Synthesis of 6H-Isoindolo[2,1-a]indol-6-ones via Palladium-Catalyzed Carbonylative Cyclization of 2-(2-Bromophenyl)-1H-indoles

Abstract

2-(2-Bromophenyl)-1H-indoles are carbonylatively cyclized under carbon monoxide pressure in toluene in the presence of a catalytic amount of PdCl₂ and PPh₃ along with a base to give 6H-isoindolo[2,1-a]indol-6-ones in high yields.

Key words

carbonylation - cyclization - heterocycles - indolones - catalysis

• References and Notes

• 1 Guillaumel J, Léonce S, Pierré A, Renard P, Pfeiffer B, Peruchon L, Arimondo PB, Monneret C. Oncol. Res. 2003; 13: 537
• 2 Guillaumel J, Léonce S, Pierré A, Renard P, Pfeiffer B, Arimondo PB, Monneret C. Eur. J. Med. Chem. 2006; 41: 379
• 3 Samorson S, Bremner JB, Ball A, Lewis K. Bioorg. Med. Chem. 2006; 14: 857
• 4 Ambrus JI, Kelso MJ, Bremner JB, Ball AR, Casadei G, Lewis K. Bioorg. Med. Chem. Lett. 2008; 18: 4294
• 5 Itahara T. Synthesis 1979; 151
• 6 Itahara T. Bull. Chem. Soc. Jpn. 1981; 54: 305
• 7 Itahara T. Heterocycles 1986; 24: 2557
• 8 He H.-F, Dong S, Chen Y, Yang Y, Le Y, Bao W. Tetrahedron 2012; 68: 3112
• 9 García A, Rodríguez D, Castedo L, Saá C, Domínguez D. Tetrahedron Lett. 2001; 42: 1903
• 10 Ponpandian T, Muthusubramanian S. Tetrahedron Lett. 2012; 53: 4248
• 11 Crawford LA, Clemence NC, McNab H, Tyas RG. Org. Biomol. Chem. 2008; 6: 2334
• 12 Kadam HK, Tilve SG. Eur. J. Org. Chem. 2013; 4280
• 13 Duncanson P, Cheong Y.-K, Motevalli M, Griffiths DV. Org. Biomol. Chem. 2012; 10: 4266
• 14 Tang T, Jiang X, Wang J.-M, Sun Y.-X, Zhu Y.-M. Tetrahedron 2014; 70: 2999
• 15 Colquhoun HM, Thompson DJ, Twigg MV. Carbonylation: Direct Synthesis of Carbonyl Compounds 1991
• 16 Tsuji J. Palladium Reagents and Catalysis . Wiley; Chichester: 1995
• 17 Handbook of Organopalladium Chemistry for Organic Synthesis. Vol. 2. Negishi E. Wiley; New York: 2002
• 18 In Modern Carbonylation Methods . Kollár L. Wiley-VCH; Weinheim: 2008
• 19 Brennführer A, Neumann H, Beller M. Angew. Chem. Int. Ed. 2009; 48: 4114
• 20 Grigg R, Mutton SP. Tetrahedron 2010; 66: 5515
• 21 Cho CS, Shim HS. Tetrahedron Lett. 2006; 47: 3835
• 22 Cho CS, Kim JU, Choi H.-J. J. Organomet. Chem. 2008; 693: 3677
• 23 Cho CS, Kim HB. Catal. Lett. 2010; 140: 116
• 24 Cho CS, Kim HB, Lee SY. J. Organomet. Chem. 2010; 695: 1744
• 25 Lee HK, Cho CS. Appl. Organomet. Chem. 2012; 26: 185
• 26 Lee HK, Cho CS. Appl. Organomet. Chem. 2012; 26: 406
• 27 Cho CS, Son JI, Yoon NS. Appl. Organomet. Chem. 2012; 26: 499
• 28 Bae YK, Cho CS. Synlett 2013; 24: 1848
• 29 Yoon IC, Cho CS. Appl. Organomet. Chem. 2015; 29: 226
