Stereospecific preparation of (Z)-α-fluorostilbenes via a kinetically controlled palladium-catalyzed cross-coupling reaction of high E/Z ratio 1-bromo-1-fluorostyrenes and aryl stannanes

Article abstract of DOI:10.1016/S0040-4039(02)00357-X

High E/Z ratios were obtained for 1-bromo-1-fluorostyrenes by isomerization from the original E/Z ratios of approximately 1:1. The palladium-catalyzed cross-coupling reaction of high E/Z ratio 1-bromo-1-fluorostyrenes with aryl stannanes gives (Z)-α-fluor

Full text of DOI:10.1016/S0040-4039(02)00357-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2877–2879
Stereospecific preparation of (Z)-a-fluorostilbenes via a
kinetically controlled palladium-catalyzed cross-coupling reaction
of high E/Z ratio 1-bromo-1-fluorostyrenes and aryl stannanes
Jianjun Xu and Donald J. Burton*
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
Received 19 November 2001; accepted 5 February 2002
Abstract—High E/Z ratios were obtained for 1-bromo-1-fluorostyrenes by isomerization from the original E/Z ratios of
approximately 1:1. The palladium-catalyzed cross-coupling reaction of high E/Z ratio 1-bromo-1-fluorostyrenes with aryl
stannanes gives (Z)-a-fluorostilbenes stereospecifically in good yields. © 2002 Elsevier Science Ltd. All rights reserved.
Fluoroorganic compounds have exhibited increased
interest as agrochemical and pharmaceutical agents in
recent years1 since it has been found that fluorine
modifies biological activity by altering the physiochemi-
cal properties of organic compounds.2 Monofluorinated
stilbenes, especially a-fluorostilbenes ArCHꢀCFAr,1
attracted our interest because they, as an important
class of fluorinated olefins,3 are potential enzyme
inhibitors.4 The stereospecific preparation of a-fluoros-
tilbenes continues to be a challenge, however. Base-pro-
moted dehydrofluorination of 1,2-difluoro-1,2-diphenyl-
ethanes leads to (E),(Z) a-fluorostilbene mixtures5
although under a certain reaction condition (E)-a-
fluorostilbenes may dominate.5c The Wadsworth–
Emmons–Horner olefination of [(RO)2P(O)CFPh]− with
substituted benzaldehydes also gives a mixture of
(E),(Z)-a-fluorostilbenes.6 McCarthy and co-workers
have described the stereospecific preparation of 1-
fluorovinyl stannanes and their coupling reaction with
aryl halides and showed the potential of this approach
for the synthesis of (Z)-a-fluorostilbenes, although it
takes several steps to prepare the starting (E)-1-
fluorovinyl stannanes.7 Recently McCarthy and co-
workers also reported the palladium-catalyzed
cross-coupling reaction of 1-bromo-1-fluorostyrenes
with organoboranes and aromatic stannanes.8 This
methodology is more straightforward compared to the
previous coupling reaction between 1-fluorovinyl stan-
nanes and aryl halides.7 A limitation of this method,
however, is the availability of pure (E)- and (Z)-1-
bromo-1-fluorostyrenes. These isomeric 1-bromo-1-
fluorostyrenes were separated by gas chromatography8
from the corresponding E,Z isomeric mixtures.9 This
methodology is unlikely to be useful for large scale
preparative synthetic purposes. A multi-step route to
(Z)-1-bromo-1-fluorostyrenes includes bromination of
(E)-2-fluoro-3-phenylacrylic acid followed by debromo-
carboxylation.10 Rolando’s isomerization from (Z) to a
high E/Z ratio of 1-bromo-1-fluorostyrenes was only
partially successful.11 McCarthy and co-workers briefly
mentioned another isomerization method from (Z) iso-
mers to E/Z=92:8 isomer mixtures using a catalytic
amount of bromine in chloroform.8a In our hands this
isomerization by Br2 was found to be low-yielding
(<20%) due to competitive addition of bromine to the
alkene. Herein we report our approach to a high E/Z
ratio 1-bromo-1-fluorostyrenes and the kinetic sep-
Scheme 1.
Keywords: fluorostilbenes; palladium-catalyzed cross-coupling; stereospecific; isomerization; bromofluoroalkenes; kinetic separation.
* Corresponding author. E-mail: donald-burton@uiowa.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00357-X

