Pyridines are the second most common nitrogen heterocycle observed in FDA approved drugs and related diazines (pyrimidines, pyrazines and pyridazines) are also widely found. Traditional methods to functionalize these heterocycles such as electrophilic aromatic substitution, direct metalation, or radical processes are limited by a number of factors including functional group compatibility, lack of regiocontrol and restricted application on complex pharmaceuticals. Our alternative approach is to selectively transform pyridines and diazines into phosphonium salts and use the unique reactivity of the phosphonium ion to enable, C–C, C–O, C–N, C–S and C–F bond constructions, as well as installing hydrogen isotopes. The reaction to make phosphonium salts uses common reagents, is trivial to perform and has a broad substrate scope including late-stage application on pharmaceuticals. The regioselectivity of the process can also be controlled enabling switching between heterocycles in polyheteroaromatic molecules. Transforming phosphonium salts into important pyridine and diazine derivatives occurs through distinct mechanistic pathways. Direct reactions with nucleophiles form C–C, C–O, C–S, C–N, and C–Hal bonds. Metal-catalyzed crosscoupling, using nickel and cobalt catalysts, is exploited for arylation and alkylation reactions and base-mediated fragmentation reactions form heteroaryl anions that will be used to install deuterium and tritium isotopes. Recently we have discovered a new strategy for heterocycle-heterocycle coupling that proceeds through a ligand-coupling process at phosphorus. Collectively, this program will provide rapid access to pyridine and diazine derivatives that have multiple applications in the pharmaceutical sciences.

Selective functionalization of pyridines and diazines via heterocyclic phosphonium salts

255th National Meeting (2018)

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