Nickel-Catalyzed Electro-Reductive Cross-Coupling of Aliphatic Amides with Alkyl Halides as a Strategy for Dialkyl Ketone Synthesis: Scope and Mechanistic Investigations

The development and in-depth study of a novel catalytic method relying on the combination of nickel catalysis and electrochemistry for the cross-electrophile coupling of alkyl amides with alkyl halides is described. This methodology takes advantages of the stability and simple access of N-acyl imides as coupling partners for the selective synthesis of dissymmetric dialkyl ketones. Noteworthy, the developed electrochemical protocol affords selective access to linear alkyl ketones when using primary alkyl bromides featuring different chain length. Mechanistic studies including cyclic voltammetry, stoichiometric reactions, and isolation of catalytic intermediates provide a set of fundamental insights into monovalent (bpy)nickel-mediated activation of alkyl halides and alkyl amides. Alkyl bromides react with electrogenerated (bpy)Ni(I) species via single-electron oxidation to give alkyl radicals. N-acyl imides are shown to undergo spontaneous C-N bond oxidative addition at both (bpy)Ni(0) and (bpy)Ni(I) species leading to Ni(II) acyl intermediates. A stable nickel(II) acyl complex has also been isolated and fully characterized, and its catalytic competency is demonstrated. Finally, electrogenerated (bpy)Ni(I)-acyl species are shown to react with both alkyl bromide and alkyl amides. Overall, these investigations allowed for a comprehensive mechanistic picture of this selective cross-electrophile coupling to be assembled.