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J. Xu, D. J. Burton / Tetrahedron Letters 43 (2002) 2877–2879
aration methodology in their palladium-catalyzed cross-
coupling reactions with aryl stannanes.
Pure (Z)-a-fluorostilbenes Z-4a–h were separated in
good yields (Table 2), by column chromatography or
column chromatography followed by recrystallization.
Isomerization was observed when 1-bromo-1-
fluorostyrenes (neat, E/Z:1:1) were stored at −20°C.
1-Bromo-1-fluorostyrenes (E/Z:1:1), which were read-
ily prepared by the literature method,9a were found to
have a higher E/Z ratio after storage at −20°C (Scheme
1). For example, 1-bromo-1-fluorostyrene changed from
an E/Z ratio of 44:56 to 85:15 after 1 week at −20°C. This
ratio increased to 88:12 when the product was kept at
−20°C for 3 months. Similar E/Z ratio changes were also
observed at room temperature. Presumably this isomer-
ization was catalyzed by a trace amount of bromine in
the mixture (Table 1).12
A variety of pure (Z) a-fluorostilbenes can be prepared
by this method as the starting materials are easy to
prepare and the reaction conditions are very mild.
Various combinations of functional groups on both
phenyl rings are available and permutation is also
possible, as demonstrated by Z-4b and Z-4f. We have
also tested the coupling reaction of 1-bromo-1-
fluorostyrenes (E/Z=88:12) and phenylboronic acid in
the presence of 4% Pd(PPh3)4 under Suzuki conditions.8
At room temperature, the reaction proceeded very
slowly, after 5 days, only 2/3 of the starting E isomers
had reacted and the E/Z ratio of the resulting a-fluoros-
tilbenes was 95:5. When above Suzuki reaction was
carried out at reflux temperature the reaction proceeded
to completion and the Z/E ratio of a-fluorostilbenes in
the mixture was 94:6. Similar coupling reaction under
Stille conditions at room temperature gave a Z/E ratio
of 98:2. Therefore, although both routes gave similar
results, Stille coupling reaction conditions are preferred
for the preparation of (Z)-a-fluorostilbenes.
The palladium-catalyzed cross-coupling reactions
between high E/Z ratio 1-bromo-1-fluorostyrenes and
aryl stannanes were studied. Aryl stannanes reacted
stereoselectively with the (E) isomers13 and very high Z/E
ratios were obtained for the resulting a-fluorostilbenes
(Scheme 2). Most (Z) isomers of 2, however, remained
unreacted, as detected by 19F NMR analysis of the
reaction mixture when the reactions were completed.
Table 1. The preparationa and isomerization (at −20°C, 1 week) of X-C6H4CHꢀCFBr
X
Time (h)
Yield (%)
E/Z after reaction
E/Z after isomerization
H
o-Cl
p-MeO
p-F
m-NO2
6
6
6
6
8
77
67
62
45
53
1a 44:56
1b 48:52
1c 66:34
1d 72:28
1e 63:37
2a 85:15b
2b 82:18
2c 81:19c
2d 87:13
2e 76:24d
a Typical reaction condition: same as in Ref. 9a except that THF was used as solvent.
b E/Z ratio increased to 88:12 after 3 months.
c E/Z ratio increased to 83:17 after 3 months.
d E/Z ratio increased to 81:19 after 3 months.
Scheme 2.
Table 2. Synthesis of (Z)-a-fluorostilbenes from high E/Z ratio 1-bromo-1-fluorostyrenes and aryl stannanes
Entry
X
Y
E/Z of vinylbromide
Time (h)
Producta (Z/E)b
Mixture Z/Ec
Yield (conversion)d
1
2
3
4
5
6
7
8
2a H
2a H
3a H
3b p-F
3a H
3b p-F
3a H
3a H
88:12
88:12
82:18
82:18
83:17
87:13
76:24
88:12
20
16
15
16
22
16
16
12
Z-4a (100:0)
Z-4b (100:0)
Z-4c (100:0)
Z-4d (100:0)
Z-4e (100:0)
Z-4f (100:0)
Z-4g (100:0)
Z-4h (100:0)
98:2
98:2
94:6
94:6
93:7
96:4
87:13
98:2
73 (83)
67 (76)
71 (87)
52 (63)
61 (74)
69 (80)
53 (70)
72 (82)
2b o-Cl
2b o-Cl
2c p-MeO
2d p-F
2e m-NO2
2f p-Cl
3a H
3a p-F
a All products gave satisfactory 19F, 1H, 13C NMR and HRMS data.
b Z/E ratio of isolated product.
c Z/E ratios of a-fluorostilbenes were determined by 19F NMR analysis of the reaction mixture when the reaction was completed.
d Isolated yield. Conversion was calculated based on the amount of (E)-1-bromo-1-fluorostyrenes in the starting E,Z mixtures.

