Multicomponent Reaction Integrating Selenium(II)–Nitrogen Exchange (SeNEx) Chemistry and Copper‐Catalyzed Azide–Alkyne Cycloaddition (CuAAC)
Wei Hou, Xiaohui Zhou, Zhikun Yang, Huhui Xia, Yan Wang, Keren Xu, Shaoneng Hou, Shuning Zhang, Dong‐Mei Cui, Peixiang Ma, Wei Zhou, Hongtao Xu
Abstract
Abstract Multicomponent reactions (MCRs) are powerful tools for rapidly constructing compound libraries with sufficient molecular diversity and complexity. Herein, to fully leverage a third aspect of molecular diversity enabled by the selenium–nitrogen exchange (SeNEx) reaction between alkynes and benzoselenazolones, a novel CuI‐catalyzed three‐component reaction has been successfully developed. This reaction integrates SeNEx with CuAAC click chemistry, enabling rapid and regioselective synthesis of 1,4,5‐trisubstituted 5‐seleno‐1,2,3‐triazoles with high atom economy and good to excellent yields (65 examples, 50%–95%). Notably, this MCR demonstrates excellent functional group tolerance and features modular, predictable, robust, mild reaction conditions, and operational simplicity (air and water compatibility). Extensive mechanism studies have revealed that this reaction proceeds by a unique SeNEx‐CuAAC tandem reaction pathway, distinguishing it from conventional copper(I)‐catalyzed interrupted click reactions. Importantly, a mononuclear σ‐bound copper(I)‐acetylide Cu1 was synthesized and confirmed to be an efficient catalyst for the SeNEx reaction. This discovery provides crucial mechanistic insights into the preferential reactivity of alkynyl groups toward SeNEx over CuAAC. Furthermore, preliminary biological activity screening identified compound 14 as a potent inhibitor of Escherichia coli ‐glucuronidase (EcGUS), with an IC 50 value of 3.16 µM. These findings underscore the significant potential of this MCR in synthetic chemistry, medical chemistry, and chemical biology.