Nickel-Catalyzed Electro-Reductive Cross-Coupling of Aliphatic N-Acyl Imides with Alkyl Halides as a Strategy for Dialkyl Ketone Synthesis: Scope and Mechanistic Investigations

Abstract

The development and in-depth study of a cross-electrophile coupling of alkyl N-acyl imides with alkyl halides relying on the combination of nickel catalysis and electrochemistry are described. This methodology takes advantages of the stability and simple access of N-acyl imides as coupling partners for the selective synthesis of dissymmetric dialkyl ketones. Noteworthy, the developed electrochemical protocol affords selective access to linear alkyl ketones when using primary alkyl bromides featuring different chain lengths. Mechanistic studies including cyclic voltammetry, stoichiometric reactions, and isolation of catalytic intermediates provide a set of fundamental insights into monovalent (bpy)­nickel-mediated activation of alkyl halides and alkyl N-acyl imides. Alkyl bromides react with electrogenerated (bpy)­Ni­(I) species via single-electron oxidation to give alkyl radicals. N-Acyl imides are shown to undergo spontaneous C–N bond oxidative addition at both (bpy)­Ni(0) and (bpy)­Ni­(I) species, leading to Ni­(II) acyl intermediates. A stable nickel­(II) acyl complex has also been isolated and fully characterized, and its catalytic competency is demonstrated. Finally, electrogenerated (bpy)­Ni­(I)–acyl species are shown to react with both alkyl bromide and alkyl N-acyl imides. Overall, these investigations allowed for a comprehensive mechanistic picture of this selective cross-electrophile coupling to be assembled.

Electroreductive Cross‐Electrophile Coupling (eXEC) Reactions

“…In 2022, Amgoune et al [38] developed an electrochemical method for XEC of alkyl N-acyl imides and alkyl halides using nickel catalyst (Scheme 6). This protocol enabled the selective synthesis of non-symmetrical dialkyl ketones, taking advantage of the stability and accessibility of N-acyl imides as coupling partners.…”

The copper-catalyzed oxidative radical process of site selective C–N bond cleavage in twisted amides: batch and continuous-flow chemistry

“…50,51 Among several attractive advantages offered by continuous-flow methods for the development of a sustainable chemical process, they feature rapid reaction, enhancement of mass-and heat-transfer, minimization of reaction volumes, operational safety, improvement in the degrees of sample-and reagent-mixing and easy scalability, thus offering a potent platform for chemical innovation. 52,53 Although, the use of ground-state destabilized amide (N-acyl imides) transformations in mechanochemistry 54 and electrochemistry 55 was reported by Szostak and Amgoune. So far, the development of the transition metal-catalyzed reaction of ground-state destabilized amides (N-acyl imides) in continuous-flow chemistry has not yet been documented.…”

Nickel-catalyzed reductive coupling of arylcarboxylic acid 2-pyridyl esters with alkyl methanesulfonates: access to alkyl aryl ketones

“…3 In recent years, transition metal catalyzed reductive coupling between an electrophilic acylating agent and an alkyl electrophile has attracted considerable attention. 4–10 These reactions avoid the use of highly reactive pregenerated organometallics, usually take place under mild conditions, and display good compatibility with functional groups. The electrophilic acyl sources used in these transformations involve acid halides, activated amides, anhydrides, and activated carboxylic acid esters such as NHP esters, 2-pyridyl esters, and S -2-pyridyl thioesters.…”