Copper-Catalyzed Synthesis of β- and δ-Carbolines by Double N-Arylation of Primary Amines

Abstract

Two efficient and practical approaches are reported for the synthesis of β- and δ-carbolines from 3,4-dibromopyridine. The synthesis is based on site-selective Cu-catalyzed double C–N coupling reactions and subsequent annulations by twofold Pd-catalyzed C–N coupling with amines.

Key words

catalysis - heterocycles - cross-coupling - cyclizations - copper

Publication History

Received: 02 February 2021

Accepted after revision: 21 March 2021

Article published online:
31 March 2021

• References and Notes

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• 20 Preparation of 3-Bromo-2-(2-bromophenyl)pyridine (1a) 2,3-Dibromopyridine (2.00 g, 8.44 mmol), 2-bromophenyl boronic acid (1.70 g, 8.44 mmol), and Pd(PPh₃)₄ (488 mg, 0.422 mmol) were added to a 250 mL Schlenk flask. The mixture was backfilled several times with argon. To the mixture were added K₂CO₃ (1 M, 25 mL), 5 drops of aqueous KOH (10%) and 35 mL of THF, then backfilled several times with argon. The reaction was heated at 70 °C for 18 h. The solvent was evaporated in vacuo. The residue was extracted with ethyl acetate and water. The organic layer was dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The yellow residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 20:1) to yield 3-bromo-2-(2-bromophenyl)pyridine (1a)^17s (2.20 g, 85%) as a colorless oil.
• 21 General Procedure for the Synthesis of 5H-Pyrido[3,2-b]indoles 3a–o 3-Bromo-2-(2-bromophenyl)pyridine (1a, 100 mg, 0.32 mmol), 4-fluoroaniline (116 mg, 0.958 mmol), copper(I) iodide (12 mg, 0.064 mmol, Aldrich, 99%), l-proline (11 mg, 0.096 mmol), and K₂CO₃ (132 mg, 0.958 mmol) were dissolved in DMSO (1.5 mL) and heated at 120 °C for 24 h. After cooling, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 5:1) to yield 5-(4-methylbenzyl)-5H-pyrido[3,2-b]indole (3b, 85 mg, 95%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.57 (s, 1 H), 8.46 (s, 1 H), 7.65 (s, 1 H), 7.56–7.50 (m, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 6.8 Hz, 2 H), 7.07 (d, J = 7.9 Hz, 2 H), 7.01 (d, J = 7.9 Hz, 2 H), 5.47 (s, 2 H), 2.29 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 141.4, 137.5, 133.5, 129.6, 127.9, 126.4, 120.2, 109.3, 21.1. HRMS (ESI): m/z calcd for C₁₉H₁₆N₂ [M + 1]⁺: 273.1386; found: 273.1401.
• 22 Preparation of 3-Bromo-4-(2-bromophenyl)pyridine (1b) 3,4-Dibromopyridine (2.00 g, 8.44 mmol), 2-bromophenylboronic acid (1.70 g, 8.44 mmol), and Pd(PPh₃)₄ (488 mg, 0.422 mmol) were added to a 250 mL Schlenk flask. The mixture was backfilled several times with argon. To the mixture were added K₂CO₃ (1 M, 25 mL), 5 drops of aqueous KOH (10%), and 35 mL of THF, then backfilled several times with argon. The reaction was heated at 70 °C for 18 h. The solvent was evaporated in vacuo. The residue was extracted with ethyl acetate and water. The organic layer was dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 20:1) to yield 3-bromo-4-(2-bromophenyl)pyridine (1b)^17m (2.30 g, 80%) as a colorless syrup.
• 23 General Procedure for the Synthesis of 9H-pyrido[3,4-b]indoles 4a–h 3-Bromo-2-(2-bromophenyl)pyridine (1a, 100 mg, 0.32 mmol), 4-fluoroaniline (116 mg, 0.958 mmol), copper(I) iodide (15.4 mg, 0.08 mmol), l-proline (11 mg, 0.096 mmol), and K₂CO₃ (132 mg, 0.958 mmol) were dissolved in DMSO (1.5 mL) and heated at 160 °C for 24 h. After cooling, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over MgSO₄, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 5:1) to yield 9-phenethyl-9H-pyrido[3,4-b]indole (4e, 61 mg, 70%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 8.72 (s, 1 H), 8.43 (d, J = 4.9 Hz, 1 H), 8.14 (dt, J = 7.9, 1.0 Hz, 1 H), 7.95 (d, J = 5.2 Hz, 1 H), 7.56 (ddd, J = 8.4, 7.1, 1.2 Hz, 1 H), 7.39–7.33 (m, 1 H), 7.32–7.23 (m, 2 H), 7.25–7.20 (m, 1 H), 7.23–7.17 (m, 2 H), 7.17 (ddt, J = 7.7, 5.7, 1.6 Hz, 1 H), 7.11–7.05 (m, 2 H), 4.59 (t, J = 7.4 Hz, 2 H), 3.15 (t, J = 7.4 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 141.1, 138.5, 138.2, 131.7, 128.8, 128.7, 128.7, 128.6, 128.5, 126.9, 126.4, 122.0, 121.1, 119.8, 109.4, 45.3, 35.5. HRMS (ESI): m/z calcd for C₁₉H₁₆N₂ [M + 1]⁺: 273.1386; found: 273.1400.