Stereospecific Dehydroxytrifluoromethoxylation of Alcohols with 2,4-Dinitro(trifluoromethoxy)benzene

Abstract

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_N1 mechanism and consequently produces racemic products. Herein, we report a stereospecific S_N2 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_N2 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.

Keywords

Trifluoromethoxylation / Alcohols / Deoxyfunctionalization / 2,4-Dinitro(trifluoromethoxy)benzene / Nucleophilic substitution / Late-stage functionalization / Chiral trifluoromethyl ethers / Isouronium intermediate

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