Stereoselective synthesis of both stereoisomers of β-fluorostyrene derivatives from a common intermediate

Article abstract of DOI:10.1021/ol200302h

The stereoselective synthesis of both cis- and trans-β-fluorostyrene derivatives from a common intermediate, (Z)-1-aryl-2-fluoro-1-(trimethylsilyl) ethenes, is described. The trans isomers are obtained by a stereospecific replacement of the silyl group in

Full text of DOI:10.1021/ol200302h

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1568–1571
Stereoselective Synthesis of Both
Stereoisomers of β-Fluorostyrene
Derivatives from a Common Intermediate
ꢀ
Gregory Landelle, Marc-Olivier Turcotte-Savard, Laetitia Angers, and
Jean-Franc-ois Paquin*
ꢀ
Canada Research Chair in Organic and Medicinal Chemistry, Departement de chimie,
1045 avenue de la Medecine, Universite Laval, Quebec, QC, Canada G1V 0A6
ꢀ
ꢀ
ꢀ
jean-francois.paquin@chm.ulaval.ca
Received January 31, 2011
ABSTRACT
The stereoselective synthesis of both cis- and trans-β-fluorostyrene derivatives from a common intermediate, (Z)-1-aryl-2-fluoro-1-(trimethylsilyl)ethenes,
is described. The trans isomers are obtained by a stereospecific replacement of the silyl group in the presence of water and a fluoride source, whereas the
preparation of the cis isomers is achieved by a bromination/desilicobromination sequence followed by reduction of the newly created C-Br bond. A
stereoselective transformation of both stereoisomers of β-fluorostyrene is also presented.
Addition of fluorine atoms on a bioactive molecule is
often used to modulate its solubility, lipophilicity, meta-
bolic stability, conformation, hydrogen-bonding ability,
or chemical reactivity. Thus, the number of drugs or
agrochemicals with at least one fluorine atom has in-
creased dramatically over the past decade.1,2 It is therefore
not surprising that a parallel interest in the development of
novel methods for the synthesis of organofluorine com-
pounds has been observed. For this purpose, two comple-
mentary approaches are generally employed: formation of
a C-F bond from a suitable functional group with a
fluorinating reagent or functionalization of simple and
readily available fluorinated synthons.1a
(1) For selected book/reviews/accounts, see: (a) Hiyama, T. In
Organofluorine Compounds; Chemistry and Applications; Yamamoto,
H., Ed.; Springer: 2000 and references therein. (b) Smart, B. E. J. Fluorine
Chem. 2001, 109, 3–11. (c) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 106,
6119–6146. (d) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005,
44, 214–231. (e) Thayer, A. M. Chem. Eng. News 2006, 84, 15–24. (f)
ꢀ
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Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029. (g) Begue, J.-P.;
Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012. (h) Prakash,
€
G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921–930. (i) Muller, K.; Faeh,
Inregardtothesecond approach, onesimplefluorinated
synthon that is surprisingly missing from the toolbox is β-
fluorostyrene (trans or cis) and its derivatives. Indeed, a
wide range of diversified fluorinated synthons could be
obtained from β-fluorostyrenes if a practical and stereo-
selective access to them was available. While numerous
C.; Diederich, F. Science 2007, 317, 1881–1886. (j) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330.
(k) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369. (l) Ma, J.-A.;
Cahard, D. Chem. Rev. 2008, 108, PR1–PR43.
ꢀ
(2) For our own efforts in this area, see: (a) Belanger, E.; Cantin, K.;
ꢀ
Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc. 2007, 129,
ꢀ
ꢀ
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1034–125. (b) Belanger, E.; Houze, C.; Guimond, N.; Cantin, K.;
Paquin, J.-F. Chem. Commun. 2008, 3251–3253. (c) Landelle, G.;
Champagne, P. A.; Barbeau, X.; Paquin, J.-F. Org. Lett. 2009, 11,
681–684. (d) Landelle, G.; Turcotte-Savard, M.-O.; Marterer, J.; Cham-
pagne, P. A.; Paquin, J.-F. Org. Lett. 2009, 11, 5406–5409. (e) Pigeon, X.;
(3) For a review on the synthesis of terminal monofluoroalkenes
including β-fluorostyrenes, see: van Steenis, J. H.; van der Gen, A.
