Lactonization as a general route to β-C(sp(3))–H functionalization

Functionalization of the β-C–H of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions(1–5). Despite efforts on β-C–H functionalizations for carbon-carbon (C-C) and carbon-heteroatom (C-Y) bond-forming reactions, these bear numerous decisive limitations, especially for industrial-scale applications, including the lack of mono-selectivity, use of expensive oxidants, and limited scope(6–13). Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C–H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here, we report a Pd-catalyzed β-C(sp(3))–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 route to myriad carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide (TBHP) as the oxidant to promote the desired selective reductive elimination from the Pd(IV) center, as well as the ease of product purification without column chromatography renders this reaction amenable to ton-scale manufacturing.