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

 

 Buy Article Permissions and Reprints All articles of this category

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.

References and Notes

• 1a Cutignano A. Tramice A. De Caro S. Villani G. Cimino G. Fontana A. Angew. Chem. Int. Ed.  2003,  42:  2633 
  CrossrefGoogle Scholar
• 1b Renneberg D. Dervan PB. J. Am. Chem. Soc.  2003,  125:  5707 
  CrossrefGoogle Scholar
• 1c Occhiato EG. Prandi C. Ferrali A. Guarna A. Venturello P. J. Org. Chem.  2003,  68:  9728 
  CrossrefGoogle Scholar
• 1d Deng J. Zhao S. Miao Z. Nat. Prod. Lett.  1993,  2:  283 
  CrossrefGoogle Scholar
• 1e Evans PA. Holmes AB. Tetrahedron  1991,  47:  9131 
  CrossrefGoogle Scholar
• 1f Joule JA. Mills K. Heterocyclic Chemistry   4th ed.:  Blackwell; Oxford: 2000. 
  CrossrefGoogle Scholar
• 2a Geronikaki AA. Dearden JC. Filimonov D. Galaeva I. Garibova TL. Gloriozova T. Krajneva V. Lagunin A. Macaev FZ. Molodavkin G. Poroikov VV. Pogrebnoi SI. Shepeli F. Voronina TA. Tsitlakidou M. Vlad L. J. Med. Chem.  2004,  47:  2870 
  CrossrefGoogle Scholar
• 2b Dutton FE. Lee BH. Johnson SS. Coscarelli EM. Lee PH. J. Med. Chem.  2003,  46:  2057 
  CrossrefGoogle Scholar
• 2c Weintraub PM. Sabol JS. Kane JM. Borcherding DR. Tetrahedron  2003,  59:  2953 
  CrossrefGoogle Scholar
• 2d Yoshida H. Shirakawa E. Honda Y. Hiyama T. Angew. Chem. Int. Ed.  2002,  41:  3247 
  CrossrefGoogle Scholar
• 2e Bujard M. Gouverneur V. Mioskowski C. J. Org. Chem.  1999,  64:  2119 
  CrossrefGoogle Scholar
• 2f Cooper CS. Klock PL. Chu DTW. Fernandes PB. J. Med. Chem.  1990,  33:  1246 
  CrossrefGoogle Scholar
• 2g Boegesoe KP. Arnt J. Boeck V. Christensen AV. Hyttel J. Jensen KG. J. Med. Chem.  1988,  31:  2247 
  CrossrefGoogle Scholar
• 2h Hodge CN. Pierce J. Bioorg. Med. Chem. Lett.  1993,  3:  1605 
  CrossrefGoogle Scholar
• 3 Hartwig JF. Modern Arene Chemistry   Astruc D. Wiley-VCH; Weinheim: 2002.  Chap. 4.
  Google Scholar
• 4 Schlummer B. Scholz U. Adv. Synth. Catal.  2004,  346:  1599 
  Google Scholar
• 5 Tsuji J. Mandai T. Synthesis  1996,  1 
  Article in Thieme ConnectGoogle Scholar
• For reviews, see:
• 6a Kunz K. Scholz U. Ganzer D. Synlett  2003,  2428 
  CrossrefGoogle Scholar
• 6b Ley SV. Thomas AW. Angew. Chem. Int. Ed.  2003,  42:  5400 
  CrossrefGoogle Scholar
• 6c Dehli JR. Legros J. Bolm C. Chem. Commun.  2005,  973 
  CrossrefGoogle Scholar
• 7a Ma D. Xia C. Jiang J. Zhang J. Tang W. J. Org. Chem.  2003,  68:  442 
  CrossrefGoogle Scholar
• 7b Ma D. Cai Q. Zhang H. Org. Lett.  2003,  5:  2453 
  CrossrefGoogle Scholar
• 7c Ma D. Xia C. Org. Lett.  2001,  3:  2583 
  CrossrefGoogle Scholar
• 7d Clement J.-B. Hayes JF. Sheldrake HM. Sheldrake PW. Wells AS. Synlett  2001,  1423 
  CrossrefGoogle Scholar
• 7e Ma D. Zhang Y. Wu S. Tao F. J. Am. Chem. Soc.  1998,  120:  12459 
  CrossrefGoogle Scholar
• 8a Wang X. Porco JA. J. Am. Chem. Soc.  2003,  125:  6040 
  CrossrefPubMedGoogle Scholar
• 8b Padwa A. Crawford KR. Rashatasakhon P. Rose M. J. Org. Chem.  2003,  68:  2609 
  CrossrefPubMedGoogle Scholar
• 8c Fredrick MO. Mulder JA. Tracey MR. Hsung RP. Huang J. Kurtz KCM. Shen L. Douglas CJ. J. Am. Chem. Soc.  2003,  125:  2368 
  CrossrefPubMedGoogle Scholar
• 8d Klapars A. Buchwald SL. J. Am. Chem. Soc.  2002,  124:  14844 
  CrossrefPubMedGoogle Scholar
• 8e Antilla JC. Klapars A. Buchwald SL. J. Am. Chem. Soc.  2002,  124:  11684 
  CrossrefPubMedGoogle Scholar
• 8f Klapars A. Huang X. Buchwald SL. J. Am. Chem. Soc.  2002,  124:  7421 
  CrossrefPubMedGoogle Scholar
• 8g Wolter M. Klapars A. Buchwald SL. Org. Lett.  2001,  3:  3803 
  CrossrefPubMedGoogle Scholar
• 8h Klapars A. Antilla JC. Huang X. Buchwald SL. J. Am. Chem. Soc.  2001,  123:  7727 
  CrossrefPubMedGoogle Scholar
• 9a Buchwald SL, Klapars A, Antilla JC, Job GE, Wolter M, Kwong FY, Nordmann G, and Hennessy EJ. inventors; Int. Patent,  WO02085838 A1. 
  CrossrefPubMed
• 9b Kwong FY. Klapars A. Buchwald SL. Org. Lett.  2002,  4:  581 
  CrossrefPubMedGoogle Scholar
• 10a Ullmann F. Ber. Dtsch. Chem. Ges.  1903,  36:  2382 
  CrossrefGoogle Scholar
• 10b For a review, see: Lindley J. Tetrahedron  1984,  40:  1433 
  CrossrefGoogle Scholar

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.