Simple bromination of activated arenes by IBX amide resin and tetraethyl-ammonium bromide

Article abstract of DOI:10.1055/s-2004-836051

A mild and operationally simple method of brominating activated aromatic compounds using a polymer supported IBX reagent (IBX amide resin) and tetraethylammonium bromide (TEAB) was developed. The activated aromatics, when reacted with IBX amide resin in the presence of TEAB, were easily converted into the brominated aromatics in high yields (>80%) at room temperature.

Full text of DOI:10.1055/s-2004-836051

LETTER
279
Simple Bromination of Activated Arenes by IBX Amide Resin and Tetraethyl-
ammonium Bromide
S
D
imple Brominatio
u
n
of
A
ctivat
k
e
d
A
renes -Ki Kim, Woo-Jae Chung, Yoon-Sik Lee*
School of Chemical Engineering, Seoul National University, Kwanak-Ku, Seoul 151-744, Korea
Fax +82(2)8769625; E-mail: yslee@snu.ac.kr
Received 2 September 2004
IBX amide resin to other organic reactions, we unexpect-
edly found that the IBX amide resin facilitated the bromi-
nation of aromatic compounds in the presence of TEAB.
Abstract: A mild and operationally simple method of brominating
activated aromatic compounds using a polymer supported IBX re-
agent (IBX amide resin) and tetraethylammonium bromide (TEAB)
was developed. The activated aromatics, when reacted with IBX To the best of our knowledge, there have been no previous
amide resin in the presence of TEAB, were easily converted into the examples of the IBX amide mediated bromination of aro-
brominated aromatics in high yields (>80%) at room temperature.
matics. Herein, we report a new, simple and clean bromi-
Key words: bromination, IBX amide, tetraethylammonium bro- nation method using IBX amide resin and TEAB
mide
(Scheme 1).
O
O
I
Brominated aromatic compounds are versatile synthetic
intermediates for many organic reactions, ranging from
the formation of functional aromatic compounds to that of
R
O
R
R
NH
Et NBr, CH Cl , r.t.
Br
X
X
X
1
aryl organometallic reagents. Consequently, a variety of
4
2
2
methods have been reported for the bromination of aro-
matics. Among the various bromination reagents that can
R = NH2, OH etc.
X = Cl, NO2
Br
2
be used, elemental bromine and N-halo compounds are
well known for their high efficiency. However, methods
Scheme 1
involving detrimental chemicals such as bromine and hy-
drogen bromide cannot be used in the open laboratory.3
Our method is based on the oxidation of the bromide ion
by IBX amide resin, ultimately leading to the formation of
the tribromide ion as an active brominating agent
Thus, a more eco-friendly, stable, regioselective, opera-
tionally simple and cost-effective bromination method is
very much needed. In recent years, several research
groups have reported environmentally acceptable bromi-
(
(
Scheme 2). Several organic ammonium tribromides
OATB) have previously been reported. We confirmed
12
4
the presence of OATB in the reaction mixture by UV
nation methods.
spectroscopy (lmax = 266 nm).13
2
-Iodoxybenzoic acid (IBX) is a versatile mild oxidizing
agent, which is widely used because of its high efficiency5,
IBX amide resin
Et4NBr
Et4NBr3
easy availability and its stability against moisture and air.
6
The use of polymer supported IBX reagents provides an
Scheme 2
additional advantage, in that they require only a simple
work up to remove the reagents from the reaction mixture
by filtration. Recent reports have shown that the use of
IBX could be extended to other elegant oxidative trans-
The aromatic compounds examined in our studies and the
results of the bromination reactions are summarized in
Table 1. The structures of the bromo compounds were
identified by means of their GC-MS data.
7
formations if used with additives. In this regard, the
oxidation of sulfides to sulfoxides with IBX and tetra-
ethylammonium bromide (TEAB) is particularly note-
In a typical experiment, a mixture of the activated arene,
IBX amide resin (1–4 equiv) and TEAB (1–4 equiv) were
8
worthy. KBr has previously been used as a catalyst in the
9
stirred in CH Cl for 0.5–2.5 hours at room temperature
oxidation of alcohols with IBX ester. The bromide ion
2
2
yielding the brominated arene.
has previously been used as an effective catalyst in the
1
0
oxidation of alcohols with PhIO.
Because aniline and phenol (entries 1 and 2) were so reac-
tive, they were converted to the corresponding di- or tri-
brominated products. When 3 equivalents of IBX amide
resin and TEAB were used, the bromination of aniline
provided mono-brominated aniline as the major product,
whereas in the case of phenol, dibromination occurred.
These results demonstrate that phenol was more reactive
than aniline under the reaction conditions employed in our
We recently initiated alcohol oxidation studies with poly-
mer supported IBX amide reagents (IBX amide resins).11
During the course of our attempts to extend the scope of
SYNLETT 2005, No. 2, pp 0279–0282
0
1.
0
2.
2
0
0
5
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836051; Art ID: U24604ST
©
Georg Thieme Verlag Stuttgart · New York

