DMSO-d6) δ 5.06 (2H, s, NHCH2CO); 7.09 (2H, br, NH); 7.22 (1H, d, Jorto = 8.8 Hz, H-4); 7.83 (1H, d, Jmeta = 2.4 Hz, H-7); 7.95 (2H, dd, Jmeta = 2.8 Hz, Jorto = 5.2 Hz, H-2′, H-6′); 7.96 (2H, dd, Jmeta = 2.4 Hz, Jorto = 8.0 Hz, H-4′, H-5′); 8.25 (1H, d, Jorto = 8.4 Hz, H-5); 11.01 (1H, s, CONH) ppm. 13C-NMR (100 MHz, DMSO-d6) δ 45.3 (NHCH2CO); 107.3 (C-7); 113.4 (C-6); 115.0 (C-2′); 119.8 (C-4′); 114.8 (C-4); 118.1 (C-6′); 122.5 (q, JC-F = 277.8 Hz, CF3); 129.5 (q, JC-F = 33.4 Hz, C-3′); 140.3 (C-5′); 134.6 (C-1′); 140.3 (C-5); 141.9 (C-7a); 142.8 (C-3a); 158.1 (C-2); 165.4 (C=O) ppm. MS (FAB): m/z 381 (M+H+1).