Bromination by means of sodium monobromoisocyanurate (SMBI)

Article abstract of DOI:10.1039/b302738d

A variety of aromatic compounds with both activating and deactivating substituents were brominated with sodium monobromoisocyanurate (SMBI) 1, diethyl ether, diethyl ether-methanesulfonic acid, trifluoroacetic acid, or sulfuric acid were employed as solvents. Thus nitrobenzene was conveniently brominated in sulfuric acid, benzene was readily monobrominated in diethyl ether-methanesulfonic acid, and phenol was selectively brominated at the ortho position under mild conditions in refluxing diethyl ether. With substituents that are easily protonated, trifluoroacetic acid may be employed as solvent in the reaction with 1, in contrast NBS was ineffective in trifluoroacetic acid. This renders 1 a superior reagent relative to NBS. In addition to aromatics, alkenes, ketones and esters were also brominated with 1. Diethyl malonate was brominated with 1 and then subjected to a Bingel reaction with NaH to afford the desired methanofullerene in reasonable yield.

Full text of DOI:10.1039/b302738d

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Bromination by means of sodium monobromoisocyanurate (SMBI)
Yukihiro Okada,a Masanori Yokozawa,a Miwa Akiba,a Kazuhiko Oishi,a Kyoji O-kawa,a
Tomohiro Akeboshi,b Yasuo Kawamura,b Seiichi Inokuma,a Yosuke Nakamuraa,c and
Jun Nishimura*a,c
a Department of Chemistry, Gunma University, Kiryu 376-8515, Japan
b Central Research Institute, Nissan Chemical Industries, LTD., Funabashi-Shi,
Chiba 274-8507, Japan
c Department of Nano-Material Systems, Graduate School of Engineering, Gunma University,
Kiryu 376-8515, Japan
Received 11th March 2003, Accepted 29th May 2003
First published as an Advance Article on the web 11th June 2003
A variety of aromatic compounds with both activating and deactivating substituents were brominated with sodium
monobromoisocyanurate (SMBI) 1, diethyl ether, diethyl ether–methanesulfonic acid, trifluoroacetic acid, or sulfuric
acid were employed as solvents. Thus nitrobenzene was conveniently brominated in sulfuric acid, benzene was readily
monobrominated in diethyl ether–methanesulfonic acid, and phenol was selectively brominated at the ortho position
under mild conditions in refluxing diethyl ether. With substituents that are easily protonated, trifluoroacetic acid may
be employed as solvent in the reaction with 1, in contrast NBS was ineffective in trifluoroacetic acid. This renders 1 a
superior reagent relative to NBS. In addition to aromatics, alkenes, ketones and esters were also brominated with 1.
Diethyl malonate was brominated with 1 and then subjected to a Bingel reaction with NaH to afford the desired
methanofullerene in reasonable yield.
Introduction
Results and discussion
Bromination is a fundamental transformation in organic chem-
istry and brominated aromatics are of paramount importance
as building blocks in organic synthesis.
Selective monobromination of aromatics
For electrophilic aromatic substitution, the arene substrates are
classified into three groups: 1) those bearing electron withdraw-
ing, deactivating substituents such as nitrobenzene, 2) those
that are moderately active like parent benzene itself and 3) the
highly reactive arenes such as phenol.
The development of modern coupling reactions,1 such as
Tamao–Kumada, Suzuki–Miyaura, Migita–Kosugi–Stille,
Negishi, Hiyama–Hatanaka, Sonogashira, and Mizorogi–Heck
reactions, has greatly increased the demand for brominated
aromatics as starting materials.
The products obtained were identified by their 1H NMR
spectra in comparison with those of commercially available
authentic samples (see Experimental section).
Although a variety of brominating reagents capable of
brominating both electron-rich and electron-deficient target
molecules2 are available ranging from Br2 itself to
Electron-deficient aromatics such as nitrobenzene and methyl
benzoate can be brominated by bromine in sulfuric acid in the
presence of silver nitrate.5 NBS and DBI have also been applied
successfully for this purpose in sulfuric acid.6 Reagent 1, which
readily dissolves in sulfuric acid, was employed in bromination
of nitrobenzene in sulfuric acid. The reaction proceeds
smoothly at around 40 ЊC as shown in eqn. (1). Bromination
data for the electron-deficient aromatics are summarized in
Table 1 and eqn. (2).
