Formal Insertion of Alkenes Into C(sp3)−F Bonds Mediated by Fluorine‐Hydrogen Bonding

• Published in: Angewandte Chemie 2023-06, Vol.135 (25), p.n/a
• Main Authors: Garg, Arushi, Gerwien, Nils J., Fasting, Carlo, Charlton, Alex, Hopkinson, Matthew N.
• Format: Article
• Language: English
• Subjects: Alcohols; Alkenes; Bonding strength; Bromides; Chemical bonds; Chemistry; Fluorides; Fluorination; Fluorine; gem-Difluorinated Groups; Hydrogen Bonding; Hydrogen bonds; Insertion; Insertion Reactions; Reagents; Styrenes
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202302860

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 Insertion reactions represent a powerful approach to prepare complex fluorinated compounds, yet they are extremely scarce. Here we report a hydrogen bonding‐mediated system that allows for activation of activated alkyl fluorides without sequestering the released fluoride in an unreactive by‐product. This allows for formal insertion of fluorinated styrenes into the C−F bond affording gem‐difluorinated products.