Functionalization of 4-Substituted Pyridines for Enantioselective Synthesis

Enantioselective synthesis using nitrogen containing heterocycles, such as pyridines, is extremely useful in drug discovery. The prevalence of pyridines in the drug market is well-documented and a mild, enantioselective method to functionalize pyridines would allow faster access to more structurally diverse pyridines, improving efficiency in the search of drug candidates. The Orellana group has developed a strategy for selective allylation of 4-substituted pyridines using mild conditions, which results in broad functional group tolerance. Reported herein are ways to expand the allyl fragment to larger linear and cyclic fragments, and attempts at the development of an enantioselective variant using palladium catalyzed decarboxylative allylation. The pathway for reductive elimination was also discovered through mechanistic experiments which revealed more of this palladium catalyzed decarboxylative allylation mechanism. Furthermore, a new method was investigated for arylation of the pyridylic position using a high-valent copper catalysis.