Electrochemically Driven Nickel Catalysis for Formal C-H Amination

Abstract

The C-H amination of arenes represents a streamlined approach to arylamines, yet most existing methods rely on preactivated nitrogen reagents or directing groups, limiting practicality and substrate generality. Herein, we report a nickel-catalyzed electroreductive formal C-H amination of aryl bromides with secondary amines, enabling efficient access to 4bromomorpholinobenzene derivatives. This halogen-enabled strategy enables formal C-H amination through transient bromine removal and reinstallation. The reaction employs electricity as a traceless redox reagent, proceeds under mild conditions without stoichiometric chemical oxidants, and exhibits broad functional group tolerance. Mechanistic studies suggest that the transformation involves electrochemically generated Ni(0) species and nitrogen-centered radicals, followed by nickel-mediated C-N bond formation and subsequent bromination. The synthetic utility of this protocol is demonstrated by gram-scale reactions, diverse downstream transformations, and a concise synthesis of the pharmaceutically relevant scaffold Entospletinib.