Bypassing the Limitations of Directed C–H Functionalizations of Heterocycles

In directed C–H activation reactions, nitrogen and sulfur atoms present in heterocyclic substrates coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C–H functionalization at an undesired position, limits the application of C–H activation reactions in heterocycle-based drug discovery.(1–5) Herein, we report a robust and synthetically useful reaction that overcomes the complications associated with performing C–H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand to promote the in situ generation of the reactive PdX(2) (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX(2) species is inherently anchored in close proximity with the target C–H bond adjacent to CONHOMe group, thus avoiding the interference from various heterocycles. Remarkably, this reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulfur, and phosphorus. Thus, this operationally simple aerobic reaction demonstrates the feasibility of bypassing a fundamental limitation that has long plagued applications of directed C–H activation in medicinal chemistry.