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

• Published in: Angewandte Chemie 2020-06, Vol.132 (23), p.9228-9233
• Main Authors: Davies, Anna V., Fitzpatrick, Keegan P., Betori, Rick C., Scheidt, Karl A.
• Format: Article
• Language: English
• Subjects: Carboxylic acids; Catalysis; Chemical synthesis; Chemistry; Construction; Enantiomers; Ketones; N-heterocyclic carbenes; Organic chemistry; photochemistry; Photoredox catalysis; radicals; reaction mechanisms
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202001824

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. The conversion of carboxylic acids into ketones using combined photoredox/ N‐heterocyclic carbene (NHC) catalysis has been developed. In situ activation of a carboxylic acid followed by generation of an acyl azolium allows productive radical–radical coupling to afford ketones in good to excellent yields. This single‐electron, reductive alkylation was applied in the late‐stage functionalization of various pharmaceutical compounds.