Direct Anodic Decarboxylative Alkylation Reaction to Pharmaceutically Relevant Quinones

Abstract

We report an electrochemical platform for the direct decarboxylative coupling of structurally diverse carboxylic acids with para‐quinones, enabling a single‐step approach to rapidly construct complex molecular architectures without pre‐functionalization, stoichiometric oxidants, or metal salts. Radical intermediates generated through direct anodic oxidation of carboxylic acids mediate efficient C(sp3)─C(sp2) decarboxylative cross‐coupling, thereby expanding the synthetic scope of electrochemical radical functionalization. The method demonstrates broad functional group tolerance across diverse carboxylic acids, with aromatic and aliphatic functionalization, and provides streamlined access to pharmaceutically relevant scaffolds, including antimalarial motifs and intermediates associated with east coast fever treatment. Additionally, the method was successfully scaled on a 2 g scale. In contrast to the majority of known procedures, this electrochemical approach preserves synthetically valuable halide substituents on the para‐quinone core, including bromides, enabling further modification of the derived product. In addition, this protocol enables selective transfer of fully deuterated methyl groups from readily available acetic acid‐d4 to pharmaceutically relevant target molecules while preserving the deuterium content, avoiding use of hazardous methylating reagents. As a representative application, the selectively deuterated antimalarial lead structure plasmidone‐d3 was synthesized successfully in two electrochemical steps from commercially available starting materials. Mechanistic investigations support a proposed electrode surface‐mediated stepwise E1C1C2E2C3 pathway.