Stereoselective preparation of (E)- and (Z)-α-fluorostilbenes via palladium-catalyzed cross-coupling reaction of high E/Z ratio and (Z)-1-bromo-1-fluoroalkenes

Article abstract of DOI:10.1021/jo060068i

A highly stereoselective method to prepare both (E)- and (Z)-α-fluorostilbenes is described. 1-Bromo-1-fluoroalkenes (E/Z ≈ 1:1), a readily available starting material, isomerizes to high E/Z ratios by storage at -20 °C or by photolysis at 254 nm. Stille

Full text of DOI:10.1021/jo060068i

Stereoselective Preparation of (E)- and (Z)-r-Fluorostilbenes via
Palladium-Catalyzed Cross-Coupling Reaction of High E/Z Ratio
and (Z)-1-Bromo-1-fluoroalkenes
Jianjun Xu and Donald J. Burton*
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
ReceiVed January 11, 2006
A highly stereoselective method to prepare both (E)- and (Z)-R-fluorostilbenes is described. 1-Bromo-
1-fluoroalkenes (E/Z ≈ 1:1), a readily available starting material, isomerizes to high E/Z ratios by storage
at -20 °C or by photolysis at 254 nm. Stille coupling between these high E/Z 1-bromo-1-fluoroalkenes
and aryl stannanes gave (Z)-R-fluorostilbenes in high stereoselectivity. (Z)-1-Bromo-1-fluoroalkenes, which
were kinetically separated from 1-bromo-1-fluoroalkenes (E/Z ≈ 1:1), can participate in Suzuki coupling
reactions to give (E)-R-fluorostilbenes stereoselectively.
Introduction
however. Several research groups have reported a base-induced
elimination reaction to prepare (E) and (Z) mixtures of R-fluoro-
stilbenes, such as dehydrofluorination6 and dehydrochlorination.7
Most of these reactions showed little stereoselectivity. Under
certain reaction conditions, in some base-promoted eliminations
it has been reported that (E)-R-fluorostilbene dominated the
(E,Z) mixture of products.6(c) Unfortunately, this reaction was
not fully investigated, and the mechanism is not clear. Wads-
worth-Horner-Emmons olefination has also been explored to
prepare R-fluorostilbenes.8 For example, diethyl R-fluoroben-
zylphosphonate reacted with aldehydes and base at low tem-
perature to afford R-fluorostilbenes in good yields. Again, this
reaction showed little stereoselectivity.8 McCarthy and co-
workers have described the stereospecific preparation of 1-fluoro-
2-substituted-vinyl stannanes9,10 and their Stille coupling reaction
with organic halides to prepare (Z)-R-fluorostilbenes.10 The
Monofluorinated analogues of natural products have received
increased attention in medicinal chemistry and agrochemistry.1
As fluorine is small (similar in size to oxygen) and has very
strong electronegativity, it is believed that fluorine can modify
the biological activity by altering the physicochemical properties
of these fluorinated compounds.2 R-Fluorostilbenes, for example,
as an important class of fluoroolefins,3 have been recently
explored as potential enzyme inhibitors,4 anti-carcinogenic
agents, and anti-oestrogenic agents.5
The preparation, especially the stereospecific preparation of
(E)- and (Z)-R-fluorostilbenes, has not been fully investigated,
(1) (a) Welch, J. T. Tetrahedron 1987, 43, 3123-3197. (b) Welch, J.
T.; Eswarakrishman, S. Fluorine in Bioorganic Chemistry; Wiley: New
York, 1991.
(2) (a) Resnati, G., Soloshnok, A., Eds. Fluoroorganic Chemistry:
Synthetic Challenges and Biomedical Rewards, Tetrahedron Symposia-in-
Print No. 58, Tetrahedron 1996, 52, 1-330. (b) Banks, R. E., Smart, B.
E., Tatlow, J. C., Eds.; Organofluorine Chemistry: Principle and Com-
mercial Applications; Plenum Press: New York, 1994.
(3) Lee, S. H.; Schwartz, J. J. Am. Chem. Soc. 1986, 108, 2445-2447.
(4) (a) McCarthy, J. R.; Huber, E. W.; Le, T.-B.; Laskovics, F. M.;
Matthews, D. P. Tetrahedron 1996, 52, 45-58. (b) Khrimian, A. P.; Demilo,
A. B.; Waters, R. M.; Liquido, N. J.; Nicholson, J. M. J. Org. Chem. 1994,
59, 8034-8039.
(5) Eddarir, S.; Abdelhadi, Z.; Rolando, C. Tetrahedron Lett. 2001, 42,
9127-9130.
(6) (a) Zupan, M.; Pollak, A. Tetrahedron Lett. 1974, 1015-1018. (b)
Zupan, M.; Pollak, A. J. Org. Chem. 1977, 42, 1559-1562. (c) Baciocchi,
E.; Ruzziconi, R. J. Org. Chem. 1984, 49, 3395-3398. (d) Lermontov, S.
A.; Zavorin, S, I.; Bakhtin, I. V.; Pushin, A. N.; Zefirov, N. S.; Stang, P.
J. J. Fluorine Chem. 1998, 1, 75-84.
(7) Gregorcic, A.; Zupan, M. J. Fluorine Chem. 1988, 41, 163-172.
(8) Tsai, H.-J. Tetrahedron Lett. 1996, 37, 629-632.