N-bromosuccinimide (NBS), there is
a continuing need
to utilize new and improved brominating reagents and
improved reaction conditions to provide superior selec-
tivity.3
Recently, sodium monobromoisocyanurate 1 (SMBI),4
a
bromonium-fixed reagent similar to NBS and dibromo-
isocyanurate (DBI), has become commercially available as
a white powder. SMBI is almost odorless, practically insoluble
in most organic solvents, and therefore easily handled in the
laboratory. As a urea trimer, compound 1 is also expected to
be environmentally friendly. Following the discovery of SMBI
as a brominating reagent, we have undertaken a systematic
study of the scope of bromination, in particular with aro-
matics, and found that it selectively monobrominates both
electron-deficient aromatics and electron-rich substrates in
reasonable yields as well as ketones and esters. In this paper, we
report facile, regioselective bromination of arenes, as well as
alkene and carbonyl compounds under appropriate reaction
conditions.
(1)
(2)
Attempted monobromination of o-dichlorobenzene and
trifluoromethylbenzene under these conditions resulted in
multibromination (see below).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 0 6 – 2 5 1 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Bromination of electron-deficient aromatics by means of 1a
Entry
Substrate
Product
Yield (%)
1
2
3
4
5
6
7
Dimethyl phenylphosphonate
Benzaldehyde
Methyl benzoate
Benzoic acid
Dimethyl isophthalate
Nitrobenzene
m-Dinitrobenzene
Dimethyl m-bromophenylphosphonate
m-Bromobenzaldehyde
Methyl m-bromobenzoate
m-Bromobenzoic acid
Dimethyl 5-bromoisophthalate
m-Bromonitrobenzene 2
1-Bromo-3,5-dinitrobenzene
91
70b
70c
40
75
95
65
a Reaction conditions: at 40 ЊC for 12 h in sulfuric acid. The ratio of substrate and 1 was 1 : 1.5. b Dibrominated products were obtained in 17% yield.
c Dibrominated products were obtained in 22% yield.
Table 2 Bromination of intermediate reactive aromatics by means of 1
Entry
Substratea
Product
Yield (%)
1
2
3
4
5
6
7
Anisole
Toluene
Benzene
o-Dichlorobenzene
m-Dichlorobenzene
Benzonitrilec
Trifluoromethylbenzenec
p-Bromoanisole
75
60
79
60
65
40
85
Bromotolueneb
Bromobenzene 3
1-Bromo-3,4-dichlorobenzene
1-Bromo-2,4-dichlorobenzene
m-Bromobenzonitrile
m-Bromotrifluoromethylbenzene
a In methanesulfonic acid–ether mixed solvent, unless otherwise noted. b A mixture of o- and p-isomers in the ratio of 60 : 40. c In trifluoroacetic acid.
In sulfuric acid, not only monobromide and multibromides but also hydrated products were produced.
For anisole, benzene, and toluene the aforementioned condi-
tions applied to bromination of nitrobenzene are unsuitable
and bromination is typically carried out with Br2 in the presence
of iron.7 However, NBS in combination with methanesulfonic
acid8 has been reported recently to be a useful brominating
reagent. We, therefore, studied the reaction of 1 with benzene in
this solvent system and found it to be comparable with NBS
(54% vs. 79%, respectively) (eqn. (3)). We postulate that the
mechanism of this reaction proceeds through activated 1 via
protonation at the carbonyl group, for example see 4 in eqn. (4)
reduce its reactivity further in strong acids. The intriguing com-
pound 8 was prepared by the sequence shown in Scheme 1 and
the overall yield from methyl m-methylbenzoate was 28%.
(3)
Scheme 1
The reactivity of “Brϩ” generated from 1 or NBS can be
manipulated via the acidity of solvents, as mentioned above.
