β-fluoroamphetamines via the stereoselective synthesis of benzylic fluorides

Article abstract of DOI:10.1021/ol100862s

A range of substituted aryl epoxides undergo efficient ring-opening hydrofluorination upon treatment with 0.33 equiv of BF₃-OEt ₂ in CH₂Cl₂ at -20 -°C to give the corresponding syn-fluorohydrins, consistent with a mechanism involving a stereoselective S_N1-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 β-fluoroamphetamines.

Full text of DOI:10.1021/ol100862s

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.
steVe.daVies@chem.ox.ac.uk
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.
(1) Kirk, K. L. Org. Process. Res. DeV. 2008, 12, 305. Muller, K.; Faeh,
C.; Diederich, F. Science 2007, 317, 1881. Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, 2004. Mikami, K.; Itoh, Y.; Yamamaka,
Y. M. Chem. ReV. 2004, 104, 1. Smart, B. E. J. Fluorine Chem. 2001, 109,
3.
(5) Gre´e, D.; Gre´e, R. Tetrahedron Lett. 2007, 48, 5435. Murthy,
A. S. K.; Tardivel, R.; Gre´e, R. Product Subclass 6: Benzylic Fluorides In
Science of Synthesis; Percy, J., Eds.; Thieme: Stuttgart, 2006; Vol. 34, p
295.
(2) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
ReV. 2008, 37, 320. Ma, J.-A.; Cahard, D. Chem. ReV. 2008, 108, PR1.
Gouverneur, V.; Bobbio, C. Org. Biomol. Chem. 2006, 4, 2065.
(3) For a recent example, see: Bio, M. M.; Waters, M.; Javadi, G.; Song,
Z. J.; Zhang, F.; Thomas, D. Synthesis 2008, 891.
(4) Purrington, S. T.; Woodard, D. L.; Cale, N. C. J. Fluorine Chem.
1990, 48, 345.
(6) (a) House, H. O. J. Am. Chem. Soc. 1956, 78, 2298. (b) Berti, G.;
Macchia, B.; Macchia, F.; Monti, L. J. Chem. Soc. C 1971, 3371. (c) Islas-
Gonza´lez, G.; Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Riera, A.;
Perica`s, M. A. Tetrahedron Lett. 2004, 45, 6337.
10.1021/ol100862s  2010 American Chemical Society
Published on Web 05/28/2010

with only very low levels of fluorine incorporation (e13%)10
being observed (Scheme 1).
Scheme 1
The formation of syn-fluorohydrin 11 from trans-epoxide
3 is consistent with a mechanism involving co-ordination of
BF3 to the oxirane oxygen and subsequent rupture of the
C-O bond to generate benzylic carbocation 16 in conforma-
tion 16A; transfer of fluorine and workup gives syn-
fluorohydrin 11. In the case of cis-epoxide 4, the carbocation
is generated in conformation 16B, which suffers from
destabilizing nonbonded interactions between the phenyl and
methyl groups. A C-C bond rotation to relieve this strain
may place the C(ꢀ)-H bond coplanar to the empty p-orbital
(e.g., in conformation 16C); a subsequent [1,2]-H-atom shift
results in the formation of phenylpropan-2-one, the observed
major product (Figure 2). This simplistic mechanistic ratio-
nale is also able to successfully account for the low levels
of fluorine incorporation observed for the range of epoxides
1, 2, and 5-8, as in none of these cases is there a significant
steric bias for the benzylic carbocation to be sufficiently long-
lived in its initial conformation for efficient fluorine transfer
to occur before side reactions can intervene.
a Calculated from 19F NMR spectroscopic analysis with fluorobenzene
c
standard. b Isolated yield of a single diastereoisomer (>99:1 dr). ∼90%
ee. d 92% ee.
Under optimized conditions, treatment of racemic (E)-ꢀ-
methylstyrene oxide 3 with 0.33 equiv of BF3·OEt2 in CH2Cl2
at -20 °C for 5 min gave fluorohydrin 11 as the major
product in >99:1 dr, which was isolated in 83% yield and
>99:1 dr, consistent with the transfer of all three fluorine
atoms of BF3·OEt2 (Scheme 1).7 The relative syn-configu-
ration within 11 was unambiguously established by single-
crystal X-ray analysis of the p-nitrobenzoate derivative 15
(Figure 1). In the enantiopure series, ring-opening hydro-
Figure 1. Chem3D representation of the single-crystal X-ray
structure of (()-15 (some H atoms omitted for clarity). Ar )
p-C6H4NO2.
Figure 2. Postulated mechanism for ring-opening hydrofluorination
with BF3·OEt2.
fluorination of (R,R)-3 (∼90% ee)8 gave fluorohydrin (R,R)-
11 in 81% yield, >99:1 dr and 92% ee9 (Scheme 1).
Treatment of (Z)-ꢀ-methylstyrene oxide 4 with BF3·OEt2
under the same conditions gave a mixture of products
containing 5%10 of syn-fluorohydrin 11 and phenylpropan-
2-one as the major component. Similar reaction with epoxides
1, 2, and 5-8 also gave rise to complex mixtures of products
The functional group tolerance of this reaction was next
probed. Treatment of epoxides 17-19 and 21-24 with
BF3·OEt2 gave the corresponding syn-fluorohydrins 27-29
and 31-34 as the major products in >99:1 dr, which were
isolated in good yields. Competing isomerization processes
(7) BF3·OEt2 has previously been demonstrated to transfer all three
fluorine atoms during the ring-opening hydrofluorination of aryl epoxides,
necessitating the use of only 0.33 equiv of this reagent; see ref 6c.
(8) A sample of (R,R)-3 was prepared by Shi epoxidation of trans-ꢀ-
methylstyrene; see: Wang, Z. X.; Shu, L.; Frohn, M.; Tu, Y.; Shi, Y. Org.
Synth. 2003, 80, 9. This procedure has been reported to give (R,R)-3 in
89-92% ee.
(9) The enantiomeric excess of (R,R)-11 was determined by conversion
to the corresponding Mosher’s ester; see: Dale, J. A.; Dull, D. L.; Mosher,
H. S. J. Org. Chem. 1969, 34, 2543.
(10) The percentage of fluorine incorporation into the reaction products
was determined by 19F NMR spectroscopic analysis with a fluorobenzene
standard.
Org. Lett., Vol. 12, No. 13, 2010
2937