10.1021/jo060068i CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/20/2006
J. Org. Chem. 2006, 71, 3743-3747
3743

Xu and Burton
TABLE 1. Preparation and Isomerization of
1-Bromo-1-fluoroalkenes 1
drawbacks of this methodology are: the preparation of the
starting (E)-1-fluorovinyl stannanes takes several steps; and the
separation of the intermediate (E) and (Z) isomers of 1-fluoro-
2-phenylvinyl sulfones is time-consuming. McCarthy and co-
workers also studied the separation of 1-bromo-1-fluorostyrene
(E,Z mixtures) using gas chromatography and separated the (Z)
isomer from the (E) isomer (actual E/Z ) 92:8).11 A Suzuki
coupling reaction between aryl boronic acids and (E)- or (Z)-
1-bromo-1-fluorostyrene was successfully utilized to prepare (Z)-
or (E)-R-fluorostilbenes.11 This method is straightforward
compared to the previous Stille coupling reaction between
1-fluoro-2-phenylvinyl stannanes and aryl halides.10 However,
the availability of the starting (E)- and (Z)-1-bromo-1-fluoro-
alkenes is a problem. In most of these reactions, mmol amounts
of 1-bromo-1-fluorostyrenes, obtained from gas chromatography
separation, were used as the starting materials, which is unlikely
to be efficient for large-scale preparative purposes. Another
synthetic method to prepare (Z)-1-bromo-1-fluoroalkenes from
(E)-2-fluoro-3-phenylacrylic acid takes several steps, and the
isomerization catalyzed by Pd(OAc)2 from (Z) to high E/Z ratio
1-bromo-1-fluoroalkenes was not fully studied.12 McCarthy and
co-workers mentioned another isomerization method from (Z)-
1-bromo-1-fluorostyrene to E/Z ) 92:8 isomer mixtures cata-
lyzed by bromine in chloroform.11a This isomerization was
shown to be low-yielding (<20%) in our hands due to the
domination of saturated products, which were formed by the
addition of bromine to the alkenes. Recently, one example was
reported for the stereoselective preparation of (Z)-R-fluorostil-
bene via R-fluorinated vinyl sulfone and R-fluorinated vinyl
germanium intermediates;13 however, this method was not
studied in detail.
entry
R
time (hr) yield (%) E/Z of 1 E/Z of 2a
1
2
3
4
5
6
7
8
Ph-
6
6
6
6
8
7
8
5
77
67
62
45
53
46
52
72
44:56
48:52
66:34
72:28
63:37
49:51
42:58
46:54
85:15b
82:18c
81:19d
87:13
o-ClC6H4-
p-MeOC6H4-
p-FC6H4-
m-NO2C6H4-
1-naphthyl-
PhCH(Me)-
n-C7H15
76:24e
49:51f
42:58f
46:54f
a E/Z ratios after leaving 1 in the freezer for 1 week. b E/Z ratio was
88:12 in 3 months. c Photolysis of this substrate at 254 nm for 1 h gave an
E/Z ratio of 78:22 from a starting E/Z ratio of 63:37. d E/Z ratio was 83:17
in 3 months. e E/Z ratio was 81:19 in 3 months. f No obvious isomerization
was observed.
SCHEME 1
cleanly isomerize to high E/Z (E/Z > 75:25) ratio 2 when they
are stored at -20 °C for 1 week (Scheme 1),14 or alternatively
by photolysis at 254 nm for 1 h. As illustrated in Table 1, for
1 (R ) aryl groups), clean isomerization occurs, and 2 (E/Z >
75:25) were successfully obtained; for 1 (R ) 1-naphthyl or
alkyl groups), no obvious isomerization was observed, however
(Table 1). This isomerization could be catalyzed by a trace
amount of bromine in the mixture of 1.
Preparation of (Z)-r-Fluorostilbenes from High E/Z
1-Bromo-1-fluoroalkenes. Recently we reported that the (E)-
isomer of 1-bromo-1-fluoroalkenes reacts faster than the cor-
responding (Z)-isomer at room temperature in palladium-
catalyzed coupling reactions at room temperature.16-18 It
provides a novel and important strategy to prepare monoflu-
orinated olefins stereoselectively. Therefore, we examined the
coupling reactions of 2 to synthesize (Z)-R-fluorostilbenes.
Both Stille and Suzuki coupling reactions could be utilized
to synthesize (Z)-R-fluorostilbenes. Therefore, we tested the
coupling reaction of 2 by both methods. Under Stille coupling
reaction conditions, PhCHdCFBr (E/Z ) 88:12) reacted
smoothly with PhSnBu3, Pd(PPh3)4/CuI in DMF at room
temperature for 20 h. 19F NMR analysis of the reaction mixture
showed that all the (E) isomer was consumed and the Z/E ratio
of the crude product was 98:2. Under Suzuki coupling reaction
conditions, 1-bromo-1-fluoro-2-phenylethene (E/Z ) 88:12)
reacted with phenylboronic acid in the presence of Pd(PPh3)4
in PhCH3/EtOH/H2O. When this reaction was carried out at
room temperature, it was very slow. When the above Suzuki
reaction was carried out at reflux temperature, the Z/E ratio of
R-fluorostilbene in the mixture was 94:6, which is not as good
as the Z/E ratio (98:2) under Stille coupling conditions.
Therefore, we selected Stille coupling reaction conditions for
the preparation of (Z)-R-fluorostilbenes.
