Stereocontrolled approach to bromofluoroalkenes and their use for the synthesis of tri- and tetrasubstituted fluoroalkenes

Article abstract of DOI:10.1021/ol8027412

(Chemical Equation Presented) An addition/elimination reaction of organolithium reagents to silylated ββf-difluorostyrene derivatives followed by a bromination/ desilicobromination reaction provides a simple and effective synthetic approach to a wide rang

Full text of DOI:10.1021/ol8027412

ORGANIC
LETTERS
2009
Vol. 11, No. 3
681-684
Stereocontrolled Approach to
Bromofluoroalkenes and Their Use for
the Synthesis of Tri- and
Tetrasubstituted Fluoroalkenes
Gre´gory Landelle, Pier Alexandre Champagne, Xavier Barbeau, and
Jean-Franc¸ois Paquin*
Canada Research Chair in Organic and Medicinal Chemistry, De´partement de chimie,
1045 aVenue de la Me´decine, UniVersite´ LaVal, Que´bec, QC, Canada G1V 0A6
jean-francois.paquin@chm.ulaVal.ca
Received November 26, 2008
ABSTRACT
An addition/elimination reaction of organolithium reagents to silylated ꢀ,ꢀ-difluorostyrene derivatives followed by a bromination/
desilicobromination reaction provides a simple and effective synthetic approach to a wide range of bromofluoroalkenes (up to >97/3). In
addition, the bromofluoroalkenes can be used in Pd-catalyzed transformations giving access to both tri- and tetrasubstituted fluoroalkenes.
The properties of a bioactive molecule can often be
modulated by adding fluorine atoms since this leads to
changes in solubility, lipophilicity, metabolic stability,
conformation, hydrogen-bonding ability, or chemical reactiv-
ity.1 Consequently, much effort has been devoted to the
development of novel methods for the synthesis of fluorinated
molecules.1a,2,3 Among the vast array of fluorine-containing
functionalities, fluoroalkenes are of particular interest since
they have potential applications in material sciences,4
medicinal chemistry,5 and organic chemistry where they can
be utilized as synthons for further functionalization.6
The stereoselective synthesis of nonfluorinated tri- and
tetrasubstituted alkenes represents a synthetic challenge even
though more approaches have been developed recently.7
However, only a few of these methods are applicable for
(4) For recent examples, see: (a) Babudri, F.; Farinola, G. M.; Naso,
F.; Ragni, R. Chem. Commun. 2007, 1003–1022. (b) Babudri, F.; Cardone,
A.; Farinola, G. M.; Martinelli, C.; Mendichi, R.; Naso, F.; Striccoli, M.
Eur. J. Org. Chem. 2008, 1977–1982.
(1) (a) Hiyama, T. In Organofluorine Compounds; Chemistry and
Applications; Yamamoto, H., Ed.; Springer: New York, 2000; and references
therein. (b) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11. (c) Thayer,
A. M. Chem. Eng. News 2006, 84, 15–24. (d) Kirk, K. L. J. Fluorine Chem.
2006, 127, 1013–1029. (e) Be´gue´, J.-P.; Bonnet-Delpon, D. J. Fluorine
Chem. 2006, 127, 992–1012. (f) Mu¨ller, K.; Faeh, C.; Diederich, F. Science
2007, 317, 1881–1886. (g) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. ReV. 2008, 37, 320–330.
(5) For recent examples, see: (a) Sciotti, R. J.; Pliushchev, M.;
Wiedeman, P. E.; Balli, D.; Flamm, R.; Nilius, A. M.; Marsh, K.; Stolarik,
D.; Jolly, R.; Ulrich, R.; Djuric, S. W. Bioorg. Med. Chem. Lett. 2002, 12,
2121–2123. (b) Van der Veken, P.; Senten, K.; Kerte`sz, I.; De Meester, I.;
Lambeir, A.-M.; Maes, M.-B.; Scharpe´, S.; Haemers, A.; Augustyns, K.
