Concise bromodecarboxylation of cinnamic acids to β-bromostyrenes

Article abstract of DOI:10.1016/j.tetlet.2009.02.003

A convenient salt-free approach to the halodecarboxylation of cinnamic acid analogs to β-bromostyrene was reported. This conversion was conducted at 0 °C in CH₂Cl₂ with only 10% of acetic acid. This protocol can be used for cinnamic

Full text of DOI:10.1016/j.tetlet.2009.02.003

Tetrahedron Letters 50 (2009) 1834–1837
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Tetrahedron Letters
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Concise bromodecarboxylation of cinnamic acids to b-bromostyrenes
Yu-Lun Huang a, Yu-Han Cheng a, Kuang-Chan Hsien a, Yeh-Long Chen a, Chai-Lin Kao a,b,
*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient salt-free approach to the halodecarboxylation of cinnamic acid analogs to b-bromostyrene
was reported. This conversion was conducted at 0 °C in CH2Cl2 with only 10% of acetic acid. This protocol
can be used for cinnamic acids with a variety of substituents, including b-methyl cinnamic acid (1d) in
60–81% yield, but not for hydroxyl- and p-methyl-cinnamic acids. Meanwhile, pyridine hydrobromide
perbromide was used as bromide source to convert 1a–2a in 59% yield.
Received 14 November 2008
Revised 2 February 2009
Accepted 3 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Bromine
Carboxylic acid
Bromodecarboxylation
Salt-free
Hunsdiecker reaction
Vinyl bromide is a useful synthon in organic synthesis, espe-
cially in palladium and copper chemistry.1 It has been used to syn-
thesize stilbenoids,2 pyridines,3 and N-alkenyloxazolidin-2-one.4
Moreover, vinyl bromide is a key agent for introducing styrene
moieties in natural product synthesis.5
be in the form of a salt for better water solubility. When carbon tet-
rachloride or chloroform was used as the reaction solvent, haloge-
nation was found to occur on the olefin of cinnamic acid.9 In
comparison, when the cinnamate ester was exposed to bromine
or chlorine in acetic acid, dihalogenation and acetoxylhalogenation
of the olefin were observed.10 In other work in this area, Cabaliero
and Johnson found that the chlorination of trans-cinnamic acid in
Halodecarboxylation of the corresponding carboxylic acid is
widely used to obtain bromides. Among existing methods, the
Hunsdiecker reaction is a popular approach; however, this reaction
requires a heavy metal salt and high reaction temperature, which
restricts its application. Besides, the classical Hunsdiecker reaction
is very inefficient for cinnamic acid analogs, for example, the bro-
modecarboxylation of cinnamic acids under classical conditions
gives the desired product in less than 15% yield.6 It is therefore
infeasible to synthesize vinyl bromide via this approach. Thereaf-
ter, several attempts to improve the Hunsdiecker reaction to con-
vert cinnamic acids to corresponding bromide was made with
various reagents and conditions, however, salt or certain equip-
ments such as microwave reactor is still needed.7
The straightforward bromination of a cinnamate salt, which
was first reported in 1921,8 gives a bromohydrin as the major
product. In addition to bromohydrin, trace amounts of bromosty-
rene are produced; this product is believed to derive from the elim-
ination of bromohydrin in the evaporation process rather than
from the bromination reaction itself. In this reaction, reaction yield
is sensitive to water volume. Therefore, the starting material must
acetic acid in the presence of lithium acetate gave
a,a,b-trichloro-
styrene and -dichloro-b-acetoxyl-styrene, and suggested that
a,a
these products were generated by further halogenations of b-chlo-
rostyrene.11 In these experiments, b-chlorostyrene was not iso-
lated from the reaction mixture. Additionally, Cabaliero and
Johnson found that the use of a salt as the reactant is crucial for
the conversion of carboxylic acids to the corresponding chlorides.
The synthesis of bromostyrene from the corresponding cinna-
mate was reported by Kingsbury and Max.12 When substituted
cinnamates were treated with bromine in methanol or water, bro-
modecarboxylation or b-lactonization occurred. Although b-bromo-
styrene was one of the products identified, the isolated mixture
contained b-bromostyrene and two further brominated com-
pounds, tribromoethylbenzene and bromohydrine. Although the
bromodecarboxylated product was identified in this experiment,
the cinnamate ion is still necessary in this reaction. If the free acid
is used instead of the salt under the same conditions, bromination
or bromohydrination of the olefin occurs without any decarboxyl-
ation. Recently, oxidative halodecarboxylation of cinnamic acid
analogs was achieved with NBS as a brominating agent.13 In the
presence of either iodosylbenzene or iodosylbenzene diacetate,
* Corresponding author. Tel.: +886 7 31211012620.
E-mail address: clkao@kmu.edu.tw (C.-L. Kao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.003

