Convenient preparation of 1-(indol-3-yl)-2,2,2-trifluoroethylamines via Friedel–Crafts reaction of α-trifluoroacetaldehyde hemiaminal

Electrophilic substitution of indole with trifluoroacetaldehyde hemiaminals 1a–f, prepared from primary amines and trifluoroacetaldehyde ethyl hemiacetal (TFAE), proceeds readily in the presence of Lewis acids. Formation of N-alkyl 1-(indol-3-yl)-2,2,2-trifluoroethylamines (2) is preferred in the presence of BF3, but yield of 2,2,2-trifluoroethyl alcohol (3) markedly increases when ZnI2 is used. A stereochemistry study clearly showed that ethylamines 2e and 2f are produced with high diastereoselective excess when the optically active hemiaminals 1e and 1f are used.