Simple and Mild Synthesis of Indoles via Hydroamination Reaction Catalysed by NHC–Gold Complexes: Looking for Optimized Conditions

Abstract

An efficient heterocyclization of 2-alkynylanilines to indole derivatives has been developed. The reaction proceeds under very mild conditions using small amounts of a gold precatalyst. A range of substrates possessing various functional groups were employed, and the substituted indoles were obtained in very good yields.

Key words

gold - hydroamination - heterocyclization - 2-alkynylanilines - indole

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• 17 Representative Procedure for the Gold(I)-Catalyzed Formation of Indole Derivatives To a solution of aniline derivative in hexane ([substrate] = 0.125 mol/L) in a Schlenk tube equipped with a Teflon-coated magnetic stirring bar, (IPr)AuCl followed by AgBF₄ were added.¹⁷ The reaction mixture was then stirred at 40 °C in an oil bath. At the end of the reaction (¹H NMR spectroscopy or TLC monitoring), the solvent was removed by vacuum evaporation. The resulting crude product was directly purified by flash column chromatography on silica gel (n-hexane–EtOAc) to afford the corresponding indole. Representative Product: 2-Butyl-1H-indole (2a) Following the general procedure 2a was obtained as a colorless oil (85% yield); R_f  = 0.56 [n-hexane–CH₂Cl₂ (1:1)]. ¹H NMR (400 MHz, CDCl3, 20 °C): δ = 7.85 (br s, 1 H), 7.57–7.55 (m, 1 H), 7.32–7.30 (m, 1 H), 7.18–7.08 (m, 2 H), 6.27 (s, 1 H), 2.76 (t, J = 7.6 Hz, 2 H), 1.76–1.70 (m, 2 H), 1.45 (dq J = 7.6, 15.2 Hz, 2 H), 0.99 (t, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃, 20 °C): δ = 140.0 (Cq), 135.8 (Cq), 128.8 (Cq), 120.9 (CH), 119.7 (CH), 119.6 (CH), 110.3 (CH), 99.4 (CH), 31.3 (CH₂), 27.9 (CH₂), 22.4 (CH₂), 13.9 (CH₃).
• 18 The [(IPr)Au]BF₄ (0.0025 equiv) was formed in situ by mixing (IPr)AuCl and AgBF₄ (1:3 molar).