Radical Reactions of Alkyl 2‑Bromo-2,2-difluoroacetates with Vinyl Ethers: “Omitted” Examples and Application for the Synthesis of 3,3-Difluoro-GABA

Addition reactions of perfluoroalkyl
radicals to ordinary or polyfluorinated
alkenes have been frequently used to synthesize perfluoroalkylated
organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate,
diethyl (bromodifluoromethyl)­phosphonate, [(bromodifluoromethyl)­sulfonyl]­benzene,
and ethyl 2-bromo-2-fluoroacetate were involved in Na2S2O4-mediated radical additions to vinyl ethers in
the presence of alcohols to give difluoro or monofluoroacetyl-substituted
acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)­sulfonyl-substituted
alkyl acetals. This methodology has also been applied as a key step
in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing
the series of isomeric difluoro GABAs. Comparison of the pKa values of 3-fluoro- and 3,3-difluoro-GABA
with that of the fluorine free parent compound showed that introduction
of each fluorine lead to acidification of both the amino and the carboxyl
functions by approximately one unit.