Pd-Catalyzed Distal Dehydrogenative δ‑Arylation and γ‑Lactonization of Acyclic Free Carboxylic Acids

Palladium-catalyzed proximal C­(sp3)–H functionalization of aliphatic carboxylic acids (both cyclic and acyclic) has been extensively investigated. In contrast, distal (γ, δ) C­(sp3)–H functionalization of aliphatic acids remains a significant challenge; with only a few engineered Pd-ligand systems demonstrating efficacy, but their application is primarily limited to cyclic acids. Herein, we report a method for distal γ, δ-dehydrogenative δ-(di)-arylation and γ-lactonization of acyclic carboxylic acids employing Pd-catalysis. Control experiments and mechanistic insights suggest that the transformation proceeds through selective activation of the distal γ-methylene C­(sp3)–H bond in the presence of the more reactive γ-methyl C­(sp3)–H bond, followed by δ-(di)-arylation of acid substrates. Interestingly, the nature of product formation is governed by the substituent present at the β-position of the aliphatic acids. Acyclic acids bearing a β-quaternary carbon with an aryl substituent undergo distal dehydrogenative diarylation followed by an intramolecular γ-lactonization (via oxypalladation), yielding γ, δ-dehydrogenative γ-lactone; while substrates with β-alkyl substitution favor intermolecular γ, δ-dehydrogenative δ-(di)­arylation.