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.
Highlights
Fluoroorganic compounds have peculiar properties, rendering them interesting for a variety of specific applications [1,2,3,4,5,6,7,8,9,10,11,12,13]
Titanium-based Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N–F-fluorinating reagents
From studies on the electrophilic fluorination with N–F reagents, it is known that some β-carbonyl compounds are α-fluorinated by simple combination of the reactants in solution at room temperature (Scheme 2b) [66,67,68,69,70,71]
Summary
Fluoroorganic compounds have peculiar properties, rendering them interesting for a variety of specific applications [1,2,3,4,5,6,7,8,9,10,11,12,13]. Research efforts of our group towards realizing metal-catalyzed fluorinations [36,37,38] and asymmetric catalytic fluorination reactions [39], successfully channeled into the discovery of a catalytic asymmetric α-fluorination of β-ketoesters (Scheme 1) by means of the reagent F–TEDA and chiral titanium Lewis acid catalysts of the TiCl2(TADDOLate) type [40,41,42].
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