As most literature methods for the preparation of (E)- and
(Z)-R-fluorostilbenes either lack stereoselectivity or suffer from
difficulty in the preparation of the starting materials, an efficient
and stereospecific method to prepare this class of compounds
is needed in medicinal chemistry and agrochemistry. Herein,
we wish to report our preparation of high E/Z and (Z)-1-bromo-
1-fluoroalkenes and their coupling reactions to synthesize (Z)-
and (E)-R-fluorostilbenes. A portion of this research was
reported as a preliminary communication.14
Results and Discussion
Preparation and Isomerization of 1-Bromo-1-fluoroal-
kenes. 1-Bromo-1-fluoroalkenes (E/Z ≈ 1:1) 1, which were
readily prepared from RCHO, CFBr3, and PPh3,15 could
potentially serve as valuable starting materials for the preparation
of (Z)- and (E)-R-fluorostilbenes. Recently, we found that they
(9) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber, E. W.;
Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am. Chem. Soc.
1991, 113, 7439-7440.
(10) (a) Chen, C.; Wilcoxen, K.; Kim, K.; McCarthy, J. R. Tetrahedron
Lett. 1997, 38, 7677-7680. (b) Chen, C.; Wilcoxen, K.; Zhu, Y.-F.; Kim,
K-i.; McCarthy, J. R. J. Org. Chem. 1999, 64, 3476-3482.
(11) (a) Chen, C.; Wilcoxen, K.; Strack, N.; McCarthy, J. R. Tetrahedron
Lett. 1999, 40, 827-830. (b) Chen, C.; Wilcoxen, K.; Huang, C. Q.; Strack,
N.; McCarthy, J. R. J. Fluorine Chem. 2000, 101, 285-290.
(12) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Bull. Soc.
Chim. Fr. 1997, 134, 741-755.
The coupling reaction of 2 with phenyltributyltin or substi-
tuted phenyltributyltin proceeded smoothly in DMF at room
temperature, with Pd(PPh3)4 (4%) and CuI (50%) as catalyst
(Scheme 2). CuI has been shown to be a very effective cocatalyst
(13) Wnuk, S. F.; Garcia, P. I., Jr.; Wang, Z. Org. Lett. 2004, 6, 2047-
2049.
(14) Xu, J.; Burton, D. J. Tetrahedron Lett. 2002, 43, 2877-2879.
(15) (a) Vanderhaar, R. W.; Burton, D. J.; Naae, D. G. J. Fluorine Chem.
1971/72, 1, 381-383. (b) Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. ReV.
1996, 96, 1641-1715. (c) Burton, D. J. J. Fluorine Chem. 1983, 23, 339-
357.
(16) Zhang, X.; Burton, D. J. J. Fluorine Chem. 2001, 112, 47-54.
(17) Xu, J.; Burton, D. J. J. Fluorine Chem. 2004, 125, 725-730.
(18) (a) Xu, J.; Burton, D. J. Org. Lett. 2002, 4, 831-833. (b) Xu, J.;
Burton, D. J. J. Org. Chem. 2005, 70, 4346-4353.
3744 J. Org. Chem., Vol. 71, No. 10, 2006

Preparation of (E)- and (Z)-R-Fluorostilbenes
TABLE 2. Preparation of (Z)-r-Fluorostilbenes 3 by Stille Coupling Reaction from 2
time
(hr)
mixture
producta
yieldd
(conversion)
entry
R
X
E/Z of 2
Z/Ec
(Z/E)b
1
2
3
4
5
6
7
8
9
Ph-
Ph-
o-ClC6H4-
o-ClC6H4-
p-MeOC6H4-
p-FC6H4-
m-NO2C6H4-
p-ClC6H4-
PhC(Me)H-
H
p-F
H
p-F
H
H
H
p-F
H
88:12
88:12
82:18
82:18
83:17
87:13
76:24
88:12
79:21
20
16
15
16
22
16
16
12
26e
98:2
98:2
94:6
94:6
93:7
96:4
87:13
98:2
95:5
3a (100:0)
3b (100:0)
3c (100:0)
3d (100:0)
3e (100:0)
3f (100:0)
3g (100:0)
3h (100:0)
3i (100:0)
73 (83)
67 (76)
71 (87)
52 (63)
61 (74)
69 (80)
53 (70)
72 (82)
36 (45)
a All products gave satisfactory 19F, 1H, and 13C NMR and HRMS data. b Z/E ratio of isolated product. c Z/E ratios of R-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-fluoroalkenes in the starting (E,Z) mixtures. e The reaction was carried out at 95 °C instead of at rt.
SCHEME 2
SCHEME 3
SCHEME 4
tested the preparation of (E)-R-fluorostilbenes starting from the
mixture of 4 and 5.
Similar to the preparation of (Z)-R-fluorostilbenes 3, we can
choose either the Stille or the Suzuki coupling reaction to
prepare (E)-R-fluorostilbenes. However, here we prefer Suzuki
coupling reaction conditions. The reasons include the follow-
ing: the coupling reactions of (Z)-1-bromo-1-fluoroalkenes 4
normally occur at 70 °C or higher temperature, which is close
to the refluxing temperature of PhCH3/EtOH/H2O in a typical
Suzuki coupling reaction; a variety of substituted aryl boronic
acids are commercially available; and no side product of
tributyltin halide, which is usually difficult to separate.
