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Updated: May 28, 2026

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives
Published on: January 19, 2016
Development of the titanium-TADDOLate-catalyzed asymmetric fluorination of β-ketoesters
Lukas Hintermann1, Mauro Perseghini, Antonio Togni
1Laboratorium für Anorganische Chemie, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
Abstract:
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 α-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.
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