2
80
D.-K. Kim et al.
LETTER
a
Table 1 Bromination of Aromatic Compounds by IBX Amide Resin and TEAB
b
Yield (%)c
Entry
1
Substrate
Product
IBX :TEAB (equiv)
Time (h)
0.5
NH2
NH2
3:3
82.8
41.5
51.6
NH2
Br
Br
(
1:6.4)d
2
OH
OH
3:3
0.5
OH
Br
Br
Br
Br
(
1:25)d
3
4
NH2
NH2
NO2
4:4
1:1
1
Br
NO2
OH
OH
2.5
0.5
38.5
95.0
3
:3
Br
Br
NO2
NO2
OH
5
6
OH
1:1
:2
2.5
0.5
94.5
94.4
2
Cl
Cl
Cl
Br
Cl
Cl
Br
OH
Cl
OH
2:2
0.5
91.7
Cl
Cl
7
8
OH
OH
2:2
0.5
0.5
–
91.8
95.2
–
Cl
Br
Cl
Cl
Cl
Cl
OH
Cl
OH
1.4:1.4
F
F
F
F
F
F
F
F
Br
9e
–
–
X
X = NO2, CHO
a
Reactions were monitored by TLC and GC-MS.
IBX amide resin.
GC-MS yields.
Confirmed by GC-MS, external method.
Unreacted aromatics (benzene, nitrobenzene, benzaldehyde, toluene, naphthalene)
b
c
d
e
experiment. Also, the bromination of 4-nitroaniline (entry dependent of the stoichiometry of the bromide employed.
) gave rise to the mono-brominated compound as the ma- In the case of the phenol derivatives (entries 4–8), bromi-
3
jor product, whereas in the case of 4-nitrophenol (entry 4), nation produced excellent yields, in spite of the presence
dibromination occurred at both the 2- and 6-position, in- of electron withdrawing substituents such as the chloro,
Synlett 2005, No. 2, 279–282 © Thieme Stuttgart · New York

