Practical and regioselective brominations of aromatic compounds using tetrabutylammonium peroxydisulfate

Article abstract of DOI:10.1016/j.tetlet.2004.04.112

Direct bromination of wide range of aromatic compounds substituted with electron donating groups such as methoxy, hydroxy, or amino groups have been achieved with high regioselectivity by the reaction with Br₂ in the presence of tetrabutylammonium peroxydisulfate 1 under mild conditions in acetonitrile in excellent yields. The use of lithium bromide as a bromination reagent afforded high yields of monobromo compounds with complete regioselectivity under neutral and mild reaction conditions in acetonitrile.

Full text of DOI:10.1016/j.tetlet.2004.04.112

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4887–4890
Practical and regioselective brominations of aromatic compounds
using tetrabutylammonium peroxydisulfate
Min Young Park, Seung Gak Yang, Vidyadhar Jadhav and Yong Hae Kim*
Center for Molecular Design and Synthesis, Department of Chemistry, Korea Advanced Institute of Science and Technology,
Taejon 305-701, South Korea
Received 25 February 2004; revised 20 April 2004; accepted 22 April 2004
Available online 13 May 2004
Abstract—Direct bromination of wide range of aromatic compounds substituted with electron donating groups such as methoxy,
hydroxy, or amino groups have been achieved with high regioselectivity by the reaction with Br2 in the presence of tetrabutyl-
ammonium peroxydisulfate 1 under mild conditions in acetonitrile in excellent yields. The use of lithium bromide as a bromination
reagent afforded high yields of monobromo compounds with complete regioselectivity under neutral and mild reaction conditions in
acetonitrile.
Ó 2004 Elsevier Ltd. All rights reserved.
Halogenated aromatic compounds have been used as
intermediates for a number of natural products and
bioactive materials1 and also proved as important and
useful reagents in organic syntheses by functionalization
through carbon–carbon bond formation of diarenes,
ethylenic, or acetylenic condensations using transition
metals.2 Especially during the past decade, numerous
methods for the direct introduction of halogen atom
into aromatic molecules have been intensively develo-
ped. Aryl bromides are often used in the syntheses of
aryl esters, aryl olefins, and other useful classes of
compounds. There are many published cases. It is well
known that bromine is more reactive than iodine in
aromatic halogenation. But it is difficult to control
monobromination using elemental bromine which only
depend on the reaction conditions3 especially for the
electron-rich aromatic compounds. Thus, there have
been numerous reported bromination reagents such as
NBS (N-bromosuccinimide),4 HBr/TBHP (t-butylhydr-
operoxide),5 quaternaryammonium tribromide,6 PHP
(pyridinium hydrobromide perbromide),7 KBr/NaBO3,8
NaBr/NaClO2/Mn(acac)3/moist montmorillonite,9 LiBr/
CAN (ceric ammoniumnitrate),10 BuOBr/zeolite,11 benzyl-
triphenyl phosphonium tribromide,12 NaBr/dimethyl
dioxirane,13 and HBr/NaBO3.14 However, many of them
suffer from regioselectivity of bromination of acti-
vated aromatic compounds, so the control over the
degree of bromination and the regioselectivity is still
needed.
Here, we describe a new practical and regioselective
bromination of activated aromatic and heterocyclic
compounds under mild reaction conditions as shown in
Scheme 1.
The peroxide 1 turned out to be a useful source of tetra-
butylammonium sulfate radical, which shows oxidizing
ability and can be readily converted to sulfate anion by
one electron transfer from substrate.15 In contrast to
K2S2O8, Na2S2O8, or (NH4)2S2O8, 1 is easily soluble in
various organic solvents such as acetonitrile, acetone,
methanol, and methylene chloride and therefore it can
be easily used in general organic reactions. Aromatic
bromination with complete regioselectivity by prevent-
ing polybromination under mild conditions has been
Br
CH3CN or
O
O
S
O
CH2Cl2
Bu4N+-O S O O
O-+NBu4
+
Br2 or LiBr +
25 o
C
R'
O
R'
OR
Keywords: Bromination; Bromonium cation; Regioselectivity; Tetra-
butylammonium peroxydisulfate; Oxidation.
OR
1
* Corresponding author. Tel.: +82-42-869-2818; fax: +82-42-869-5818;
e-mail: kimyh@kaist.ac.kr
Scheme 1. Bromination of aromatic compounds with tetrabutyl-
ammonium peroxydisulfate.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rigths reserved.
doi:10.1016/j.tetlet.2004.04.112

