Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 47, Pages 19648-19654Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c11059
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Funding
- Merck KGaA, Darmstadt, Germany [RG2020]
- NIGMS [R35 GM 131680]
- NSF Graduate Research Fellowship
- NIH [3R01GM118510-03S1, 3R01GM087605-06S1]
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A photochemically mediated method has been successfully developed for the defluorinative alkylation of ethyl trifluoroacetate, providing an efficient pathway for the synthesis of novel gem-difluoro analogs. This method can also be used for the hydroalkylation of a diverse suite of alkenes, expanding the range of substrates for the reaction.
The installation of gem-difluoromethylene groups into organic structures remains a daunting synthetic challenge despite their attractive structural, physical, and biochemical properties. A very efficient retrosynthetic approach would be the functionalization of a single C-F bond from a trifluoromethyl group. Recent advances in this line of attack have enabled the C-F activation of trifluoromethylarenes, but limit the accessible motifs to only benzylic gem-difluorinated scaffolds. In contrast, the C-F activation of trifluoroacetates would enable their use as a bifunctional gem-difluoromethylene synthon. Herein, we report a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate. A novel mechanistic approach was identified using our previously developed diaryl ketone HAT catalyst to enable the hydroalkylation of a diverse suite of alkenes. Furthermore, electrochemical studies revealed that more challenging radical precursors, namely trifluoroacetamides, could also be functionalized via synergistic Lewis acid/photochemical activation. Finally, this method enabled a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds.
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