Chemoselective bromination of active methylene and methyne compounds by potassium bromide, hydrochloric acid and hydrogen peroxide

Article abstract of DOI:10.1055/s-2006-948207

Active methylene and methyne compounds can be chemoselectively brominated in high yields using potassium bromide, hydrochloric acid, and hydrogen peroxide at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948207

LETTER
2287
Chemoselective Bromination of Active Methylene and Methyne Compounds
by Potassium Bromide, Hydrochloric Acid and Hydrogen Peroxide
Chemoselective
B
romi
a
nation of
A
s
ctive Met
a
hylene and
y
M
ethyne
C
o
u
mpounds ki Kirihara,*a Shiho Ogawa,a Takuya Noguchi,a,b Kumiko Okubo,a Yoshinari Monma,c Ikuko Shimizu,c
Ryuji Shimosaki,c Akihiko Hatano,a Yoshiro Hirai*b
a
Department of Materials and Life Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi,
Shizuoka 437-8555, Japan
Fax +81(538)450110; E-mail: kirihara@ms.sist.ac.jp
b
Faculty of Science, Department of Chemistry, Toyama University, 3190 Gofuku, Toyama 930-8555, Japan
c
Konica Minolta Chemical Co. Ltd., 6909-9 Oono, Fukuroi, Shizuoka 437-1112, Japan
Received 15 May 2006
O
O
O
O
Abstract: Active methylene and methyne compounds can be
chemoselectively brominated in high yields using potassium
bromide, hydrochloric acid, and hydrogen peroxide at room temper-
ature.
KBr, H2O2, aq HCl
toluene, r.t.
R1
R2
R1
R2
Br
1
2
Key words: halogenation, halaides, green chemistry, bromination,
active methylene compounds
Scheme 1
and aqueous HCl (8.0 equiv) in chloroform.6 We further
examined the reaction, and found that the monobrominat-
ed compound could be obtained in the absence of the
tantalum(V) catalyst. The most appropriate conditions are
the treatment of 1 with KBr (5.0 equiv), HCl (5.0 equiv),
and H2O2 (20.0 equiv) in toluene at room temperature
with stirring by a magnetic stirrer (Table 1).
Halogenated active methylene and methyne compounds
are very important synthetic intermediates for the nucleo-
philic substitutions in synthetic organic chemistry. The
classical methods of halogenation of active methylene and
methyne compounds 1 are the reaction with bromine1 or
sulfuryl chloride,2 however, they suffer from drawbacks
such as toxicity of the reagents, generation of acidic
gasses after the reaction, or overhalogenation of the
aromatic rings in 1. Although a number of new methods
of this transformation have previously been developed,
most of them have severe disadvantages such as the
production of undesirable waste.3–5
Several compounds with general structure 1 were exam-
ined under the reaction conditions, and the monobromi-
nated compounds 2 quantitatively obtained in most cases.
These results are summarized in Table 2. It is notable that
the aromatic ring (entries 1 and 2), the ester group (entries
3–6), the amide group (entries 1 and 2) were inert under
the given reaction conditions. Unfortunately, allyl aceto-
acetate (1k) did not provide the desired compound but
complex mixture (entry 8). In this case, the alkene part of
1k also might react with the bromonium ion equivalent.
Khan and co-workers recently developed chemoselective
bromination of active methylene compounds by employ-
ing the vanadium pentoxide catalyzed (V2O5) oxidation of
ammonium bromide (NH4Br) by hydrogen peroxide
(H2O2).5 The reaction conditions of this method are very
mild, and the reaction affords a product in high yield with
high chemoselectivity. However, there are still some
problems such as the use of a toxic vanadium compound
as the catalyst and dichloromethane as the solvent.
Furthermore, we found that the use of a mechanical stirrer
instead of a magnetic stirrer is effective in driving the
reaction. In the case of using a mechanical stirrer, 1 quan-
titatively reacted with KBr (1.0 equiv), HCl (1.0 equiv),
and H2O2 (1.2 equiv) in toluene at room temperature to
afford monobrominated compounds (Table 3). These
results mean that effective agitation is very important in
this reaction.
We now describe the chemoselective bromination of 1 by
potassium bromide, hydrochloric acid and 30% hydrogen
peroxide in toluene (Scheme 1). This method provides the
desired monobromide 2 in high yields, while producing
only nontoxic potassium chloride and water as waste.
A plausible reaction mechanism is as follows. Bromide
ion (Br–) was oxidized into the bromo ion (Br+) equivalent
by H2O2,9 and the resulting Br+ reacted with the enol form
of the active methylene (or methyne) compound
(Scheme 2). Hydrochloric acid works as a catalyst to form
enol, and neutralizes potassium hydroxide derived from
potassium bromide.
During the course of our study of the tantalum(V)-cata-
lyzed oxidation of halogen anions to halogen cation
equivalents,6–8 we found that 1,3-diphenylpropane-1,3-di-
one could be quantitatively monobrominated by treatment
with TaCl5 (0.1 equiv), KBr (8.0 equiv), H2O2 (8.0 equiv)
SYNLETT 2006, No. 14, pp 2287–2289
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-948207; Art ID: U05506ST
© Georg Thieme Verlag Stuttgart · New York
The general experimental procedure of the bromination is as
follows:

