Catalyst-Controlled Chemoselective γ-C(sp³)-H Lactonization of Carboxylic Acid: Methyl versus Methylene

Despite recent advances in ligand-enabled C(sp³)-H functionalization of native substrates, controlling chemoselectivity in the presence of methyl and methylene C(sp³)-H bonds remains a significant challenge. Herein, we report the first example of the Pd(II)-catalyzed chemoselective lactonization of γ-methyl and methylene C(sp³)-H bonds of carboxylic acids. Exclusive chemoselectivity of methyl or methylene γ-lactonization was achieved by using two different classes of Quinoline-Pyridone ligands. The bidentate ligand coordinating with Pd(II) via five-membered chelation favors γ-methyl C-H lactonization, whereas the ligand forming six-membered chelation affords γ-methylene C-H lactonization exclusively. Taking into account our previous findings, we show that the impact of ligand bite angle on chemoselectivity is different for five-membered and six-membered cyclopalladation processes. This method provides simple and versatile access to γ-lactones, including spiro- and fused ring systems. Deuterium incorporation experiments suggest that this observed chemoselectivity arises from both the C-H activation and C-O bond forming steps.