Palladium-Catalyzed Indole and Azaindole Synthesis by Direct Annulation of Electron-Poor o-Chloroanilines and o-Chloroaminopyridines with Aldehydes

Abstract

A practical process for the synthesis of 2-unsubstituted indoles and azaindoles has been developed by the palladium-catalyzed direct annulation of electron-poor o-chloro/bromoanilines and o-chloroaminopyridines with aldehydes. Coupled with the previous results of Jia and Zhu, this allows rapid access to a variety of 2-unsubstituted indoles and azaindoles starting from simple and easily accessible precursors.

Key words

indole - azaindole - palladium - annulation - ligand

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11

Reaction of o-chloroaniline with phenylacetaldehyde (1.0 equiv or 3.0 equiv) gave the expected indole in 55 and 70% yield, respectively. Reaction of 2-chloro-5-methoxyaniline with methyl (S)-2-N,N-di-tert-butoxycarbonyl-5-oxo­-pentanoate (1.0 equiv or 3.0 equiv) gave the 6-methoxy-tryptophan derivative in 21 and 25% yield, respectively. Reaction of 2-chloro-5-methylaniline with phenylacet-aldehyde (1.0 equiv or 3.0 equiv) gave the 5-methyl-3-phenyl-1H-indole in 56 and 67% yield, respectively. ^¹H NMR (300 MHz, CDCl₃): δ = 8.08 (br s, 1 H), 7.77 (s, 1 H), 7.70 (dd, J = 1.2, 7.4 Hz, 2 H), 7.49 (t, J = 7.4 Hz, 2 H), 7.35-7.31 (m, 3 H), 7.10 (d, J = 8.4 Hz, 1 H), 2.52 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 135.7, 134.9, 129.6, 128.7, 127.5, 125.9, 125.8, 124.0, 121.9, 119.4, 117.8, 111.0, 21.6.