J. Med. Chem. 2005, 48, 1768–1780. (c) Niida, A.; Tomita, K.; Mizumoto,
M.; Tanigaki, H.; Terada, T.; Oishi, S.; Otaka, A.; Inui, K.-i.; Fuji, N. Org.
Lett. 2006, 8, 613–616. (d) Alloatti, D.; Giannini, G.; Cabri, W.; Lustrati,
I.; Marzi, M.; Ciacci, A.; Gallo, G.; Tinti, M. O.; Marcellini, M.; Riccioni,
T.; Guglielmi, M. B.; Carminati, P.; Pisano, C. J. Med. Chem. 2008, 51,
2708–2721.
(2) For recent reviews in this area, see: (a) Ma, J.-A.; Cahard, D. Chem.
ReV. 2004, 104, 6119–6146. (b) Shimizu, M.; Hiyama, T. Angew. Chem.,
Int. Ed. 2004, 44, 214–231. (c) Bobbio, C.; Gouverneur, V. Org. Biomol.
Chem. 2006, 4, 2065–2075. (d) Surya Prakash, G. K.; Hu, J. Acc. Chem.
Res. 2007, 40, 921–930. (e) Pacheco, M. C.; Purser, S.; Gouverneur, V.
Chem. ReV. 2008, 108, 1943–1981
.
(6) For example, see: (a) Hara, S. In Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; ACS Symposium Series 911; American Chemical
Society: Washington, DC, 2005; pp 121-172, and references therein. (b)
Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem., Int. Ed.
2007, 46, 1290–1292.
´
(3) For our own work in this area, see: (a) Be´langer, E.; Cantin, K.;
Messe, O.; Tremblay, M.; Paquin, J.-F. J. Am. Chem. Soc. 2007, 129, 1034–
´
1035. (b) Be´langer, E.; Houze´, C.; Guimond, N.; Cantin, K.; Paquin, J.-F.
Chem. Commun. 2008, 3251–3253
.
10.1021/ol8027412 CCC: $40.75
Published on Web 01/14/2009
2009 American Chemical Society

the preparation of tri- or tetrasubstituted fluoroalkenes.
Consequently, stereocontrolled and practical access to tri-
and tetratetrasubstituted fluoroalkenes remains a synthetic
challenge, in particular when one or more of the substituents
are aryl groups.6a,8-10
CF3CH2I.11 These alkenes are ideal substrates to undergo
carbolithiation for the following reasons: (a) electron-
deficient character and (b) polarization due to the +Iπ effect
of the fluorine atoms,1a the resonance effect (+R) of
fluorine,1a as well as the ꢀ-effect of the silicon.12 Upon
carbolithiation, the generated carbanion is stabilized by the
R effect of the silicon12 and the inductive effect (-Iσ)1a and
negative hyperconjugation of fluorine.1a,13 Finally, the loss
of a fluorine atom as a leaving group via ꢀ elimination would
produce silylated fluoroalkenes (3 or 4). While literature
Herein, we document a novel stereocontrolled method for
the preparation of tri- and tetrasubstituted fluoroalkenes using
an addition/elimination reaction of organolithium reagents
to silylated ꢀ,ꢀ-difluorostyrene derivatives (1 or 2) followed
by a bromination/desilicobromination reaction (Scheme 1).
precedence indicated that this would be
a viable
strategy,9e,14,15 questions remained as to whether or not this
reaction would present useful selectivity and if it would be
possible to later substitute the silyl group with a more
versatile substituent.
Scheme 1. Stereoselective Approach to Bromofluoroalkenes
Table 1. Initial Results: Addition/Elimination Sequencea
entry
substrate
R
product
yieldb (%)
Z/Ec
This sequence provides an effective synthetic approach to a
wide range of bromofluoroalkenes (5) with moderate to
excellent stereocontrol (up to >97/3). In addition, the
bromofluoroalkenes can be used in Pd-catalyzed transforma-
tions giving access to both tri- and tetrasubstituted fluoro-
alkenes.
