Mild and Selective Palladium-Catalyzed Pyridylic Allylation of 4-Alkylpyridines

Abstract

Pyridines and related heterocycles enjoy widespread occurrence in biologically relevant natural products and drug-like molecules. Therefore, new methods that facilitate their synthesis and incorporation into drug-like structures will likely have a significant impact on the drug development process. This is especially true when these methods accomplish selective functionalization and allow a broad functional group tolerance. Reported herein is a new strategy for the selective allylation of 4-alkylpyridine derivatives. Our methodology exploits well-established alkylidene dihydropyridine intermediates as substrates for a Pd-catalyzed decarboxylative allylation reaction, which installs a synthetically versatile allyl group at the 4-pyridylic position. The use of a weak base and the absence of a Lewis acid in our method enables the allylation of 4-alkylpyridines with exceptional functional group tolerance. Moreover, the compatibility of the proposed pyridylic allylation strategy extends beyond simple 4-alkylpyridines to more sophisticated 3- and 4-disubstituted pyridines.