Iridium-Catalyzed Direct and Site-Selective C-H Heteroarylation, Alkenylation, and Alkylation of Indoles
Tian Cao1,2, Wanqi Hu1,3, Linlu Hao1,3
1Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
Abstract:
Indoles and coumarins represent prominent structural motifs in a wide range of biologically active molecules. Combining these two privileged scaffolds offers immense potential for innovation in drug discovery. Herein, we unveil a regioselective iridium-catalyzed approach for the direct C-H heteroarylation, alkenylation, and alkylation of indoles using iodonium ylides through a metal carbene-induced C-H insertion mechanism, accessing a series of novel 4-hydroxy-3-indolyl-coumarins and analogues. The method demonstrates a wide substrate scope, good tolerance for functional groups, scalability with low catalyst loading (as low as 0.2 mol %), and mild reaction conditions. Notably, Compound 3v significantly enhanced GABAARs-α1β3γ2L activity, suggesting potential as a lead for antiepileptic and sedative drug discovery. Moreover, preliminary screening assays indicate that some other compounds exhibit moderate inhibitory effects against the pancreatic cancer cell line.
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