J. Chem. Soc., Perkin Trans. 1 2002, 2117–2133.
ꢀ
ꢀ
Bergeron, M.; Barabe, F.; Dube, P.; Frost, H. N.; Paquin, J.-F. Angew.
Chem., Int. Ed. 2010, 49, 1123–1127.
r
10.1021/ol200302h
Published on Web 02/21/2011
2011 American Chemical Society

We have recently described the first stereocontrolled
method for the preparation of 1,1-diaryl-2-fluoroethenes
(6, Scheme 1).2d First, 1-aryl-1-bromo-2-fluoroethenes (4)
are generated using an addition/elimination reaction of
hydride to silylated β,β-difluorostyrene derivatives (1)
followed by a bromination/desilicobromination sequence.
Subsequent Suzuki-Miyaura coupling with a variety of
boronic acids gives access to the desired 1,1-diaryl-2-
fluoroethenes. Based on these results, we envisioned that
the intermediate 2 could potentially be used as a common
precursor to give direct and stereoselective access to both
isomers of β-fluorostyrene derivatives. We report herein
that the trans-β-fluorostyrene derivatives (3) can be pre-
pared by a stereospecific replacement of the silyl group in
the presence of water and a fluoride source whereas the
preparation of cis-β-fluorostyrenes (5) can be achieved by
the reduction of the C-Br bond created from the bromi-
nation/desilicobromination sequence of 2 (Scheme 1).
Scheme 1. Stereoselective Approaches to Both Isomers of β-
Fluorostyrenes
synthetic routes to β-fluorostyrenes3 have been described,
the majority are either nonselective4 or display low to high
selectivity.5 This is problematic since, in most cases, it is
impossible to separate the isomers by flash chromatogra-
phy, and this mixture of geometrical isomers may impact
the stereochemical purity of the product generated by a
further transformation. Methods providing exclusively
one isomer are rare with two notable exceptions.6,7 Indeed,
while the fluorination of trans-β-lithiostyrene generated
from trans-β-iodostyrene with PhSO2N(F)t-Bu is a known
transformation,6 when we tried to reproduce this result
using NFSI instead,8 we obtained a moderate conversion
(55%) of an inseparable mixture (ca. 1:1) of trans-β-
fluorostyrene and styrene.9 More recently, a silver(I) tri-
flate mediated transformation of styrylboronic acid into
trans-β-fluorostyrene using Selectfluor was reported by
Ritter.7 To the best of our knowledge, no stereocontrolled
access to the cis isomer has ever been reported.
Scheme 2. Synthesis of trans-β-Fluorostyrene Derivatives a,b
(4) (a) Schlosser, M.; Zimmermann, M. Synthesis 1969, 75–76. (b)
Inbasekaran, M.; Peet, N. P.; McCarthy, J. R.; LeTourneau, M. E.
J. Chem. Soc., Chem. Commun. 1985, 678–679. (c) Petasis, N. A.; Yudin,
A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah, G. A. Synlett 1997, 606–
608. (d) Wang, Q.; Wei, H.-x.; Schlosser, M. Eur. J. Org. Chem. 1999,
3263–3268. (e) Zhu, L.; Ni, C.; Zhao, Y.; Hu, J. Tetrahedron 2010, 66,
5089–5100. (f) Prakash, G. K. S; Shakhmin, A.; Zibinsky, M.; Ledneczki,
I.; Chacko, S.; Olah, G. A. J. Fluorine Chem. 2010, 131, 1192–1197.
(5) (a) Schlosser, M.; Christmann, K.-F. Synthesis 1969, 38–39. (b)
Burton, D. J.; Greenlimb, P. E. J. Org. Chem. 1975, 40, 2796–2801. (c)
Hayashi, S.-i.; Nakai, T.; Ishikawa, N.; Burton, D. J.; Naae, D. G.;
Kesling, H. S. Chem. Lett. 1979, 983–986. (d) Cox, D. G.; Gurusamy, N.;
Burton, D. J. J. Am. Chem. Soc. 1985, 107, 2811–2812. (e) Purrington,
S. T.; Pittman, J. H. Tetrahedron Lett. 1987, 28, 3901–3904. (f) Uno, H.;
Sakamoto, K.; Semba, F.; Suzuki, H. Bull. Chem. Soc. Jpn. 1992, 65,
210–217. (g) Galli, C.; Guarnieri, A.; Koch, H.; Mencarelli, P.;
Rappoport, Z. J. Org. Chem. 1997, 62, 4072–4077. (h) Kataoka, K.;
Tsuboi, S. Synthesis 2000, 452–456. (i) van Steenis, J. H.; van der Gen, A.
