Synthesis of Carbazoles by Gold(I)-Catalyzed Carbocyclization of 2-(Enynyl)indoles

Abstract

A new synthetic protocol for carbazoles through gold(I)-catalyzed intramolecular hydroarylation of (Z)-2-(enynyl)indoles was achieved in good yields. The requisite (Z)-2-(enynyl)indoles were synthesized stereoselectively by trimethylgallium-promoted, Z-selective Wittig olefination of N-alkylindole-2-carboxaldehydes with propargyl ylides. Substrates possessing both alkyl as well as aromatic groups are well tolerated under these reaction conditions.

Key words

(Z)-Wittig olefination - 2-(enynyl)indoles - gold catalysis - carbocyclization - carbazoles

References and Notes

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12

Typical procedure for the Z -selective Wittig olefination: To a degassed solution of propargyl ylide 4a (395 mg, 1.2 mmoL) in anhydrous THF (5 mL) under an N₂ atmosphere, was added Me₃Ga (1.0 M in hexane, 1.5 mL, 1.5 mmoL) and the mixture was stirred for 10 min at 0 ˚C. To this reaction mixture was added a solution of N-methylindole-2-carboxaldehyde (3a; 158 mg, 1.00 mmoL) in THF (5 mL) and stirring was continued for 5 h. After completion of the reaction as indicated by TLC, the reaction was quenched with ice-cold water and extracted with EtOAc (3 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography over silica gel (100-200 mesh) to afford the pure Z-isomer (154 mg, 79%) and E-isomer (27 mg, 14%). 1-Methyl-2-[( Z )-pent-1-en-3-ynyl]-1 H -indole (1a′): Brown paste. IR (neat): 2928, 1733, 1430, 1224, 1119 cm^-¹. ^¹H NMR (CDCl₃, 500 MHz): δ = 2.21 (s, 3 H, CH₃), 3.71 (s, 3 H, NCH₃), 5.77 (d, J = 11.4 Hz, 1 H, indolyl-CH=CH), 6.70 (d, J = 11.4 Hz, 1 H, indolyl-CH=CH), 7.14-7.15 (m, 1 H, ArH), 7.21-7.30 (m, 2 H, ArH), 7.55 (s, 1 H, indolyl-C(3)H), 7.69 (d, J = 7.6 Hz, 1 H, ArH). ^¹³C NMR (CDCl₃, 125 MHz): δ = 5.2, 29.5, 78.9, 95.5, 102.9, 108.5, 109.3, 119.9, 121.2, 122.5, 125.3, 127.8, 128.5, 136.1. MS (EI): m/z = 195 [M⁺]. Anal. Calcd for C₁₄H₁₃N: C, 86.12; H, 6.71; N, 7.17. Found: C, 85.98; H, 6.76; N, 7.17. 1-Methyl-2-[( E )-pent-1-en-3-ynyl]-1 H -indole(1a): Black paste.
IR (neat): 2917, 1735, 1425, 1222, 1123 cm^-¹. ^¹H NMR (CDCl₃, 500 MHz): δ = 2.08 (s, 3 H, CH₃), 3.78 (s, 3 H, NCH₃), 6.23 (d, J = 15.3 Hz, 1 H, indolyl-CH=CH), 6.75 (s, 1 H, indolyl-C(3)H), 6.96 (d, J = 16.05 Hz, 1 H, indolyl-CH=CH), 7.12 (t, J = 7.6 Hz, 1 H, ArH), 7.23 (t, J = 7.6 Hz, 1 H, ArH), 7.28 (d, J = 8.4 Hz, 1 H, ArH), 7.59 (d, J = 7.6 Hz, 1 H, ArH). ^¹³C NMR (CDCl₃, 125 MHz): δ = 4.7, 29.8, 79.3, 89.5, 99.3, 109.3, 110.4, 120.1, 120.7, 122.2, 127.8, 128.5, 137.4, 138.3. MS (EI): m/z = 195 [M⁺]. Anal. Calcd for C₁₄H₁₃N: C, 86.12; H, 6.71; N, 7.17. Found: C, 86.25; H, 6.65; N, 7.10

13

Typical procedure for the carbocyclization of ( Z )-(2-enynyl) indoles: To an air-dried Schlenk flask under N₂ atmosphere was added 5 mol% AuCl(Ph₃P) and 5 mol% AgSbF₆, followed by nitromethane (1 mL) and the mixture was stirred for 15 min at room temperature. A solution of 5a (1.0 mmoL) in nitromethane (2 mL) was added and the mixture was stirred at 60 ˚C. After completion of the reaction as indicated by TLC, the reaction was quenched in water and extracted with EtOAc (3 × 20 mL). The organic layer was dried with anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford pure 4,9-dimethyl-carbazole (2a) as a colorless solid. Mp 105-106 ˚C (Lit.^¹6 105-105.5 ˚C). IR (KBr): 3055, 3025, 2952, 2928, 2855, 1625, 1599, 1560, 1467, 1420, 1132 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.97 (s, 3 H, Ar-CH₃), 3.89 (s, 3 H, NCH₃), 7.09-7.13 (m, 1 H, ArH), 7.30-7.35 (m, 2 H, ArH), 7.45-7.50 (m, 1 H, ArH), 7.55-7.59 (m, 1 H, ArH), 8.25-8.29 (m, 1 H, ArH). ^¹³C NMR (125 MHz, CDCl₃): δ = 20.9, 29.1, 106.2, 108.4, 119.0, 120.7, 121.5, 122.5, 123.6, 125.2, 125.6, 133.6, 141.1, 141.2. MS (EI): m/z = 195 [M⁺]. Anal. Calcd for C₁₄H₁₃N: C, 86.12; H, 6.70; N, 7.08. Found: C, 85.95; H, 6.75; 7.20