ORGANIC
LETTERS
2010
Vol. 12, No. 13
2936-2939
ꢀ-Fluoroamphetamines via the
Stereoselective Synthesis of Benzylic
Fluorides
Alexander J. Cresswell,† Stephen G. Davies,*,† James A. Lee,† Paul M. Roberts,†
Angela J. Russell,† James E. Thomson,† and Melloney J. Tyte‡
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K., and Syngenta, Jealott’s Hill International
Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
Received April 15, 2010
ABSTRACT
A range of substituted aryl epoxides undergo efficient ring-opening hydrofluorination upon treatment with 0.33 equiv of BF3·OEt2 in CH2Cl2 at
-20 °C to give the corresponding syn-fluorohydrins, consistent with a mechanism involving a stereoselective SN1-type epoxide ring-opening
process. The benzylic fluoride products of these reactions are valuable templates for further elaboration, as demonstrated by the preparation
of a range of aryl-substituted ꢀ-fluoroamphetamines.
The incorporation of fluorine into organic molecules frequently
has a dramatic impact on their physical, chemical, and biological
properties,1 and compounds bearing fluorine at stereogenic
centers are of mounting interest in medicinal chemistry.2 The
benzylic fluoride motif is an effective isosteric replacement for
benzylic C-H or C-OH groups in many pharmaceutical and
agrochemical candidates,3 and chiral benzylic fluorides have
found application in the synthesis of fluorinated ferroelectric
liquid crystals.4 However, a shortage of reliable, generally
applicable methods for the stereoselective synthesis of this class
of compounds has meant that this motif remains underutilized
in drug discovery.5 Nucleophilic fluorination strategies toward
benzylic fluorides typically suffer from partial or total racem-
ization/epimerization due to the intermediacy of benzylic
carbocations.5 A few isolated examples of the stereoselective
ring-opening hydrofluorination of aryl epoxides using BF3·OEt2
have been reported,6 although the generality of this process has
yet to be explored. Considering the significant practical and
economic benefits (i.e., low cost, high fluorine content and ease
of handling in standard glassware) we investigated the utility
of BF3·OEt2 as a nucleophilic fluorine source and report herein
our results within this area.
† University of Oxford.
‡ Syngenta.
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10.1021/ol100862s 2010 American Chemical Society
Published on Web 05/28/2010