LETTER
Simple Bromination of Activated Arenes
281
fluoro and nitro groups. In particular, 2,3,5,6-tetrafluo- 2.5 h, etc.) in CH
Cl
(10 mL), the reaction was terminated by fil-
2
2
tration and the filtered resin was washed (15 × 3 mL) with CH Cl ,
rophenol (entry 8) was converted to the corresponding
bromo compound when 1.4 equivalents of IBX amide res-
in and TEAB were used. It means that our method was
very efficient and opened an opportunity to gain easy ac-
cess to a variety of bromoorganics. Furthermore, reaction
2
2
and then the filtrate and the washing solvent was combined and
evaporated. The product was dissolved again in EtOAc and purified
by short silica column (about 5 mL). The yield was measured by
GC-MS.
1
4
of soluble IBX amide with 2,6-dichlorophenol in DMSO
solution gave 4-bromo-2,6-dichlorophenol within 0.5
Acknowledgment
1
5
hours, which was confirmed by GC-MS. Although the
The authors wish to acknowledge the financial assistance provided
soluble IBX amide and the IBX amide resin showed sim- by the Nano Bioelectronics and Systems Research Center of Seoul
ilar reactivity, recovery of iodoso compound, reduced National University, Intelligent Microsystem Center, which carries
st
out some of the 21 century’s Frontier R&D Projects sponsored by
the Korea Ministry of Science & Technology and the Brain Korea
product of IBX amide, was troublesome in solution-phase
chemistry. Moreover, our method avoids the use of highly
polar organic solvents such as DMSO. Bromination stud-
ies with various arenes revealed that only activated arenes
2
1 Program supported by the Ministry of Education.
underwent bromination, and this to yield preferably the References
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(
(
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(
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an activated IBX amide resin by using the previous proce-
1
1
(3) Clark, J. H.; Ross, J. C.; Macquarrie, D. J.; Barlow, S. J.;
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Figure 1 Bromination results after repetitive use of regenerated
IBX amide resin; substrate: 2,6-dichlorophenol, IBX amide re-
sin:TEAB (equiv) = 2:2, reaction time: 0.5 h.
(
In conclusion, we presented an environmentally accept-
able and convenient method for the bromination of acti-
vated arenes, using IBX amide resin and TEAB in CH Cl2
2
2
002, 41, 996. (c) Nicolaou, K. C.; Montagnon, T.; Baran, P.
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rather hazardous and cumbersome classical bromination
methods.
(
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Experimental Section
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To a reaction vial (20 mL) containing IBX amide resin (1 g, 0.987
mmol, 100–200 mesh), TEAB (207.4 mg, 0.987 mmol) and an
aromatic compound (1 equiv or 1/2 equiv or 1/3 equiv or 1/4 equiv)
were added. After shaking for appropriate time (0.5 h or 2 h or
(
2003, 44, 9251.
Synlett 2005, No. 2, 279–282 © Thieme Stuttgart · New York

2
82
D.-K. Kim et al.
LETTER
product was purified by dry column chromatography
(
12) (a) Buckles, R. E.; Popov, A. I.; Zelezny, W. F.; Smith, R. J.
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affording the desired N-benzyl-2-iodobenzamide (2.4 g,
1
yield 88%). H NMR (300 MHz, CDCl , 25 °C): d = 7.85 (d,
3
1 H, J = 9 Hz), 7.25–7.42 (m, 7 H), 7.05–7.11 (m, 1 H), 6.05
(s, 1 H), 4.64 (d, 2 H, J = 6 Hz). To a solution of N-benzyl-
2-iodobenzamide (2.4 g, 7.1 mol) in CH Cl (50 mL), oxone
2
2
(5.7 g, 1.3 equiv) was added. The reaction mixture was
warmed to 40–45 °C over 20 min and stirred at this
1
Moriwaki, M.; Tanaka, T.; Fujisaki, S.; Kakinami, T.;
temperature for 24 h (0.21 g, yield 20%). H NMR (300
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6
(
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1 H, J = 6 Hz), 8.22 (d, 1 H, J = 6 Hz), 7.95 (t, 1 H, J = 15
Hz), 7.75 (t, 1 H, J = 15 Hz), 7.27–7.36 (m, 5 H), 4.58 (d, 2
H, J = 6 Hz).
(
13) Soulard, M.; Block, F.; Hatterer, A. J. Chem. Soc., Dalton
Trans. 1981, 2300.
(
14) Thionyl chloride (5.9 mL) was added to 2 g (8 mmol) of 2-
iodobenzoic acid under stirring and was refluxed for 1 h.
After cooling the reaction mixture, excess thionyl chloride
was removed in vacuo to give the 2-iodobenzoyl chloride
which was used without further purification. To a solution of
the above 2-iodobenzoyl chloride in CH Cl , 2 equiv of
(15) 2,6-Dichlorophenol (22 mg, 0.135 mmol) was added to a
solution of IBX amide (100 mg, 0.27 mmol) and TEAB (57
mg, 0.27 mmol) in DMSO (2 mL). After 0.5 h, the reaction
mixture was diluted with H O (20 mL), extracted with Et O
2
2
(6 × 20 mL), and the organic layers was dried (MgSO ) and
4
evaporated. The crude product was purified by dry column
chromatography to give 4-bromo-2,6-dichlorophenol (30.6
mg, yield 94%).
2
2
benzyl amine (1.76 mL) were added and the mixture was
stirred at r.t. for 2 h. The reaction mixture was washed with
EtOAc and the solvent was removed in vacuo. The crude
Synlett 2005, No. 2, 279–282 © Thieme Stuttgart · New York