Eur. J. Org. Chem. 2001, 897–910. (j) Greedy, B.; Gouverneur, V. Chem.
Commun. 2001, 233–234.
a See Supporting Information for details concerning the reaction
conditions. bIsolated yield of the fluorostryrene for 2 steps (from 1).
cThe product is contaminated with ca. 2% of 4-ethynylanisole. dEsti-
mated yield by NMR as the product is contaminated with ca. 30% of
1-ethynylnaphthalene.
Our stategy for the synthesis of trans-β-fluorostyrenes
relied on protodesilylation of 2 with retention of the alkene
geometry.10 The requisite (Z)-1-aryl-2-fluoro-1-(trime-
thylsilyl)ethenes (2) were prepared using an addition/elim-
ination reaction of hydride to silylated β,β-difluorostyrene
derivatives (1) as described previously2d and were used
crude after an aqueous workup. A survey of various
(6) (a) Lee, S.-H.; Schwartz, J. J. Am. Chem. Soc. 1986, 108, 2445–
2447. (b) Lee, S.-H.; Riediker, M.; Schwartz, J. Bull. Korean Chem. Soc.
1998, 19, 760–766.
(7) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860–2863.
(8) PhSO2N(F)t-Bu is not commercially available and has to be
prepared using elemental fluorine.
(9) Marterer, J.; Paquin, J.-F. Unpublished results.
(10) (a) Chan, T. H.; Fleming, I. Synthesis 1979, 761–786. (b) Oda,
H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron 1985,
41, 3257–3268. (c) Colvin, E. W. Silicon Reagents in Organic Synthesis;
Academic Press Limited: London, 1988 and references therein.
Org. Lett., Vol. 13, No. 6, 2011
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experimental conditions for the stereospecific protodesily-
lation led to the finding of the optimal conditions [TBAF,
H2O (2 equiv), THF, 40 °C]. The scope of the addition/
elimination reaction of a hydride followed by a stereospe-
cific protodesilylation is presented in Scheme 2. In all the
cases, the β-fluorostyrenes were isolated in moderate to
good yields in two steps (averages of 55-80% per step) as
the trans isomer only (vide infra). Notably, with the excep-
tion of 3a, the synthesis of pure trans isomers of 3b-h have
not been reported before while 3i and 3j were unknown
compounds though potentially interesting fluorinated syn-
thons. It should be noted that all of these compounds
display significant volatility rendering their isolation on a
small scale (0.4-1.4 mmol) challenging.
percentage of (E)-2 detected in the crude mixture indicates
that the elimination is still a competing process.
For the preparation of the cis-fluorostyrenes, we envi-
sioned a palladium-catalyzed reduction of the C-Br
bond13 of 1-aryl-1-bromo-2-fluoroethenes (4). The latter
were prepared using an addition/elimination reaction of
hydride to silylated β,β-difluorostyrene derivatives (1)
followed by a bromination/desilicobromination reaction
to afford 4 in 51-86% yields (1 f 4, Scheme 1).2d
Scheme 4. Synthesis of cis-β-Fluorostyrene Derivativesa,b
Scheme 3. Mechanistic Hypothesis
a See Supporting Information for details concerning the reaction
conditions. bIsolated yield of the fluorostyrene. cThe product is con-
taminated with ca. 3% of the trans isomer.
The scope of the synthesis of cis-β-fluorostyrenes (5)
from the reduction of 1-aryl-1-bromo-2-fluoroethenes (4)
is presented in Scheme 4. In all the cases, the β-fluorostyr-
enes were isolated in moderate to good yields (56-73%) as
the cis isomer only indicating that no scrambling of the
geometry occurred at the reduction with the exception of
5e where ca. 3% of the trans isomer was observed. Here
again, with the exception of 5a,14 the synthesis of the pure
cis isomer of 5b-e had not been reported before.