Following typical Suzuki coupling reaction conditions (with
minor changes, such as C6H6 is replaced by toluene and Na2-
CO3 is replaced by K2CO3),11a,21 a mixture of 4 and 5 reacted
with Pd(PPh3)4, XC6H4B(OH)2 (X) substituted groups), and
K2CO3 in PhCH3/EtOH/H2O at reflux temperature (Scheme 4).
19F NMR analysis of the reaction mixture showed that all the
(Z)-1-bromo-1-fluoroalkene 4 was consumed; the crude product
had a Z/E ratio of 0:100; and the reduced products did not
participate in the reaction. Workup followed by column chro-
matography gave the desired (E)-R-fluorostilbenes 6 in high
yields (Table 3). Some products, however, were found to have
an obvious tendency to isomerize in the course of separation
(Table 3, entries 3 and 5). This Suzuki coupling reaction also
works very well for those 4 whose R ) alkyl groups, where
the corresponding (E)-monofluoroalkene products were suc-
cessfully separated in high yields (Table 3, entries 5-7).
in Stille coupling reactions.10b,19 The reaction was shown to be
stereoselective, and high Z/E ratios were observed for the crude
products in the reaction mixture by 19F NMR analysis. Pure
(Z)-R-fluorostilbenes were isolated in good yields (Table 2) by
either column chromatography or column chromatography
followed by recrystallization. The reaction conditions for the
preparation of (Z)-R-fluorostilbenes are very mild. Various
combinations of functional groups on both phenyl rings are
available and permutation is also possible, as demonstrated in
Table 2 (entries 2 and 6). Alkyl group substituted 1-bromo-1-
fluoroalkene can also selectively couple with aryl stannane at
higher temperature (95 °C) to afford the corresponding (Z)-
monofluoroalkene (Table 2, entry 9).
Recently, Rolando and co-workers synthesized two (Z)-R-
fluorostilbenes, fluorinated resveratrol and pterostilbene, by
Suzuki coupling of 1-bromo-1-fluoroalkenes ((E,Z) mixtures).5
High yields (71-86%) of products were achieved in this Suzuki
coupling step, starting from 1-bromo-1-fluoroalkenes (E/Z ≈
1:1 when they were prepared). Probably the selectivity is
partially due to the high E/Z ratio of the starting materials before
the coupling reaction.
Preparation of (E)-r-Fluorostilbenes from (Z)-1-Bromo-
1-fluoroalkenes. (Z)-1-Bromo-1-fluoroalkenes have been shown
to participate in Suzuki coupling reactions to give (E)-R-
fluorostilbenes.11 Recently we reported the preparation of (Z)-
1-bromo-1-fluoroalkenes 4 by the kinetic reduction method from
1 using HCOOH/NBu3/DMF.18 Most (Z) isomers 4 were not
separated from the corresponding reduced products 5 at this
stage (Scheme 3). As 4 has been shown to be a good starting
material in a series of palladium-catalyzed coupling reactions
to prepare (Z)-1-fluorovinyl phosphonates,16 (E)-monofluo-
roenynes,12,20 and (E)-R-fluoro-R,â-unsaturated esters,18 we
Conclusion
A straightforward method to prepare both (Z)- and (E)-R-
fluorostilbenes has been developed. 1-Bromo-1-fluoroalkenes
(E/Z ≈ 1:1) were found to isomerize to high E/Z ratios after
storage at -20 °C or by photolysis at 254 nm. These high E/Z
ratio 1-bromo-1-fluoroalkenes can undergo a Stille coupling
reaction with aryl stannanes to afford (Z)-R-fluorostilbenes
(20) Zhang, X.; Burton, D. J. J. Fluorine Chem. 2001, 112, 317-324.
(21) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513-519. (b) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405-
1408.
(19) (a) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L.
S. J. Org. Chem. 1994, 59, 5905-5911. (b) Lu, L.; Burton, D. J.
Tetrahedron Lett. 1997, 38, 7673-7676.
J. Org. Chem, Vol. 71, No. 10, 2006 3745

Xu and Burton
TABLE 3. Preparation of 6 by Suzuki Coupling Reaction from 4
General Procedure for the Preparation of (E)-r-Fluorostil-
benes 6. To a round-bottom flask containing Pd(PPh3)4 (0.046 g,
0.04 mmol, 4 mol %), K2CO3 (0.415 g, 3.0 mmol), and toluene/
EtOH/H2O (15 mL, 3 mL, 3 mL respectively), a mixture of 4 and
5 (contains 4 1.0 mmol) was added, and the resulting suspension
was stirred at room temperature for 15 min. Following the addition
of aryl boronic acid (1.2 mmol), the resulting mixture was refluxed
for 8 h. After the reaction was completed, the reaction mixture was
transferred to a separatory funnel with 200 mL of ethyl ether. The
organic phase was washed with water (3 × 20 mL) and brine (3 ×
20 mL) and dried over anhydrous MgSO4. The solvent was removed
by rotary evaporation, and the resulting mixture was separated by
silica gel column chromatography.
time
(hr)
yieldb
(%)
entry
R
E/Z of 4
X
Z/E of 6a
1
2
3
4
5
6
7
Ph-
0:100
0:100
0:100
0:100
0:100
0:100
0:100
m-Ac
H
m-NO2
o-Cl
H
4
8
8
6
10
6
0:100 6a
0:100c 6b
11:89d 6c
5:95c 6d
4:96d 6e
0:100 6f
0:100 6g
83
82
90
90
85
92
93
o-ClC6H4-
o-ClC6H4-
o-ClC6H4-
1-naphthyl-
PhC(CH3)H-
PhC(CH3)H-
o-Cl
m-Ac
8
a All products gave satisfactory 19F, 1H, and 13C NMR, GC-MS, and
HRMS data. b The yield of 6 is based on the amount of 4 in a starting
material mixture of 4 and 5. c The product contains 2-3% of (1E,3E)-o-
Cl-C6H4-CHdCF-CHdCF-C6H4-Cl-o that could not be separated.
d The product had an obvious tendency to isomerize at room temperature
in the course of separation.
