Rapid Access to Butenolides via Pd(II)-Catalyzed C−H Activation Cascade Enabled by Bidentate Ligand Design

Selective and multiple functionalization of C−H bonds can rapidly increase molecular complexity and expand chemical space. Particularly valuable are tandem reactions where directed C−H bond activation is combined with further functionalizations by careful control of reaction parameters. Herein, we report a catalytic protocol that couples α,β-desaturation of aliphatic cyclic carboxylic acids with subsequent vinyl C−H olefination and cyclization, providing a practical route for upgrading common aliphatic feedstock acids into diversified butenolide motifs. This tandem dehydrogenation−olefination−lactonization sequence facilitates the construction of γ-alkyl α,β-butenolides, which typically remain inaccessible via standard preparative routes, a streamlined, one-step procedure. To enable this, we have developed bidentate keto-tethered pyridine−pyridone ligands, which proved crucial for achieving this tandem reactivity. This catalytic cascade was found to be applicable to a wide range of carboxylic acid substrates and coupling partners, including allyl alcohols, activated olefins, and styrene derivatives. Further functionalization of the α,β-double bond allows for the installation of covalent warheads, which are valuable for targeted covalent drug discovery.