LAUSR

Nickel-catalyzed reductive cross-electrophile coupling reactions are becoming increasingly important in organic synthesis, but application at scale is limited by three interconnected challenges: a reliance on amide solvents (complicated workup, regulated), the generation of stoichiometric Zn salts (complicated isolation, waste disposal issue), and mixing/activation challenges of zinc powder. We show here an electrochemical approach that addresses these three issues: the reaction works in acetonitrile with diisopropylethylamine as the terminal reductant in a simple undivided cell (graphite(+)/nickel foam(-)). The reaction utilizes a combination of two ligands, 4,4'-di-tert-butyl-2,2'-bipyridine and 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine. Studies show that, alone, the bipyridine nickel catalyst predominantly forms protodehalogenated aryl and aryl dimer, whereas the terpyridine nickel catalyst predominantly forms bialkyl and product. By combining these two unselective catalysts, a tunable, general system results because excess radical formed by the terpyridine catalyst can be converted to product by the bipyridine catalyst. As the aryl bromide becomes more electron rich, the optimal ratio shifts to have more of the bipyridine nickel catalyst. Lastly, examination of a variety of flow-cell configurations establishes that batch recirculation can achieve higher productivity (mmol product/time/electrode area) than single-pass, that high flow rates are essential to maximizing current, and that two flow cells in parallel can nearly halve the reaction time. The resulting reaction is demonstrated on gram scale and should be scalable to kilogram scale.