Comprehensive Summary The trifluoromethoxy group features high electronegativity and strong lipophilicity, making it a valuable substituent in drug discovery and materials science. To fully elucidate its function, the efficient preparation of stereodefined analogues is essential. The established dehydroxytrifluoromethoxylation reaction, while synthetically useful, follows an S N 1 mechanism and consequently produces racemic products. Herein, we report a stereospecific S N 2 dehydroxytrifluoromethoxylation reaction of alcohols using commercially available and low‐cost 2,4‐dinitro(trifluoromethoxy)benzene (DNTFB) as the trifluoromethoxide source. The reaction employs fluoro‐ N,N,N',N' ‐ tetramethylformamidinium hexafluorophosphate (TFFH) as a dual activator, which both activates the alcohol toward isouronium formation and provides a fluoride ion to liberate the CF₃O ‐ anion from DNTFB. Under mild conditions, a range of primary and secondary alcohols undergo efficient conversion with excellent functional group tolerance. Notably, enantioenriched secondary alcohols react with complete configurational inversion, confirming the S N 2 pathway. The synthetic utility is further demonstrated by gram‐scale synthesis and functionalization of complex bioactive molecules. This stereospecific method offers a highly efficient, low‐cost, and broadly applicable strategy for the late‐stage modification of complex drug molecules, providing a practical entry to optically pure alkyl trifluoromethyl ethers.
Peng et al. (Tue,) studied this question.