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.

Activation of C–C bonds has the potential to revolutionize how molecules are made by altering the carbon skeleton and enabling new synthetic routes. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of linear 3-carbon fragments, but this reactivity is unknown. In this study we show how a new type of C–C activation catalyst, that relies upon a different, metalloradical mechanism, can enable new subsequent reactivity: the cross- coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3- difunctionalized, ring-opened products. A mixture of experiment and theory sheds light on how cooperation between the redox-active ligand and the nickel catalyst enables the C–C bond activation step, suggesting how this approach could be applied in other systems.

Activation of C-C bonds has the potential to revolutionize how molecules are made by altering the carbon skeleton and enabling new synthetic routes. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of linear 3-carbon fragments, but this reactivity is unknown. In this study we show how a new type of C-C activation catalyst, that relies upon a different, metalloradical mechanism, can enable new subsequent reactivity: the crosscoupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3difunctionalized, ring-opened products. A mixture of experiment and theory sheds light on how cooperation between the redox-active ligand and the nickel catalyst enables the C-C bond activation step, suggesting how this approach could be applied in other systems.One-Sentence Summary: A new C-C activation mechanism unlocks new subsequent reactivity and a new approach to using cyclopropyl ketones in synthesis.

Activation of C–C bonds has the potential to revolutionize how molecules are made by altering the carbon skeleton and enabling new synthetic routes. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of linear 3-carbon fragments, but this reactivity is unknown. In this study we show how a new type of C–C activation catalyst, that relies upon a different, metalloradical mechanism, can enable new subsequent reactivity: the cross- coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3- difunctionalized, ring-opened products. A mixture of experiment and theory sheds light on how cooperation between the redox-active ligand and the nickel catalyst enables the C–C bond activation step, suggesting how this approach could be applied in other systems.

Reactions that cleave C–C bonds and enable functionalization at both carbon sites are powerful strategic tools in synthetic chemistry. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of 3-carbon fragments, but general approaches to net C–C activation / difunctionalization are unknown. Herein we demonstrate the cross-coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-opened products. A combination of experimental and theoretical studies rule out more established mechanisms and shed light on how cooperation between the redox-active terpyridine (tpy) ligand and the nickel atom enables the C–C bond activation step. The reduced (tpy•–)NiI species activates the C–C bond via a concerted asynchronous ring-opening transition state. The resulting alkylnickel(II) intermediate can then be engaged by aryl-, alkenyl-, and alkylzinc reagents to furnish cross-coupled products. This allows quick access to products that are difficult to make by conjugate addition methods, such as β-allylated and β-benzylated enol ethers. The utility of this approach is demonstrated in the synthesis of a key (±)-taiwaniaquinol B intermediate and the total synthesis of prostaglandin D1.