A new and facile method for stereoselective synthesis of (E)-styryl bromides by the reduction of 1,1-dibromoalkenes using LiAlH4-EtOAc (1:1)

Article abstract of DOI:10.1055/s-2004-822322

A facile method for stereoselective synthesis of (E)-styryl bromides by the reduction of 1,1-dibromoalkenes using LiAlH₄-EtOAc (1:1) is described. We believe that the present procedure is a good alternative to the Tokuda's microwave method with good stereoselectivity.

Full text of DOI:10.1055/s-2004-822322

986
SHORT PAPER
A New and Facile Method for Stereoselective Synthesis of (E)-Styryl Bromides
by the Reduction of 1,1-Dibromoalkenes Using LiAlH4–EtOAc (1:1)
Synthesis of
(
E
)-S
i
tyryl Br
d
omides by th
e
e
Reductio
o
n of 1,1-Dibromoa
H
lkenes oribe,a Kazuhiro Kondo,*b Hiroaki Okuno,a Toyohiko Aoyama*b
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
b
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Fax +81(52)8363439; E-mail: kazuk@phar.nagoya-cu.ac.jp, aoyama@phar.nagoya-cu.ac.jp
Received 2 February 2004; revised 20 February 2004
We chose LiAlH4 as a simple reducing reagent,14 and be-
gan with optimization of reaction conditions using 1,1-di-
bromo-2-(4-methoxyphenyl)ethene as a substrate. The
selected results are shown in entries 1-4, Table 1. As
shown in entry 1, when using 2 mol equivalents of LiAlH4
(THF, –40 °C), the desired (E)-bromostyrene was ob-
tained in low yield with poor selectivity in a ratio of 2 (E-
isomer):1 (Z-isomer):3 (styrene). After intensive screen-
ing of reaction conditions such as solvents and additives,
the addition of EtOAc (LiAlH4–EtOAc = 1:1) as an addi-
tive was found to improve significantly the yield and the
stereoselectivity (E/Z/styrene = >20:1:2, entry 2).15 We
assume that the effective reducing agent is Li(EtO)2AlH2,
although further investigation to clarify the detailed role
of EtOAc is needed. On the other hand, the addition of
EtOH gave less satisfactory results (entries 3 and 4). The
addition of stoichiometric quantities of EtOH (2–3 equiv)
with LiAlH4, leads to Li(EtO)2AlH2 or Li(EtO)3AlH, but
the alkoxides rapidly undergo disproportionation.16 This
disproportionation may cause lower selectivity than the
LiAlH4–EtOAc (1:1) system.
Abstract: A facile method for stereoselective synthesis of (E)-styr-
yl bromides by the reduction of 1,1-dibromoalkenes using LiAlH4–
EtOAc (1:1) is described. We believe that the present procedure is
a good alternative to the Tokuda’s microwave method with good
stereoselectivity.
Key words: 1,1-dibromoalkenes, LiAlH4–EtOAc, styryl bromides
(E)- and (Z)-Vinyl bromides are very useful intermediates
in organic synthesis and the development of methods for
their stereoselective synthesis is of considerable impor-
tance. Their use as precursors to vinyl anion such as vinyl
lithium1a and as coupling partners in a wide range of tran-
sition metal-catalyzed coupling reactions1b has stimulated
a great deal of interest in their synthesis. A number of one-
or two-step procedures exist for stereoselective synthesis
of (Z)-vinyl bromide.2 However, efficient synthesis of
(E)-vinyl bromides seems to be somewhat underdevel-
oped, although Takai’s CHBr3–CrCl2 method,3 the hydro-
metalation-bromination methods4 and the decarboxy-
lation methods of cinnamic acid derivatives,5 perform this
transformation well in a number of favorable cases.6 Re-
duction of 1,1-dibromoalkenes, readily available from a
simple reaction of an aldehyde with CBr4 and PPh3,7 rep-
resents a practical alternative to the stereoselective syn-
thesis of (E)-vinyl bromide. Several procedures for the
reduction of 1,1-dibromoalkenes to the corresponding vi-
nyl bromides have been reported, which is induced by var-
ious reagents, such as alkyl metal reagents,8 In,9 Sm,10
Bu3SnH–Et3B,11 and (RO)2POH12. However, these syn-
thetic methods have some drawbacks, including very low
reaction temperature8 (–94 °C to –110 °C), limitation of
substrates and/or unfavorable ratios of the E/Z isomers. In
2002, Tokuda et al. reported a good stereoselective syn-
thesis of (E)-styryl bromides by microwave-induced re-
duction using a (EtO)2POH–EtONa–EtOH system (E/Z =
>20–16:1; various 1,1-dibromo-2-arylethenes as sub-
strates).13 Herein, we would like to report a facile method
for stereoselective synthesis of (E)-styryl bromides by the
reduction of 1,1-dibromoalkenes using LiAlH4–EtOAc
(1: 1) in THF.
