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

The development and in-depth study of a cross-electrophile coupling of alkyl N-acyl imides with alkyl halides relying on the combination of nickel catalysis and electrochemistry are 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 lengths. 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 N-acyl imides. 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 N-acyl imides. Overall, these investigations allowed for a comprehensive mechanistic picture of this selective cross-electrophile coupling to be assembled.本文详述了以镍催化（nickel catalysis）与电化学（electrochemistry）结合为核心策略，实现烷基N-酰基酰亚胺（alkyl N-acyl imides）与烷基卤代烃（alkyl halides）之间的交叉亲电偶联（cross-electrophile coupling）反应的开发与深度研究。该方法借助N-酰基酰亚胺作为偶联底物所具备的稳定性与易得性，实现了不对称二烷基酮（dissymmetric dialkyl ketones）的选择性合成。值得注意的是，当使用不同碳链长度的一级烷基溴代物时，所开发的电化学方案可选择性制备直链烷基酮。本研究通过循环伏安法（cyclic voltammetry）、计量反应（stoichiometric reactions）以及催化中间体（catalytic intermediates）分离等手段开展机理研究，对一价(bpy)镍介导的烷基卤代烃与烷基N-酰基酰亚胺活化过程获得了一系列基础性认知。烷基溴代物通过单电子氧化（single-electron oxidation）过程，与电化学原位生成的(bpy)Ni(I)活性物种反应生成烷基自由基（alkyl radicals）。实验证实，N-酰基酰亚胺可在(bpy)Ni(0)与(bpy)Ni(I)两种活性物种上发生自发的C-N键氧化加成（C–N bond oxidative addition），进而生成Ni(II)酰基中间体（Ni(II) acyl intermediates）。本研究还分离得到一种稳定的Ni(II)酰基配合物并完成了完整表征，同时验证了其催化活性。最后，实验证实电化学原位生成的(bpy)Ni(I)-酰基物种可同时与烷基溴代物及烷基N-酰基酰亚胺发生反应。综上，本研究完整构建了该选择性交叉亲电偶联反应的机理全貌。