Palladium-Catalyzed Methylene β-C–H Fluorination of Native Amides

Selective fluorination of C(sp3)-H bonds is a highly valuable transformation in organic synthesis and drug discovery. However, achieving methylene C-H fluorination of native substrates remains a significant challenge, as it typically requires external directing groups to facilitate catalyst-substrate binding. Herein, we report a ligand-accelerated Pd-catalyzed methylene β-C-H fluorination of native amides using a bidentate neutral amide-pyridone ligand. This ligand design features the enhancement of catalyst-substrate interactions via stabilization of the cationic palladium center and acceleration of methylene C-H activation, enabling the stereo- and site-selective fluorination of native amides under relatively mild conditions. Notably, Pd(II)-catalyzed methylene C-H activation of weakly coordinating native amides has not been reported to date. This method is compatible with native amides derived from selected drug molecules and Weinreb amides, demonstrating potential utility in drug discovery and other applications.