Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids**

Abstract

As a key element in the construction of complex organic scaffolds, the formation of C−C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single‐electron chemistry have enabled new methods for the formation of various C−C bonds. Disclosed herein is the development of a novel single‐electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N‐heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late‐stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Carbene and Photocatalyst-Catalyzed Decarboxylative Radical Coupling of Carboxylic Acids and Acyl Imidazoles to Form Ketones

“…Upon the above mechanistic studies and previous reports [51][52][53][54][55][56][57][58][88][89] , a catalytic cycle involving NHC and photo catalysis was proposed (Figure 4). The acyl imidazoles (1) can be pre-prepared or in situ formed via the reaction of a carboxylic acid with CDI (Carbonyldiimidazole) as the condensation reagent.…”

“…Multi-component radical relay reactions provide a powerful tool for the synthesis of complex skeletons from simple and readily accessible starting materials. [80][81][82] While signi cant progress has been achieved in NHC and photocatalyst co-catalyzed ketone synthesis, [51][52][53][54][55][56][57][58] three-component radical relay coupling that allows various carbon radicals involved is still limited. 70 To test the feasibility of our coupling reaction in muti-component radical relay reactions, alkenes were incorporated into the system as a third coupling partners.…”

“…43 Hong reported that Breslow intermediate can also be oxidized by Katritzky pyridinium salts followed by deaminative cross-coupling to forge ketones. 49 Very recently, studies from Scheidt, [51][52][53] Studer, [54][55][56][57] and our laboratories 58 found that NHC-derived azolium ester intermediates (int. II) can undergo singleelectron-reduction to generate radical intermediates for further couplings to form ketones (Figure 1b, bottom).…”

“…II) can undergo singleelectron-reduction to generate radical intermediates for further couplings to form ketones (Figure 1b, bottom). Scheidt [51][52] and our group 58 used Hantzsch esters as precursors of the other transient radical intermediates to furnish two-component coupling reactions (Figure 1c). Studer reported a tri uoromethyl radical initiated three-component coupling for the synthesis of b-Tri uoromethylated ketones (Figure 1d).…”

“…bring undesired operations and pose limitations on substrate scopes. 70 In addition, despite the seminal work achieved in NHC and photocatalyst cocatalyzed ketone synthesis, [51][52][53][54][55][56][57][58] three-component radical relay coupling that involves various carbon radicals is still limited. 70 Here we disclose a new and operationally simple strategy for coupling of acyl imidazoles and carboxylic acids to form ketones (Figure 1e, right), in which the carboxylic acids were directly used as radical precursors.…”