Hydrogen Bond Directed Photocatalytic Hydrodefluorination: Overcoming Electronic Control

The photocatalytic C–F functionalization of highly fluorinated arenes is a powerful method for accessing functionalized multifluorinated arenes. The decisive step in the determining regioselectivity in fluorine functionalization is fluoride fragmentation from the radical anion of the multifluorinated arene. To date, the availability of regioisomers has been dictated by the innate electronics of the fluorinated arene, limiting the synthetic utility of the chemistry. This study investigates the remarkable ability of a strategically located hydrogen bond to transcend the normal regioselectivity of the C–F functionalization event. A significant rate acceleration is additionally observed for hydrodefluorination of fluorines that can undergo intramolecular hydrogen bonds that form 5–8-membered cycles with moderately acidic N–H’s. The hydrogen bond is expected to facilitate the fragmentation not only by bending the C–F bond of the radical anion out of planarity but also by increasing the exothermicity of the fluoride extrusion step through protonation of the naked fluoride. Finally, the synthetic utility of the method is demonstrated in an expedited synthesis of the trifluorinated α-phenyl acetic acid derivative required for the commercial synthesis of Januvia, an antidiabetic drug. This represents the first synthesis of a commercially important multifluorinated arene via a defluorination strategy and is significantly shorter than the current strategy.高氟芳烃（highly fluorinated arenes）的光催化C-F官能化（photocatalytic C–F functionalization）是制备官能化多氟芳烃（multifluorinated arenes）的高效手段。在氟官能化反应中，决定区域选择性的关键步骤是多氟芳烃自由基阴离子（radical anion）发生氟离子碎裂过程。迄今为止，区域异构体（regioisomers）的生成路径均由氟芳烃的固有电子效应所决定，极大限制了该类反应的合成应用价值。本研究探究了精准定位的氢键（hydrogen bond）能够打破C-F官能化反应固有区域选择性的非凡能力。此外，对于可与中等酸性N-H基团（moderately acidic N–H’s）形成5至8元环分子内氢键的氟原子，其加氢脱氟（hydrodefluorination）反应的速率可得到显著提升。研究表明，氢键不仅可通过使自由基阴离子的C-F键偏离平面构象来促进碎裂过程，还可通过裸露氟离子（naked fluoride）的质子化（protonation）作用增强氟离子脱离步骤（fluoride extrusion step）的放热性（exothermicity），从而加速反应。最后，本方法的合成应用价值通过一条快速合成路线得到验证：该路线可制备抗糖尿病药物捷诺维（Januvia）商业化合成所需的三氟代α-苯基乙酸衍生物（trifluorinated α-phenyl acetic acid derivative）。本研究首次通过脱氟策略（defluorination strategy）实现了具有商业价值的多氟芳烃的合成，且该路线较现有合成方案显著缩短。