Synthesis of Dibenzo-Fused Seven-Membered Heterocycles via Copper-Catalyzed Cyclization of 2-Haloaniline Compounds

Abstract

A one-step synthesis of dibenzo-fused seven-membered nitrogen heterocycles from acetophenones/benzophenones and 2-haloanilines, via a copper-catalyzed amination, was developed. The reaction involves amination followed by intramolecular cyclization.

Key words

heterocycles - copper catalyst - arylation-cyclization - 2-haloaniline

References and Notes

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11

Typical Procedure for the Preparation of Dibenzo-Fused Seven-Membered Nitrogen Heterocycles Compounds: A mixture of 1a (60.8 mg, 0.45 mmol), 2b (69.9 mg, 0.3 mmol), Cu₂O (4.3 mg, 0.03 mmol) and K₂CO₃ (62.1 mg, 0.45mmol) was placed in xylene (1.0 mL) under Ar at 145 °C in a round-bottomed flask. When the reaction was considered complete as determined by TLC analysis, the reaction mixture was allowed to cool to r.t., and the mixture was extracted with EtOAc. The combined organic extracts were washed with H₂O and sat. brine. The organic layers were dried over MgSO₄, and filtered. Solvents were evaporated under reduced pressure. The residue was purified by chromatography on silica gel (hexanes-EtOAc, 10:1) to afford 7,11-dimethyl-5H-dibenzo[b,e][1,4]diazepine (3a; 53.9 mg, 88%) as a yellow solid; mp 133-135 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.23 (s, 3 H), 2.54 (s, 3 H), 4.86 (s, 1 H), 6.48 (s, 1 H), 6.65-6.68 (d, J = 8.4 Hz, 1 H), 6.80-6.83 (d, J = 7.5 Hz, 1 H), 6.94-6.99 (m, 1 H), 7.03-7.05 (d, J = 6.0 Hz, 1 H), 7.19-7.31 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.6, 28.4, 119.2, 120.2, 122.8, 124.8, 127.9, 129.0, 129.3, 131.6, 136.6, 138.1, 142.2, 153.0, 168.9. IR (KBr): 761, 1281, 1459, 1630, 3278, 3348 cm^-1. EI-MS: m/z = 222 [M⁺], 207, 192, 111 cm^-1. Anal. Calcd for C₁₅H₁₄N₂: C, 81.05; H, 6.35; N, 12.60. Found: C, 80.87; H, 6.09; N, 12.71.7-Chloro-11-methyl-5 H -dibenzo[ b , e ][1,4]diazepine (3c): The reaction mixture was chromatographed using hexanes-EtOAc (10:1) to afford 3c (58.2 mg, 85%) as a brown solid. ¹H NMR (300 MHz, CDCl₃): δ = 2.52-2.53 (m, 3 H), 4.89 (s, 1 H), 6.65-6.68 (d, J = 7.5 Hz, 2 H), 6.95-7.06 (m, 3 H), 7.22-7.32 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.5, 119.5, 119.6, 123.3, 124.1, 129.0, 129.4, 131.8, 131.9, 134.8, 139.2, 143.4, 152.3, 170.1. IR (KBr): 758, 1456, 1631, 3272, 3356 cm^-1. EI-MS: m/z = 242 [M⁺], 207. Anal. Calcd for C₁₄H₁₁ClN₂: C, 69.28; H, 4.57; N, 11.54. Found: C, 69.37; H, 4.38; N, 11.45.1-[2-(2-Amino-5-methyl-3-nitrophenylamino)phen-yl]ethanone (4e): The reaction mixture was chromatographed using hexanes-EtOAc (30:1) to afford 4e (68.4 mg, 85%) as an orange solid. ¹H NMR (300 MHz, CDCl₃): δ = 2.26 (s, 3 H), 2.67 (s, 3 H), 6.26 (s, 2 H), 6.55-6.58 (d, J = 8.7 Hz, 1 H), 6.76-6.82 (t, J = 7.2 Hz, 1 H), 7.23-7.34 (m, 2 H), 7.84-7.90 (t, J = 7.5 Hz, 2 H), 10.03 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.1, 28.0, 114.2, 117.2, 119.0, 123.7, 125.2, 128.4, 132.4, 132.6, 135.1, 135.5, 140.6, 148.8, 201.8. IR (KBr): 750, 1225, 1450, 1576, 1638, 3373, 3472 cm^-1. EI-MS: m/z = 285 [M⁺], 195, 120. Anal. Calcd for C₁₅H₁₅N₃O₃: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.31; H, 5.10; N, 14.87.2,7,8-Trimethyl-11-phenyl-5 H -dibenzo[ b , e ][1,4]di-azepine (3g): The reaction mixture was chromatographed using hexanes-EtOAc (50:1) to afford 3g (66.5 mg, 76%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ = 2.13 (s, 6 H), 2.17 (s, 3 H), 4.81 (s, 1 H), 6.45 (s, 1 H), 6.61-6.64 (d, J = 7.5 Hz, 1 H), 6.78 (s, 1 H), 7.02-7.09 (m, 1 H), 7.22 (s, 1 H), 7.36-7.41 (m, 3 H), 7.70-7.74 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.8, 19.0, 20.4, 119.4, 120.8, 127.2, 127.9, 129.5, 129.6, 131.6, 131.9, 132.1, 132.4, 135.2, 138.4, 140.2, 141.5, 152.0, 168.7. IR (KBr): 695, 731, 1464, 1613, 2920, 3329 cm^-1. EI-MS: m/z = 312 [M⁺], 297. Anal. Calcd for C₂₂H₂₀N₂: C, 84.58; H, 6.45; N, 8.97. Found: C, 84.59; H, 6.53; N, 8.89.2-Chloro-7-methyl-11-phenyl-5 H -dibenzo[ b , e ][1,4]di-azepine (3i): The reaction mixture was chromatographed using hexanes-EtOAc (50:1) to afford 3i (71.7 mg, 80%) as an orange solid. ¹H NMR (300 MHz, CDCl₃): δ = 2.25 (s, 3 H), 4.90 (s, 1 H), 6.49 ( s, 1 H), 6.67-6.70 (d, J = 8.1 Hz, 1 H), 6.86-6.89 (d, J = 8.1 Hz, 1 H), 6.96-6.97 (m, 1 H), 7.18-7.25 (m, 2 H), 7.38-7.45 (m, 3 H), 7.68-7.71 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.7, 120.4, 121.0, 125.2, 127.7, 128.1, 128.7, 128.9, 129.4, 130.1, 131.4, 131.6, 137.3, 138.1, 140.8, 141.7, 152.8, 167.1. IR (KBr): 1450, 1615, 3269, 3348 cm^-1. EI-MS: m/z = 318 [M⁺], 283, 268, 214. Anal. Calcd for C₂₀H₁₅ClN₂: C, 75.35; H, 4.74; N, 8.79. Found: C, 75.43; H, 4.87; N, 8.98.2-Chloro-7,8-dimethyl-11-phenyl-5 H -dibenzo[ b , e ][1,4]diazepine (3j): The reaction mixture was chromatographed using hexanes-EtOAc (50:1) to afford 3j (72.8 mg, 78%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ = 2.11-2.24 (m, 6 H), 4.87 (s, 1 H), 6.43 (s, 1 H), 6.64-6.66 (m, 1 H), 6.95-6.96 (m, 1 H), 7.09 (s, 1 H), 7.15-7.23 (m, 1 H), 7.37-7.46 (m, 3 H), 7.68-7.71 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.8, 19.1, 120.9, 120.9, 127.6, 128.1, 128.8, 129.3, 129.6, 130.0, 131.4, 131.5, 132.5, 135.7, 138.2, 139.4, 140.8, 153.1, 167.1. IR (KBr): 696, 731, 1462, 1617, 2920, 3341 cm^-1. EI-MS: m/z = 332 [M⁺], 297, 214, 111. Anal. Calcd for C₂₁H₁₇ClN₂: C, 75.78; H, 5.15; N, 8.42. Found: C, 75.67; H, 5.05; N, 8.48.7-Bromo-2-chloro-11- m -tolyl-5 H -dibenzo[ b , e ][1,4]di-azepine (3m): The reaction mixture was chromatographed using hexanes-EtOAc (50:1) to afford 3m (75.1 mg, 68%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ = 3.26 (s, 3 H), 4.94 (s, 1 H), 6.71-6.73 (d, J = 8.1 Hz, 1 H), 6.87 (s, 1 H), 6.99-7.00 (m, 1 H), 7.14-7.18 (m, 2 H), 7.24-7.30 (m, 3 H), 7.38 (s, 1 H), 7.56 (s, 1 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 21.7, 120.1, 122.7, 123.3, 126.8, 127.0, 127.1, 128.8, 129.2, 130.1, 130.5, 131.3, 131.9, 132.8, 138.2, 140.3, 140.7, 145.7, 154.8, 168.7. IR (KBr): 628, 764, 825, 1026, 1652, 2253, 3414 cm^-1. EI-MS: m/z = 396 [M⁺], 361. Anal. Calcd for C₂₀H₁₄BrClN₂: C, 60.40; H, 3.55; N, 7.04. Found: C, 60.55; H, 3.36; N, 7.18.7-Methyl-5 H -dibenzo[ b , e ][1,4]diazepine (3o): The reaction mixture was chromatographed using hexanes-EtOAc (10:1) to afford 3o (34.3 mg, 60%) as a dark red solid. ¹H NMR (300 MHz, CDCl₃): δ = 2.20 (s, 3 H), 4.84 (s, 1 H), 6.30 (s, 1 H), 6.44-6.47 (d, J = 7.5 Hz, 1 H), 6.72-6.74 (d, J = 7.5 Hz, 2 H), 6.83-6.88 (t, J = 7.5 Hz, 1 H), 6.99-7.04 (t, J = 7.5 Hz, 2 H), 7.11-7.16 (t, J = 14.7 Hz, 1 H), 8.04 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 20.6, 118.3, 120.5, 122.4, 124.6, 126.3, 130.5, 131.9, 132.6, 137.6, 138.7, 142.3, 151.8, 162.1. IR (KBr): 746, 1456, 1588, 2920, 3355 cm^-1. EI-MS: m/z = 208 [M⁺]. Anal. Calcd for C₁₄H₁₂N₂: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.64; H, 5.67; N, 13.53.