A Voltage-Controlled Strategy for Modular Shono-Type Amination

Shono-type oxidation to generate functionalized heterocycles is a powerful method for late-stage diversification of relevant pharmacophores; however, development beyond oxygen-based nucleophiles remains underdeveloped. The limited scope can often be ascribed to constant current electrolysis resulting in potential drifts that oxidize a desired nucleophilic partner. Herein, we report a voltage-controlled strategy to selectively oxidize a broad scope of substrates, enabling modular C-N bond formation from protected amine nucleophiles. We implement an electroanalytically guided workflow using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) to identify oxidation potentials across a range of heterocyclic substrates. Controlled potential electrolysis (CPE) selectively generates α-functionalized C-N products in moderate to good yields using carbamate-, sulfonamide-, and benzamide-derived nucleophiles. The importance of voltage control is further exemplified through a systematic study comparing our developed CPE method to constant current electrolysis (CCE) protocols. Voltage-guided CCE and traditionally optimized CCE reveal the importance of maintaining voltage control for high yields and selectivity over a broad scope; a case study with a morpholine-derived substrate illustrates the negative impact of potential drifting under CCE. Sulfonamide drugs, which have significant oxidation potential overlap with model substrates, are rendered competent nucleophiles under CPE. Lastly, sequential voltage-controlled C-N and C-O functionalization of a model substrate generates difunctionalized pyrrolidines further broadening the utility of this reaction.