Cu-Catalyzed Cross-Coupling of (Hetero)Aryl Halides with Malonates: One-Pot Assembly of α-Arylacetic Acid Scaffolds

Abstract

Abstract A direct synthesis of α-arylacetic acids from (hetero)aryl chlorides and bromides and malonates via Cu/oxalamide-catalyzed cross-coupling with tandem hydrolysis and decarboxylation is described. Enabled by tailored oxalamide ligand L4, the reaction proceeds smoothly under mild conditions with low catalyst loadings, exhibits a broad substrate scope, and can be scaled to the gram scale and applied in the late-stage modification of complex drug intermediates. Systematic evaluation of the steric and electronic properties of oxalamide ligands, combined with density functional theory (DFT) calculations, elucidates that the ortho-sp2-hybridized nitrogen atom on the ligand is indispensable for catalytic activity. The nitrogen atom coordinates with the sodium cation in the oxidative addition transition state (TS-OA-1a), stabilizing the transition state and lowering the activation barrier through favorable noncovalent interaction.