Bipyridines are commonly found in a range of chemical applications including pharmaceuticals, materials, and ligands for metal catalysis. Due to the ubiquity of bipyridines, methods for the synthesis of this scaffold are in high demand. Metal-catalyzed cross-couplings are an essential part of the organic chemist’s toolbox for biaryl synthesis, but these methods are less effective when coupling heteroarenes or even fail completely. A practical and powerful method for pyridine functionalization is the Minisci reaction in which a carbon-centered radical adds to an activated heteroaromatic ring; however, a Minisci coupling between two pyridine partners has not been reported. This is likely due to an electronic incompatibility between the activated pyridine and the pyridyl radical coupling partner as well as a lack of control over selectivity for the correct pyridine acceptor. Our lab made an unexpected observation that led to the development of an alternative, metal-free pyridine-pyridine cross-coupling reaction that overcomes these deficiencies of the Minisci reaction. Cyanopyridines were successfully coupled with pyridyl phosphonium salts with complete regio- and cross-selectivity to form a variety of 2,4’-bipyridines. Importantly, phosphonium salts were found to be the only effective radical precursors under the reaction conditions. After an extensive experimental and computational mechanistic investigation, the reaction was found to proceed through a unique coupling between two boryl-stabilized, dearomatized pyridyl radicals. This discovery provides a mild, mechanistically distinct method for the synthesis of valuable bipyridines.

Synthesis of 2,4’-bipyridines via a unique radical coupling of cyanopyridines and heteroaryl phosphonium salts

ACS Fall 2020 Virtual Meeting

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