Amination by lithium alkylamide reagents of ketimines derived from 2-(trifluoromethyl)anilines and methyl halophenyl ketones and their cyclization products 2-(halophenyl)quinolin-4-amines

Abstract

The title ketimines containing a fluorine atom at position 2 of the phenyl group are efficiently cyclized under mild conditions to N-[2-(dimethylamino)ethyl]-2-(2-fluorophenyl)quinolin-4-amines by the reaction with a lithium reagent derived from N, N-dimethylethylenediamine. The facile regioselective displacement of C2-F in the presence of another fluorine atom at the phenyl group by the same reagent or N-lithio- N′-methylpiperazide at a higher temperature is explained in terms of a complex induced proximity effect (CIPE) process. The CIPE process is operative in amination of the 2-fluorophenyl ketimines by the more reactive piperazide reagent prior cyclization to quinolines. The 2-chlorophenyl derivatives are much less reactive in the CIPE assisted amination.