A Dual Fe(LMCT)/Ni(SH2) Catalytic Platform Enables Methylation of Native Carboxylic Acids by Direct Peripherical Editing

This study presents a novel and general method for the direct decarboxylative methylation of native carboxylic acids, addressing a significant gap in late-stage methylation chemistry. By integrating ligand-to-metal charge transfer (LMCT) photo-catalysis with a synergistic SH2 catalytic system, we achieve site-selective methylation of Csp3-CO2H bonds in a single step. The platform utilizes a photoactive iron-LMCT catalyst to generate alkyl radicals directly from native carboxylic acids, while cumyl peroxide is strategically used as both an oxidant enabling iron catalytic turn-over and also as a radical methyl source. The selective coupling of the methyl radical to the carboxylic acid-derived radical is then insured by a nickel-based SH2 catalyst. This methodology demonstrates broad applicability, successfully methylating a wide range of tertiary, secondary, and primary carboxylic acids with excellent functional group compatibility. Mechanistic investigations support the proposed dual catalytic cycle and provide insights into the roles of each catalyst. This approach offers a robust alternative to traditional C-H methylation strategies, showcasing the versatility and potential of combining LMCT and SH2 manifolds in synthetic chemistry.