Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
J Am Chem Soc. 2021 Dec 1;143(47):19648-19654. doi: 10.1021/jacs.1c11059. Epub 2021 Nov 18.
The installation of -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 -difluorinated scaffolds. In contrast, the C-F activation of trifluoroacetates would enable their use as a bifunctional -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 -difluoro analogs of FDA-approved pharmaceutical compounds.
尽管 -二氟亚甲基基团具有吸引人的结构、物理和生化性质，但将其引入有机结构中仍然是一项艰巨的合成挑战。一个非常有效的反合成方法将是从三氟甲基基团中官能化单个 C-F 键。在这方面的最新进展使得能够对三氟甲基芳基进行 C-F 活化，但可访问的图案仅限制为苄基 -二氟化支架。相比之下，三氟乙酸酯的 C-F 活化将能够将其用作双功能 -二氟亚甲基合成子。在此，我们报告了一种用光化学介导的方法从商品原料中脱氟烷基化的方法：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颖的机理方法，以实现各种烯烃的氢烷基化。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/光化学活化进行官能化。最后，该方法实现了 FDA 批准的药物化合物的新型 -二氟类似物的简洁合成方法。
