Synthesis of Carbazoles and 1,2-Dihydrocarbazoles by Domino ‘Twofold Heck-6π-Electrocyclization’ Reactions of Di- and Tribromo-N-methylindoles

Abstract

The palladium(0)-catalyzed Heck cross-coupling reaction of 2,3-dibromo- and 2,3,6-tribromo-N-methylindole, using Pd(OAc)₂ as the catalyst and a novel biaryl monophosphine ligand developed by Buchwald and co-workers, afforded the corresponding di- and trialkenylindoles in high yields. The formation of 1,2-­dihydrocarbazoles by a domino ‘twofold Heck-6π-electrocyclization’ was observed when the reaction was carried out at 120 ˚C rather than 90 ˚C.

Key Words

cross-coupling - electrocyclic reactions - nitrogen heterocycles - Heck reaction - palladium

References and Notes

• Reviews:
• 1a Brossi A. In The Alkaloids   Vol. 26:  Cordell GA. Academic Press; New York: 1985.  p.1 
• 1b Bhattacharrya P. Chakraborthy DP. Prog. Chem. Org. Nat. Prod.  1987,  52:  160 
• 1c Maryanoff BE. Reitz AB. Chem. Rev.  1989,  89:  863 
• 1d Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 
• 1e Chakraborty DP. Roy S. Prog. Chem. Org. Nat. Prod.  1991,  57:  71 
• 1f Chakraborty DP. In The Alkaloids   Vol. 44:  Cordell GA. Academic Press; New York: 1993.  p.257 
• 1g Knölker H.-J. Top. Curr. Chem.  2005,  244:  115 
• 1h Knölker H.-J. Reddy KR. In The Alkaloids   Vol. 65:  Cordell GA. Academic Press; Amsterdam: 2008.  p.1 
• 1i Pindur U. Chimia  1990,  44:  406 
• 1j Bergman J. Pelcman B. Pure Appl. Chem.  1990,  62:  1967 
• 1k Moody CJ. Synlett  1994,  681 
• 1l Kirsch GH. Curr. Org. Chem.  2001,  5:  507 
• 1m Lemster T. Pindur U. Recent Res. Dev. Org. Bioorg. Chem.  2002,  5:  99 
• 1n Knölker H.-J. Curr. Org. Synth.  2004,  1:  309 
• For some recent contributions, see:
• 2a Bedford RB. Betham M. J. Org. Chem.  2006,  71:  9403 
• 2b Lebold TP. Kerr MA. Org. Lett.  2007,  9:  1883 
• 2c Watanabe T. Ueda S. Inuki S. Oishi S. Fujii N. Ohno H. Chem. Commun.  2007,  4516 
• 2d Jean DJ. Poon SF. Schwarzbach JL. Org. Lett.  2007,  9:  4893 
• 2e Liu C.-Y. Knochel P. J. Org. Chem.  2007,  72:  7106 
• 2f Naffziger MR. Ashburn BO. Perkins JR. Carter RG. J. Org. Chem.  2007,  72:  9857 
• 3a Forke R. Krahl MP. Däbritz F. Jäger A. Knölker H.-J. Synlett  2008,  1870 
• 3b Forke R. Krahl MP. Krause T. Schlechtingen G. Knölker H.-J. Synlett  2007,  268 
• 4 Ackermann L. Althammer A. Angew. Chem. Int. Ed.  2007,  46:  1627 
• 5 Pindur U. Heterocycles  2008,  27:  1253 
• 6 Kano S. Sugino E. Shibuya S. Hibino S. J. Org. Chem.  1981,  46:  3856 
• 7 Pindur U. Adam R. Helv. Chim. Acta  1990,  73:  827 
• 8 Review: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
• 9 Dang TT. Rasool N. Dang TT. Reinke H. Langer P. Tetrahedron Lett.  2007,  48:  845 
• 10 Dang TT. Dang TT. Ahmad R. Reinke H. Langer P. Tetrahedron Lett.  2008,  49:  1698 
• 11 Dang TT. Villinger A. Langer P. Adv. Synth. Catal.  2008,  350:  2109 
• 12 Liu Y. Gribble GW. Tetrahedron Lett.  2000,  41:  8717 
• 13 Voigt K. von Zezschwitz P. Rosauer K. Lansky A. Adams A. Reiser O. de Meijere A. Eur. J. Org. Chem.  1998,  1521 ; and references cited therein
• 14 Tang S. Li J.-H. Xie Y.-X. Wang N.-X. Synthesis  2007,  1535 
• 16 Billingsley K. Buchwald SL. J. Am. Chem. Soc.  2007,  129:  3358 ; and references cited therein.
• 17 Li HJ. Wang L. Eur. J. Org. Chem.  2006,  5099 
• 20 Kawasaki I. Yamashita M. Ohta S. Chem. Pharm. Bull.  1996,  44:  1831 

15

Synthesis of 2,3-Dibromo- N -methylindole (2a) To a THF solution (20 mL) of N-methylindole (1, 1.0 mL, 8.0 mmol) was added portionwise NBS (3.30 g, 18.4 mmol) at -78 ˚C, and the soln was stirred at this temperature for 4 h. To the soln was added water (25 mL). The organic and the aqueous layer were separated and the latter was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with a saturated aqueous soln of NaHCO₃, dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified by flash silica column chromatography (pure heptanes) to yield 2a as a colorless solid (1.83 g, 90%).

