Novel Synthesis of 5-Substituted 5H-Benzo[b]carbazole-6,11-diones via Double Buchwald–Hartwig Reaction

Abstract

2-Bromo-3-(2-bromophenyl)naphthalene-1,4-dione was synthesized as a key precursor to obtain a number of functionalized benzo[b]carbazole-6,11-diones by double Buchwald–Hartwig coupling reaction.

Key words

quinone - anilines - Buchwald–Hartwig reaction - carbazole - one-pot

• References and Notes

• 1 Thomson RH. Naturally Occurring Quinones IV . Chapman and Hall; London: 1997: 583
• 2a Hong SY, Chung KH, You HJ, Choi IH, Chae MJ, Han JY, Jung OJ, Kang SJ, Ryu CK. Bioorg. Med. Chem. Lett. 2004; 14: 3563
• 2b Tandon VK, Yadav DB, Chaturvedi AK, Shukla PK. Bioorg. Med. Chem. Lett. 2005; 15: 3288
• 2c Ryu CK, Kang HY, Yi YJ, Shin KH, Lee BH. Bioorg. Med. Chem. 2000; 10: 1589
• 2d Ryu CK, Choi KU, Shim JY, You HJ, Choi IH, Chae MJ. Bioorg. Med. Chem. 2003; 11: 4003
• 2e Ryu CK, Han JY, Jung OJ, Lee SK, Lee JY, Jeong SH. Bioorg. Med. Chem. Lett. 2005; 15: 679
• 3a Kuo SC, Ibuka T, Huang LJ, Lien JC, Yean SR, Hung SC, Lednicer D, Morris-Natschke S, Lee KH. J. Med. Chem. 1996; 39: 1447
• 3b Gomez-Monterrey IM, Campiglia P, Mazzoni O, Novellino E, Diurno MV. Tetrahedron Lett. 2001; 42: 5755
• 3c Gomez-Monterrey IM, Grieco P, Diurno MV, Bolongnese A, Colla PL, Novellino E. Bioorg. Med. Chem. 2003; 11: 3769
• 3d Lee HJ, Kim JS, Park SY, Suh ME, Kim HJ, Seo EK, Lee CO. Bioorg. Med. Chem. 2004; 12: 1623
• 3e Manzanaro S, Vicent MJ, Martín MJ, Salvador-Tormo N, Pérez JM, Blanco MM, Avendaño C, Menéndez JC, Fuente JA. Bioorg. Med. Chem. 2004; 12: 6505
• 3f Benites J, Valderrama JA, Rivera P, Rojo L, Campos N, Pedro M, Nascimento MS. J. Bioorg. Med. Chem. 2008; 16: 862
• 4a Tandon VK, Chhor RB, Singh RV, Rai S, Yadav DB. Bioorg. Med. Chem. Lett. 2004; 14: 1079
• 4b Tandon VK, Singh RV, Yadav DB. Bioorg. Med. Chem. Lett. 2004; 14: 2901
• 4c Tandon VK, Yadav DB, Singh RV, Yaish M, Chaturvedi AK, Shukla PK. Bioorg. Med. Chem. Lett. 2005; 15: 3463
• 4d Tandon VK, Yadav DB, Singh RV, Chaturvedi AK, Shukla PK. Bioorg. Med. Chem. Lett. 2005; 15: 5324
• 5 Thomson RH. Naturally Occuring Quinones IV . Blackie Academic; London: 1997
• 6a Lin AJ, Cosby LA, Shansky CW, Sartorelli AC. J. Med. Chem. 1972; 15: 1247
• 6b Moore HW. Science 1977; 197: 527
• 6c Arcamone F. Cancer Res. 1985; 45: 5995
• 6d Monneret C. Eur. J. Med. Chem. 2001; 36: 483
• 7a Chen X, Smith GD, Waring P. J. Appl. Phycol. 2003; 15: 269
• 7b Bernardo PH, Chai ChL. L, Heath GA, Mahon PJ, Smith GD, Waring P, Wilkes BA. J. Med. Chem. 2004; 47: 4958
• 8 Cheun-Arom T, Chanvorachote P, Sirimangkalakitti N, Chuanasa T, Saito N, Abe I, Suwanborirux K. J. Nat. Prod. 2013; 76: 1468
• 9a Diederich F, Stang PJ. Metal-catalyzed cross-coupling reactions. Wiley-VCH; Weinheim: 1998
