Zinc-Free, Scalable Reductive Cross-Electrophile Coupling Driven by Electrochemistry in an Undivided Cell

Abstract

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.

Keywords: cross-coupling; cross-electrophile coupling; electrochemistry; flow; mechanism; multimetallic catalysis; nickel.

Scheme 1.. Electrochemical Cross-Electrophile Coupling for Large Scale Applications.

Scheme 2.. Ligand Effects on Reaction Yield.^a

^aStandard Conditions: Aryl Br (0.4 mmol), Alkyl Br (0.4 mmol), NiBr₂•3H₂O (0.04 mmol), Varying ratios of L1 / L2 (0.044 mmol), TBAPF₆ (0.04 mmol), DIPEA (1.6 mmol), MeCN (2 mL), 70 °C, 10 mA, Ni foam cathode (surface area = 7.5 cm²), graphite anode. ^bCorrected GC yield vs dodecane. ^cAverage of data from two reactions. A) Aryl Br = ethyl 4-bromobenzoate, Alkyl Br = 1-bromo-3-phenylpropane, B) Aryl Br = 4-bromobenzotrifluoride, Alkyl Br = ethyl 4-bromobutyrate, C) Aryl Br = 4-bromotoluene, Alkyl Br = ethyl 4-bromobutyrate

Scheme 3.. Proposed Multimetallic Mechanism for Two-Catalyst Cross-Electrophile Coupling XEC.^a

^a Based upon CV data, we depict oxidative addition at (L1)Ni^IX and at (L2)Ni⁰. It is important to note that oxidative addition could occur from either oxidation state, but results in the same arylnickel(II) intermediate. Similarly, this proposal does not attempt to account for potential ligand exchange processes.

Scheme 4:. Substrate Scope in Batch^a,b

^aReactions were conducted in an undivided cell and run on 0.4 mmol scale in MeCN (2 mL). ^bIsolated yields are shown. ^cContains <2% alkyl dimer that was inseparable. ^d1:3 ratio of L1/L2., ^e1:1 ratio of L1/L2. ^f5:1 ratio of L1/L2.

Scheme 5:. Optimization of Electrochemical Cross-Electrophile Coupling in Flow.

^aCorrected GC yield vs 1,3,5-trimethoxybenzene. ^bLigands = 3:1 L1/L2. ^c4 F/mol, ^dCorrected GC yield vs dodecane. ^eIsolated yield.