Scheme 2a
a All Compounds Are Single Diastereoisomers (>99:1 dr). b A 69:31 mixture of 33 and 59 was produced. c Reaction required 30 min to proceed to
conversion. Ar ) p-C6H4NO2.
to give carbonyl compounds were observed in most cases;
in fact, migration of the R substituent to give aldehydes 50,
55, and 56 represented the major (and in the latter two cases
exclusive) product upon reaction of epoxides 20, 25, and
26, which bear R groups of high migratory aptitude (Scheme
2). The relative syn-configurations within fluorohydrins
27-34 were assigned by analogy to that unambiguously
established for 11. In support of these assignments, the
relative syn-configuration within 34 was unambiguously
determined by single-crystal X-ray analysis of the p-
nitrobenzoate derivative 57 (Figure 3), and the relative syn-
on the basis of the reaction proceeding via an SN2-type
epoxide opening.6c In light of our results, however, the
stereochemistry of these fluorohydrin products has been
reassigned by Perica`s et al. as syn.11
The effect of the electronic nature of the aryl group was
investigated by application of the optimized reaction condi-
tions to a range of (E)-ꢀ-methylstyrene oxides 60-70
(g90:10 dr) bearing aryl substituents with Hammett σ+
substituent constants ranging from -0.78 to +0.61.12 Ring-
opening hydrofluorination of 63 and 64 (X ) p-F, m-OMe)
gave the corresponding fluorohydrin products 74 and 75
(>99:1 dr). The more electron-deficient species 65-69 (X
) p-Cl, p-Br, m-F, m-Cl, m-Br) required a reaction time of
10 min for complete consumption of starting materials to
give fluorohydrins 76-80 (>99:1 dr). Fluorohydrins 74-80
were isolated in good yields after chromatography. However,
reaction of the electron-rich species 60-62 (X ) p-OMe,
p-Me, p-Ph) resulted in mixtures of products, including the
corresponding arylpropan-2-one as a major component.
Reaction of 70 (X ) p-CF3) proceeded with incomplete
conversion to give a mixture of products including fluoro-
hydrin 81, although this was not isolated in pure form. The
relative configurations within fluorohydrins 74-80 were
assigned as syn by analogy to that unambiguously proven
for 11; in all cases, the C(1)H-C(2)H coupling constant was
6.8 Hz, which is supportive of the assigned syn-stereochem-
istry.13 Assuming that these reactions proceed via the
intermediacy of a benzylic carbocation, these results suggest
that a compromise in carbocation stability versus reactivity
Figure 3. Chem3D representation of the single-crystal X-ray
structure of 57 (some H atoms omitted for clarity). Ar )
p-C6H4NO2.
(11) See the correction to: Rodr´ıguez-Escrich, S.; Popa, D.; Jimeno, C.;
Vidal-Ferran, A.; Perica`s, M. A. Org. Lett. 2005, 7, 3829; Org. Lett. 2010,
12, DOI: 10.1021/ol1008735.
(12) Brown, H. C.; Okamoto, Y. J. Am. Chem. Soc. 1958, 80, 4979.
(13) This is consistent with the value of 7.1 Hz observed for syn-
fluorohydrin 11 versus 4.8 Hz for the corresponding anti-diastereoisomer.
A correlation between relative stereochemistry and vicinal 1H NMR 3J
coupling constant for a range of ꢀ-fluoro-ꢀ-phenylamines has previously
been reported; see: Hamman, S.; Bena¨ıssa, T.; Be´guin, C. G. Magn. Reson.
Chem. 1988, 26, 621.
configurations within 30, 31 and 34 were correlated via the
common diol 58. The ring-opening hydrofluorination of some
O-protected 3-phenyl glycidols (including 21) with BF3·OEt2
has previously been reported by Perica`s et al., with anti-
configurations being assigned to the fluorohydrin products
2938
Org. Lett., Vol. 12, No. 13, 2010

