Fluorine Gas as a Selective Difluorinating Reagent

Abstract

The development of organofluorine chemistry has revolutionised the way many agrochemical and pharmaceutical companies design and screen potential new active ingredients. As part of these advances, several methods of selectively introducing C-F, >CF2 or -CF3 groups into a range of organic compounds has been developed.

In this thesis, we describe the selective syntheses of >CF2 groups using fluorine gas (F2) by transformation of >CH2 groups α- to carbonyl systems. Our fluorination methodology was applied to a range of 1,3-diketone, 1,3-diester, 1,3-ketoester and ester substrates to produce the corresponding CF2C=O derivatives. The reactivity of F2 was mediated by the addition of various nitrogen bases, with the addition of quinuclidine appearing to afford the best selectivity for the selective synthesis of >CF2 containing compounds which could, in principle, be scaled up to manufacturing quantities.

Further reactions of some of the difluoroesters synthesised during this project were investigated. The ArCF2X moiety is of particular interest currently to the life science industries due to the beneficial physicochemical and pharmacokinetic properties that the incorporation of fluorine provides. In particular, amidation reactions were successfully performed to generate a new synthetic route to difluoroamides.

Finally, selective fluorinations of aromatic systems using F2 in basic media was attempted to complement previous literature on the fluorination of these systems in acidic media.