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 the protodehalogenated aryl and aryl dimer, whereas the terpyridine
nickel catalyst predominantly forms the bialkyl and product. By combining
these two unselective catalysts, a tunable, general system results
because excess radicals formed by the terpyridine catalyst can be
converted to the 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. Finally, examination of a variety
of flow-cell configurations establishes that batch recirculation can
achieve higher productivity (mmol product/time/electrode area) than
single-pass flow, that high flow rates are essential for 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.