may be necessary for successful incorporation of fluorine,
meaning that the rate of both cation formation and cation
trapping by fluorine must outpace competing side reactions
(Scheme 3).
quent Staudinger reduction providing anti-ꢀ-fluoroamphet-
amines (()-89, (RS,ꢀR)-89,18 and 90-95 in good yield and
as single diastereoisomers (Scheme 4).
Scheme 4
Scheme 3
a Isolated yield of a single diastereoisomer (>99:1 dr). b 92% ee. c 93%
ee.
a Isolated yield of a single diastereoisomer (>99:1 dr).
The utility of these fluorinated building blocks was
demonstrated by the synthesis of a range of aryl-substituted
ꢀ-fluoroamphetamines,14 a motif that has been utilized in
SAR studies toward agrochemical fungicides15 and nitric
oxide synthase inhibitors.16 18F-Labeled ꢀ-fluoroamphet-
amines have also been studied as potential radiotracers for
in vivo diagnostic imaging.17 Sequential treatment of syn-
fluorohydrins (()-11, (R,R)-11, and 75-80 with mesyl
chloride and sodium azide gave the corresponding anti-ꢀ-
fluoroazides (()-82, (1R,2S)-82,18 and 83-88, with subse-
In conclusion, the ring-opening hydrofluorination of a
range of substituted aryl epoxides upon treatment with 0.33
equiv of BF3·OEt2 in CH2Cl2 proceeds rapidly at -20 °C to
give the corresponding syn-fluorohydrins, consistent with a
mechanism involving a stereoselective SN1-type process. The
reaction manifold is able to tolerate a range of functionality
within the basic aryl epoxide framework, including modestly
electron-withdrawing groups on the aromatic ring. The syn-
fluorohydrin products of these reactions are useful building
blocks for further elaboration, as demonstrated by the
preparation of a range of ꢀ-fluoroamphetamines.
(14) Bena¨ıssa, T.; Hamman, S.; Be´guin, C. G. J. Fluorine Chem. 1988,
38, 163. Hamman, S.; Be´guin, C. G. J. Fluorine Chem. 1987, 37, 191.
Alvernhe, G. M.; Ennakoua, C. M.; Lacombe, S. M.; Laurent, A. J. J. Org.
Chem. 1981, 46, 4938. Wade, T. N. J. Org. Chem. 1980, 45, 5328.
(15) Stierli, D.; Taylor, J. J.; Walter, H.; Worthington, P. A.; Rajan, R.
WO Patent 2007141009 A1, 2007.
Acknowledgment. We thank Syngenta for a CASE
studentship (A.J.C.) and the Oxford Chemical Crystal-
lography Service for the use of their X-ray diffractometers.
(16) Rehwinkel, H.; Hoelscher, P.; Jaroch, S.; Suelzle, D.; Hillmann,
M.; Burton, G. A.; McDonald, F. M. DE Patent 10162114 A1, 2003.
Rehwinkel, H.; Hoelscher, P.; Jaroch, S.; Suelzle, D.; Hillmann, M.; Burton,
G. A.; McDonald, F. M. WO Patent 2001081323 A1, 2001.
(17) Lehmann, L.; Thiele, A.; Heinrich, T.; Brumby, T.; Halldin, C.;
Gulyas, B.; Nag, S. WO Patent 2009052970 A2, 2009. Van Dort, M. E.;
Jung, Y.-W.; Sherman, P. S.; Kilbourn, M. R.; Wieland, D. M. J. Med.
Chem. 1995, 38, 810.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) The enantiomeric excesses of (1R,2S)-82 and (RS,ꢀR)-89 were
determined by chiral GC analyses, for which the authors would like to thank
Carole J. R. Bataille.
OL100862S
Org. Lett., Vol. 12, No. 13, 2010
2939