Abstract
An electrochemically driven, nickel-catalyzed reductive coupling of N-hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical cell and employs a tertiary amine as the reductant. This decarboxylative C(sp3)–C(sp2) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.
Highlights
The formation of Csp3−Csp[2] bonds is a powerful means of synthesizing high-value chemicals.[1]
Most methods make use of organometallic compounds as transmetalating agents, which are reminiscent of classic Kumada, Negishi, and Suzuki couplings.[2]
The needs of using these highly sensitive, less functional group compatible organometallic reagents necessitated the development of additional modes of nickel-catalyzed Csp3−Csp[2] bond formation using native functional groups as latent nucleophiles. These include cross-coupling methods that combine singleelectron-transfer catalytic cycles of nickel with iridium photoredox cocatalysts[3] and cross-electrophile reductive couplings relying on an exogenous, stoichiometric metallic powder reductant (e.g., Zn, Mn) to transfer electrons to nickel catalysts.[4]
Summary
Doyle elegantly utilized an Ir-photoredox/Ni dual catalyst system to achieve decarboxylative Csp3−Csp[2] coupling (Figure 1). LED light) or stoichiometric amounts of metal reductants, we thought direct reduction of NHP esters using electric current would be a much more energy efficient and safer method to introduce reactive radical species into a catalytic cycle.[6]. We reasoned that cathodic reduction of the redox active NHP ester 19,10 would result in a decarboxylative fragmentation resulting in generation of the Csp[3] radical 2 (Figure 2). Alkyl radical 2 is intercepted by a homogeneous nickel catalyst, which could be either Ni(0) or Ni(II) generated from oxidative addition of aryl halides. The challenge in this case is whether or not a highly reactive radical
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