• 9b King AO, Yasuda N. Top. Organomet. Chem. 2004; 6: 205
• 9c Carey JS, Laffan D, Thomson C, Williams MT. Org. Biomol. Chem. 2006; 4: 2337
• 10a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
• 10b Suzuki A. J. Organomet. Chem. 1999; 576: 147
• 10c Chemler SR, Trauner D, Danishefsky SJ. Angew. Chem. Int. Ed. 2001; 40: 4544
• 11a Kosugi M, Kameyama M, Migita T. Chem. Lett. 1983; 927
• 11b Wolfe JP, Rennels RA, Buchwald SL. Tetrahedron 1996; 52: 7525
• 11c Hartwig JF. Angew. Chem. Int. Ed. 1998; 37: 2046
• 11d Wolfe JP, Wagaw S, Marcoux JF, Buchwald SL. Acc. Chem. Res. 1998; 31: 805
• 11e Hartwig JF. Acc. Chem. Res. 1998; 31: 852
• 11f Hartwig JF. Pure Appl. Chem. 1999; 71: 1417
• 11g Yang BH, Buchwald SL. J. Organomet. Chem. 1999; 576: 125
• 11h Muci AR, Buchwald SL. Top. Curr. Chem. 2002; 219: 131
• 12a Nozaki K, Takahashi K, Nakano K, Hiyama T, Tang H.-Z, Fujiki M, Yamaguchi S, Tamao K. Angew. Chem. Int. Ed. 2003; 42: 2051
• 12b Kitawaki T, Hayashi Y, Ueno A, Chida N. Tetrahedron 2006; 62: 6792
• 12c Zhou Y, Verkade JG. Adv. Synth. Catal. 2010; 352: 616
• 13a Vanelle P, Maldonado J, Madadi N, Gueiffier A, Teulade J.-C, Chapat J.-P, Crozet MP. Tetrahedron Lett. 1990; 31: 3013
• 13b Crozet MP, Giraud L, Sabuco J.-F, Vanelle P, Barreau M. Tetrahedron Lett. 1991; 32: 4125
• 13c Delmas F, Gasquet M, Timon-David P, Madadi N, Vanelle P, Vaille A, Maldonado J. Eur. J. Med. Chem. 1993; 28: 23
• 13d Amiri-Attou O, Terme T, Vanelle P. Molecules 2005; 10: 545
• 13e Amiri-Attou O, Terme T, Vanelle P. Synlett 2005; 3047
• 13f Montana M, Terme T, Vanelle P. Tetrahedron Lett. 2006; 47: 6573
• 13g Curti C, Laget M, Ortiz Carle A, Gellis A, Vanelle P. Eur. J. Med. Chem. 2007; 42: 880
• 13h Crozet MD, Botta C, Gasquet M, Curti C, Remusat V, Hutter S, Chapelle O, Azas N, De Meo MP, Vanelle P. Eur. J. Med. Chem. 2009; 44: 653
• 14 2-Bromo-3-(2-bromophenyl)naphthalene-1,4-dione (3) To a mixture of 2,3-dibromonaphthalene-1,4-dione (0.786 g, 2.49 mmol) and boronic acid (0.5 g, 2.49 mol%) in toluene (10 mL) was added Pd(PPh₃)₄ (0.172 g, 0.15 mmol) and 2 M aq Na₂CO₃ solution (5 mL). The resulting mixture was stirred at 80 °C overnight. After cooling the mixture was diluted with CH₂Cl₂, washed 3 times with H₂O, and dried over MgSO₄. After filtration and evaporation, the crude product was purified by silica gel chromatography (CH₂Cl₂–PE, 5:5) giving 3 as yellow crystals, mp 126 °C, yield 1.2 g (62%). ¹H NMR (200 MHz, CDCl₃): δ = 7.22 (dd, 1 H, J = 7.4, 1.8 Hz, ArH), 7.30–7.49 (m, 2 H, ArH), 7.7 (dd, 1 H, J = 7.9, 1.2 Hz, ArH), 7.76–7.85 (m, 2 H, Ar), 8.14–8.27 (m, 2 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 122.0 (C), 127.6 (2 × CH), 127.8 (CH), 128.3 (C), 129.9 (CH), 130.8 (CH), 131.3 (C), 131.7 (C), 132.9 (CH), 134.3 (CH), 134.7 (CH), 136.2 (C), 140.4 (C), 150.2 (C), 178.0 (CO), 180.6 (CO). Anal. Calcd for C₁₆H₈Br₂O₂: C, 49.02; H, 2.06. Found: C, 49.65; H, 1.98.