(E)-1-(3-Acetylphenyl)-1-fluoro-2-phenylethene (6a). Similarly,
a mixture of (Z)-1-bromo-1-fluoro-2-phenyl-ethene (contains (Z)-
1-bromo-1-fluoroalkene, 0.10 g, 0.5 mmol, E/Z ) 0:100) and the
reduced products, Pd(PPh3)4 (0.023 g, 0.02 mmol), K2CO3 (0.207
g, 1.5 mmol), and m-AcC6H4B(OH)2 (0.098 g, 0.6 mmol), was
reacted in toluene/EtOH/H2O (15 mL/3 mL/3 mL) for 4 h. After
workup and silica gel column chromatography (ethyl acetate/
hexanes ) 10:90, Rf ) 0.31), 0.10 g of liquid was obtained, yield
83%. 19F NMR (CDCl3) δ -99.1 (d, 3JFH(cis) ) 20.2 Hz, 1F) ppm;
1H NMR (CDCl3) δ7.97 (m, 1H), 7.92 (dm, J ) 7.9 Hz, 1H), 7.60
(d, J ) 7.6 Hz, 1H), 7.39 (t, J ) 7.7 Hz, 1H), 7.22-7.26 (m, 3H),
7.16-7.19 (m, 2H), 6.56 (d, 3JHF(cis) ) 21.3 Hz, 1H), 2.44 (s, 3H)
ppm; 13C NMR (CDCl3) δ 197.2, 156.6 (d, 1JCF ) 246.8 Hz), 137.0,
133.3 (d, J ) 12.2 Hz), 132.3 (d, J ) 5.2 Hz), 131.9, 128.8, 110.1
stereoselectively. (Z)-1-Bromo-1-fluoroalkenes could be ob-
tained after kinetic reduction of the E/Z ≈ 1:1 mixture by
HCOOH/NBu3/DMF. The Suzuki coupling reaction between
aryl boronic acids and a mixture of (Z)-1-bromo-1-fluoroalkene
and the reduced products lead to (E)-R-fluorostilbenes stereo-
selectively. This route to both (Z)- and (E)-R-fluorostilbenes is
highly stereoselective, highly efficient, and should be suitable
for scale-up preparation compared to existing methods.
(d, J ) 30.9 Hz) ppm; GC-MS m/z (relative intensity) 241 (M+
+
1, 16), 240 (M+, 96), 226 (11), 225 (76), 207 (19), 197 (81), 196
(100), 177 (21), 176 (25), 170 (26), 98 (28); HRMS calculated
240.0950 for C16H13OF; observed, 240.0948.
Experimental Section
The preparation and characterization of 3a, 3b, 3c, 3d, 3e, 3f,
3g, and 3h were described in the preliminary communication;14
their 1H and 13C NMR spectra are included in the Supporting
Information of this article.
(E)-2-(2-Chlorophenyl)-1-fluoro-1-phenylethene (6b). Simi-
larly, a mixture of (Z)-1-bromo-1-fluoro-2-(2-chlorophenyl)-ethene
(contains (Z)-1-bromo-1-fluoroalkene, 0.236 g, 1.0 mmol, E/Z )
0:100) and the reduced products, Pd(PPh3)4 (0.046 g, 0.04 mmol),
K2CO3 (0.415 g, 3.0 mmol), and PhB(OH)2 (0.146 g, 1.2 mmol),
was reacted in toluene/EtOH/H2O (15 mL/3 mL/3 mL) for 8 h.
After workup and silica gel column chromatography (hexanes
100%, Rf ) 0.44), 0.19 g of a colorless liquid was obtained (contains
General Procedure for the Preparation of (Z)-r-Fluorostil-
benes 3. To a round-bottom flask containing Pd(PPh3)4 (4 mol %)
and dry DMF, 1-bromo-1-fluorostyrene (high E/Z ratio, includes
(E) isomer 1.0 equiv) was added, and the resulting solution was
stirred at room temperature for 15 min. Following the addition of
CuI (0.5 equivalent) and phenyltributyltin (1.2 equivalent), the
resulting mixture was stirred at room temperature. When the
reaction was completed, Co(OAc)2‚4H2O (1.6 equivalent) was
added to the mixture to remove tributyltin halide side products.22
The mixture was added directly to a silica gel column. Subsequent
recrystallization from hexanes gives white crystals if the product
is a solid.
