Photochemical C–F Activation Enables Defluorinative Alkylation of Trifluoroacetates and -Acetamides,Journal of the American Chemical Society

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Photochemical C–F Activation Enables Defluorinative Alkylation of Trifluoroacetates and -Acetamides
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2021-11-18 , DOI: 10.1021/jacs.1c11059
Mark W Campbell ₁ , Viktor C Polites ₁ , Shivani Patel ₁ , Juliette E Lipson ₁ , Jadab Majhi ₁ , Gary A Molander ₁

Affiliation

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.

中文翻译：

光化学 C–F 活化可实现三氟乙酸和乙酰胺的脱氟烷基化

尽管宝石-二氟亚甲基具有诱人的结构、物理和生化特性，但将其安装到有机结构中仍然是一项艰巨的合成挑战。一种非常有效的逆合成方法是将来自三氟甲基的单个 C-F 键功能化。这一系列攻击的最新进展使三氟甲基芳烃的 C-F 活化成为可能，但将可访问的基序限制为仅苄基宝石-二氟化支架。相比之下，三氟乙酸盐的 C-F 活化将使它们能够用作双功能宝石-二氟亚甲基合成子。在此，我们报告了一种光化学介导的商品原料脱氟烷基化方法：三氟乙酸乙酯。使用我们之前开发的二芳基酮 HAT 催化剂确定了一种新的机制方法，以实现多种烯烃的加氢烷基化。此外，电化学研究表明，更具挑战性的自由基前体，即三氟乙酰胺，也可以通过协同路易斯酸/光化学活化进行功能化。最后，该方法为 FDA 批准的药物化合物的新型宝石-二氟类似物提供了一种简洁的合成方法。

更新日期：2021-12-01

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