Abstract
2,4-Difluorophenol, 2,5-difluorophenol, 2,3-difluorophenol, 3,5-difluorophenol, 3,4-difluorophenol,
2,4,5-trifluorophenol and 2,3,4-trifluorophenol were converted into all 18 possible
di- or trifluorinated hydroxybenzoic acids (1a-c, 4a-c, 9a-c, 12a,b, 14a-c, 17a,b, 18a,b), all of them new compounds. The phenolic hydrogen atom was replaced by a methoxymethyl
or, less frequently, by a triisopropylsilyl group, which exerted an ortho activating or ortho shielding effect, respectively. Sites flanked by two electronegative substituents
(fluorine, alkoxy) were deprotonated with particular ease. They had to be silenced
by the reversible attachment of a metalation-blocking trimethylsilyl group or of a
metalation-deflecting chlorine atom if the metal was to be introduced elsewhere. In
all cases but one, the stage was thus set for an intramolecular competition between
metalation at an oxygen-adjacent or a fluorine-adjacent site. It proved indeed possible
to secure the desired regioflexibility in either way by relying on an appropriate
substrate-reagent matching. This demonstrates once more the potential of the organometallic
approach to diversity-oriented synthesis.
Key words
alkyllithiums - carboxylation - (de-)chlorination -
(de-)silylation - fluorophenols - organometallic reactions - protective groups - regioselectivity
- superbases
