The Negishi Cross-Coupling Reaction

Organ, M. G.; Diner, C.


The Negishi cross-coupling reaction is a carbon-carbon bond forming reaction between an organozinc reagent and an organo(pseudo)halide. The reaction has an extremely broad scope and can form bonds between all hybridizations of the reactive carbon atoms in both coupling partners. The reaction tolerates many protic or electrophilic functionalities and is celebrated for its relative ease in forging linkages to heteroarenes. The reaction is generally palladium-catalyzed but other first-row metal catalysts can be used effectively in certain cases. Many organozinc reagents are commercially available while others can be made from more reactive organometallics, aryl halides, or by direct zincation of (hetero)arenes.

This chapter covers some of the major breakthroughs since the reaction’s inception but mainly focuses on the current state-of-the-art (up to mid-2017) in cross-coupling as well as organozinc reagent formation. An overview of the mechanistic features of the reaction for both palladium- and nickel-catalyzed reactions is provided as well as an analysis of the resulting regio- and stereoselectivity issues. A summary of the scope of the reaction partners is provided as well as a Tabular Survey providing examples covering the gambit of potential nucleophile/electrophile combinations. A thoughtful selection of examples from the literature along with their experimental procedures, and a comparison of the Negsihi reaction with other cross-coupling methodologies are also included.