General C(sp²)–C(sp³) Cross-Electrophile Coupling Reactions Enabled by Overcharge Protection of Homogeneous Electrocatalysts

Abstract

Cross-electrophile coupling (XEC) of alkyl and aryl halides promoted by electrochemistry represents an attractive alternative to conventional methods that require stoichiometric quantities of high-energy reductants. Most importantly, electroreduction can readily exceed the reducing potentials of chemical reductants to activate catalysts with improved reactivities and selectivities over conventional systems. This work details the mechanistically-driven development of an electrochemical methodology for XEC that utilizes redox-active shuttles developed by the energy-storage community to protect reactive coupling catalysts from overreduction. The resulting electrocatalytic system is practical, scalable, and broadly applicable to the reductive coupling of a wide range of aryl, heteroaryl, or vinyl bromides with primary or secondary alkyl bromides. The impact of overcharge protection as a strategy for electrosynthetic methodologies is underscored by the dramatic differences in yields from coupling reactions with added redox shuttles (generally >80%) and those without (generally <20%). In addition to excellent yields for a wide range of substrates, reactions protected from overreduction can be performed at high currents and on multigram scales.

Electrochemical Generation and Use in Organic Synthesis of C‐, O‐, and N‐Centered Radicals

“…c) Hansen's electrochemical coupling in acetonitrile [67] . d) Sevov's electrochemical coupling conditions [70] . *Current density (J) calculated from the RVC electrode reported dimensions and the approximate surface area of the RVC of 100 PPI, 66 cm 2 /cm 3 [53] …”

Recent Advances in Asymmetric Catalytic Electrosynthesis

“…Reductive dehalogenation is a classic transformation in electrosynthesis [113] that includes stereoselective examples using cobalt catalysis [99,100]. The principle is relevant for transition metal-catalyzed reductive cross-electrophile couplings [114][115][116], and an enantioselective coupling of alkenyl and benzyl halides using a chiral Ni catalyst was demonstrated by Reisman and co-workers under electrochemical conditions [117]. Electrochemical catalyst activation and turnover granted C(sp 2 )-C(sp 3 ) bond formation without the need for sensitive organometallic reagents or metal powder reductants, and products bearing allyl stereocenters were obtained under mild conditions.…”

Recent Advances in Metal-Catalyzed, Electrochemical Coupling Reactions of sp2 Halides/Boronic Acids and sp3 Centers

“…A recent advance in cross-electrophile coupling was reported by Sevov et al (Scheme 5). 41 Using catalyst C1, they identified that a major issue in this class of coupling was overreduction of the ligand, resulting in a much less catalytically active nickel species. This overreduction occurred when the current flowing into the reaction exceeded the rate of catalyst turnover and resulted in a higher effective voltage, or overcharge in the cell.…”