Therefore, 8 was first subjected to reactions with 1 and NBS in
sulfuric acid as solvent. Reagent 1 gave the monobrominated
product 9a together with multibrominated products (eqn. (5)),
while NBS exhibited more regioselectivity towards mono-
bromination. The result showed that in the acidic media 1
produces a more reactive (less selective) electrophile (“Brϩ”)
relative to that via NBS. Since the optimum reaction conditions
for the reaction of 1 with aromatics are already determined, we
examined the effect of temperature and acidity on the reaction
of 8 and 1. Changing the reaction temperature in the range
of 0 to 40 ЊC did not have much effect on the reaction, but
changing the solvent from sulfuric acid to trifluoroacetic acid
had a pronounced effect, as shown in Table 3.
The reaction of 1 with 8 in trifluoroacetic acid gave an
entirely different product from that in sulfuric acid. The prod-
uct was isolated and characterized by several spectroscopic
methods including 1H NMR spectroscopy and was determined
to be 9b, a regioisomer of 9a. Under identical reaction condi-
tions no reaction was observed for NBS with 8. It was found
that NBS in trifluoroacetic acid produces less bromine9 than
1 as shown in Fig. 1. Although the mechanism for bromine
(4)
The molar ratio of methanesulfonic acid : 1 was changed
from 0.5 to 3 and the highest yield of bromobenzene was
obtained at the 1 : 1 ratio. When the ratio was larger than 1,
further bromination occurred (up to 15% of the mixture). Thus
keeping the reagent to acid ratio at 1 : 1 ensures that the reac-
tion can be controlled at the monosubstitution level. The data
are summarized in Table 2. Dichlorobenzenes successfully
afforded monobrominated products under these conditions.
The reaction did not proceed in the solvents ether or CH2Cl2
without the addition of acid.
The data indicate that there is no appreciable difference in
reactivity and selectivity between 1 and NBS. We believe that
this is because of a leveling effect due to the high reactivity of
the arene substrate and “Brϩ” species generated. However, if
both reactivities are appropriately reduced, then, the difference
between the two reagents (1 versus NBS) can be studied. There-
fore aminomethylbenzoic acid derivative 8 was chosen as a
substrate, because it is moderately more reactive than the
electron-deficient benzoic acid, but is less reactive than toluene;
moreover it has several sites for protonation which would
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 0 6 – 2 5 1 1
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Table 3 Bromination of 8 by 1 and NBS
Yield (%)b
Entry
Reagenta
Solvent
Time/h
Temp.
9a
9b
Dibromide
1
2
3
4
5
6
1 (1.5)
NBS(1.5)
1 (1.1)
1 (1.5)
1 (1.5)
NBS(1.5)
H2SO4
H2SO4
H2SO4
2
5
3
24
4
24
rt
rt
0 ЊC
40 ЊC
rt
45(40c)
50
47
0
0
0
0
0
0
0
41
13
26
0
0
0
Methanesulfonic acid–ether
CF3COOH
CF3COOH
51(41c)
0
rt
a The amount of reagent (eq.) is shown in parentheses. b Obtained by gas chromatography. c Isolated yield.
Table 4 Bromination of phenol by means of 1 in CH2Cl2
Product yield (%)c
Ratiod
Entry
Ratioa
Time/h
Conv.b (%)
o-(10)
p-(11)
2,4-(12)
2,6-(13)
2,4,6-(14)
o-/p-
1
2
0.5
0.5
1.0
1.0
1.0
2.0
3.0
4.0
1
2.5
1
1
1
1
1
5
32(71)e
32
69
69
65
78
46
45
29
19
19
13
10
26
15
8
3
3
5
4
10
9
6
5
9
3
4
7
3
5
17
34
100
79 : 21
78 : 22
84 : 16
89 : 11
64 : 36
75 : 25
78 : 22
—
3
55(70)e
28
4f
5g
6
5
77(100)e
89
100
13
17
21
7
8
9
100
a The ratio of 1 and phenol. b Based on the phenol. c Based on the conversion. Determined by GC. d The ratio of o-bromophenol and p-bromophenol.
e Yield of bromides, based on 1 in the parentheses. f Diethyl ether was used as solvent. g NBS was used instead of 1.
in bromination on the relatively activated ortho-position.
Consequently for the preparation of the isomer 9a, NBS or 1 in
sulfuric acid is useful as a brominating reagent, while 1 in tri-
fluoroacetic acid is highly recommended, when the isomer 9b is
the target.
