Transient Directing Groups for Enhancing Affinity between Native Substrates and Transition Metal C–H Activation Catalysts

Conspectus In the past two decades, transition metal-catalyzed C–H activation has emerged as an attractive and valuable strategy for enabling novel disconnections in the synthesis of natural products and pharmaceuticals. Substrate-directed C–H activation, which employs pre-coordination of a substrate’s functional group with the catalyst to recruit it for C–H metalation with high site-selectivity, is a particularly powerful approach. Early directed C–H activations relied on bespoke directing groups with separate installation and removal steps, reducing synthetic efficiency and practicality (limited functional group tolerance, substrate scope). The development of C–H activation methods which use functional groups native to common building blocks and synthetic intermediates would be highly valuable. In this account, we highlight the discovery and development of a transient directing group (TDG) platform for Pd-catalyzed C–H activation reactions of native aldehydes, ketones, and amines. This approach leverages the reversible imine formation event between the substrate and a complementary TDG motif to transiently generate the optimal L,X-type assembly capable of recruiting Pd catalysts for a diverse range of C–H activation reactions, including C–C, C–halogen, C–O, and C–N bond formations. We also describe the application of pyridone ligands in concert with the TDG approach to amplify the reactivity of the Pd catalysts and to activate previously inaccessible C–H bonds. Finally, we cover notable applications of Pd-catalyzed TDG C–H activation in complex molecule synthesis.