(532cc) Mechanistic Investigation of Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Amines

In medical chemistry, the selective addition of a single methyl group at targeted positions within the particular pharmaceutical intermediates can dramatically increase their bioactivity. Despite the significant advances in novel synthetic approaches, the selective C(sp³)–H methylation of complex amines, which occupy an exclusive position (>75%) in medical agents, remains limited. Herein, a synthetic strategy involving Shono oxidation followed by the subsequent methylation of the N, O-acetal intermediate was proposed to realize the α-methylation of complex protected amines, and the reaction mechanism of the electrochemical process was investigated. This methylation pathway enabled recalcitrant amines to be readily activated and showed significantly higher Faradaic efficiencies (FE) of 69% by employing CF₃CH₂OH (TFE), rather than the conventional methanol (FE = 9%), as a solvent. Contradictory to the traditional electrochemical-chemical-electrochemical-chemical events (E1-C1-E2-C2), our DFT results indicate an alternative proton-concerted electron transfer (PCET) mechanism based on constant hydrogen electrode free energy models and inner-sphere electron transfer theories. The second electron step (E2) is calculated to be barrierless in accordance with the Marcus theory, and most likely occurs simultaneously with the previous proton transfer step (C1) via a PCET pathway. This mechanistic insight is consistent with experimental results of cyclopropane-substituted substrates. Despite an easily triggered process with low kinetic barriers (5-7 kcal/mol), the ring-opening of sulfonyl cyclopropane radicals (products of step C1) was not observed as its competing pathway is the barrierless E2. Our detailed mechanistic investigations provide important insights to show that the selective oxidation of protected amines important in pharmaceutical syntheses proceeds via a PCET mechanism. These results can help to guide future developments for improved electrochemical C(sp³)–H oxidation protocol for late-stage methylation, which features broad reaction scope and high functional group compatibility.