Trifluoromethylbenzene and benzonitrile were unreactive
to 1 in ether containing methanesulfonic acid. Therefore, tri-
fluoroacetic acid was used as a solvent for these substrates. Both
gave the desired monobromides via bromination by 1 as shown
in Table 2 (entries 6 and 7).
Phenol, an electron-rich aromatic compound, can easily react
Fig. 1 Time-course of bromine formation in trifluoroacetic acid.
Absorbance at 405 nm is plotted. [1] = [NBS] = 4.4 × 10Ϫ2 mol LϪ1
with bromine in water and the reaction is apt to give tribromo-
phenol, and monobromination is difficult to control. Among
several methods to make monobromophenol,10 Pearson’s
method is practical for o-bromophenol, although it has to be
carried out at Ϫ70 ЊC with bromine.10b On the other hand,
recently Oberhauser reported a convenient method to make
p-bromophenol.10d
.
As shown in Table 4 and eqn. (6), the reaction of 1 and
phenol was found to give o-bromophenol selectively. NBS, sol-
uble in both dichloromethane and diethyl ether, was used
instead of 1, but o-/p-isomer ratio (64 : 36) was lower than that
for 1 under the same reaction conditions (see Table 4, entry 5).
Monobromination of phenol with 1 was usually complete
within 1 h and further heating did not change the products
composition. The ratio of starting materials influences the
product ratio or selectivity. The conditions outlined in entry 2 in
Table 4 are recommended as the optimized ones to synthesize
o-bromophenol selectively.
(5)
The effect of water on this reaction was significant. When the
reaction was carried out under sufficiently anhydrous condi-
tions, it did not proceed at all. Hence, it is recommended to add
a few drops of water to the solvent (100 mg per 100 mL of
solvent), even though the commercially available 1 has 10%
water in the crystal or powder. The data infer that water
contained in the reagent is not active in the reaction.
p-Cresol was also brominated to give 2-bromo-4-methyl-
phenol in 37% yield under the same conditions as above.
Hydroquinone, however, was not only brominated, but
also oxidized to 2-bromo-p-benzoquinone 15 in 15% yield
formation is not known in this system, it is believed that NBS
generates the Brϩ cation more slowly than 1 or does not
produce bromine through the cation.
The formation of 9a is considered to stem from protonation
of the amide-nitrogen and/or carboxylate-oxygen thus making
the substituent(s) more electron-withdrawing and hence attack
is directed to the 3-position (meta to both strong deactivating
groups). On the other hand, 8 does not appear to be appreciably
protonated in the relatively weak trifluoroacetic acid, resulting
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 0 6 – 2 5 1 1
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(6)
Table 5 Bromination of 18 by 1 and subsequent Bingel reaction
diethyl ether, in diethyl ether containing methanesulfonic acid
or in trifluoroacetic acid, and in sulfuric acid, respectively: i.e.,
phenol was selectively brominated at the o-position in refluxing
diethyl ether. Benzene was readily monobrominated in diethyl
ether containing methanesulfonic acid. Nitrobenzene was con-
veniently converted to bromonitrobenzene in sulfuric acid. The
reactivity of 1 can be lowered by protonation in sulfuric acid,
trifluoroacetic acid or methanesulfonic acid–ether, and using
ether containing a trace of water. It is noteworthy that 1 can be
used in trifluoroacetic acid while NBS cannot. Alkenes, ketones
and esters were also brominated by 1. Diethyl malonate was
brominated by 1 and then subjected to Bingel reaction with
NaH to afford a methanofullerene in reasonable yield.
18
Entry
R1
R2
Yield of 19 (%)a
1
2
3
COOEt
COOMe
CN
COOEt
COOMe
COOMe
49(37)
12 (2)
16 (4)
a The monoadduct yield was based on fullerene used. All runs also
afforded bisadducts whose yields are given in parentheses.
(eqn. (7)).11 During the reaction, the starting hydroquinone was
also oxidized to p-benzoquinone 16 exclusively.
Experimental
General
(7)
Gas mass spectra were taken by a GCMS spectrometer with a
gas chromatograph equipped by an SE capillary column.
HPLC analysis was carried out with an HPLC apparatus (ODS,
methanol). NMR spectra were recorded on a 500 MHz FT
NMR spectrometer using TMS as internal standard.
