Regioselective C(sp3)-H functionalization of carboxylic acids enabled by iron radical ligand transfer

Abstract: Directed radical C–H functionalization emerges as a powerful method of preparing complex molecules and bioactive motifs, addressing limitations of noble-metal usage, harsh conditions in pair-electron chemistry and excessive substrate loading in non-selective radical C–H activation. However, previous approaches were often limited to the usage of oxidative, unstable radical precursors prepared in multistep and/or reliance of expensive photocatalyst/additive, resulting in less functionality tolerance and economy. The development of a sustainable reaction manifold that can accommodate different classes of C(sp3)–H bonds (1o, 2o, 3o), acyclic/cyclic scaffolds of carboxylic acids remain challenging. Here we report a general regioselective C(sp3)–H functionalization of carboxylic acids enabled by iron radical ligand transfer (RLT) to construct medicinally relevant C–O and C–N bonds. Problematic substrate classes (methylene C–H etc.) in organometallic activation or radical polar-crossover and C–H classes of diverse carboxylic acid scaffolds are all addressed. Critical to the success is the adoption of earth-abundant, multifunctional iron which not only serves as radical initiator in C–H abstraction, but also as radical sequester to deliver X-type ligand to transient alkyl radical through RLT. Preliminary mechanistic studies support a radical nature of this RLT platform, indicating a powerful mean of directed radical C–H functionalization of feedstock chemicals.