Development of a Metal- and Oxidant-Free Enzyme–Photocatalyst Hybrid System for Highly Efficient C-3 Acylation Reactions of Indoles with Aldehydes

An enzyme–photocatalyst hybrid system has been developed for aldehyde-based indole C-3 acylation. The concept of this process is to form a C–N bond through the three-component Mannich reaction of aldehydes, amines, and indoles, thereby introducing an aminomethyl group on the indole ring. Next, this system catalyzed the formation of the corresponding imide ion from the Mannich product, followed by rapid hydrolysis to give the final C-3 carbonyl indole product. More than 30 indole C-3 acylated products (up to 93% yield) were successfully synthesized under mild conditions, and indole derivatization of two bioactive substances (probenecid and cholesterol) was realized. The mechanistic study provides theoretical support for the construction of photoenzyme catalytic systems. This is an example of enzyme–light-activated C-3 acylation of indoles under very mild reaction conditions, without the use of transition metal catalysts, metal salts, and additional oxidants. This efficient enzyme–photocatalyst hybrid system provides a strategy for the development of photoenzyme catalysis fields.