A novel simple and efficient bromination protocol for activated arenes

Article abstract of DOI:10.1016/j.tetlet.2008.12.016

An efficient, high yielding, and environmentally benign bromination using an alkali metal bromide as the bromine source is disclosed. Investigation of the protocol revealed that the method operates for activated arenes producing the corresponding monobrominated products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.12.016

Tetrahedron Letters 50 (2009) 831–833
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel simple and efficient bromination protocol for activated arenes
a
b
a
a,*
Anna Tsoukala , Lucia Liguori , Giovanni Occhipinti , Hans-René Bjørsvik
a
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
Fluens Synthesis AS, Thormøhlensgate 55, N-5008 Bergen, Norway
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, high yielding, and environmentally benign bromination using an alkali metal bromide as the
bromine source is disclosed. Investigation of the protocol revealed that the method operates for activated
arenes producing the corresponding monobrominated products in good to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 27 October 2008
Revised 25 November 2008
Accepted 3 December 2008
Available online 7 December 2008
Keywords:
Bromination
Oxidation
Redox
Chemoselectivity
Green chemistry
Electrophilic substitution
Methoxyphenyl moieties constitute essential parts of a large
number of biologically active compounds, natural products, and
pharmaceutical chemicals, and thus represent an important syn-
thetic building block for the synthesis of such compounds. For this
purpose, the corresponding methoxyphenyl bromides are fre-
quently utilized as substrates.
we needed access to 2-bromo-3,4,5-trimethoxy-1-methylbenzene
2a, Scheme 1.
Our general plan for the investigation and development of
new synthetic pathways embraces the requirement that the
processes should be environmentally benign as well as applicable
for large-scale syntheses. These requirements eliminate most of
the commonly used reagents for bromination, for example,
N-bromosuccinimide.
Aryl bromides can be prepared by means of the classical Sand-
1
meyer reaction. In addition, regioselective nuclear bromination of
activated aromatic and heteroaromatic compounds can also be
It is known that nitric acid can oxidize bromide ions with for-
mation of molecular bromine and nitrous acid, Scheme 2. This
reaction was thoroughly investigated and revealed to be an equi-
performed by means of N-bromosuccinimide with tetrabutylam-
2
monium bromide present as a phase-transfer catalyst or using
3
dioxane dibromide. Selective monobromination of electron-rich
librium directed strongly toward the bromide ion (K
1
= 1.6 Â
4
À6
À4 12
arenes has also been reported using CuBr
2
or alkali metal bro-
10
the standard reduction potentials
M ). The small positive value of the difference between
5
6
13
mides in the presence of concentrated H
2
SO
4
or various oxidants,
(D
E = E
2
1
À E = 0.147 V) of the
7
8
sometimes in the presence of acids and/or catalysts. Several of
these methods are, however, saddled with various drawbacks
making them environmentally unfriendly and unsuitable for
large-scale industrial use due to (1) low atom economy as the large
N-succinimide molecular fragment is used as the bromine carrier,
two half-reactions of the overall redox process suggests that a
reaction equilibrium shifted toward the bromide ion rather than
bromine, which is in full agreement with the experimentally deter-
1
3
mined value of K1. Thus, the observed result of this redox process
is that a very small quantity of Br
ture at the reaction equilibrium.
2
is present in the reaction mix-
(
2) the requirement of auxiliary reagents, (3) toxic solvents as
the reaction medium, and (4) harsh reaction conditions.
A current project in our laboratory is dedicated to the design
and development of new synthetic pathways to phenol-based anti-
oxidants and their intermediates,9 which also comprises the dis-
covery of new pathways toward coenzyme Q10. For this purpose,
HNO3 + (CH3CO)2O
CH3
,10
CH3
add. time reaction time
Br
30 min.
45 min.
KBr
add. temp.
H CO
OCH3
H3CO
OCH3 (CH CO) O
reaction temp.
3
3
2
o
20
C
o
OCH3
20
C
OCH3
1a
2a (>95%)
*
Corresponding author. Tel.: +47 55 58 34 52; fax: +47 55 58 94 90.
E-mail address: hans.bjorsvik@kj.uib.no (H.-R. Bjørsvik).
Scheme 1. An efficient high yielding bromination process.11
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.016

