A Mild Approach for the Synthesis of Indoles from N-(2-Iodo-aryl)form­amides and Phenylacetylene by a Copper(I)- and Palladium-Catalyzed Cascade Process

Abstract

An efficient one-pot copper(I)- and palladium-catalyzed synthesis of indoles from N-(2-iodo-aryl)formamides and phenyl­acetylene is described. The cascade reaction comprises a Sonogashira cross-coupling, an intramolecular C–N bond formation, and hydrolysis of the intermediate indole-1-carbaldehyde promoted by the same catalyst and base systems.

Key words

indole - cascade reaction - copper(I) and palladium catalyst - N-(2-iodo-aryl)formamide - hydrolysis

• References and Notes

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• 17 General Procedure for the Synthesis of Indoles 5 To a DMF (5 mL) solution of a mixture of 4 (1 mmol), phenylacetylene (2, 1.010 mmol), and PCy₃ (0.25 mmol) in a two-necked round-bottomed flask fitted with condenser, Et₃N (7 equiv), Pd(OAc)₂ (5 mol%), and CuI (10 mol%) were added, and the reaction mixture was allowed to stir at 110 °C under argon atmosphere. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was allowed to cool to r.t, diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined organic layers we dried over Na₂SO₄, filtered, and concentrated in vacuum to furnish the crude product which was then purified by column chromatography using silica gel (60–120 mesh) and PE–EtOAc (10:1) as eluent. 5-Methyl-2-phenyl-1H-indole (5a) White solid; mp 210–211 °C. ¹H NMR (200 MHz, CDCl₃): δ = 8.11 (s, 1 H), 7.56–7.52 (m, 2 H), 7.36–7.14 (m, 5 H), 6.93(d, J = 8.2 Hz, 1 H), 6.65(d, J = 1.4 Hz, 1 H), 2.36 (s, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 138.1, 135.3, 132.7, 129.7, 129.6, 129.2, 127.8, 125.2, 124.2, 120.5, 110.8, 99.7, 21.7. Anal. Calcd (%) for C₁₅H₁₃N: C, 86.92; H, 6.32; N, 6.76. Found: C, 86.84; H, 6.41; N, 6.70