Reagent 1 was kindly provided by Nissan Chemical Ind.,
Co. Ltd., and used without further purification. Other materials
and reagents were commercially available and were used with-
out further purification.
N,N-Dimethylaniline and aniline reacted with 1 under the
same conditions as those used for phenol and gave p-bromo-
anilines in 45 and 50% yields, respectively.
Bromination of alkene, ketone, and ester functionalities
Cyclohexene was readily brominated by 1 in acetic acid to
give trans-1-acetoxy-2-bromocyclohexane 17 in 70% yield
(eqn. (8)).12
Bromination of nitrobenzene in sulfuric acid (general procedure)
Nitrobenzene (1.23 g, 10 mmol) and 1 (3.45 g, 15 mmol,
1.5 equiv.) were dissolved in sulfuric acid (9.8 g) and heated to
40 ЊC for 12 h with stirring. After cooling, the reaction mixture
was poured on to ice–water (20 mL), and extracted by ether
(10 × 3 mL). The combined organic extracts were washed
with 5% NaOH (10 mL) and then with water (10 × 3 mL), dried
over Na2SO4, and distilled under reduced pressure. Yield of
m-bromonitrobenzene 2 was 1.95 g (95%). 1H NMR (CDCl3):14
2, δ 7.45 (1H, t, J = 8.2 Hz), 7.84 (1H, d, J = 8.2 Hz), 8.19 (1H,
d, J = 8.2 Hz), 8.40 (1H, s); MS(Mϩ, m/z), 201, 203.
(8)
The α-position of cyclohexanone was readily brominated by
1. Diethyl malonate was converted to the corresponding
bromomalonate by 1, and with a subsequent Bingel reaction13
was designed as a one-pot reaction: i.e., the malonate was
brominated in o-dichlorobenzene by 1 in situ with stirring
overnight, [60]fullerene and NaH were added, and the reaction
mixture was stirred for several hours.13 Filtration of the precipit-
ates gave the crude reaction products (eqn. (9)). The results are
summarized in Table 5.
1H NMR spectra (CDCl3) of products from dimethyl
phenylphosphonate, benzaldehyde, methyl benzoate, dimethyl
isophthalate, m-dinitrobenzene: dimethyl m-bromophenyl-
phosphonate,15 δ 3.78 (6H, d, J = 2.1 Hz), 7.37 (1H, dt, J = 4.9 &
10.4 Hz), 7.71 (1H, d, J = 29.6 Hz), 7.74 (1H, t, J = 4.9 Hz), 7.93
(1H, d, J = 29.6 Hz); MS(Mϩ, m/z), 264, 266. m-Bromo-
benzaldehyde,16 δ 7.43 (1H, t, J = 7.9 Hz), 7.77 (1H, d,
J = 7.9 Hz), 7.82 (1H, d, J = 7.9 Hz), 8.03 (1H, s), 9.97 (1H, s);
MS(Mϩ, m/z), 184, 186. Methyl m-bromobenzoate,16 δ 3.93
(3H, s), 7.32 (1H, t, J = 8.0 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.98
(1H, d, J = 7.6 Hz), 8.18 (1H, s); MS(Mϩ, m/z), 214, 216.
Dimethyl 5-bromoisophthalate,17 δ 8.36 (2H, s), 8.61 (1H, s);
MS(Mϩ, m/z), 272, 274. 1-Bromo-3,5-dinitrobenzene,18 δ 8.71
(2H, s), 9.01 (1H, s).
Bromination of benzene in ether containing methanesulfonic acid
(general procedure)
(9)
Benzene (0.78 g, 10 mmol) and 1 (2.30 g, 10 mmol, 1 equiv.)
were heated at 40 ЊC (bath temperature) in ether (5 mL) con-
taining methanesulfonic acid (0.96 g, 10 mmol, 1 equiv.) for 6 h
under stirring. After cooling, the reaction mixture was poured
on to ice water (20 mL), and extracted with ether (10 × 3 mL).
Conclusion
Commercially available powdered 1 has proven to be a useful as
a bromination reagent. Electron-rich, intermediate reactivity,
and electron-deficient aromatics were brominated by 1 in
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 0 6 – 2 5 1 1
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The combined organic solution was washed by 5% NaOH
(20 mL) and then with water (10 × 3 mL), dried over Na2SO4,
and distilled by a ball distillation apparatus. Yield of bromo-
benzene 3 was 1.25 g (79%). 1H NMR (CDCl3): 3, δ 7.24 (2H, t,
J = 8.2 Hz), 7.29 (1H, t, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz).
