From Mono-N-Protected Amino Acids to Pyridones: A Decade of Evolution of Bifunctional Ligands for Pd(II)-Catalyzed C–H Activation

ConspectusFunctionalization of carbon–hydrogen (C–H) bonds has emerged as a powerful strategy in modern organic synthesis, offering efficient routes to build molecular complexity from simple and abundant substrates. Among various transition-metal catalysts, palladium(II) complexes have proven particularly versatile for C–H activation, owing to the diverse reactivity of carbon–palladium bonds. To advance this approach, the discovery of ligands that can accelerate C–H activation as well as subsequent steps in the catalytic cycle is the pivotal driving force. While ligand development has long been integral to Pd(0) catalysts for activating electrophiles, notably in cross-coupling and asymmetric catalysis, the most common electron-donating ligands often inhibit Pd(II)-catalyzed C–H activation, as an electrophilic palladium center is often preferred. Hence the discovery of a suitable concerted metalation–deprotonation (CMD) motif that can be incorporated into bidentate ligands is critical. This design concept led us to discover a series of highly reactive bifunctional ligands that enhance reactivity and control site-selectivity as well as enantioselectivity.In 2008, our laboratory introduced the first bifunctional mono-N-protected amino acid (MPAA) ligands, which incorporate an N-acyl group bearing a carbonyl with the required proximity and geometry to serve as an internal CMD base thereby significantly accelerating C–H bond cleavage. Building on this concept, we identified pyridone as a potent CMD-active group capable of further enhancing the efficiency of Pd(II)-catalyzed C–H activation. Following the initial development of monodentate pyridone ligands, a series of bifunctional bidentate pyridone ligands unlocked previously inaccessible transformations of methylene C–H bonds within abundant substrates bearing native functional groups such as carboxylic acids, amides, and alcohols.In this Account, we summarize our efforts in the rational design of different classes of pyridone-based ligands for Pd(II)-catalyzed diverse C–H functionalization. Emphasis is placed on site-selective and enantioselective functionalization at methylene and remote C–H positions, and we examine how ligand architecture dictates both reactivity and enantioselectivity. Special attention is given to the use of bidentate pyridone ligands in enabling transformations of synthetically valuable native substrates. We conclude with a perspective on the continued design of novel bifunctional bidentate pyridone ligands to achieve the following goals: realization of enantioselective acyclic methylene C–H activation; development of diverse methylene C–H functionalization beyond dehydrogenation and a handful of C–C/C–O bond formations; expanding native substrates to ketones, alcohols, and amines.