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Ligand-Enabled β-C(sp3)–H Lactonization: A Stepping Stone for General and Practical β-C–H Functionalizations
β-C–H functionalization of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions. Despite two decades of effort on β-C–H functionalizations, reported reactions bear numerous challenges, especially for industrial-scale applications due to the use of expensive oxidants and poor scope. For example, arylation reactions are only compatible with aryl iodides but not the more practical aryl bromides and chlorides, alkylations are limited to primary alkyl coupling partners; fluorination and amination reactions have not been possible using free carboxylic acids as directing groups. The unselective formation of mono- and di-functionalized products is another major drawback. Herein, we report an unprecedented palladium-catalyzed β-C(sp3)–H lactonization of aliphatic acids enabled by a mono-N-protected β-amino acid ligand. The highly strained and reactive β-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl, and amino groups at the β position of the parent acid, thus providing a one-for-all strategy to synthesize a myriad of carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide (TBHP) as the oxidant, as well as the ease of product purification without column chromatography renders this reaction amenable to ton-scale manufacturing.