School of Natural and Environmental Sciences, Newcastle University Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Institut für Chemie und Biochemie, Freie Universität Berlin, Fabeckstrasse 34-36, 14195, Berlin, Germany.
Angew Chem Int Ed Engl. 2023 Jun 19;62(25):e202302860. doi: 10.1002/anie.202302860. Epub 2023 May 11.
C-F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C-F bonds and the low reactivity of the fluoride released upon C-F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C-F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C-F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.
C-F 插入反应是制备有价值的氟化化合物的一种有吸引力的方法。然而，C-F 键的高强度和 C-F 键断裂时释放的氟化物的低反应性意味着此类过程在文献中极为罕见。在这里，我们报告了一种反应体系，该体系使用氢键供体克服了这些挑战，这些供体既能激活 C-F 键，又能允许与氟化物进行后续反应。在六氟异丙醇的存在下，苄基和炔丙基氟化物能够有效地在α-氟化苯乙烯上进行形式上的 C-F 键插入。该过程不需要任何额外的氟化试剂，在温和的条件下进行，并提供具有偕二氟基团的产物，偕二氟基团在药物化学中越来越受到关注。此外，易得的有机溴化物可以直接参与一锅法反应，避免了有机氟化物的分离。
