The Regioexhaustive Functionalization of Difluorophenols and Trifluoro­phenols Through Organometallic Intermediates

 

 Buy Article Permissions and Reprints All articles of this category

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.

References

• 1 Schlosser M. Eur. J. Org. Chem.  2001,  3975 
  CrossrefGoogle Scholar
• 2 Review: Schlosser M. Angew. Chem.  2004,  in press 
  Google Scholar
• 3 Katsoulos G. Takagishi S. Schlosser M. Synlett  1991,  731 
  Article in Thieme ConnectGoogle Scholar
• 4 Marzi E. Mongin F. Spitaleri A. Schlosser M. Eur. J. Org. Chem.  2001,  2911 
  CrossrefGoogle Scholar
• 5 Rauchschwalbe G. Schlosser M. Helv. Chim. Acta  1975,  58:  1094 
  CrossrefGoogle Scholar
• 6 Schlosser M. Franzini L. Synthesis  1998,  707 ; and reference 14 cited therein
  Article in Thieme ConnectGoogle Scholar
• 7 Schlosser M. Gorecka J. Castagnetti E. Eur. J. Org. Chem.  2003,  452 
  CrossrefGoogle Scholar
• 8 Takagishi S. Schlosser M. Synlett  1991,  119 
  Article in Thieme ConnectGoogle Scholar
• 9 Bobbio C. Schlosser M. Eur. J. Org. Chem.  2001,  4533 
  CrossrefGoogle Scholar
• 10 Schlosser M. Marull M. Eur. J. Org. Chem.  2003,  1569 
  CrossrefGoogle Scholar
• 11 Marvel CS. Porter PK. Org. Synth. Coll. Vol. I   Wiley; New York: 1941.  p.369 
  Google Scholar
• 12 Weidner-Wells MA. Fraga-Spano SA. Synth. Commun.  1996,  26:  2775 
  CrossrefGoogle Scholar