Selenylation Chemistry Suitable for On‐Plate Parallel and On‐DNA Library Synthesis Enabling High‐Throughput Medicinal Chemistry

Click chemistry is a concept wherein modular synthesis is used for rapid functional discovery. To this end, continuous discovery of clickable chemical transformations is the pillar to support the development of this field. This report details the development of a clickable C3‐H selenylation of indole that is suitable for on‐plate parallel and DNA‐encoded library (SeDEL) synthesis via bioinspired LUMO activation strategy. This reaction is modular, robust and highly site‐selective, and it features a simple and mild reaction system (catalyzed by nonmetallic B(C6F5)3 at room temperature), high yields and excellent functional group compatibility. Using this method, a library of 1350 indole‐selenides was parallel synthesized in an efficient and practical manner, enabling the rapid identification of 3 ai as a promising compound with nanomolar antiproliferative activity in cancer cells via in situ phenotypic screening. These results indicate the great potential of this new clickable selenylation reaction in high‐throughput medicinal chemistry and chemical biology. A bioinspired clickable selenylation reaction of indole has been developed by using benzoselenazole as selenylation reagent under nonmetallic B(C6F5)3 catalysis. The practical application of the reaction has been well demonstrated in on‐DNA and on‐microplate parallel synthesis of indole‐selenides.