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

A transition metal-free synthesis of 1,2,5-trisubstituted 1<i>H</i>-indoles by a deprotonation-S_NAr 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 <i>N</i>,<i>N</i>-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.