1
2
3
4
5
6
1a
t-Bu
n-Bu
Ph
t-Bu
n-Bu
Ph
3a
3b
3c
4a
4b
4c
81
86
76
72
61
63
87/13
80/20
50/50
90/10
83/17
75/25
2a
a Reaction conditions: 1 or 2 (1 mmol), RLi (2 mmol), THF (7 mL) at
-78 °C to rt for 1 h (see the Supporting Information for details); b Isolated
yield of the combined isomers; c Determined by 19F NMR and/or 1H NMR
spectroscopic analysis of the crude product.
In our initial plan, we envisioned that silylated ꢀ,ꢀ-
difluorostyrene derivatives (1 or 2) would be suitable
substrates for an addition/elimination reaction with organo-
lithium reagents. Various derivatives of 1 and 2 are readily
available in two steps from commercially available
In our initial screening experiments, we found that the
addition/elimination proceeded readily at -78 °C in THF
with different organolithium reagents (Table 1).15-17 In all
cases, both geometrical isomers were easily separable by
(7) Review: Flynn, A. B.; Ogilvie, W. W. Chem. ReV. 2007, 107, 4698–
4745. Highlights: Reiser, O. Angew. Chem., Int. Ed. 2006, 45, 2838–2840.
(8) For access to trisubstituted fluoroalkenes, see, for example: (a) Okada,
M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa, H.; Taguchi, T.
Tetrahedron Lett. 2002, 43, 5845–5847. (b) Pacheco, C.; Gouverneur, V.
Org. Lett. 2005, 7, 1267–1270. (c) Dutheuil, G.; Paturel, C.; Lei, X.; Couve-
Bonnaire, S.; Pannecouke, X. J. Org. Chem. 2006, 71, 4316–4319. (d)
Andrei, D.; Wnuk, S. F. J. Org. Chem. 2006, 71, 405–408. (e) Akana, J. A.;
Bhattacharya, K. X.; Mu¨ller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2007,
(11) (a) Anilkumar, R.; Burton, D. J. J. Fluorine Chem. 2005, 126, 457–
463. (b) Okano, T.; Ito, K.; Ueda, T.; Muramatsu, H. J. Fluorine Chem.
1986, 32, 377–388.
129, 7736–7737
.
(12) (a) Chan, T. H.; Fleming, I. Synthesis 1979, 761–786. (b) Colvin,
E. W. Silicon Reagents in Organic Synthesis; Academic Press Limited:
London, 1988;. and references therein.
(9) For access to tetrasubstituted fluoroalkenes, see: (a) Fish, P. V.;
Reddy, S. P.; Lee, C. H.; Johnson, W. S. Tetrahedron Lett. 1992, 33, 8001–
8004. (b) Kim, B. T.; Min, Y. K.; Asami, T.; Park, N. K.; Kwon, O. Y.;
Cho, K. Y.; Yoshida, S. Tetrahedron Lett. 1997, 38, 1797–1800. (c) Percy,
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Croteau, R.; Coates, R. M. J. Am. Chem. Soc. 2005, 127, 7834–7842. (g)
Zoute, L.; Dutheuil, G.; Quirion, J.-C.; Jubault, P.; Pannecoucke, X.
Synthesis 2006, 3409–3418. (h) Hara, S.; Guan, T.; Yoshida, M. Org. Lett.
2006, 8, 2639–2641. (i) Guan, T.; Yoshida, M.; Hara, S. J. Org. Chem.
(13) Dixon, D. A.; Fukunaga, T.; Smart, B. E. J. Am. Chem. Soc. 1986,
108, 4027–4031
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(14) (a) Hayashi, S.-i.; Nakai, T.; Ishikawa, N. Chem. Lett. 1980, 935–
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24, 5616–5618. (c) Martin, S.; Sauveˆtre, R.; Normant, J.-F. J. Organomet.
Chem. 1984, 264, 155–161. (d) Lee, J.; Tsukazaki, M.; Snieckus, V.