8
32
A. Tsoukala et al. / Tetrahedron Letters 50 (2009) 831–833
K
1
= 1.6 10-6 M-4
We believed that this reaction equilibrium could be used for a
controlled production of molecular bromine, in which a telescoped
subsequent step could take part in a selective bromination and
thus promote the redox process to operate toward the production
NO
3
+
2Br
+
3H
Br
2
+ HNO
2
+ H
2
O
(1)
NO
Br
3
+ 3H
2e
+
2e
2Br
HNO
2
+
H
2
O
E
1
2
= 0.940 V
= 1.087 V
- E
(2)
(3)
2
+
E
ΔE = E
2
1
= 0. 147 V (4)
2
of more Br . This reaction sequence could be continued until the
Scheme 2. Nitric acid-bromide reaction and the reverse nitrous acid-bromine
reaction.
bromide source or the substrate 1 was consumed.
We designed a protocol for this purpose using the easily han-
dled potassium bromide as the bromine source. The substrate,
1
,2,3-trimethoxy-5-methylbenzene 1a, and KBr were mixed in ace-
tic anhydride. In an effort to accomplish better control of the pro-
duction of Br and thus the selectivity, the nitric acid oxidant was
Table 1
Results of the bromination of a series of arenes 1a–i
2
Entry
1a
Substrate1
Product2
Yielde (%)
>95
added dropwise as a solution in acetic anhydride. The addition of
the oxidant was conducted at 20 °C, and the reaction mixture
was kept at the same temperature throughout the bromination
reaction. Details regarding the bromination process are provided
CH3
CH3
Br
H CO
OCH3
H CO
OCH3
3
3
11
in Scheme 1 and in note . It is important to emphasize the envi-
1a
OCH3
2a
OCH3
ronmentally benign aspects of the disclosed bromination protocol:
(
1) a very small quantity of molecular bromine is present through-
CH3
CH3
out the whole reaction, (2) the quantity of nitric acid is also low at
any time during the reaction, (3) the oxidant is used only in a stoi-
chiometric quantity, (4) the solvent is acceptable even for large-
scale use, and (5) the reaction is performed at room temperature.
In order to investigate the generality of this bromination proto-
col, a series of substituted arenes (Table 1) were submitted to the
bromination conditions described in Scheme 1.
2
92
86
82
77
39
39
36
—
Br
OCH3
1
1
b
c
2b
OCH3
O
O
Br
3
The obtained results (Table 1) show that the bromination proto-
col operates excellently with activated arenes (see 1a–1e). Our ori-
ginal target product, 2-bromo-3,4,5-trimethoxy-1-methylbenzene
OH
OCH3
OH
2c OCH3
1
4
2
a, was obtained in a yield of >95%. Benzene derivatives substi-
Br
tuted only with electron-withdrawing groups such as 4-chloroben-
zoic acid 1i did not react. In general, the yields of the various
brominated products increase with the number of electron-donat-
ing groups (1a > 1c > 1f). Moreover, the regioselectivity of the reac-
tions is in agreement with the known directing ability of the
substituent groups.
4
H CO
OCH3
H CO
OCH3
3
3
1d
OCH3
2d
OCH3
OCH3
OCH3
Br
Taken as a whole, the results strongly suggest that the bromin-
ation operates according to an electrophilic substitution by means
5
H3CO
H3CO
+
15
1e
OCH3
2e OCH3
of the Br ion. Br is a deactivating group, thus monobrominated
arenes are considerably less reactive compared to the starting
arene. This fact explains the high selectivity of the novel bromina-
tion protocol disclosed herein.
O
O
6b
7c
8
In conclusion, a new, simple, efficient, and cheap bromination
protocol is disclosed. Moreover, the process can be considered to
be ‘green’ compared to other procedures. The method involves re-
agents that can be handled easily even on large scale making it
suitable also for industrial scale applications.
Br
1f
OCH3
O
2f
OCH3
O
Br
1
g
2g
Acknowledgments
OH
OH
Br
Economic support from Denomega AS, the Nutrition research
program at the University of Bergen, Fluens Synthesis AS, and the
Research Council of Norway (G.O) is gratefully acknowledged.
O
O
O
O
O
O
2h
1
h
Supplementary data
HO
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.016.
9d
—
1
i
Cl
References and notes
a
Isolated yield.
b
A by-product was also obtained (ꢀ25%), the structure of which was not
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1