4888
M. Y. Park et al. / Tetrahedron Letters 45 (2004) 4887–4890
Table 1. Bromination reaction of aromatic compounds with bromine
and tetrabutylammonium peroxydisulfate
accomplished by lithium bromide in the presence of 1.
The results obtained are reported herein.
CH2Cl2
25 oC
Br2
Br
+
+
1
RO
RO
Compound 1 was successfully prepared by mixing two
equivalents of tetrabutylammonium hydrogen sulfate
and potassium persulfate in water. After stirring for
30 min at 25 °C, the desired product was extracted with
methylene chloride, washed with distilled water, dried
over anhydrous MgSO4, and concentrated under re-
duced pressure to give the pure precipitate solid, which
met elemental analysis.15a The white solid 1 is stable for
a couple of months at 25 °C and can be stored in the
refrigerator almost permanently.
a
b
Substrate
Time
(h)
Product
Yielda
(%)
MeO
MeO
Br
1
1
96
2a
2b
H2N
H2N
Br
2
3
1
86
87
3a
3b
4b
4b
4c
Various electron-rich aromatic compounds were bro-
minated with bromine in the presence of 1 at 25 °C in
methylene chloride to give monobrominated products
with high regioselectivity. The results obtained are
summarized in Table 1.
MeO
OMe
MeO
OMe
Br
0.5
4a
MeO
OMe
Br
69b
Monobrominations exclusively occurred at the p-posi-
tion of methoxy or amino group (Table 1, entries 1, 2, 3,
5, and 6). When p-position of methoxy group was
blocked with a substituent, only o-bromination occurred
(Table 1, entries 4 and 7). Since bromination of aniline
and methoxybenzene proceeded more slowly compared
with that of dimethoxybenzene, the reaction appears to
be related to the electron density of the aromatic com-
pounds. In bromination also, we may conclude that
p-orientation is more favorable than o-orientation from
the fact that 1,3-dimethoxybenzene was more readily
brominated than 1,4-dimethoxybenzene (Table 1, entries
3 and 4). In order to compare the regioselectivities in the
absence of 1, when 4a was reacted with Br2 in AcOH, a
mixture of monobrominated product 4b and dibromi-
nated product 4c was obtained (Table 1, entry 30).
MeO
OMe
30
0.1
17b
4a
MeO
Br
OMe
Br
4b þ 4c
(4b/4c ¼
4:1)
MeO
OMe
MeO
MeO
OMe
4
5
1
1
93
Br
5a
5b
CH2Cl
CH2Cl
Br
82
MeO
OMe
OMe
While, complete regioselectivity of monobromination of
1,2,3-trimethoxybenzene (9a) with bromine and 1 failed:
a mixture of mono- (9b) and dibrominated (9c) products
was obtained in the ratio of 6:1. The elongated reaction
time (6 h) with 4a also caused the formation of a small
amount of dibrominated product (monobrominated 4b:
ca. 90%, dibrominated product 4c: ca. 10%). To over-
come this problem, a milder bromination system was
designed using lithium bromide and 1. The direct use of
hazardous molecular bromine can be avoided by the use
of neutral salt of LiBr. Various activated aromatic
compounds reacted with lithium bromide in the pres-
ence of 1 in acetonitrile at 25 °C to give the corres-
ponding monobrominated products in excellent yields
with complete regioselectivity. In a representative
experimental, lithium bromide (261 mg, 3 mmol) and 1
(2.03 g, 3 mmol) were added to a solution of 4a (139 mg,
1.0 mmol, CH3CN: 20 mL) at 25 °C with stirring. When
the reaction was complete, the reaction mixture was
quenched into distilled water (20 mL) and extracted with
ethylether (3 ꢀ 10 mL). The organic layer was washed
with distilled water (20 mL), dried over anhydrous
MgSO4, filtered, and then concentrated under reduced
pressure to give the crude product, which was purified
by a silica gel column chromatography (silica gel 60:
0.040–0.063 mm, eluent: ethyl acetate/n-hexane ¼ 1/10,
6a
6b
7b
MeO
OMe
MeO
Br
OMe
6
7
0.5
93
86
NHAc
NHAc
7a
MeO
Me
MeO
Br
Me
2
NHAc
NHAc
8a
8b
OMe
Br
Br
OMe
OMe
OMe
OMe
9b
8
3
Ca. 90c
OMe
OMe
9a
OMe
OMe
Br
9c
a Isolated yield.
b In the absence of 1, the reaction was carried out in AcOH.
c The yield of mixture of 9b and 9c: the ratio of 9b and 9c (6:1) was
determined by 1H NMR and the intensity of them 9b (m=e; 245.99)/9c
(m=e; 323.90) ¼ ca. 6:1.