Having optimized the reaction conditions, substrate gen-
erality was investigated. The results are shown in entries
5–11. A variety of aryl-substituted dibromoalkenes with
electron-donating or withdrawing groups were converted
to the corresponding styryl bromide in good yields with
E/Z = >20–18:1 selectivities (entries 5–10). This proce-
dure allows for the presence of bromo, chloro and fluoro
groups on the benzene ring (entries 5 and 10). The 5 mmol
scale reaction (entry 9) also gave the same selectivity,
compared with the ca. 0.3 mmol scale reaction (entry 8).
Unfortunately, the stereoselectivity of the alkyl-substitut-
ed dibromoalkene was low (entry 11). In most cases, the
stereoselectivity is comparable to that of Tokuda’s micro-
wave-induced (EtO)2POH–EtONa–EtOH system.13
The present procedure a provides new and facile two-step
method for stereoselective synthesis of (E)-styryl bro-
mides from aryl aldehydes, and is a good alternative to the
Tokuda’s microwave method.13
IR spectra were measured on a JASCO IR Report-100 diffraction
1
grating IR spectrophotometer. H (270 MHz) and 13C NMR (68
MHz) spectra were measured on a JEOL JNM-EX-270 NMR spec-
trometer. EI and FAB MS spectra were measured on a JEOL
JMS-SX-102A instrument. Commercially available LiAlH4 was
used without any further purification. THF was distilled from Na/
benzophenone ketyl under a nitrogen atmosphere. EtOAc was dis-
SYNTHESIS 2004, No. 7, pp 0986–0988
Advanced online publication: 14.04.2004
DOI: 10.1055/s-2004-822322; Art ID: F01704SS.pdf
© Georg Thieme Verlag Stuttgart · New York
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SHORT PAPER
Synthesis of (E)-Styryl Bromides by the Reduction of 1,1-Dibromoalkenes
987
Table 1 Optimized Conditions and Substrate Generalitya
Entry
Substrate
Ar =
Additive
(mol equiv)
Time
(h)
Yield
(%)b
Ratio
(E/Z:styrene)c
1
2
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
none
7
6
31
76
70
12e
86
75g
82
69
74
83
60
2:1:3
>20:1:2
18:1:2
13:1:2
>20:1:1
19:1:1
19:1:2
19:1:3
19:1:3
18:1:<1
3:2:<1
EtOAc (2)d
EtOH (4)
EtOH (6)
EtOAc (2)
EtOAc (3)
EtOAc (2)
EtOAc (2)
EtOAc (2)
EtOAc (2)
EtOAc (2)
3
10
13
3
4
5
6f
7
4-MeO2CC6H4
4-MeC6H4
12
6
8
4-i-PrC6H4
4-i-PrC6H4
2-F-4-BrC6H4
PhCH2CH2
4
9h
10
11
5
2
13
a Reaction conditions: Substrate (ca. 0.3 mmol), LiAlH4 (ca. 0.6 mmol), additive, THF at –40 °C.
b Combined yield (E + Z).
c Determined by 1H NMR analysis of the crude product.
d 1 Mol equiv of EtOAc gave less satisfactory results. 3 Mol equiv of EtOAc resulted in no reaction.
e The starting substrate was recovered in 61% yield.
f 3 Mol equiv of LiAlH4 was used.
g The CO2Me group was also reduced to the CH2OH group.
h Run with 5 mmol substrate.
tilled after drying with CaH2. Silica gel column chromatography
was performed on Fuji silysia PSQ 60B.
IR (neat): 1610, 1510, 880 cm–1.
1H NMR (CDCl3): d = 1.25 (d, J = 6.9 Hz, 6 H), 2.90 (sept, J = 6.9
Hz, 1 H), 7.23 (d, J = 8.2 Hz, 2 H), 7.45 (s, 1 H), 7.48 (d, J = 8.2 Hz,
2 H).
13C NMR (CDCl3): d = 23.86, 34.05, 88.43, 126.37, 128.31, 132.65,
136.63, 149.38.
The known dibromoalkenes shown below were prepared according
to the published procedure.7 Their physical data were comparable to
those of the corresponding literature: 1,1-dibromo-2-(4-chlorophe-
nyl)ethane,17 1,1-dibromo-2-(4-methoxycarbonylphenyl)ethane,17
1,1-dibromo-2-(4-methoxyphenyl)ethane,17 1,1-dibromo-4-phenyl-
1-butene,8d 1,1-dibromo-2-(4-tolyl)ethene.17
EIMS: m/z = 306 [M+], 304 [M+], 302 [M+], 128 [bp].