Products from anisole, toluene, o-dichlorobenzene, and
m-dichlorobenzene were also identified by the comparison of
their 1H NMR spectra with those of authentic samples. 1H
NMR (CDCl3): p-bromoanisole,16 δ 3.81 (3H, s), 6.79 (2H, d,
J = 8.8 Hz), 7.38 (2H, d, J = 8.8 Hz). o-Bromotoluene,16 δ 2.40
(3H, s), 7.04 (1H, t, J = 8.2 Hz), 7.20 (1H, t, J = 8.2 Hz), 7.23
(1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz). p-Bromotoluene,16
δ 2.30 (3H, s), 7.05 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz).
1-Bromo-3,4-dichlorobenzene,16 δ 7.32 (1H, d, J = 8.6 Hz), 7.35
(1H, d, J = 8.6 Hz), 7.62 (1H, s). 1-Bromo-2,4-dichloro-
benzene,19 δ 7.12 (1H, d, J = 8.6 Hz), 7.47 (1H, s), 7.55 (1H, d,
J = 8.6 Hz).
s), 3.92 (3H, s), 4.45 (2H, d, J = 5.9 Hz), 5.99 (1H, s), 7.59 (1H,
s), 7.85 (1H, s), 8.07 (1H, s). Anal. Calcd. C, 51.23%; H, 5.53%;
N, 4.27%. Found C, 50.92%; H, 5.43%; N, 4.17%.
The same reaction in trifluoroacetic acid gave 9b in 54 mg
1
(41% isolated yield). H NMR (CDCl3): 9b, δ 1.24 (H, s), 3.90
(3H, s), 4.53 (2H, d, J = 5.9 Hz), 6.15 (1H, s), 7.63 (1H, d,
J = 8.3 Hz), 7.80 (1H, dd, J = 2.0 & 8.4 Hz), 7.98 (1H, d, J = 2.2
Hz). Anal. Found C, 51.50%; H, 5.75%; N, 3.99% for C,
51.23%; H, 5.53%; N, 4.27%.
Benzonitrile and trifluoromethylbenzene also gave the mono-
bromides by the reaction in trifluoroacetic acid: m-bromo-
benzonitrile,16 δ 7.36 (1H, t, J = 8.0 Hz), 7.60 (1H, dt, J = 1.4 &
8.0 Hz), 7.75 (1H, dt, J = 1.4 & 8.0 Hz), 7.80 (1H, d, J = 1.4 Hz).
m-Bromo(trifluoromethyl)benzene,16 δ 7.37 (1H, t, J = 8.0 Hz),
7.57 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.78 (1H, s).
Bromination of phenol in CH2Cl2 or ether (general procedure)
Phenol (1.0 g) and 1 (0.5 to 3 equiv.) were heated in CH2Cl2
(40 mL with a drop of water) under reflux. After the prescribed
period, the reaction mixture was cooled, filtered, passed
through a short column of sodium thiosulfate, and then
analyzed by gas chromatography (GC), using naphthalene as
an internal standard. The products were identified by com-
parison with authentic samples:16 Actually, o-bromo- (10),
p-bromo-(11), 2,4-dibromo- (12), 2,6-dibromo- (13), and 2,4,6-
tribromophenol (14), showed 1H NMR peaks at δ 5.53 (1H, s),
6.80 (1H, dt, J = 1.5 & 7.9 Hz), 7.02 (1H, dd, J = 1.5 & 8.2 Hz),
7.23 (1H, dt, J = 1.5 & 7.9 Hz), 7.44 (1H, dd, J = 1.5 & 8.3 Hz),
4.79 (1H, s), 6.73 (2H, d, J = 8.9 Hz), 7.34 (2H, d, J = 8.9 Hz),
5.49 (1H, s), 6.91 (1H, d, J = 8.9 Hz), 7.33 (1H, dd, J = 2.5 &
8.9 Hz), 7.60 (1H, d, J = 2.5 Hz), 5.86 (1H, s), 6.71 (1H, t,
J = 8.0 Hz), 7.44 (2H, d, J = 7.9 Hz), 5.88 (1H, s) and 7.59 (2H,
s), respectively. MS(Mϩ, m/z) for 10 (or 11), 12 (or 13), and 14
were 172 and 174, 250, 252, and 254, 328, 330, 332, and 334,
respectively.