M. Y. Park et al. / Tetrahedron Letters 45 (2004) 4887–4890
4889
4b: 213 mg, 98%). The results obtained are summarized
in Table 2.
formed for the practical purpose to give 9b in high yield
(82%). The bromination occurred at only p-position of
electron donating group: o-brominated isomers were not
detected. In the case of m-methoxyphenol (10a), only
p-bromo-m-methoxyphenol (10b, p-position was bro-
minated toward OH group) was obtained. When the
reaction of 4a with LiBr–H2SO4 in the absence of 1 was
carried out, no bromination occurred: starting material
4a was recovered quantitatively. These results indicate
that 1 takes an important role in these bromination
reactions. Some heterocycles (13a and 14a) were also
successfully brominated with lithium bromide and 1 at
25 °C in acetonitrile in high yields. However, less acti-
vated aromatic compounds such as anisole or toluene
did not give brominated products under the same reac-
tion conditions.
In comparison with the system using bromine and 1, the
LiBr system needed longer reaction time but resulted in
high yields and complete regioselectivity in monobro-
minations. m-Methoxyanisole (4a) gave o-bromo-m-
methoxyanisole (4b) in quantitative yield (98%). A large
scale bromination reaction (9a: 4.33 g, 25.7 mmol, 1:
43.5 g, 64.2 mmol, LiBr: 5.6 g, 64.2 mmol) was per-
Table 2. Bromination of aromatic compounds with lithium bromide
and tetrabutylammonium peroxydisulfate
MeCN
25 oC
+
LiBr
+
1
Br
RO
RO
a
b
Although the mechanism for the bromination with
lithium bromide and 1 is not clear but the reaction
appears to be initiated via formation of tetrabutylam-
monium sulfate radical A by homolysis of 1. The sulfate
radical A may oxidize bromide anion to bromonium
cation.10 The electrophilic attack of bromonium cation
at p-position of activated aromatic compounds produces
the intermediate B, which is readily converted to bro-
minated product. However, there is an alternative pos-
sibility to form a radical cation C16 by one electron
transfer, which may convert to a radical intermediate D
(Scheme 2).
Substrate
Time
(h)
Product
Yielda
(%)
MeO
OMe
MeO
OMe
1
8
98
Br
4a
4b
MeO
OMe
MeO
HO
OMe
Br
10
2
8
8
0b
4a
4b
HO
OMe
OMe
Br
75
In conclusion, we have developed a complete regio-
selective bromination of activated aromatic compounds
under the mild conditions using 1 as an oxidant. The
stable peroxydisulfate 1 can be readily prepared, which
can be handled easily and safely. Thus, it can be prac-
tically used for oxyhalogenation reaction. Bromination
with bromine in the presence of 1 gave the monobro-
minated products, respectively, in high to excellent
yields as the major products in short reaction time. In
contrast to using bromine, bromination with lithium
bromide resulted in only monobrominated products
with complete regioselectivity in good to excellent yields
under neutral and mild conditions. In this reaction,
10a
10b
NH Boc
OMe
NH Boc
OMe
Br
3
4
24
24
71c
MeO
MeO
11a
11b
OMe
OMe
85
Br
12a
12b
OMe
OMe
OMe
Br
OMe
OMe
5
6
36
8
83 (82d)
O
S
O
O
S
O
Br-
OMe
Br+
+
2 Bu4N+ -
O
O-
Bu N+ -
O
O
.
1
2
4
9a
9b
A
Br
95
H+
MeO
Br
CO2Et
CO2Et
MeO
MeO
N
H
N
H
Br+
H
OMe
OMe
OMe
13a
13b
Br
B
Br
Me
- e
A
H+
or
7
8
86
CN
CN
Me
N
N
Me
Me
MeO
MeO
MeO
Br-
A
- e
14a
14b
H
Br
H
Br
OMe
OMe
OMe
a Isolated yield.
b In the absence of 1, but with 1 equiv of H2SO4.
c Excess amount of 1 (3 equiv) was used.
C
D
d Large scale (9a: 4.33 g, 25.7 mmol; 1: 43.5 g, 64.2 mmol; LiBr: 5.6 g,
64.2 mmol).
Scheme 2. Proposed mechanism for the bromination with lithium
bromide and tetrabutylammonium peroxydisulfate.

4890
M. Y. Park et al. / Tetrahedron Letters 45 (2004) 4887–4890
K.; Ramachandraiah, G.; Bedekar, A. V. Tetrahedron
Lett. 2003, 44, 4085.
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