Catalyst-Controlled\nChemoselective γ‑C(sp<sup>3</sup>)–H Lactonization\nof Carboxylic Acid: Methyl versus\nMethylene

Despite\nrecent advances in ligand-enabled C(sp<sup>3</sup>)–H\nfunctionalization of native substrates, controlling chemoselectivity\nin the presence of methyl and methylene C(sp<sup>3</sup>)–H\nbonds remains a significant challenge. Herein, we report the first\nexample of the Pd(II)-catalyzed chemoselective lactonization of γ-methyl\nand methylene C(sp<sup>3</sup>)–H bonds of carboxylic acids.\nExclusive chemoselectivity of methyl or methylene γ-lactonization\nwas achieved by using two different classes of Quinoline-Pyridone\nligands. The bidentate ligand coordinating with Pd(II) via five-membered\nchelation favors γ-methyl C–H lactonization, whereas\nthe ligand forming six-membered chelation affords γ-methylene\nC–H lactonization exclusively. Taking into account our previous\nfindings, we show that the impact of ligand bite angle on chemoselectivity\nis different for five-membered and six-membered cyclopalladation processes.\nThis method provides simple and versatile access to γ-lactones,\nincluding spiro- and fused ring systems. Deuterium incorporation experiments\nsuggest that this observed chemoselectivity arises from both the C–H\nactivation and C–O bond forming steps.