2% (E,E)-o-ClC6H4CHdCFCFdCHC6H4Cl-o, which could not be
3
separated), yield 82%. 19F NMR (CDCl3) δ -96.6 (d, JFH(cis)
)
1
20.5 Hz, 1F) ppm; H NMR (CDCl3) δ 7.23-7.41 (m, 6H), 7.16
(td, J ) 7.7 Hz, J ) 1.6 Hz, 1H), 7.09 (dd, J ) 7.8 Hz, J ) 1.5
3
Hz, 1H), 7.02 (tm, J ) 7.4 Hz, 1H), 6.53 (d, JHF(cis) ) 20.5 Hz,
1H) ppm; 13C NMR (CDCl3) δ 158.7 (d, JCF ) 246.7 Hz), 133.9
1
(d, J ) 3.9 Hz), 132.7 (d, J ) 13.2 Hz), 131.3 (d, J ) 30.4 Hz),
130.8, 129.5 (d, J ) 6.3 Hz), 128.6, 128.2, 127.9 (d, J ) 5.8 Hz),
127.1, 126.5, 106.6 (d, J ) 32.8 Hz) ppm; GC-MS m/z (relative
intensity) 235 (4), 234 (M+ + 2, 30), 233 (M+ + 1, 13), 232 (M+,
58), 198 (17), 197 (31), 196 (100), 194 (20), 177 (33), 176 (21),
170 (20), 98 (38), 97 (13), 88 (19), 85 (39), 75 (16); HRMS
calculated 232.0455 for C14H10F35Cl; observed, 232.0462.
(Z)-1-Fluoro-1,3-diphenyl-1-butene (3i). Similarly, a mixture
of 1-bromo-1-fluoro-3-phenyl-1-butene (0.229 g, 1.0 mmol,
E/Z ) 79:21), Pd(PPh3)4 (0.037 g, 0.032 mmol), PhSnBu3 (0.51 g,
1.40 mmol, 1.8 equiv), and CuI (0.08 g, 0.40 mmol) in DMF (4
mL) was reacted at 95 °C for 26 h. 19F NMR analysis of the reaction
mixture showed that the Z/E ratio of the crude product was 95:5.
Silica gel column chromatography (ethyl acetate/hexanes )
10:90, Rf ) 0.67) gave a colorless liquid (0.08 g), yield 36% (the
conversion is 45% based on the amount of the consumed (E)-1-
bromo-1-fluoroalkenes). (Z) 100%. 19F NMR (CDCl3) δ -121.3
(d, 3JFH(trans) ) 37.6 Hz) ppm; 1H NMR (CDCl3) δ 7.17-7.62 (m,
(E)-2-(2-Chlorophenyl)-1-fluoro-1-(3-nitrophenyl)ethene (6c).
Similarly, a mixture of (Z)-1-bromo-1-fluoro-2-(2-chlorophenyl)-
ethene (contains (Z)-1-bromo-1-fluoroalkene, 0.236 g, 1.0 mmol,
E/Z ) 0:100) and the reduced products, Pd(PPh3)4 (0.046 g, 0.04
mmol), K2CO3 (0.415 g, 3.0 mmol), and m-NO2C6H4B(OH)2 (0.200
g, 1.2 mmol), was reacted in toluene/EtOH/H2O (15 mL/3 mL/3
mL) for 8 h. After workup and silica gel column chromatography
(ethyl acetate/hexanes ) 7:93, Rf ) 0.32), 0.25 g of a colorless
liquid was obtained, yield 90%. Z/E ) 11:89 (The product partially
isomerized in the course of separation). 19F NMR (CDCl3) δ -100.3
(d, 3JFH(cis) ) 20.7 Hz, 1F) ppm; 1H NMR (CDCl3) δ 8.22 (m, 1H),
8.16 (dm, J ) 8.4 Hz, 1H), 7.60 (dm, J ) 7.7 Hz, 1H), 7.45 (dd,
J ) 7.8 Hz, J ) 3.7 Hz, 2H), 7.22-7.28 (m, 1H), 7.07-7.13 (m,
3
10H), 5.54 (dd, JHF(trans) ) 36.6 Hz, J ) 9.5 Hz, 1H), 4.14 (dq,
J ) 9.4 Hz, J ) 7.0 Hz, 1H); 1.46 (d, J ) 9.0 Hz, 3H) ppm; 13C
NMR (CDCl3) δ 155.6 (d, 1JCF ) 245.9 Hz), 145.6, 132.5 (d, J )
29.5 Hz), 128.5 (d, J ) 2.4 Hz), 128.4 (d, J ) 2.5 Hz), 127.2 (d,
J ) 6.1 Hz), 126.8, 126.2, 124.0 (d, J ) 7.8 Hz), 111.2 (d, J )
17.6 Hz), 34.7 (d, J ) 5.4 Hz), 21.8 ppm; GC-MS m/z (relative
intensity) 226 (M+, 37), 211 (86), 191 (21), 133 (100), 109 (20),
77 (19); HRMS calculated 226.1158 for C16H15F; observed,
226.1149.
3
2H), 6.69 (d, JHF(cis) ) 20.0 Hz, 1H) ppm; 13C NMR (CDCl3) δ
155.9 (d, 1JCF ) 249.6 Hz), 148.1, 134.0 (d, J ) 2.9 Hz), 133.4 (d,
J ) 5.0 Hz), 132.9 (d, J ) 28.7 Hz), 131.5 (d, J ) 12.6 Hz), 130.5,
129.9, 129.4, 129.3, 127.0, 124.1, 122.6, 129.0 (d, J ) 32.1 Hz)
(22) Blumenthal, E. J. Ph.D. Thesis, University of Iowa, Iowa City, Iowa,
2000; p 128.