• 15a Best WM, Sims CG, Winslade M. Aust. J. Chem. 2001; 54: 401
• 15b Molina TM, Navarro C, Moreno A, Csaky AG. Org. Lett. 2009; 11: 4938
• 16 General Procedure for the Double Buchwald–Hartwig Reaction for the Synthesis of 5-Substituted 5H-benzo[b]carbazole-6,11-diones 6a–k A mixture of 2-bromo-3-(2-bromophenyl)naphthalene-1,4-dione (3, 0.1 g, 0.25 mmol), aniline (1.5 g, 0.38 mmol equiv) in toluene (10 mL), K₂CO₃ (105 g, 0.76 mmol), Pd(OAc)₂ (0.0098 g, 0.05 mmol), and BINAP (0.042 g, 0.06 mmol) was placed in a 4 mL sealed vial in a Biotage microwave-reactor cavity. The mixture was irradiated at 100 °C for 2 h. After cooling, the reaction mixture was diluted with CH₂Cl₂, washed with H₂O (3 × 40 mL), and dried over MgSO₄. After filtration and evaporation, the crude product was purified by silica gel chromatography (CH₂Cl₂–PE, 5:5). 5-(4-Nitrophenyl)-5H-benzo[b]carbazole-6,11-dione (6a) Yellow solid; mp 287 °C. ¹H NMR (200 MHz, CDCl₃): δ = 7.15–7.20 (m, 1 H, ArH), 7.44–7.50 (m, 2 H, ArH), 7.65–7.79 (m, 5 H, ArH), 8.05 (dd, 2 H, J = 7.0, 1.7 Hz, ArH), 8.25 (dd, 2 H, J = 7.0, 1.0 Hz, ArH), 8.46–8.56 (m, 2 H, ArH). ¹³C NMR (50 MHz, CDCl₃): δ = 111.5 (CH), 124.1 (C), 124.2 (CH), 124.9 (2 × CH), 125.3 (CH), 126.7 (2 × CH), 128.4 (CH), 129.0 (2 × CH), 133.3 (2 × C), 133.5 (CH), 133.9 (C), 134.3 (CH), 135.3 (C), 140.5 (C), 142.5 (C), 147.9 (C), 177.7 (CO), 181.7 (CO). Anal. Calcd for C₂₂H₁₂N₂O₄: C, 71.74; H, 3.28; N, 7.61. Found: C, 71.66; H, 3.22; N, 7.61.
• 17 Compounds 5a,b were formed by the same protocol but using Cs₂CO₃ as base. 2-(2-Bromophenyl)-3-(4-nitrophenylamino)naphthlene-1,4-dione (5a) Orange solid; mp 220 °C. ¹H NMR (200 MHz, CDCl₃): δ = 6.84 (d, 2 H, J = 8.9 Hz, ArH), 6.89–7.14 (m, 3 H, ArH), 7.31 (dd, 1 H, J = 8.0, 0.7 Hz, ArH), 7.70–7.87 (m, 4 H, ArH), 7.89 (s, 1 H, NH), 8.20 (dd, 2 H, J = 7.6, 1.4 Hz, ArH). ¹³C NMR (50 MHz, CDCl₃) :δ = 119.4 (C), 122.8 (2 × CH), 123.5 (2 × CH), 124.6 (CH), 126.7 (CH), 127.2 (CH), 127.3 (CH), 129.9 (CH), 130.2 (C), 132.3 (CH), 133.0 (CH), 133.1 (C), 133.2 (C), 134.0 (C), 134.4 (CH), 140.8 (C), 143.1 (C), 143.7 (C), 181.6 (CO), 182.4 (CO). Anal. Calcd for C₂₂H₁₃BrN₂O₄: C, 58.82; H, 2.92; N, 6.24. Found: C, 85.77; H, 2.87; N, 6.33. 2-(2-Bromophenyl)-3-(phenylamino)naphthalene-1,4-dione (5b) Red solid; mp 161 °C.¹H NMR (200 MHz, CDCl₃): δ = 6.78–6.99 (m, 7 H, ArH), 7.24 (d, 1 H, J = 9.6 Hz, ArH), 7.69–7.82 (m, 3 H, ArH), 8.18 (dd, 2 H, J = 7.6, 1.4 Hz, ArH). ¹³H NMR (50 MHz, CDCl₃): δ = 116.3 (C), 124.5 (2 × CH), 125.2 (CH), 125.3 (C), 126.5 (CH), 126.6 (CH), 127.0 (CH), 127.9 (2 × CH), 129.0 (CH), 130.4 (C), 132.3 (CH), 132.5 (CH), 132.8 (CH), 133.5 (C), 134.5 (C), 135.1 (CH), 136.9 (C), 141.9 (C), 181.6 (CO), 188.9 (CO).