Y.-L. Huang et al. / Tetrahedron Letters 50 (2009) 1834–1837
1835
Table 2
O
O
Results for the reactions of cinnamic acid analogs with bromine
HO
HO
OH
OH
Entry Substrate Product
Isolated
yield (%)
OH
O
6
7
Br
OH
Figure 1. Two compounds subjected to bromodecarboxylation.
1
67
OMe
OMe
1a
2a
the yield of halostyrene is 32–89%. Cinnamic acid can also be con-
verted to bromostyrene by applying diphosphorous tetraiodide in
combination with tetraethylammonium bromide in CS2.14
O
Br
OH
Me
In addition, b-halostyrene can be prepared from the
corresponding carboxylic acid via carboxyl-halo-elimination of
cinnamic acid derivatives. For example, treatment of dibromophe-
nylpropionic acid with triethylamine in DMF at room temperature
affords b-bromostyrene. However, only the cis-olefin is obtained
and two steps are considered necessary.15 Although there are prac-
tical approaches for converting cinnamic acids to bromostyrene,
the methods developed to date have drawbacks including the
requirement for multiple steps, complex or dangerous reagents,
and tedious work-up procedures. Thus, a convenient halodecarb-
oxylation method is still needed (Fig. 1)
Herein, we report a convenient approach to the halodecarboxy-
lation of cinnamic acid analogs that does not require any salt.
Firstly, 2-methoxycinnamic acid (1a) was treated with bromine
in chloroform at 0 °C and b-bromo-2-methoxystyrene (2a) was iso-
lated in 23% yield. The low solubility of compound 1a in CHCl3 may
be the reason for the low yield. To improve the solubility of 1a, ace-
tic acid was added to the reaction media and CH2Cl2 was used in-
stead of CHCl3. The results are summarized in Table 1 and the
reaction proceeds in 10% v/v acetic acid in CH2Cl2 yielding com-
pound 2a in 67%. To the best of our knowledge, this is the most
convenient process for this kind of transformation (Scheme 1).
Encouraged by this result, we subjected various cinnamic acid
analogs, including fluorinated, aminated, hydroxylated, and meth-
oxylated analogs, to the reaction conditions established above; the
results are summarized in Table 2. The reaction afforded b-bromo-
styrenes in moderate to good yield, except the p-methylated and
hydroxylated ones. In the case of the b-methylated analog 1d,
the reaction gave the dibromide 2d in 60% yield and did not give
any of the monobromodecarboxylated products. These results
show that this bromodecarboxylation can be carried out while
there is a substituent on the b-position. Besides, para-methylcin-
2
3
66
81
N
Me
N
Me
Me
2b
1b
O
Br
Br
OH
F
2c
F
1c
Br
Me
O
O
OH
OH
4
5
6
7
8
60 (45)a
N/A
29
OMe
OMe
2d
1d
Starting materialb
OMe
1e
O
O
O
OH
Br
Me
Me
3
1f
Br
OH
66
O
O
O
1g
4
namic acid (1f) was converted to
a-bromolactone (3) in only 29%
yield and no bromostyrene was found.
O
O
O
OH
50
Me
Br
Me
1h
Table 1
5
Results of reactions of 1a with 1.5 equiv of bromine in different reaction conditions
Acetic acid in CH2Cl2 (%)
Yield of 2a (%)
a
The 45% yield was calculated based on the amount of 1e and 60% yield was
obtained based on the amount of bromine used in reaction.
5
62
63
67
60
bThe only identified compound in reaction mixture is the starting material.
10
20
30
In comparison to compound 1a, 2-hydroxy-cinnamic acid (6), a
free hydroxyl analog of 1a, gave a complicated result under the
same reaction conditions. Remarkably, 2-hydroxy-cinnamic acid
is not completely soluble in CH2Cl2 with up to 30% acetic acid,
which may hinder this reaction. To confirm that the behavior of
6 was due to its solubility in the solvent, we subjected 3,4-dihydr-
oxyl cinnamic acid (7) to the same reaction conditions; this reac-
tion also gave a complicated result. Our findings thus indicate
that fluoro, methoxy, and sec-amino groups are tolerated under
these reaction conditions, but those compounds that are not solu-
O
Br
Br2
OH
CHCl3
OMe
OMe
1a
2a
Scheme 1.

