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Stereospecific Dehydroxytrifluoromethoxylation of Alcohols with 2,4-Dinitro(trifluoromethoxy)benzene
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DOI：10.1002/cjoc.70626.png)
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Abstract
En 中文
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 SN1 mechanism and consequently produces racemic products. Herein, we report a stereospecific SN2 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 SN2 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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