2288
M. Kirihara et al.
LETTER
Table 1 Reaction Conditions of Bromination of 1a
O
O
O
O
catalyst, KBr, H2O2, aq HCl
solvent, r.t.
Ph
Ph
2a
Ph
Ph
Br
1a
Catalyst TaCl5 (equiv)
Solvent
CHCl3
KBr (equiv)
H2O2 (equiv)
HCl (equiv)
Time (h)
Yield (%)
0.2
0.2
–
8
8
8
8
2
2
Quant.
Quant.
99
Toluene
Toluene
Toluene
Toluene
8
8
8
8
8
8
–
1.2
5
2
1.2
5
24
2
67
–
20
Quant.
Table 2 The Reaction Using a Magnetic Stirrer
Table 3 The Reaction Using a Mechanical Stirrer
5.0 equiv KBr, 20 equiv H2O2,
5.0 equiv HCl
1.0 equiv KBr, 1.2 equiv H2O2,
1.0 equiv HCl
O
O
O
O
O
O
O
O
R1
R2
R1
R2
R1
R2
toluene, r.t.
R1
R2
toluene, r.t.
Br
Br
1
1
2
2
Entry
1
1
Time (h) Yield
Entry
1
1
Time (h) Yield (%)
3
Quant.
Quant.
Cl
8
99
O
O
O
O
Ph
Ph
O
1b
N
H
OC12H25
2
3
6
Quant.
(88a)
Cl
1b
O
2
5
NHCOC17H35
N
H
O
O
OC12H25
N
H
1a
1c
OMe
3
99
NHCOC17H35
1c
O
O
3
4
5
6
1.5
1.5
1.5
0.5
Quant.
Quant.
Quant.
Quant.
O
O
N
H
Ph
OEt
OMe
1f
O
O
O
O
a The yields after recrystallization from n-hexane.
OBn
OEt
OEt
1g
O
H
O
O
O
O
1h
R1
R2
R1
R2
O
Br
H2O2
"Br+"
Br–
1i
Scheme 2
7
8
0.5
Quant.
O
Using a Magnetic Stirrer
A mixture of 1 (1.5 mmol), KBr (835 mg, 7.5 mmol), 1 M HCl (7.5
mL, 7.5 mmol) and 30% H2O2 (3.4 mL, 30 mmol) in toluene (7.5
mL) was placed in a 50-mL flask and stirred by a magnetic stirrer at
r.t. The reaction was monitored by TLC. After 1 disappeared on
TLC, sat. aq Na2S2O3 (10 mL) and sat. aq NaHCO3 (10 mL) were
added to the reaction mixture. The organic layer was separated and
the aqueous phase was extracted with EtOAc (2 × 20 mL). The com-
O
1j
2
Complex
mixture
O
O
O
1k
Synlett 2006, No. 14, 2287–2289 © Thieme Stuttgart · New York

LETTER
Chemoselective Bromination of Active Methylene and Methyne Compounds
2289
bined organic phase was washed with brine, dried over anhyd
MgSO4, and evaporated to afford the product.
References
(1) Nield, C. H. J. Am. Chem. Soc. 1945, 67, 1145.
(2) (a) Burch, H. A. J. Med. Chem. 1972, 15, 429.
Using a Mechanical Stirrer
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188. (c) Gilchrist, T. L.; Sanchez Romero, O. A.; Wasson, R.
C. J. Chem. Soc., Perkin Trans. 1 1989, 353.
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(2.72 g, 21.8 mmol) and 35% H2O2 (2.54 g, 26.16 mmol) in toluene
(250 mL) was placed in a 500-mL four-necked flask and stirred by
the mechanical stirrer [HEIDON 600G, crescent-shaped steering
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monitored by high-performance liquid chromatography (HPLC).
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washed with H2O (100 mL), 5% aq Na2S2O3 (100 mL) and H2O
(100 mL), respectively. The solvent was evaporated to afford the
product.
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Synlett 2006, No. 14, 2287–2289 © Thieme Stuttgart · New York