Abstract
Connecting two carbon atoms is both a routine and fascinating challenge in modern synthetic chemistry. In this work, we establish a palladium-catalyzed cross-dehydrogenative coupling (CDC) of the α-carbon of β-ketoesters with the C3-benzylic position of indoles as a direct and efficient approach to C(sp3)-C(sp3) bond formation. This study uncovers the unexpected directing effect of indole in the selective activation of aliphatic C-H bonds, significantly broadening the scope of CDC reactions. The developed protocol exhibits high tunability, a broad substrate scope, and excellent yields under mild conditions, highlighting its potential for late-stage functionalization in pharmaceutical and material science applications. Additionally, the transformation integrates well into one-pot and multicomponent processes as well as enables stereoselective functionalization of the steroid core. Kinetic studies and density functional theory (DFT) calculations provide key mechanistic insights into the reaction pathway. Initial π-coordination of indole to palladium directs selective C(sp)–H activation via agostic interaction. The C–C coupling is proposed to proceed with the involvement of Pd(IV) intermediates, highlighting the critical role of the oxidant in the process. Product decomplexation emerges as the likely rate-determining step, consistent with the observed first-order dependence of the reaction rate on catalyst concentration.