• 30 While this manuscript was being prepared, Chinese researchers announced a palladium-catalyzed carbonylative cyclization of 2-(2-iodophenyl)-1H-indoles leading to 6H-isoindolo[2,1-a]indol-6-ones via a patent. However, compared with their results, higher product yields were observed with our conditions. See: Huang Q, Fu S, Li B, Zhang X, Lin S. CN Patent 104892614, 2015
• 31 Not shown in Table 1, the reaction also proceeded under 1 atm of carbon monoxide to produce 2a in 69% yield.
• 32 6H-Isoindolo[2,1-a]indol-6-ones; General Procedure: To a 50-mL stainless steel autoclave were added 1 (0.5 mmol), PdCl₂ (0.004 g, 0.025 mmol), PPh₃ (0.013 g, 0.05 mmol), base (3 mmol) and solvent (5 mL). After the system was flushed and then pressurized with carbon monoxide, the reaction mixture was allowed to react at 80–110 °C for 5 h. The mixture was then cooled to r.t., and filtered through a short column of silica gel (EtOAc) to remove inorganic salts. Removal of the solvent left a crude mixture, which was separated by thin layer chromatography [silica gel 60 GF₂₅₄ (Merck), MeOH–CH₂Cl₂] to give the desired products 2. Except for the known 2a–d, 2g and 2m,^{14 ,33} all new products prepared by the above procedure were characterized spectroscopically as shown below. 4-Chloro-6H-isoindolo[2,1-a]indol-6-one (2e): solid; yield: 104 mg (82%); mp 182–183 °C. ¹H NMR (500 MHz, CDCl₃): δ = 6.61 (s, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 7.22 (dd, J = 7.9, 1.0 Hz, 1 H), 7.29 (dd, J = 7.7, 0.9 Hz, 1 H), 7.33–7.36 (m, 1 H), 7.48–7.53 (m, 2 H), 7.74 (d, J = 7.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 103.13, 119.55, 120.56, 121.11, 124.85, 125.74, 127.94, 129.38, 132.57, 133.42, 133.94, 134.11, 137.49, 140.99, 161.19. Anal. Calcd for C₁₅H₈ClNO: C, 71.02; H, 3.18; N, 5.52. Found: C, 70.88; H, 3.15; N, 5.60. 2,4-Dichloro-6H-isoindolo[2,1-a]indol-6-one (2f): solid; yield: 101 mg (70%); mp 249–250 °C. ¹H NMR (500 MHz, CDCl₃): δ = 6.80 (s, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.39–7.44 (m, 1 H), 7.56–7.60 (m, 2 H), 7.80 (d, J = 7.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 101.30, 118.23, 121.43, 124.64, 125.59, 126.07, 128.35, 129.86, 133.09, 133.14, 133.78, 134.52, 135.71, 141.42, 161.21. Anal. Calcd for C₁₅H₇Cl₂NO: C, 62.53; H, 2.45; N, 4.86. Found: C, 62.43; H, 2.50; N, 4.95. 11-Butyl-6H-isoindolo[2,1-a]indol-6-one (2h): solid; yield: 103 mg (75%); mp 68–69 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.87 (t, J = 7.4 Hz, 3 H), 1.31–1.40 (m, 2 H), 1.59–1.66 (m, 2 H), 2.75 (t, J = 7.6 Hz, 2 H), 7.02–7.07 (m, 1 H), 7.15–7.20 (m, 2 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.36–7.43 (m, 2 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.14, 22.88, 24.62, 32.13, 113.54, 120.62, 120.81, 121.32, 123.69, 125.42, 126.54, 128.17, 133.61, 133.86, 134.14, 134.60, 135.17, 135.34, 162.41. Anal. Calcd for C₁₉H₁₇NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.80; H, 6.15; N, 5.20. 