Development of the titanium-TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

Lukas Hintermann, Mauro Perseghini, Antonio Togni

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30 Scopus citations


Titanium-based Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N-F-fluorinating reagents. Asymmetric catalysis with TADDOLato-titanium(IV) dichloride (TADDOL = α,α, α',α'-tetraaryl-(1,3-dioxolane-4,5-diyl)-dimethanol) Lewis acids produces enantiomerically enriched a-fluorinated β-ketoesters in up to 91% enantiomeric excess, with either F-TEDA (1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) in acetonitrile solution or NFSI (N-fluorobenzenesulfonimide) in dichloromethane solution as fluorinating reagents. The effects of various reaction parameters and of the TADDOL ligand structure on the catalytic activity and enantioselectivity were investigated. The absolute configuration of several fluorination products was assigned through correlation. Evidence for ionization of the catalyst complex by chloride dissociation, followed by generation of titanium β-ketoenolates as key reaction intermediates, was obtained. Based on the experimental findings, a general mechanistic sketch and a steric model of induction are proposed.

Original languageEnglish
Article number166
Pages (from-to)1421-1435
Number of pages15
JournalBeilstein Journal of Organic Chemistry
StatePublished - 17 Oct 2011


  • Asymmetric catalysis
  • Fluorination
  • Fluoroorganic compounds
  • Titanium


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