Pd(ii)-catalyzed meta-C-H bromination and chlorination of aniline and benzoic acid derivatives

Abstract

The classic electrophilic bromination leads to ortho- and para-bromination of anilines due to their electron-rich properties. Herein we report the development of an unprecedented Pd-catalyzed meta-C-H bromination of aniline derivatives using commercially available N-bromophthalimide (NBP), which overcomes the competing ortho/para-selectivity of electrophilic bromination of anilines. The addition of acid additives is crucial for the success of this reaction. A broad range of substrates with various substitution patterns can be tolerated in this reaction. Moreover, benzoic acid derivatives bearing complex substitution patterns are also viable with this mild bromination reaction, and meta-C-H chlorination is also feasible under similar reaction conditions. The ease of the directing group removal and subsequent diverse transformations of the brominated products demonstrate the application potential of this method and promise new opportunities for drug discovery.