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D.; Bouvet, D.; Rock, M. H. J. Org. Chem. 1996, 61, 9111–9114. (f)
Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 1917–
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(15) Ichikawa, J.; Fukui, H.; Ishibashi, Y. J. Org. Chem. 2003, 68, 7800–
(10) A notable exception is when the fluoroalkene is part of a cyclic
system; see, for example: (a) Hossain, M. A. Tetrahedron Lett. 1997, 38,
49–52. (b) Ichikawa, J.; Wada, Y.; Kuroki, H.; Mihara, J.; Nadano, R. Org.
7805
.
(16) The reaction also proceeds in Et2O with similar results
.
(17) Other nucleophiles such as Grignard or organozinc reagents do not
react under these conditions
Biomol. Chem. 2007, 5, 3956–3962
.
.
682
Org. Lett., Vol. 11, No. 3, 2009

simple flash chromatography.18 From these initial results, it
can be seen that using a bulkier RLi and/or silyl group results
in increased selectivity (up to 90/10 ) Z/E ratio).19
Table 2. Stereoselective Preparation of (Z)-5 from 1 or 2 in the
One-Pot Procedurea
Having established the basic reactivity of this class of
substrate, we then sought to investigate the transformation
of the silyl group. In particular, we were interested in finding
a reaction that would transform the silyl group into a halide,
thus opening the way to a wide range of metal-catalyzed
transformations. We first evaluated a bromination/desilico-
bromination reaction.15,20 This two step/one-pot procedure
allows for the conversion of vinylsilanes into vinyl bromides
with inversion of configuration at the carbon bearing the silyl
group due to the geometrical requirement for both steps
(trans bromination followed by anti elimination). Unexpect-
edly, when the reaction was tested on (Z)-3a, the desired
product 5a was isolated in 80% yield but as the Z isomer
(Z/E ) >97/3) instead of the expected E isomer, as
confirmed by single-crystal X-ray analysis (Scheme 2).18
Scheme 2
.
Isomeric Enrichment via Bromination/
Desilicobromination
More surprisingly, reaction of (E)-3a occurred with partial
inversion furnishing 5a as a mixture (Z/E ) 70/30). The
unexpected selectivity of the bromination/desilicobromination
reaction might be due to a change in mechanism for the
bromination step, and we are currently investigating this
reaction in more detail.12b,21 Nevertheless, these results open
the way to isomeric enrichment since the opposite geo-
metrical isomer of the silylated fluoroalkene 3 (or 4) is
converted to the same Z isomer of the bromofluoroalkene 5.
This idea was tested on an isomeric mixture of 3a (Z/E )
a See the Supporting Information for details concerning the reaction
c
conditions. b Isolated yield of the combined isomers. Determined by 19F
NMR and/or 1H NMR spectroscopic analysis of the crude product. d A
number of unidentified nonfluorinated side products were also isolated.
87/13), which upon reaction gave the desired product (Z)-
5a as a single isomer (Z/E ) >97/3). Similarly, reaction of
isomeric mixture of 3c (Z/E ) 50/50) gave the bromofluo-
roalkene 5c as an enriched mixture in favor of the Z isomer
(Z/E ) 70/30).
This interesting aspect of the reaction has been further
exploited by carrying out the entire transformation (1 (or 2)
f 5) as a one-pot sequence, thus avoiding the purification
of the intermediate (3 or 4) while generating C-C and C-Br
bonds in a single flask. The scope of the addition/elimination
reaction of organolithium reagents followed by a bromina-
tion/desilicobromination reaction is presented in Table 2. In
(18) The stereochemistry of the major product was unambiguously
confirmed by single-crystal X-ray analysis. See the Supporting Information
for more details.
(19) Silylated ꢀ,ꢀ-difluorostyrene with [Si] ) TBS has been prepared
but is unreactive under these conditions with either t-BuLi or PhLi.
(20) Fisher, R. P.; On, H. P.; Snow, J. T.; Zweifel, G. Synthesis 1982,
127–129
.
(21) (a) Brook, A. G; Duff, J. M.; Reynolds, W. F. J. Organomet. Chem.
