Four‐Selective Pyridine Alkylation via Wittig Olefination of Dearomatized Pyridylphosphonium Ylides

Abstract

Methods to synthesize alkylated pyridines are valuable because these structures are prevalent in pharmaceuticals and agrochemicals. We have developed a distinct approach to construct 4-alkylpyridines using dearomatized pyridylphosphonium ylide intermediates in a Wittig olefination-rearomatization sequence. Pyridine N-activation is key to this strategy, and N-triazinylpyridinium salts enable coupling between a wide variety of substituted pyridines and aldehydes. The alkylation protocol is viable for late-stage functionalization, including methylation of pyridine-containing drugs. This approach represents an alternative to metal-catalyzed sp 2 -sp 3 cross-coupling reactions and Minisci-type processes. Scheme 1. Design plan for pyridine alkylation via Wittig olefinationrearomatization of pyridylphosphonium ylides.