Anal. Calcd for C11H12Br2: C, 43.46; H, 3.98. Found: C, 43.22; H,
3.99.
The physical data of the new dibromoalkenes are shown below.
1,1-Dibromo-2-(4-bromo-2-fluorophenyl)ethane
The published procedure7 was used to afford the title dibromoalk-
ene as a colorless oil; yield: 90%.
IR (CHCl3): 1600, 1485, 864 cm–1.
1H NMR (CDCl3): d = 7.26 (br d, J = 9.9 Hz, 1 H), 7.30 (br d, J =
9.9 Hz, 1 H), 7.46 (s, 1 H), 7.65 (t, J = 8.1 Hz, 1 H).
13C NMR (CDCl3): d = 92.95 (d, J = 2.2 Hz), 119.21 (d, J = 24.6
Hz), 122.39 (d, J = 13.4 Hz), 122.76 (d, J = 9.5 Hz), 127.20 (d, J =
3.9 Hz), 128.82 (d, J = 4.5 Hz), 130.30 (d, J = 2.8 Hz), 158.98 (d,
J = 254.3 Hz).
Stereoselective Synthesis of (E)-1-Bromo-2-(4-methoxyphe-
nyl)ethene by the Reduction of 1,1-Dibromo-2-(4-methoxyphe-
nyl)ethane; Typical Procedure
To a stirred solution of 1,1-dibromo-2-(4-methoxyphenyl)ethene
(91.7 mg, 0.314 mmol) and EtOAc (55.0 mg, 0.620 mmol) in THF
(1.0 mL) was gradually added LiAlH4 (23.8 mg, 0.627 mmol) at
–40 °C. The mixture was stirred for 6 h at the same temperature and
quenched with a small amount of acetone. To the mixture was then
added Na2SO4·10H2O. The whole mixture was stirred for 1 h at r.t.
and filtered through Celite to remove white precipitates. After con-
centration, the ratio of the (E)- and (Z)-1-bromo-2-(4-methoxyphe-
EIMS: m/z = 362 [M+], 360 [M+], 358 [M+], 356 [M+], 83 [bp].
1
nyl)ethene, and 4-methoxystyrene was determined by H NMR
analysis of the crude product. Purification by silica gel column
(hexane) gave 1-bromo-2-(4-methoxyphenyl)ethene (50.8 mg,
76%) as a >20:1 mixture of E- and Z-isomers. The physical data
were comparable to those reported in literature.13
Anal. Calcd for C8H4Br3F: C, 26.78; H, 1.12. Found: C, 26.85; H,
1.16.
1,1-Dibromo-2-(4-isopropylphenyl)ethene
The published procedure7 was used to afford the title dibromoalk-
ene as a colorless oil; yield: (89%).
Synthesis 2004, No. 7, 986–988 © Thieme Stuttgart · New York

988
H. Horibe et al.
SHORT PAPER
The physical data of the other known monobromoalkenes shown
below were comparable to those of the corresponding literature:
(E)-1-bromo-2-(4-chlorophenyl)ethane,13 (E)-1-bromo-4-phenyl-1-
butene,18 (E)-1-bromo-2-(4-tolyl)ethene.13
Chem. Soc., Perkin Trans. 1 1992, 2725. (d) Petasis, N. A.;
Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567. (e) Hoshi,
M.; Tanaka, H.; Shirakawa, K.; Arase, A. Chem. Commun.
1999, 627. (f) Miller, R. B.; McGarvey, G. J. Org. Chem.
1978, 43, 4424. (g) Lipshutz, B. H.; Keil, R.; Ellsworth, E.
L. Tetrahedron Lett. 1990, 31, 7257. (h) Lipshutz, B. H.;
Lindsley, C.; Bhandari, A. Tetrahedron Lett. 1994, 35,
4669. (i) Huang, X.; Wang, J.-H.; Yang, D.-Y. J. Chem.
Soc., Perkin Trans. 1 1999, 673.
The physical data of the new monobromoalkenes are shown below.
(E)-1-Bromo-2-(4-bromo-2-fluorophenyl)ethene
Colorless viscous oil.
IR (CHCl3): 1598, 1482, 938 cm–1.
1H NMR (CDCl3): d = 6.94 (d, J = 14.0 Hz, 1 H), 7.12 (d, J = 14.0
Hz, 1 H), 7.18–7.33 (m, 3 H).
13C NMR (CDCl3): d = 110.39 (d, J = 8.4 Hz), 119.60 (d, J = 25.1
Hz), 121.83 (d, J = 9.5 Hz), 122.69 (d, J = 12.9 Hz), 127.64 (d, J =
3.9 Hz), 128.68 (d, J = 4.5 Hz), 129.43 (d, J = 1.7 Hz), 159.22 (d,
J = 254.3 Hz).
