N-heterocyclic carbene and photocatalyst-catalyzed rapid access to indole ketones via radical C(sp 3 )–H acylation

• Published in: Green chemistry : an international journal and green chemistry resource : GC Vol. 26; no. 9; pp. 5397 - 5408
• Main Authors: Nie, Guihua, Tu, Ting, Liao, Tianhui, Liu, Donghan, Ye, Wenjun, Ren, Shi-Chao
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 07.05.2024
• Subjects: Acylation; Biological activity; Catalysis; Catalysts; Chemical synthesis; Hydrogen bonds; Indoles; Ketones; Photocatalysts; Regioselectivity; Substitutes; Substrates
• ISSN: 1463-9262; 1463-9270
• DOI: 10.1039/D4GC00653D

The direct C(sp 3 )–H functionalization reactions enable the development of green and streamlined synthetic routes for structurally complex molecules by circumventing the pre-activation of the substrates. Herein, we disclose an atom- and step-economic synthetic approach for rapid access to both α-(2-indolyl) ketones and α-(3-indolyl) ketones, which are privileged structures in bioactive molecules and organic synthesis, though generally prepared by bespoke multi-step strategies. The reaction proceeded via direct acylation of indole benzylic C(sp 3 )–H bond under the NHC and photocatalyst catalysis. The mild conditions, broad substrate scope, and predictable regioselectivity among multiple potential reactive sites enable efficient access to α-indolyl ketones from readily available 2- or 3-alkyl-substituted indoles. Furthermore, the competitive reaction at the 2- or 3-benzylic position of the 2,3-dialkyl-substituted indoles was systematically studied. Further transformation and bioactivity studies of the obtained α-(2- or 3-indolyl) ketones highlight the potential utility of this method.