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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.
Yan et al. (Wed,) studied this question.