Transient Directing Groups for Enhancing Affinity between Native Substrates and Transition Metal C-H Activation...

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.