Advances in Pyridine C−H Functionalizations: Beyond C2 Selectivity

The pyridine core is a crucial component in numerous FDA-approved drugs and Environmental Protection Agency (EPA) regulated agrochemicals. It also plays a significant role in ligands for transition metals, alkaloids, catalysts, and various organic materials with diverse properties, making it one of the most important structural frameworks. However, despite its significance, direct and selective functionalization of pyridine is still relatively underdeveloped due to its electron-deficient nature and the strong coordinating ability of nitrogen. Among the variety of synthetic transformation, direct functionalization of C-H bond is straightforward and atom economical approach and it's advantageous for late-stage functionalization of pyridine containing drugs. In recent years, innovative strategies for regioselective C-H functionalization of pyridines and azines have emerged, offering numerous benefits such as high regioselectivity, mild conditions, and enabling transformations that were challenging with traditional methods. This review emphasizes the latest advancements in meta and para-C-H functionalization of pyridines through various approaches, including pyridine phosphonium salts, photocatalytic methods, temporary de-aromatization, Minisci-type reactions, and transition metal-catalyzed C-H activation techniques. We discuss the advantages and limitations of these current methods and aim to inspire further progress in this significant field.