From Difluoromethyl 2-Pyridyl Sulfone to Difluorinated Sulfonates: A Protocol for Nucleophilic Difluoro(sulfonato)methylation

摘要

Fluorine, characterized by its small size and high electronegativity, often furnishes organic molecules with unequalled chemical and biological properties including stability, lipophilicity, and bioavailability. The sulfonic acid functional group has not only found its use in modern materials such as proton-exchange membranes and surfactants, but also in synthetic molecules with important biological and pharmacological activities such as antiulcer, antibacterial, antipseudomonal, and squalene synthase inhibition activities. Based on this scenario, a,a-difluorinated sulfonate derivatives, as an important subclass of lightly fluorinated compounds, are of great interest in life and materials sciences. Furthermore, owing to the isopolar and isosteric characters of the difluoromethylene group to an oxygen atom, difluorinated sulfonates can be exploited to replace the labile sulfate esters. Although α,α-difluorinated phosphonic acids have, been used to inhibit and probe enzymes and proteins that bind or hydrolyze phosphate for many years, only in recent years, attention has been paid on α,α-difluorinated sulfonates to design effective sulfatase inhibitors. Moreover, in relation with the perfluorinated sulfonic acids and their derivatives, the performance of these difluorinated counterparts are also of great interest in materials science owing to their acidity and facile biodegradability. Thus, many α,α-difluorinated sulfonates have been synthesised using different protocols, including the electrophilic fluorination of the sulfonates, dehalosulfination or -sulfonation of α,α-difluoroalkyl halides, sulfonation of 1,1-difluoroalkenes, sulfination of α,α-difluorosilanes, and fluorinated sultone rearrangements. Apparently, one of the disadvantages of these protocols is that the fluorine atoms and sulfonato group have to be incorporated sequentially.