1H-Indoles from Deoxybenzoin Schiff Bases by Deprotonation—SNAr Cyclization

TL;DR

A new method for making 1H-indoles without using transition metals is described, using a sequence of deprotonation and SNAr cyclization from deoxybenzoin Schiff bases.

Contribution

The paper introduces a transition metal-free synthesis of 1,2,5-trisubstituted 1H-indoles via deprotonation–SNAr cyclization of deoxybenzoin Schiff bases.

Findings

The synthesis uses Friedel-Crafts acylation to prepare deoxybenzoins from activated aromatic compounds.

Schiff bases were formed by slow distillation of toluene from heated solutions of deoxybenzoin and amines.

Benzyl and phenethyl amines gave excellent yields, while volatile amines resulted in low yields.

Abstract

A transition metal-free synthesis of 1,2,5-trisubstituted 1H-indoles by a deprotonation–SNAr cyclization sequence from 1-aryl-2-(2-fluoro-5-nitrophenyl)ethan-1-one (deoxy-benzoin) Schiff bases is reported. The starting deoxybenzoins were prepared by Friedel-Crafts acylation of activated aromatic compounds by 2-(2-fluoro-5-nitrophenyl)acetyl chloride with AlCl3 or the corresponding acid with (CH3SO2)2O. The Schiff bases were generated by slow distillation of toluene (18–24 h) from a heated solution of each deoxybenzoin (1 equiv) with a benzyl- or phenethylamine, a high-boiling aliphatic amine, or an aniline derivative (5 equiv). Subsequent addition of N,N-dimethylformamide, 2 equiv of anhydrous K2CO3, and heating at 90–95 °C for 18–24 h completed the synthesis. Benzyl-, phenethyl-, and high-boiling amines gave excellent yields while the heating requirements for the initial condensation made volatile aliphatic amines difficult to use and gave low yields. Aniline reactivities correlated with substituent-derived base strength, although modified conditions allowed some yields to be improved. Several anticipated competing processes had minimal impact on the outcome of the cyclizations.

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