Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

Electrochemically Enabled, Nickel-Catalyzed Amination.

Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar-Cl, Ar-Br, Ar-I, Ar-OTf), amine types (primary and secondary), and even alternative X-H donors (alcohols and amides).