Direct C(sp(3))-H Acylation by Mechanistically Controlled Ni/Ir Photoredox Catalysis

Abstract

Conspectus Synthetic chemists have consistentlyaimed to develop efficientmethods for synthesizing ketones, which are essential building blocksin organic chemistry and play significant roles in bioactive molecules.Recent efforts have focused on using photoredox catalysis, which enablespreviously inaccessible activation modes, to synthesize ketones throughthe cross-coupling of an acyl electrophile and simple C(sp(3))-H bonds. Over the past few years, we have worked on developingeffective and versatile approaches for directly acylating activatedhydrocarbons to forge ketones. Initially, thioesters were exploredas the acyl source to achievethe direct acylation of ethers, but an unexpected thioesterificationreaction was observed instead. To gain insights into this reactivity,we conducted the optimization of reaction conditions, substrate scopeevaluation, and mechanistic studies. Drawing from our understandingof Ni/Ir photocatalysis obtained in this study, we subsequently developeda method for the direct acylation of simple hydrocarbons. The useof less-reactive amides as the acyl electrophiles was found to becritical for suppressing undesired pathways. This seemingly counterintuitivereactivity was carefully studied, revealing a substrate-assisted reactionmechanism in which the suppressed oxidative addition leads to early-stagenickel oxidation and C-H activation. To address the drawbacksof this method, which primarily arosefrom decarbonylative and transmetallative side pathways, we employed N-acyllutidiniums as the acyl electrophile. This preventedundesired decomposition pathways, enabling the use of & alpha;-chiralacyl substrates with the retention of their stereochemistry, particularlythose derived from & alpha;-amino acids. The developed versatile methodologyallowed us to access a diverse range of & alpha;-amino ketones andtheir homologues. Despite the elegant utility of Ni/photoredoxcatalysis in developingnew synthetic methodologies, the precise behavior of nickel catalystsunder redox conditions is incompletely understood. To gain insightinto this behavior and develop new chemical reactions, we used a combinationof experimental and computational methods. Our investigations revealedthat devised adjustments to the reaction conditions in nickel/photoredoxcatalysis can result in significant differences in the reaction outcomes,providing chemists with opportunities to tailor reactions throughcarefully designed mechanistic strategies. We believe that continuedefforts to study and apply nickel redox modulation will lead to thediscovery of additional organic transformations.