3746 J. Org. Chem., Vol. 71, No. 10, 2006

Preparation of (E)- and (Z)-R-Fluorostilbenes
ppm; GC-MS m/z (relative intensity) 280 (2), 279 (M+ + 2, 10),
278 (4), 277 (M+, 30), 232 (6), 230 (12), 225 (10), 224 (11), 212
(7), 197 (15), 196 (100), 195 (28), 194 (45), 183 (24), 175 (27),
170 (30), 169 (189), 168 (17), 99 (18), 98 (18), 87 (18), 75 (34),
74 (27); HRMS calculated 277.0306 for C14H9NO2F35Cl; observed,
277.0297.
the reduced products, Pd(PPh3)4 (0.046 g, 0.04 mmol), K2CO3
(0.415 g, 3.0 mmol), and o-ClC6H4B(OH)2 (0.188 g, 1.2 mmol),
was reacted in toluene/EtOH/H2O (15 mL/3 mL/3 mL) for 6 h.
After workup and silica gel column chromatography (ethyl acetate/
hexanes ) 1:99, Rf ) 0.25), 0.24 g of a colorless liquid was
obtained, yield 92%. 19F NMR (CDCl3) δ -96.8 (d, 3JFH(cis) ) 18.0
1
(E)-1,2-Di(2-chlorophenyl)-1-fluoroethene (6d). Similarly, a
mixture of (Z)-1-bromo-1-fluoro-2-(2-chlorophenyl)-ethene (con-
tains (Z)-1-bromo-1-fluoroalkene, 0.118 g, 0.5 mmol, E/Z ) 0:100)
and the reduced products, Pd(PPh3)4 (0.023 g, 0.02 mmol), K2CO3
(0.207 g, 1.5 mmol), and o-ClC6H4B(OH)2 (0.094 g, 0.6 mmol),
was reacted in toluene/EtOH/H2O (15 mL/3 mL/3 mL) for 6 h.
After workup and silica gel column chromatography (ethyl acetate/
hexanes ) 5:95, Rf ) 0.36), 0.12 g of a colorless liquid was
obtained (contains 3% (E,E) o-ClC6H4CHdCFCFdCHC6H4Cl-o,
which could not be separated), yield 90%. 19F NMR (CDCl3) δ
Hz, 1F) ppm; H NMR (CDCl3) δ 7.47 (dm, J ) 8.0 Hz, 1H),
7.36-7.40 (m, 1H), 7.25-7.35 (m, 4H), 7.18-7.22 (m, 2H), 7.16
(m, 1H), 5.69 (dd, 3JHF(cis) ) 18.2 Hz, J ) 11.0 Hz, 1H), 3.25 (dqd,
J ) 10.8 Hz, J ) 7.0 Hz, J ) 3.4 Hz, 1H), 1.37 (dd, J ) 7.0 Hz,
J ) 0.9 Hz, 3H) ppm; 13C NMR (CDCl3) δ 154.2 (d, 1JCF ) 247.4
Hz), 145.1, 134.2, 131.7, 131.0 (d, J ) 28.7 Hz), 130.9, 129.9,
128.5, 126.6, 126.57, 126.3, 115.4 (d, J ) 21.5 Hz), 36.6 (d, J )
5.8), 22.3 ppm; GC-MS, m/z (relative intensity) 263 (M+ + 3, 6),
262 (M+ + 2, 39), 261 (M+ + 1, 15), 260 (M+, 85), 247 (60), 245
(100), 225 (71), 210(64), 209 (42), 207 (22), 189 (27), 183 (22),
169 (37), 167 (74), 147 (27), 143 (24), 133 (61), 109 (37), 104
(23), 101 (23). HRMS calculated 260.0768 for C16H14F35Cl;
observed, 260.0760.
(E)-1-(3-Acetylphenyl)-1-fluoro-3-phenyl-1-butene (6g). Simi-
larly, a mixture of (Z)-1-bromo-1-fluoro-3-phenyl-1-butene (con-
tains (Z)-1-bromo-1-fluoroalkene, 0.229 g, 1.0 mmol, E/Z ) 0:100)
and the reduced products, Pd(PPh3)4 (0.046 g, 0.04 mmol), K2CO3
(0.415 g, 3.0 mmol), and m-AcC6H4B(OH)2 (0.197 g, 1.2 mmol),
was reacted in toluene/EtOH/H2O (15 mL/3 mL/3 mL) for 8 h.
After workup and silica gel column chromatography (ethyl acetate/
3
1
-88.9 (d, JFH(cis) ) 18.3 Hz, 1F) ppm; H NMR (CDCl3) δ 7.43
(d, J ) 8.1 Hz, 1H), 7.35 (d, J ) 8.1 Hz, 2H), 7.28 (d, J ) 7.8 Hz,
1H), 7.21 (d, J ) 8.1 Hz, 1H), 7.09 (t, J ) 7.9 Hz, 1H), 6.92 (t,
J ) 7.5 Hz, 1H), 6.78 (d, 3JHF(cis) ) 17.9 Hz, 1H), 6.77 (d, J ) 8.1
1
Hz, 1H) ppm; 13C NMR (CDCl3) δ 157.0 (d, JCF ) 252.2 Hz),
134.1, 133.8 (d, J ) 4.5 Hz), 131.9, 131.7 (d, J ) 13.1 Hz), 131.2
(d, J ) 2.6 Hz), 130.8, 130.1, 129.8, 129.3, 128.5, 126.9, 126.4,
109.6 (d, J ) 31.3 Hz) ppm; GC-MS m/z (relative intensity) 270
(M+ + 4, 2), 268 (M+ + 2, 11), 266 (M+, 17), 231 (7), 230 (7),
196 (100), 194 (16), 176 (6), 175 (9), 170 (6), 115 (8), 97 (20);
HRMS calculated 266.0065 for C14H935Cl2F; observed, 266.0056.