1976, 121, 293–306. (b) Miller, R. B.; McGarvey, G. J. Org. Chem. 1978,
43, 4424–4431
.
Org. Lett., Vol. 11, No. 3, 2009
683

all the cases, the bromofluoroalkenes were isolated in good
to excellent yield (up to 90%) with good to excellent
stereocontrol (up to >97:3) in favor of the (Z)-isomer. A
number of substrates (1a-d, 2a-b) can be used including
two bearing a chlorine atom (entries 8 and 9), a useful
synthetic handle for further elaboration. From the point of
view of the organolithium reagent, various alkyl- and
aryllithiums can be used including a functionalized one such
as 3-lithiotrifluoromethylbenzene (entry 4).22 It is important
to note that, in most cases, both geometrical isomers were
easily separable by simple flash chromatography.
Scheme 4
.
Stereoselective Preparation of Both Geometrical
Isomer of 9
Scheme 3. Synthetic Elaboration of (Z)-5a
nation reaction) to furnish the (Z)-bromofluoroalkenes 5c and
5g in good yield and selectivity (Table 2, entries 6 and 8).
In the last step, a Suzuki reaction is performed on the
bromofluoroalkene with the proper arylboronic acid partner
(i.e., 3-Cl-C6H4B(OH)2 and PhB(OH)2, respectively) to give
both stereoisomers of the tetrasubstituted fluoroalkene 9 in
excellent yields. Thus, both stereoisomers can be selectively
obtained in four steps from commercially available CF3CH2I.
In conclusion, we have described a novel, stereocontrolled
method for the preparation of tri- and tetrasubstituted
fluoroalkenes using an addition/elimination reaction of org-
anolithium reagents to silylated ꢀ,ꢀ-difluorostyrene deriva-
tives followed by a bromination/desilicobromination reaction.
This short and simple synthetic sequence provides an
effective synthetic approach to a wide range of bromofluo-
roalkenes with moderate to excellent stereocontrol (up to
>97/3). In addition, the bromofluoroalkenes can be used in
Pd-catalyzed transformations giving access to both tri- and
tetrasubstituted fluoroalkenes. Further expansion of the scope,
mechanistic studies and application of this methodology for
the synthesis of bioactive compounds are currently underway.
To illustrate the utility of these bromofluoroalkenes, we
carried out a number of synthetic transformations on (Z)-5a
as demonstrated in Scheme 3. For example, (Z)-5a can be
converted into single isomers of tetrasubstituted fluoroalkenes
6 and 7 via Suzuki-Miyaura or Sonoghashira cross-coupling
in 82% and 45% yields (nonoptimized), respectively. Simi-
larly, the bromine atom can be reduced to produce the
trisubstituted fluoroalkene 8 as a single isomer in 47% yield
(nonoptimized).23
Finally, the versatility of this methodology can be il-
lustrated by the fact that, in the case of 1,1-diaryl-2-
fluoroethene derivatives, both stereoisomers can be obtained
by a simple change in the synthetic sequence (Scheme 4).
For example, both 2a and 2b can be obtained from the same
precursor, CF3CH2I, in two steps by using the proper aryl
iodide (PhI vs 3-Cl-C6H4I).11 These compounds can then be
submitted to the one-pot procedure (addition/elimination
reaction of PhLi followed by a bromination/desilicobromi-
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, Merck Frosst Centre for Thera-
peutic Research, the Fonds de recherche sur la nature et les
technologies, and the Universite´ Laval.
Supporting Information Available: General experimental
procedures, specific details for representative reactions, and
isolation and spectroscopic information for the new com-
pounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) Leroux, F.; Schlosser, M.; Zohar, E.; Marek, I. In The Chemistry
of Organolithium Compounds; Rappoport, Z., Marek, I., John Wiley & Sons
Ltd.: Chichester, 2004; pp 435-493, and references therein.
(23) Xu, J.; Burton, D. J. Org. Lett. 2002, 4, 831–833.
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