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

•Asymmetric functionalization of indoles with CF3CH(NH2) was accomplished. 2-Substitued product was obtained by reaction of 2-lithiated indoles and CF3-imine. Preparation of the 3-substituted isomers was achieved by Friedel–Crafts reactions.•These methods provide a way to fluorinated indoles of pharmaceutical potential.

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.

Graphical abstractWe described asymmetric functionalization of indoles with (2,2,2-trifluoro)ethylamine moiety by using chiral CF3-imine as a common reagent with chemo-selectivity in the positions-2 or -3, which proceeded through Mannich reaction and Friedel–Crafts reaction, respectively.Figure optionsDownload full-size imageDownload as PowerPoint slide