Silyl Radical Mediated Cross-Electrophile Coupling of N-Acyl-imides with Alkyl Bromides under Photoredox/Nickel Dual Catalysis

Abstract

A photoredox Ni-catalyzed cross-coupling of N-acyl-imides with unactivated alkyl bromides has been developed that enables efficient access to a variety of functionalized alkyl ketones, including unsymmetrical dialkyl ketones, under very mild and operationally practical conditions. The reaction that operates without the need for any preformed carbon nucleophile proceeds via the combination of two different bond activation processes, i.e. Ni-catalyzed imide activation via C(acyl)-N bond cleavage, and (TMS)3Si radical-mediated alkyl halide activation via halogen-atom abstraction. Transition metal-catalyzed acylation of organometallic compounds is a well-established key transformation in organic chemistry that is of high relevance to the synthesis of a plethora of carbonyl-containing compounds, including ketones. 1 Besides classical acyl-transfer reagents (e.g., acyl chlorides, anhydrides, and thioesters) that are typically employed in these reactions, resonance destabilized amides have recently emerged as new potent electrophiles. These bench-stable acyl electrophiles are equally well accessible from abundant carboxylic acids, and have been shown to engage in cross-coupling reactions with organometallic nucleophiles. 2 Nickel catalysis has been particularly highlighted as a very powerful strategy to forge C(acyl)-C(sp 2) bonds via C-N bond activation of amides, allowing the efficient preparation of valuable ketones. 3 While the remarkable properties of nickel 4 unlocked the development of challenging cross-coupling reactions with C(sp 3)-hybridized substrates, 4a it is striking to note that the conversion of amides to alkyl ketones via C(acyl)-C(sp 3) bond formation remains extremely rare. It is even more surprising that it could provide convenient synthetic methods to this versatile class of carbonyl compounds with notable applications spanning drug lead and natural product synthesis, as well as for their propensity to undergo functional group interconversion. The very few examples documented so far consist of nickel-catalyzed cross-couplings with organometallic reagents that are reminiscent of Negishi and Suzuki reactions. For instance, Garg and co-workers reported the acylation of alkylzinc reagents with N-tosyl and N-Boc amides. 5 The group of Rueping investigated the cross-coupling of N-(Me)Ph amides with alkylboranes. 6 In a different approach, Molander and coworkers developed the cross-coupling of N-acyl-succinimides with alkyltrifluoroborates via single-electron transmetalation with the aid of visible-light mediated photoredox catalysis (Scheme 1a). 7,8

Nickel-Catalyzed Reductive Cross-Couplings: New Opportunities for Carbon–Carbon Bond Formations through Photochemistry and Electrochemistry

“…A related approach was developed by Li and co-workers 123 for the reductive acylation of acylimidazoles with aryl and alkyl bromides in the presence Zn as the reductant. Interestingly, Amgoune and coworkers 124 recently realized a nickel/photo dual catalyzed reductive cross-coupling of amides and alkyl bromides for the synthesis of alkyl ketones (Scheme 15c). The reaction proceeded well with various functionalities on the phenyl ring of the amides.…”

C(sp3)–H Bond Acylation with N-Acyl Imides under Photoredox/ Nickel Dual Catalysis

“…The process was designed to follow a radical relay pathway where a silyl radical is generated photocatalytically and serves as an abstracting agent to activate the alkyl bromide through homolytic C-Br bond cleavage (Scheme 1A). 10 Another exciting challenge that we subsequently considered was the design of an alternative strategy that would rely on the selective C(sp 3 )-H bond activation of simple alkanes through a radical hydrogen-atom transfer (HAT) process. 11,12 The groups of Doyle and Molander independently demonstrated that organohalides could serve as both coupling partners and sources of halide radicals that act as potent H-abstracting agents in Ni/photoredox cross-coupling reactions with aliphatic substrates.…”

From Esters to Ketones via a Photoredox‐Assisted Reductive Acyl Cross‐Coupling Strategy

“…This photoredox‐assisted reductive strategy has been quickly applied in nickel‐catalyzed C−C cross‐couplings between aryl and alkyl halides [13] . Strikingly, only one isolated example regarding ketones synthesis [14] was recently reported by Amgoune lab [13m] with using N ‐acyl‐imides as acyl donors (Scheme 1 A‐3). However, 3°‐radicals are still incompatible, which remains challenging in cross‐coupling reactions for the construction of quaternary carbon centers [13a,j, 15] …”