1836
Y.-L. Huang et al. / Tetrahedron Letters 50 (2009) 1834–1837
results indicate that the absence of the salt and the characters of
O
the bromonium ion are important issues. In addition, the formation
of the bromonium ion could shed light on the influence of the sub-
stituent on the phenyl ring in this reaction.
Br
PyHBr3
OH
CH2Cl2, 59%
OMe
OMe
In conclusion, a convenient single-step protocol for synthesiz-
ing b-bromostyrene has been described. This reaction yields the
desired compounds in moderate to good yield for reactants with
various substituents except p-methyl and hydroxyl group. Based
on current results, an olefin, phenyl ring, or carboxylic acid is a
necessary structural moiety for this type of conversion. In compar-
ison to previous finding, this protocol uses only 10% of acetic acid
and no salt is necessary in this reaction. In this study, we also find
the requirement of formation of b-lactone or vinyl bromide. Fur-
thermore, the solubility of the starting material in the reaction
medium is a critical factor. Moreover, PyHBr3 was proven as good
agent to replace bromine in this reaction. We are currently study-
ing the scope and limitations of this reaction with other substi-
tuted cinnamic acids and heterocyclic analogs as well as with
different halogenated agents.
Representative procedure: To a solution of 2-methoxycinnamic
acid (1a, 0.5 g, 2.8 mmol) in a mixture of CH2Cl2 (18 mL) and acetic
acid (2 mL) was added a solution of bromine (0.1 M, 1.5 equiv) in
CH2Cl2 (40 mL) dropwise at 0 °C. After addition, the reaction was
stirred at the same temperature for an additional 1 h. To consume
the excess bromine, cyclohexene (5 mL) was added to the reaction
mixture and the mixture was stirred for a further 30 min. After re-
moval of solvent, the resulting mixture was partitioned between
H2O and CH2Cl2. The organic extracts were washed with water,
brine, and dried (Na2SO4). Evaporation of the solvent followed by
chromatography of the residue over silica gel (Hex/EA = 30:1)
afforded the desired compound 2a. 1H NMR (400 MHz, CDCl3): d
3.86 (s, 3H), 6.88 (dd, 1H, J = 8, 1 Hz), 6.91 (d, 1H, J = 14 Hz), 6.93
(dd, 1H, J = 8, 1 Hz), 7.24–7.29 (m, 2H), 7.31 (d, 1H, J = 14 Hz). 13C
NMR (100 MHz, CDCl3): d 55.4, 107.9, 111.0, 120.7, 124.8, 128.0,
129.3, 133.0, 156.6. HRMS: calcd for C9H9BrO: 211.9837; found
211.9839.
1a
2a
Scheme 2.
CO2
R
Br
Br
R
Route a
Br2
O
O
H
O
Br-
Br
OH
Br2
R
O
Br
O
Route b
R
R
O
O
Scheme 3.
ble in the reaction media (e.g., 2-hydroxy- and 3,4-dihydroxyl cin-
namic acid) are not. Furthermore, determination of the olefin con-
figuration from the coupling constant of the two olefinic protons
disclosed that all of the reactions gave trans-b-bromostyrene. The
configuration of 2d was predicted by comparing C-13 resonance
signal of olefin moiety to reported data.16
To examine the behavior of an
a,b-unsaturated system, and
thus gain insight into the reaction mechanism, we subjected 3-
(2-methoxyphenyl)propionic acid (1e) to the reaction conditions
indicated above. When 1e was treated with bromine, the only
identified compound in reaction mixture is starting material. In
combination with previous results,10 the present findings indicate
that both the carboxylic acid and olefinic moieties are critical for
the conversion of the
a,b-unsaturated acid to the corresponding
Acknowledgments
b-bromostyrene.
Furthermore, E-4-phenyl-2-butenoic acid (1g) was used as the
starting material in this reaction. Instead of bromodecarboxyla-
tion, bromolactonization occurred and compound 4 was identified
as the main product. Meanwhile, reaction of 2-methylhexenoic
acid (1h) under the same conditions afforded bromo-b-lactone
5. The similar transformation has been observed.7c We propose
that 3, 4, and 5 were formed via a bromonium intermediate lead-
ing to lactonization rather than decarboxylation. The results for
these reactions suggest that hyperconjugation of the carboxylic
acid, olefin, and phenyl ring is necessary for the bromodecarboxy-
lation and this fact may explain the various observations we have
here.
Instead of volatile bromine, pyridine hydrobromide perbromide
(PyHBr3), a solid produced according to the literature procedure,17
was used as bromide source. To the solution of 1a in CH2Cl2 with
10% of AcOH was added PyHBr3 as solid in three portions and
59% of 2a was collected. This result indicates that bromine can
be replaced in this reaction and the application of PyHBr3 makes
this approach more convenient and safer (Scheme 2).
We are grateful to the National Science Council of the Republic
of China (NSC 96-2113-M-037 -007 -MY2 and NSC 96-2323-B-037
-003) as well as Center of Excellence for Environmental Medicine
(KMU-EM-97-3.3c) for their support of this study.
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