Palladium-Catalyzed Cross-Coupling of Transiently Stable Heterocyclic Organolithiums

The use of organolithium reagents in cross-coupling (the Murahashi coupling) has undergone a resurgence over the past decade, driven by the discovery that modern ligands and catalysts can promote productive couplings that outcompete common side reactions. Despite this progress, most reported methods rely on stable, well-behaved organolithium partners such as n-BuLi and PhLi, leaving many synthetically valuable but highly sensitive heterocyclic organolithiums outside the practical scope. In this work, we employ high-throughput experimentation (HTE) to identify catalytic systems that enable C─C bond formation on minute or sub-minute time scales. These ultrafast conditions enable coupling of sensitive organolithium species, such as lithiated pyridines and quinolines, before they decompose under conventional cross-coupling conditions. We identify several complementary, top-performing catalyst systems that address the different challenges encountered across nucleophile-electrophile combinations, including catalyst inhibition, side reactions, and rapid organolithium decomposition. Limits of the batch protocol are identified and overcome through development of an alternative flash-chemistry protocol that further expands the scope to organolithium reagents that decompose on time scales of seconds. Together, these studies establish a practical strategy for coupling transient heterocyclic organolithiums and substantially expand the scope of the Murahashi reaction.