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
A novel Ni/photoredox-catalyzed acylation of aliphatic substrates, including simple alkanes and dialkyl ethers, has been developed. The method combines C–N bond activation of amides with a radical relay mechanism involving hydrogen-atom transfer. The protocol is operationally simple, employs bench-stable N-acyl imides as acyl-transfer reagents, and permits facile access to alkyl ketones under very mild conditions.
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