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

Authors
  • Hintermann, Lukas
  • Perseghini, Mauro
  • Togni, Antonio
Type
Published Article
Journal
Beilstein Journal of Organic Chemistry
Publisher
Beilstein-Institut
Publication Date
Jan 01, 2011
Volume
7
Pages
1421–1435
Identifiers
DOI: 10.3762/bjoc.7.166
PMID: 22043253
Source
Medline
Keywords
License
Unknown

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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