The only side products isolated are the corresponding
alkynes (7). Interestingly, the fluorostyrenes were always
isolated as single isomers even though the crude intermedi-
ates 2 were not totally isomerically pure (Z/E = 83/17 to
>97/3) depending on the substitution pattern.11 A possi-
ble explanation for this phenomenon is found in Scheme 3
where we postulate that the minor isomer ((E)-2) is kine-
tically destroyed under the reaction conditions. Indeed, the
fact that we do not observe the cis isomer seems to indicate
that the anti-elimination between the silyl group and the
fluorine atom is facile12 under those conditions and kine-
tically overrides the stereospecific protodesilylation. On
the contrary, in (Z)-2, the silyl group and the fluorine atom
are cis tooneanotherwhich woulddisfavorthe elimination
over the stereospecific protodesilylation. However, the fact
that the amount of alkyne (7) isolated exceeds the
Scheme 5. Diels-Alder of Both Isomers of β-Fluorostyrene
with 1,3-Diphenylisobenzofuran
To illustrate the potential utility of trans- and cis-β-
fluorostyrenes as fluorinated synthons, their Diels-Alder
(11) See Supporting Information for more details.
(13) Xu, J.; Burton, D. J. Org. Lett. 2002, 4, 831–833.
(14) Goumans, T. P. M.; van Alem, K.; Lodder, G. Eur. J. Org.
Chem. 2008, 435–443.
(12) (a) Bach, R. D.; Evans, J. C. J. Am. Chem. Soc. 1986, 108, 1374–
1379 and references therein. (b) Cho, B. R.; Cho, N. S.; Lee, S. K. J. Org.
Chem. 1997, 62, 2230–2233 and references therein.
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Org. Lett., Vol. 13, No. 6, 2011

reaction with 1,3-diphenylisobenzofuran (8) was examined
(Scheme 5).15 When trans-β-fluorostyrene (3a) was used, a
moderate yield of the cycloadduct (9) was isolated as an
endo/exo mixture (60/40) with respect to the fluorine
atom.16 Using cis-β-fluorostyrene (5a) led to the pure endo
isomer (10) in 44% yield. This transformation illustrates
the rationale for a stereoselective access to both isomers of
β-fluorostyrene without which diastereoselective prepara-
tion of the cycloadducts (9 and 10) would have been
difficult.
derivatives from a common intermediate, (Z)-1-aryl-2-
fluoro-1-(trimethylsilyl)ethenes. The short and simple syn-
thetic sequences provide an effective synthetic approach to
both stereoisomers of a wide range of β-fluorostyrene
derivatives with excellent stereocontrol. Further expansion
of the scope and application of this methodology for the
preparation of novel fluorinated synthons are currently
underway.
Acknowledgment. This work was supported by the
Canada Research Chair Program, the Natural Sciences
and Engineering Research Council of Canada, the Canada
Foundation for Innovation, the Fonds de recherche sur la
nature et les technologies (FQRNT), Merck Frosst Centre
for Therapeutic Research, FQRNT Centre in Green
In conclusion, we have described a stereoselective method
for the preparation of both cis- and trans-β-fluorostyrene
(15) (a) Ernet, T.; Haufe, G. Tetrahedron Lett. 1996, 37, 7251–7252.
€
(b) Ernet, T.; Maulitz, A. H.; Wurthwein, E.-U.; Haufe, G. J. Chem.
Soc., Perkin Trans. 1 2001, 1929–1938.
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Chemistry and Catalysis, and the Universite Laval.
(16) For other examples where the selectivity of a Diels-Alder
reaction is influenced by the presence of a fluorine atom, see: (a)
Crowley, P. J.; Percy, J. M.; Stansfield, K. Tetrahedron Lett. 1996, 37,
8237–8240. (b) Percy, J. M. Top. Curr. Chem. 1997, 193, 131–195. (c) Ito,
H.; Saito, A.; Taguchi, T. Tetrahedron Lett. 1998, 9, 1979–1987. (d) Ito,
H.; Saito, A.; Taguchi, T. Tetrahedron Lett. 1998, 9, 1988–1994. (e)
Haufe, G. In Vinyl Fluorides in Cycloadditions, in Fluorinated Synthons;
Soloshonok, V., Ed.; ACS Symposium Series 911; American Chemical
Society: Washington, D.C., 2005; pp 155-172.
Supporting Information Available. General experimen-
tal procedures, specific details for representative reac-
tions, and isolation and spectroscopic information for the
new compounds prepared. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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