Palladium (II)‐Catalyzed C−H Activation with Bifunctional Ligands: From Curiosity to Industrialization

Abstract In 2001, our curiosity to understand the stereochemistry of C−H metalation with Pd prompted our first studies in Pd(II)‐catalyzed asymmetric C−H activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1. poor reactivity of simple Pd salts with native substrates; 2. few strategies to control site selectivity for remote C−H bonds; 3. the lack of chiral catalysts to achieve enantioselectivity via asymmetric C−H metalation, and 4. low practicality due to limited coupling partner scope and the use of specialized oxidants. These challenges necessitated new strategies in catalyst and reaction development. For reactivity , we developed approaches to enhance substrate–catalyst affinity together with novel bifunctional ligands which participate in and accelerate the C−H cleavage step. For site‐selectivity , we introduced the concept of systematically modulating the distance and geometry between a directing template, catalyst, and substrate to selectively access remote C−H bonds. For enantioselectivity , we devised predictable stereomodels for catalyst‐controlled enantioselective C−H activation based on the participation of bifunctional ligands. Finally, for practicality , we have developed varied catalytic manifolds for Pd(II) to accommodate diverse coupling partners while employing practical oxidants such as simple peroxides. These advances have culminated in numerous C−H activation reactions, setting the stage for broad industrial applications.