11-Butyl-2-chloro-6H-isoindolo[2,1-a]indol-6-one (2i): solid; yield: 94 mg (61%); mp 130–131 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.86 (t, J = 7.2 Hz, 3 H), 1.28–1.37 (m, 2 H), 1.53–1.61 (m, 2 H), 2.64 (t, J = 7.6 Hz, 2 H), 7.06 (dd, J = 8.4, 2.0 Hz, 1 H), 7.16–7.21 (m, 2 H), 7.34–7.39 (m, 2 H), 7.57–7.60 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.12, 22.90, 24.56, 32.06, 114.27, 119.88, 120.45, 121.54, 125.59, 126.47, 128.61, 129.30, 132.10, 133.85, 133.92, 134.87, 135.84, 136.60, 162.20. Anal. Calcd for C₁₉H₁₆ClNO: C, 73.66; H, 5.21; N, 11.44. Found: C, 73.60; H, 5.14; N, 11.60. 11-Heptyl-6H-isoindolo[2,1-a]indol-6-one (2j): solid; yield: 116 mg (73%); mp 64–66 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.78 (t, J = 6.8 Hz, 3 H), 1.14–1.37 (m, 8 H), 1.61–1.68 (m, 2 H), 2.74 (t, J = 7.6 Hz, 2 H), 7.03–7.07 (m, 1 H), 7.15–7.21 (m, 2 H), 7.29–7.31 (m, 1 H), 7.37–7.44 (m, 2 H), 7.64–7.66 (m, 1 H), 7.76–7.78 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.27, 22.85, 24.91, 29.34, 29.78, 30.01, 31.97, 113.55, 120.64, 120.89, 121.33, 123.70, 125.44, 126.55, 128.18, 133.61, 133.88, 134.16, 134.60, 135.20, 135.35, 162.44. Anal. Calcd for C₂₂H₂₃NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.10; H, 7.25; N, 4.48. 11-Isopropyl-6H-isoindolo[2,1-a]indol-6-one (2k): solid; yield: 95 mg (73%); mp 114–115 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.51 (d, J = 7.5 Hz, 6 H), 3.46 (sept, J = 7.5 Hz, 1 H), 7.12–7.16 (m, 1 H), 7.26–7.33 (m, 2 H), 7.49–7.53 (m, 1 H), 7.54–7.56 (m, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.76–7.78 (m, 1 H), 7.90–7.92 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 22.46, 26.57, 113.78, 121.99, 122.13, 123.59, 125.53, 126.56, 127.08, 128.22, 133.41, 133.64, 134.03, 134.20, 134.30, 135.26, 162.56. Anal. Calcd for C₁₈H₁₅NO: C, 82.73; H, 5.79; N, 5.36. Found: C, 82.60; H, 5.82; N, 5.43. 2-Chloro-11-isopropyl-6H-isoindolo[2,1-a]indol-6-one (2l): solid; yield: 109 mg (74%); mp 197–198 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.49 (d, J = 7.0 Hz, 6 H), 3.40 (sept, J = 7.0 Hz, 1 H), 7.21 (dd, J = 8.3, 1.5 Hz, 1 H), 7.29–7.32 (dt, J = 7.5, 1.0 Hz, 1 H), 7.49–7.52 (m, 2 H), 7.61 (d, J = 7.5 Hz, 1 H), 7.74 (d, J = 7.5 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 22.37, 26.43, 114.38, 121.69, 122.30, 125.60, 126.08, 126.42, 128.57, 129.03, 132.36, 133.81, 133.99, 134.61, 134.89, 135.18, 162.26. Anal. Calcd for C₁₈H₁₄ClNO: C, 73.10; H, 4.77; N, 4.74. Found: C, 73.30; H, 4.68; N, 4.80.
• 33 Signori AM, Latocheski E, Albuquerque BL, Faggion D, Bisol TB, Meier L, Domingos JB. New J. Chem. 2015; 39: 1574