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

Abstract

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.

Ruthenium(II)-enabled para-selective C–H difluoromethylation of anilides and their derivatives

“…5c ). The ·CF 2 CO 2 Et radical can be generated from 2-bromo-2,2-difluoroacetates, as reported by the groups of Ackermann 25 , Wang 26 , and Kondratov 65 . Thus, we directly treated the substrate 1a with 2 in the presence of the radical initiator.…”

Stereoselective access to trisubstituted fluorinated alkenyl thioethers

“…The generation of a difluoroacetate radical promoted by a well-defined copper complex was established by these studies. Compared to other strategies to introduce a fluorine atom or a fluorinated group, [19][20][21]23,[33][34][35][36][37][38][39] this method allowed the generation of a radical under mild conditions, without requirement of light irradiation, expensive metal or radical initiator, which constitutes a real asset. It allows an easy access to fluorinated chemical platform of interest, since post-functionalizations of these substrates are possible thanks to the versatility of the ester function.…”

Photocatalytic Difluoromethylation Reactions of Aromatic Compounds and Aliphatic Multiple C–C Bonds

“…The phosphonodifluoromethylation of alkenes has been documented to proceed through diverse methods such as nucleophilic addition [47][48][49][50][51][52][53][54], transition metal catalysis [55][56][57][58], photoredox catalysis (by oxidative quenching cycles) [59][60][61][62][63], or radical ATRA reactions [64][65][66][67][68][69], as depicted in Scheme 15.…”