Robust Catalytic S<sub>E</sub>Ar H/D Exchange of Arenes with D<sub>2</sub>O: Metal‐Free Deuteration of Natural Complexes and Drugs
Zhenguo Zhang, Yongheng Lv, Wan Qing Renee Ong, Xuefei Zhao, Xuefei Zhao, Zhenhua Jia, Zhenhua Jia, Teck‐Peng Loh
Abstract
O as the terminal deuterating reagent has been developed. This metal-free protocol employs a triaryl carbenium as the mediator and showcases a wide applicability in the late-stage deuteration of various natural products and small-molecule drugs. Gram-scale deuteration was successfully demonstrated with β-Estradiol, highlighting the method's practicability. Detailed mechanistic insights, supported by DFT calculations, unveiled the essential role of in situ generated acidic species in this electrophilic aromatic substitution process. This newly developed method offers a sustainable and versatile alternative to traditional metal-catalyzed H/D exchange techniques, addressing challenges such as the use of expensive metals, impurity formation, and the necessity for residual metal removal from the final products.