Two-step, regioselective, multigram-scale synthesis of 2-(trifluoromethyl)indoles from 2-nitrotoluenes

Abstract The acylation of 2-nitrotoluenes using ethyl trifluoroacetate, one of the least expensive sources of a trifluoromethyl group, produces intermediate 2-nitrobenzyl trifluoromethyl ketones which, without the need for isolation, are cyclized under the action of Zn/AcOH providing 2-(trifluoromethyl)indoles unsubstituted at the C3 position. The developed method avoids the use of expensive catalysts and harsh reaction conditions. The method is readily scalable without a significant decrease in performance upon going from 10- to 250-mmol scale.