18

General procedure for Heck cross-coupling reactions. In a pressure tube (glass bomb) a suspension of Pd(OAc)₂ (12 mg, 0.05 mmol, 1.25 mol% per Br) and dicyclohexyl (2",6"-dimethoxybiphenyl-2-yl) phosphine (L) (41 mg, 0.10 mmol) in DMF (5 mL) was purged with argon and stirred at 20 ˚C to get a yellowish or brownish transparent soln. To the stirred soln were added the brominated indole 2a,b (1.0 mmol), Et₃N (1.1 mL, 8.0 mmol) and the acrylate (1.25 equiv. per Br). The reaction mixture was stirred at 120 ˚C for 48 h. The soln was cooled to 20 ˚C, poured into H₂O, and CH₂Cl₂ (25 mL each), and the organic and the aqueous layer were separated. The latter was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with H₂O (3 × 20 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc).
Diethyl 9-Methyl-2,9-dihydro-1 H -carbazole-2,3-dicarboxylate (5b) Product 5b was prepared starting with 2a (367 mg, 1.0 mmol) as a yellow solid (297 mg, 93%), mp 100-103 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 1.10 (s, 3 H, CH₃), 1.30 (s, 3 H,CH₃), 2.90 (dd, 1 H_α, J = 8.8, 17.1 Hz, H-1), 3.50 (dd, 1 H_β, J = 2.6, 17.2 Hz, H-1), 3.60 (s, 3 H, NCH₃), 3.90-4.10 (m, 3 H, H_α and CH₂O), 4.20 (q, J = 7.1, 13.5 Hz, 2 H, CH₂O), 7.10-7.20 (m, 3 H, ArH), 7.50-7.60 (m, 1 H, ArH), 7.90 (s, 1 H, H-4). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.0 (CH₃), 13.5 (CH₃), 22.8 (CH₂), 28.7 (CH, C-4), 37.7 (NCH₃), 59.3 (CH₂O), 60.1 (CH₂O), 108.3 (C), 108.6 (CH), 115.4 (C), 116.9, 120.0, 120.8 (CH), 124.1(C), 131.2 (CH), 137.0, 138.6 (C), 166.3, 172.3 (CO). IR (KBr): ν = 2981, 2928, 2854(w), 1725(s), 1629, 1599(w), 1470 1454(m), 1372, 1261, 1238(s), 1109, 1079, 147(m), 787, 747, 723, 608, 561(w)cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 325(89) [M - 2]⁺(carbazole), 280(13), 252(100), 208(07), 179(13). HRMS (ESI⁺): m/z calcd for C₁₉H₁₉NO₄ [M - 2]⁺(carbazole): 325.13141; found: 325.13161.

19

Dibutyl 9-Methyl-9 H -carbazole-2,3-dicarboxylate (6)
To xylene (5 mL) were added 5c (100 mg, 0.26 mmol) and Pd/C (10 mg, 10 mol%). The soln was stirred under reflux for 48 h under argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 6 as a light yellow solid (99 mg, 100%). ^¹H NMR (250 MHz, CDCl₃): δ = 0.90 (t, 3 H, J = 7.4 Hz, CH₃), 0.90 (t, 3 H, J = 7.3 Hz, CH₃), 1.30-1.50 (m, 4 H, 2 CH₂), 1.60-1.80 (m, 4 H, 2 CH₂), 3.80 (s, 3 H, NCH₃), 4.30 (t, 2 H, J = 6.8 Hz, CH₂O), 4.30 (t, 2 H, J = 6.7 Hz, CH₂O), 7.20-7.30 (m, 1 H, ArH), 7.30-7.40 (m, 1 H, ArH), 7.40-7.50 (m, 1 H, ArH), 7.60 (s, 1 H, H-1), 8.00-8.10 (m, 1 H, ArH), 8.40 (s, 1 H,
H-4). ^¹³C NMR (62 MHz, CDCl₃): δ = 13.7, 13.8 (CH₃), 19.2, 19.3 (CH₂), 29.4 (NCH₃), 30.6, 30.8 (CH₂), 65.3, 65.7 (CH₂O), 109.0, 109.1, 120.2, 121.0 (CH), 121.7, 122.2 (C), 122.4 (CH), 123.6 (C), 127.1 (CH), 131.1, 141.5, 142,1 (C), 167.9, 169.4 (CO). IR (KBr): ν = 2956, 2931, 2871(w), 1709(s), 1464, 1387, 1362, 1340, 1325(m)1255, 1221(s), 1131, 1106, 1077, 1045(m), 950, 902, 843, 829(w), 784, 743, 721(m), 632, 608, 561(w)cm^-¹. GC-MS (EI, 70 eV):
m/z (%) = 381(56) [M⁺], 308(15), 280(100), 224(87), 212(27), 206(77), 180(10), 152(11). HRMS (EI, 70 eV):
m/z calcd for C₂₃H₂₇NO₄ [M⁺]: 381.19401; found: 381.19422.