Facile, Metal-free, Highly Para-Selective Room Temperature Monobromination of Aniline Analogs

Abstract

A highly para-selective, room temperature, direct bromination of aniline and analogs with N-bromosuccinimide is reported herein. Benzylic bromination was not observed in substrates with competing benzylic hydrogens. Cyano, amide, ester, carboxylic acid, methoxy, N-alkyl and N,N-dialkyl groups, morpholine, and piperazine rings were tolerated. Gram-scale reaction was demonstrated with selected substrates. This para-selective bromination methodology was used in our one-pot sequential chlorination and iodination demonstrative synthesis of mixed dihalo- and trihalo-aniline analogs. The ortho-para transition states and the corresponding sigma complexes’ energy differences were determined to account for the high para-selectivity of aniline bromination. Both differences are comparable in values, but the energy difference for the sigma complexes is slightly greater than the energy difference of the transition states.