Direct C(sp³)–H Acylation by Mechanistically Controlled Ni/Ir Photoredox Catalysis

Abstract

Metrics & MoreArticle RecommendationsCONSPECTUS: Synthetic chemists have consistently aimed to develop efficient methods for synthesizing ketones, which are essential building blocks in organic chemistry and play significant roles in bioactive molecules. Recent efforts have focused on using photoredox catalysis, which enables previously inaccessible activation modes, to synthesize ketones through the cross-coupling of an acyl electrophile and simple C(sp 3 )−H bonds. Over the past few years, we have worked on developing effective and versatile approaches for directly acylating activated hydrocarbons to forge ketones. Initially, thioesters were explored as the acyl source to achieve the direct acylation of ethers, but an unexpected thioesterification reaction was observed instead. To gain insights into this reactivity, we conducted the optimization of reaction conditions, substrate scope evaluation, and mechanistic studies. Drawing from our understanding of Ni/Ir photocatalysis obtained in this study, we subsequently developed a method for the direct acylation of simple hydrocarbons. The use of less-reactive amides as the acyl electrophiles was found to be critical for suppressing undesired pathways. This seemingly counterintuitive reactivity was carefully studied, revealing a substrate-assisted reaction mechanism in which the suppressed oxidative addition leads to early-stage nickel oxidation and C−H activation.To address the drawbacks of this method, which primarily arose from decarbonylative and transmetallative side pathways, we employed N-acyllutidiniums as the acyl electrophile. This prevented undesired decomposition pathways, enabling the use of α-chiral acyl substrates with the retention of their stereochemistry, particularly those derived from α-amino acids. The developed versatile methodology allowed us to access a diverse range of α-amino ketones and their homologues. Despite the elegant utility of Ni/photoredox catalysis in developing new synthetic methodologies, the precise behavior of nickel catalysts under redox conditions is incompletely understood. To gain insight into this behavior and develop new chemical reactions, we used a combination of experimental and computational methods. Our investigations revealed that devised adjustments to the reaction conditions in nickel/photoredox catalysis can result in significant differences in the reaction outcomes, providing chemists with opportunities to tailor reactions through carefully designed mechanistic strategies. We believe that continued efforts to study and apply nickel redox modulation will lead to the discovery of additional organic transformations.

Nickel/photoredox-catalyzed three-component silylacylation of acrylates via chlorine photoelimination

“…These observations collectively suggest the involvement of radical species in the reaction pathway. In further explorations, we replaced benzoyl chloride with N -acylsuccinimide, a substrate known for its straightforward oxidative addition with Ni(0) species, 14 but the desired product was not detected. However, the addition of LiCl as an external chloride source led to the formation of the product 4a, albeit with low yield (4%) (see the ESI † ).…”

“…Particularly, the ligand-to-metal charge transfer (LMCT) within Ni( iii )–chloride complexes presents an elegant method for catalytically generating chlorine radicals under mild conditions (Scheme 1c). 11–14 Building upon foundational work by the Doyle group, 12 notable advancements have been achieved by combining Ni-catalyzed cross-coupling with chlorine radical-mediated C–H bond activation through HAT. Nevertheless, the inherent electrophilicity of chlorine radicals, coupled with the subtle electronic distinctions among neighboring C–H bonds, often results in low site-selectivity.…”

Nickel-Catalyzed Functionalization Reactions Involving C–H Bond Activation via an Amidate-Promoted Strategy and Its Extension to the Activation of C–F, C–O, C–S, and C–CN Bonds

“…The need to develop other types of transformations continues. In fact, the integration of photoredox or electrochemistry with nickel catalysis has already begun. In addition, the development of asymmetric reactions, which have mainly involved the use of precious metals, is also attractive and needs to be investigated further.…”

Decatungstate-photocatalyzed direct acylation of N-heterocycles with aldehydes

“…2 Acylation, in particular, is essential for altering the chemical and pharmacokinetic properties of heterocycles and has been a fundamental transformation in organic synthesis. 3 Historically, the Friedel–Crafts acylation has been a cornerstone transformation within organic chemistry, enabling the incorporation of acyl groups into aromatic and heteroaromatic systems. 3 c ,4 However, Friedel–Crafts acylation generally requires electron-rich substrates.…”