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

Abstract

CÀ F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of CÀ F bonds and the low reactivity of the fluoride released upon CÀ 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 CÀ F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal CÀ 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 onepot process that avoids the isolation of organic fluorides.

Conformational Mapping, Interactions, and Fluorine Impact by Combined Spectroscopic Approaches and Quantum Chemical Calculations

“…The selection of fluorine (F) atom as a substituent is due to its unique properties as the most electronegative element and its promise for new drug design. 48,49 This high electronegativity may lead to highly polarized C−F bonds, weakly polarizable lone pair electrons, and weak HB acceptor abilities, which might impact the conformational preferences and properties relative to those of their nonfluorinated counterparts. Specifically, the outcomes of site-specific fluorine substitution at the ortho-and parapositions of PEA, 32−34 namely, 2-FPEA and 4-FPEA, respectively, were assessed.…”