Chemistry - A European Journal
10.1002/chem.202001905
FULL PAPER
Table 4. Variation of the benzylic fluoride.[a]
activation reactions. Considering that a large variety of chiral
thioureas are already reported, our results may open the door to
asymmetric transformations involving C–F bond activation.
Acknowledgements
We thank Aline Lacoudre (CESAMO, UMR 5255) for X-ray
crystallography of compounds 2c (CCDC 1950215) and 2h
(
CCDC 1950216). This work was supported by the Université de
Bordeaux, the Centre National de la Recherche Scientifique
CNRS), the Natural Sciences and Engineering Research Council
(
of Canada (NSERC), the FRQNT Network for Research on
Protein Function, Engineering, and Applications (PROTEO),
Université Laval and the New Jersey Institute of Technology
(
NJIT). Calculations were performed on the Kong cluster at NJIT.
Keywords: benzyl amines • benzyl fluorides • C–F activation •
organocatalysis • thiourea
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a] See the Supporting Information for the detailed experimental conditions. [b]
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Finally, this reaction is not limited to amines as nucleophiles
as promising preliminary results were obtained with both S- and
O-based nucleophiles (Scheme 1). Indeed, reaction of benzylic
fluoride 1 under the optimized conditions using either sodium
thiophenoxide (PhSNa) or sodium phenoxide (PhONa) provided
the corresponding products (42 and 43) in 88 and 52% yield,
respectively.
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Scheme 1. Preliminary results with S- and O-based nucleophiles.[a]
[
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4
bond activation reaction using a thiourea catalyst. Ti(OiPr) as a
fluoride scavenger was shown to be a key additive for the turnover
of the catalyst. This system has been used for the amination of
benzylic fluorides and the corresponding benzylic amines, a motif
featured in numerous pharmaceuticals, were obtained in
moderate to excellent yields. Preliminary results with S- and O-
based nucleophiles were also presented. DFT calculations
revealed how seemingly weak interactions like hydrogen bonds to
fluorine can have a large influence on transition states of C–F
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6
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