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

Abstract

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.

Electrochemical Reduction of [Ni(Mebpy)3]2+: Elucidation of the Redox Mechanism by Cyclic Voltammetry and Steady‐State Voltammetry in Low Ionic Strength Solutions

“…Of specific interest to our current research, a Ni(II) 4,4′‐dimethyl‐2,2′‐bipyridine complex, [Ni(Mebpy) 3 ] 2+ , has been recently reported as a catalyst for electrochemically‐driven aryl amination reactions . During this process, [Ni(Mebpy) 3 ] 2+ is reduced, under a constant applied current, yielding a catalytically active Ni species in the bulk solution, which has yet to be identified.…”

Organic Electrosynthesis: Applications in Complex Molecule Synthesis

“…Among the many examples, the methodology was utilized for drug modification by N ‐arylation of amoxapine and paroxetine (Scheme ). A mechanistic study of the system was recently published, enabling development of improved reaction conditions that were applicable to a broader scope of complex substrates . In the postulated mechanism, cathodic reduction of Ni II to Ni I introduces the catalyst to the productive cycle and enables oxidative addition of the aryl halide to form a Ni III ‐aryl species.…”

Electrochemical Reduction of [Ni(Mebpy)3]2+. Elucidation of the Redox Mechanism by Cyclic Voltammetry and Steady-State Voltammetry in Low Ionic Strength Solutions.

“…Nickel-based molecular electrocatalysts have been extensively studied for a variety of reductive reactions ranging from H 2 evolution [1,2] and CO 2 reduction [3,4] to reductive cross-coupling in the formation of complex carbon skeletons. [5,6,7] Such catalysts commonly utilize an electrochemical reduction step to generate a reactive oxidation state of the Ni complex from which the catalytic cycle is initiated. However, experimental methods to determine the exact nature, and mechanism of reactivity of the catalytically active Ni complex are often restricted by the short time scales of its existence within a catalytic reaction mixture.…”

“…Of specific interest to our current research, a Ni(II) 4,4'dimethyl-2,2'-bipyridine complex, [Ni(Mebpy) 3 ] 2 + , has been recently reported as a catalyst for electrochemically-driven aryl amination reactions. [5] During this process, [Ni(Mebpy) 3 ] 2 + is reduced, under a constant applied current, yielding a catalytically active Ni species in the bulk solution, which has yet to be identified. During the past three decades, the reduction of tris (bipyridine)Ni(II) complexes have been extensively investigated, with conflicting conclusions reported in the literature.…”