(5) (a) Barton, D. H. R.; Lacher, B.; Zard, S. Z. Tetrahedron
Lett. 1985, 26, 5939. (b) Graven, A.; Jørgensen, K. A.; Dahl,
S.; Stanczak, A. J. Org. Chem. 1994, 59, 3543.
(c) Chowdhury, S.; Roy, S. Tetrahedron Lett. 1996, 37,
2623. (d) Kuang, C.; Senboku, H.; Tokuda, M. Synlett 2000,
1439. (e) Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369.
(f) You, H.-W.; Lee, K.-J. Synlett 2001, 105. (g) Sinha, J.;
Layek, S.; Mandal, G. C.; Bhattacharjee, M. Chem.
Commun. 2001, 1916.
EIMS: m/z = 282 [M+], 280 [M+], 278 [M+], 120 [bp].
(6) Another method: Haack, R. A.; Penning, T. D.; Djurić, S.
W.; Dziuba, J. A. Tetrahedron Lett. 1988, 29, 2783.
(7) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc.
1962, 84, 1745.
Anal. Calcd for C8H5Br2F: C, 34.32; H, 1.80. Found: C, 34.58; H,
2.08.
(E)-1-Bromo-2-(4-hydroxymethylphenyl)ethane
(8) (a) Charreau, P.; Julia, M.; Verpeaux, J.-N. J. Organomet.
Chem. 1989, 379, 201. (b) Harada, T.; Katsuhira, T.; Oku,
A. J. Org. Chem. 1992, 57, 5805. (c) Grandjean, D.; Pale, P.
Tetrahedron Lett. 1993, 34, 1155. (d) Harada, T.;Katsuhira,
T.; Hara, D.; Kotani, Y.; Maejima, K.; Kaji, R.; Oku, A. J.
Org. Chem. 1993, 58, 4897. (e) Fakhfakh, M. A.; Franck,
X.; Hocquemiller, R.; Figadére, B. J. Organomet. Chem.
2001, 624, 131.
Colorless plates; mp 71 °C (EtOAc–hexane).
IR (nujol): 3320, 1610, 1515, 938 cm–1.
1H NMR (CDCl3): d = 1.92 (br s, 1 H), 4.66 (s, 2 H), 6.76 (d, J =
14.0 Hz, 1 H), 7.09 (d, J = 14.0 Hz, 1 H), 7.24–7.34 (m, 4 H).
13C NMR (CDCl3): d = 64.87, 106.49, 126.13, 127.22, 135.11,
136.63, 140.77.
EIMS: m/z = 214 [M+], 212 [M+], 133, 105 [bp], 103.
(9) Ranu, B. C.; Samanta, S.; Guchhait, S. K. J. Org. Chem.
2001, 66, 4102.
Anal. Calcd for C9H9BrO: C, 50.73; H, 4.26. Found: C, 50.51; H,
4.34.
(10) Wang, L.; Li, P.; Xie, Y.; Ding, Y. Synlett 2003, 1137.
(11) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima,
K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143.
(12) (a) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. J. Org.
Chem. 1981, 46, 3745. (b) Abbas, S.; Hayes, C. J.; Worden,
S. Tetrahedron Lett. 2000, 41, 3215.
(13) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron 2002, 58,
1491.
(14) The use of other reagents, such as Li(i-Bu)2BuAlH, LiEt3BH
and Li(s-Bu)3BH, gave less satisfactory results. In the case
of NaBH4, no reaction occurred.
(E)-1-Bromo-2-(4-isopropylphenyl)ethane
Colorless oil.
IR (neat): 1608, 1515, 938 cm–1.
1H NMR (CDCl3): d = 1.24 (d, J = 6.9 Hz, 6 H), 2.88 (sept, J = 6.9
Hz, 1 H), 6.70 (d, J = 14.0 Hz, 1 H), 7.07 (d, J = 14.0 Hz, 1 H), 7.18
(d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H).
13C NMR (CDCl3): d = 23.91, 33.97, 105.43, 125.99, 126.74,
133.43, 136.89, 149.06.
(15) When the reaction time was made longer from 2 h to 7 h, an
increase in the ratio of the styrene was observed as shown
below (Scheme 1).
FABMS: m/z = 225 [M+ + 1], 223 [M+ + 1].
Anal. Calcd for C11H13Br: C, 58.69; H, 5.82. Found: C, 58.30; H,
5.72.
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Scheme 1
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Synthesis 2004, No. 7, 986–988 © Thieme Stuttgart · New York