Synthesis of fluorine compounds based on special property of fluorine compounds

Abstract

This review describes new syntheses of organofluorine compounds taking advantage of the special properties of fluorine compounds as synthones. The main reactions presented are as follows: 1) Trifluoromethylation of aryl or alkyl halides. Application of this reaction for the synthesis of fluorine analogues of nucleic acid bases is discussed. 2) Some syntheses of trifluoromethyl compounds using the Diels-Alder or the 1,3-dipolar reaction, trifluoromethylated carbene, and photoreaction. 3) The Friedel-Crafts reaction of 3,3,3-trifluoropropene, where linear alkylation occurs due to electronic effect of the trifluoromethyl group in good contrast with the Friedel-Crafts reaction of propene. 4) The ene reaction of trifluoromethylated carbonyl compounds, which work as good enophiles. Application of this reaction to the synthesis of trifluoro analogues of terpenes is discussed. 5) The ene reaction of trifluoromethylated imines. 6) Reaction of halothane, which has a highly acidic hydrogen and two halogens adjacent to the trifluoromethyl group and shows interesting reactivities with various bases and metals to give products with unexpected structures. 7) Reaction of 2-bromo-2,2-difluoroacetate with Cu, where the cross-coupling reaction, Michael-type reaction, and radical reaction for different types of difluoroacetates are presented. 8) Reaction of 2-bromo-2,2-difluoroacetate in the presence of Rh catalyst. This reaction provided a new methodology for the introduction of fluoroalkyl substituents to the α-position of α,β-unsaturated ketones. The Rh catalyst solved some difficulties in the introduction of difluoroacetate to carbonyl compounds (Reformatsky reaction). Application of this reaction to imines provided easy access to β,β-difluoro-β-lactams. © 2006 The Pharmaceutical Society of Japan.