Functionalization of Pyridines at Remote Synthetic Landscapes via Undirected Metalation and Capture

The undirected functionalization of pyridines at positions remote to the N-atom remains an outstanding problem in organic synthesis. The inherent challenges associated with overriding the strong directing influence of the embedded N-atom within pyridine was overcome through the use of n-butylsodium which provided us an avenue to generate 4-sodiopyridine over traditionally observed 2-metalated products when organolithium bases are utilized. The freshly generated 4- sodiopyrdine was found to undergo transition metal free alkylation reactions directly with a variety of primary organic halides bearing diverse functional groups. In addition, after transmetalation to zinc chloride a simple and efficient Negishi cross-coupling protocol was formulated for a variety of aromatic and heteroaromatic halides. The robustness of this protocol was demonstrated through the late-stage installation of 4-pyridyl fragments into a variety of complex active pharmaceutical ingredients including loratadine and prochlorperazine. This protocol not only unlocks a new avenue to prepare 4-subsituted pyridines but highlights the preparative advantages and differences of organosodium bases over their lithium counterparts.