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

Munawar Hussain; Đãng Thanh Tùng; Peter Langer

doi:10.1055/s-0029-1217357

LETTER

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

Munawar Hussain^a, Đãng Thanh Tùng^a, Peter Langer*^a,b
^a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
^b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: peter.langer@uni-rostock.de;

Abstract

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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

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Referenzen

References and Notes

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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%).

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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.

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.

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