General asymmetric synthesis of 2,2,2-trifluoro-1-(1H-indol-3- and -2-yl)ethanamines

Abstract

This work describes an asymmetric functionalization of the pyrrole ring of an indole structure with (2,2,2-trifluoro)ethylamine moiety allowing for general access to two novel classes of trifluoromethyl-containing indoles. We found that under the Friedel–Crafts reaction conditions (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine (1) easily reacts with indole derivatives affording the target 3-substituted products, while LDA-promoted reactions proceed exclusively at the 2-position. We demonstrate that both approaches feature wide substrate scope, high chemical yields and diastereoselectivities, which render these reactions readily applicable for straightforward preparation of biologically interesting compounds containing chiral CF3CH(NH2) and indole groups. The mechanistic rationales accounting for the observed mode of stereochemical preferences are proposed.