(E)-1-Fluoro-1-phenyl-2-(1-naphthyl)ethene (6e). Similarly, a
mixture of (Z)-1-bromo-1-fluoro-2-(naphthalene-2-yl)-ethene (con-
tains (Z)-1-bromo-1-fluoroalkene, 0.251 g, 1.0 mmol, E/Z ) 0:100)
and the reduced products, Pd(PPh3)4 (0.046 g, 0.04 mmol), K2CO3
(0.415 g, 3.0 mmol), and PhB(OH)2 (0.146 g, 1.2 mmol), was
reacted in toluene/EtOH/H2O (15 mL/3 mL/3 mL) for 10 h. After
workup and silica gel column chromatography (ethyl acetate/
hexanes ) 3:97, Rf ) 0.28), 0.21 g of a colorless liquid was
obtained, yield 85%. Z/E ) 4:96 (The product partially isomerized
in the course of separation). 19F NMR (CDCl3) δ -99.9 (d,
hexanes ) 10:90, Rf ) 0.33), 0.25 g of a colorless liquid was
3
obtained, yield 93%. 19F NMR (CDCl3) δ -102.2 (d, JFH(cis)
)
1
21.7 Hz, 1F) ppm; H NMR (CDCl3) δ 7.97 (d, J ) 8.4 Hz, 2H),
7.63 (d, J ) 7.6 Hz, 1H), 7.50 (tm, J ) 7.6 Hz, 1H), 7.21-7.38
(m, 5H), 5.72 (dd, 3JHF(cis) ) 21.8 Hz, J ) 10.9 Hz, 1H), 3.68 (dqd,
J ) 10.6 Hz, J ) 6.8 Hz, J ) 2.6 Hz, 1H), 2.53 (s, 3H), 1.43 (dm,
J ) 6.9 Hz, 3H) ppm; 13C NMR (CDCl3) δ 196.0, 154.2 (d,
1JCF ) 244.3 Hz), 144.4 (d, J ) 2.4 Hz), 136.0, 131.1 (d, J ) 29.9
Hz), 130.8, 130.75, 127.7, 127.6, 126.6 (d, J ) 5.0 Hz), 125.6,
125.4, 112.9 (d, J ) 23.3 Hz), 35.6 (d, J ) 9.5 Hz), 25.3, 22.8
ppm; GC-MS m/z (relative intensity) 269 (M+ + 1, 7), 268 (M+,
46), 254 (15), 253 (88), 225 (16), 209 (17). 205 (16), 191 (20),
189 (15), 175 (31), 147 (17), 133 (32), 119 (22), 109 (19), 95 (17),
77 (17); HRMS calculated 268.1263 for C18H17FO; observed,
268.1251.
1
3JFH(cis) ) 21.7 Hz, 1F) ppm; H NMR (CDCl3) δ 8.09 (dd, J )
6.3 Hz, J ) 3.7 Hz, 1H), 7.86 (dd, J ) 6.3 Hz, J ) 3.5 Hz, 1H),
7.74-7.79 (m, 1H), 7.51 (dd, J ) 6.4 Hz, J ) 3.3 Hz, 2H), 7.25-
7.33 (m, 4H), 7.11-7.22 (m, 3H), 6.87 (d, 3JHF(cis) ) 21.2 Hz, 1H)
ppm; 13C NMR (CDCl3) δ 158.3 (d, 1JCF ) 247.1 Hz), 133.6, 131.9
(d, J ) 2.8 Hz), 131.7, 131.3 (d, J ) 3. 6 Hz), 131.1, 129.1, 128.5,
128.0, 127.9, 127.6 (d, J ) 6.1 Hz), 127.4, 126.2 (d, J ) 13.8 Hz),
125.6, 124.7, 107.0 (d, J ) 30.8 Hz) ppm; GC-MS m/z (relative
intensity) 249 (M+ + 1, 21), 248 (M+, 100), 246 (44), 244 (21),
233 (28), 228 (50), 226 (38), 220 (15), 170 (29), 123 (20), 113
(22), 110 (20); HRMS calculated 248.1001 for C18H13F; observed,
248.1004.
Acknowledgment. We thank the National Science Founda-
tion for their financial support of this work.
Supporting Information Available: Experimental procedures
for the synthesis of 3a, 3b, 3c, 3d, 3e, 3f, 3g, and 3h and their
1
characterization by 19F, H, and 13C NMR, GC-MS, and HRMS;
copies of 1H and 13C NMR spectra of compounds 3a-3i, and 6a-
6g; and photolytic isomerization example of 1 to 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
(E)-1-(2-Chlorophenyl)-1-fluoro-3-phenyl-1-butene (6f). Simi-
larly, a mixture of (Z)-1-bromo-1-fluoro-3-phenylethene (contains
(Z)-1-bromo-1-fluoroalkene, 0.229 g, 1.0 mmol, E/Z ) 0:100) and
JO060068I
J. Org. Chem, Vol. 71, No. 10, 2006 3747