J. Xu, D. J. Burton / Tetrahedron Letters 43 (2002) 2877–2879
2879
In a typical experiment, Pd(PPh3)4 (0.08 g, 0.07 mmol)
and dry DMF (4 ml) were added to a 25 ml dry
round-bottom flask equipped with a magnetic stirring
bar and a N2 tee. 1-Bromo-1-fluoro-2-(4-methoxy-
phenyl)-ethylene (0.46 g, 2.0 mmol, E/Z=83:17) was
added and the resulting solution was stirred at room
temperature for 15 min. CuI (0.16 g, 0.83 mmol) and
phenyltributylstannane (0.85 g, 2.32 mmol) were added
to the mixture sequentially, and the reaction mixture
was stirred at room temperature for 22 h. 19F NMR
analysis of the reaction mixture showed that the reac-
tion was completed. The reaction mixture was directly
added to a silica gel column (ethyl acetate:hexanes=
5:95, Rf=0.33) and the white solid collected was further
purified by recrystallization from hexanes to give Z-4e,
white crystal, mp 97–99°C, 0.28 g (61%). The conver-
sion was 74% based on the amount of (E)-1-bromo-1-
fluorostyrene in the starting E,Z mixture. 19F NMR
Fluoroorganic Chemistry: Synthetic Challenges and
Biomedical Rewards, Tetrahedron Symposia in-Print No.
58, Tetrahedron 1996, 52, 1.
2. Organofluorine Chemistry: Principle and Commercial
Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C.,
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3. (a) Fluorination in Organic and Bioorganic Chemistry;
Welch, J. T., Ed.; American Chemical Society, 1991; (b)
Lee, S. H.; Schwartz, J. J. Am. Chem. Soc. 1986, 108,
2445.
4. (a) McCarthy, J. R.; Huber, E. W.; Le, T.-B.; Laskovics,
F. M.; Matthews, D. P. Tetrahedron 1996, 52, 45; (b)
Khrimian, A. P.; Demilo, A. B.; Waters, R. M.; Liquido,
N. J.; Nicholson, J. M. J. Org. Chem. 1994, 59, 8034.
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1015; (b) Zupan, M.; Pollak, A. J. Org. Chem. 1977, 42,
1559; (c) Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1984,
49, 3395.
6. Tsai, H.-J. Tetrahedron Lett. 1996, 37, 629.
7. (a) Chen, C.; Wilcoxen, K.; Kim, K.-i.; McCarthy, J. R.
Tetrahedron Lett. 1997, 38, 7677; (b) Chen, C.; Wilcoxen,
K.; Zhu, Y.-F.; Kim, K.-i.; McCarthy, J. R. J. Org.
Chem. 1999, 64, 3476.
8. (a) Chen, C.; Wilcoxen, K.; Strack, N.; McCarthy, J. R.
Tetrahedron Lett. 1999, 40, 827; (b) Chen, C.; Wilcoxen,
K.; Huang, C. Q.; Strack, N.; McCarthy, J. R. J. Fluorine
Chem. 2000, 101, 285.
9. (a) Vanderhaar, R. W.; Burton, D. J.; Naae, D. G. J.
Fluorine Chem. 1971/72, 1, 381; (b) Burton, D. J.; Yang,
Z.-Y.; Qiu, W. Chem. Rev. 1996, 96, 1641; (c) Burton, D.
J. J. Fluorine Chem. 1983, 23, 339.
10. (a) Elkik, E.; Francesch, C. Bull. Soc. Chim. Fr. 1973,
1277, 1281; (b) Etemad-Moghadam, G.; Seyden-Penne, J.
Bull. Soc. Chim. Fr. 1985, 448; (c) Elkik, E.; Francesch,
C. Bull. Soc. Chim. Fr. 1986, 423.
11. Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C.
Bull. Soc. Chim. Fr. 1997, 134, 741.
3
1
(CDCl3) l −117.7 (d, JFH(trans)=39.9 Hz, 1F) ppm; H
NMR (CDCl3) l 7.61 (tm, J=8.2 Hz, 4H), 7.30–7.42
3
(m, 3H), 6.91 (dm, J=8.8 Hz, 2H), 6.26 (d, JHF(trans)
=
39.9 Hz, 1H), 3.83 (s, 3H) ppm; 13C NMR (CDCl3) l
158.7 (d, J=1.7 Hz), 155.9 (d, JCF=255.3 Hz), 133.1
1
(d, J=28.2 Hz), 130.2 (d, J=8.2 Hz), 128.51, 128.47,
126.3 (d, J=4.3 Hz), 123.9 (J=7.2 Hz), 114.0, 105.4 (d,
J=10.9 Hz), 55.2 ppm; GC–MS, m/z (relative inten-
sity): 230 (M++ 2, 3), 229 (4), 228 (M+, 100), 213 (69),
196 (13), 185 (25), 183 (51), 170 (35), 165 (75), 133 (19),
114 (15); HRMS calcd 228.0950 for C15H13OF, found
228.0945.
In conclusion, we have described the isomerization of
1-bromo-1-fluorostyrenes (from E/Z:1:1 to high E/Z
ratios). Room temperature coupling reactions of these
high E/Z ratio 1-bromo-1-fluorostyrenes with aryl stan-
nanes in the presence of Pd(PPh3)4/CuI stereospecifi-
cally gave (Z)-a-fluorostilbenes in good yields via
kinetic separation.
12. Subsequently, we found that the isomerization could be
facilitated by photolysis of the E/Z mixture at 254 nm.
For example, an E/Z mixture of o-Cl-C6H4CHꢀCFBr
(E/Z=63:37) cleanly isomerized to an E/Z mixture of
78:22 after photolysis at 254 nm for 1 h. Longer photoly-
sis time produced increasing amounts of impurities.
13. The kinetic separation of the E/Z 1-bromo-1-fluorostyre-
nes has been demonstrated to occur in the oxidative
addition step of the reaction between the 1-bromo-1-
fluorostyrenes and Pd(0).14,15
Acknowledgements
We gratefully acknowledge the National Science Foun-
dation for financial support of this research.
References
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15. Zhang, X.; Burton, D. J. J. Fluorine Chem. 2001, 112,
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