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Synthesis 2004(10): 1609-1618  
DOI: 10.1055/s-2004-829110
PAPER
© Georg Thieme Verlag Stuttgart · New York

The Regioexhaustive Functionalization of Difluorophenols and Trifluoro­phenols Through Organometallic Intermediates

Elena Marzi, Joanna Gorecka, Manfred Schlosser*
Institut des Sciences et Ingénierie Chimiques (ISIC, BCh), Ecole Polytechnique Fédérale, 1015 Lausanne, Switzerland
Fax: +41(21)6939365; e-Mail: manfred.schlosser@epfl.ch;
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Publication History

Received 10 February 2004
Publication Date:
23 June 2004 (online)

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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