Synthesis of methyl m-(N-pivaloylaminomethyl)benzoate 8
Methyl m-methylbenzoate (5.12 g, 34 mmol) and NBS (7.29 g,
1.2 equiv.) in acetonitrile (680 mL) were irradiated with a 400 W
high-pressure mercury lamp in a Pyrex vessel for 15 min at
room temperature. The reaction mixture was concentrated
under reduced pressure. The residue was added to excess hexane
and the precipitates were removed. The solution was evapor-
ated to give a yellow liquid (7.82 g, 100%). 1H NMR (CDCl3): 5,
δ 3.93 (3H, s), 4.52 (2H, s), 7.43 (1H, t, J = 7.7 Hz), 7.59 (1H, d,
J = 7.9 Hz), 7.97 (1H, d, J = 7.7 Hz), 8.07 (1H, s).
Compound 5 (7.82 g, 34 mmol) and NaN3 (8.87 g, 4.0 equiv.)
were heated in EtOH (140 mL) for 18 h under reflux and with
stirring. The reaction mixture was filtrated, evaporated, poured
into water (50 mL), and extracted with ether (50 × 3 mL). The
combined organic extracts were washed with water (50 × 3 mL),
dried over MgSO4, and evaporated. Yield of compound 6 was
6.52 g (100%). 1H NMR (CDCl3): 6, δ 3.94 (3H, s), 4.41 (2H, s),
7.47 (1H, t, J = 7.7 Hz), 7.53 (1H, d, J = 7.7 Hz), 8.00 (1H, s),
8.02 (1H, d, J = 7.5 Hz).
Other products from p-cresol and hydroquinone show the
1
following data: H NMR (CDCl3): 2-bromo-4-methylphenol,16
Compound 6 (3.82 g, 20 mmol), PPh3 (5.76 g, 1.1 equiv.), and
H2O (3.60 g, 10 equiv.) were dissolved in THF (770 mL) and the
mixture was stirred at room temperature for 24 h. It was poured
into 1 M HCl (100 mL), and extracted with ether (100 mL). The
aqueous phase was made basic by 5% NaOH (50 mL) and then
extracted with ether (100 × 3 mL), dried over MgSO4, and
evaporated. The product was separated by GPC. Yield of com-
pound 7 was 1.12 g (34%). 1H NMR (CDCl3): 7, δ 3.92 (3H, s),
3.94 (2H, s), 7.41 (1H, t, J = 7.6 Hz), 7.53 (1H, d, J = 7.7 Hz),
7.92 (1H, d, J = 7.7 Hz), 8.01 (1H, s).
δ 5.37 (1H, s), 6.91 (1H, d, J = 8.3 Hz), 7.02 (1H, dd, J = 1.5 &
8.3 Hz), 7.27 (1H, d, J = 1.5 Hz). 15,16 δ 6.84 (1H, dd, J = 2.1 &
10.3 Hz), 6.98 (1H, d, J = 10.3 Hz), 7.32 (1H, d, J = 2.1 Hz).
16,16 δ 6.98 (4H, s).
N,N-Dimethylaniline and aniline were brominated under the
1
same conditions. H NMR (CDCl3): p-bromo-N,N-dimethyl-
aniline,16 δ 2.92 (6H, s), 6.59 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J =
8.8 Hz); p-bromoaniline, δ 4.10 (2H, s), 6.56 (2H, d, J = 7.5 Hz),
7.23 (2H, d, J = 7.5 Hz).
Pivaloyl chloride (3.27 g, 2.0 equiv.) was added to 7 (2.23 g,
14 mmol) and NEt3 (2.73 g, 2.0 eq.) in dichloromethane
(400 mL) at 0 ЊC for 1 h with stirring. The reaction mixture was
poured into water (50 mL), and extracted with ether (50 ×
3 mL). The combined organic extracts were washed with 1 M
HCl (100 × 2 mL), aqueous NaCl (100 × 2 mL), dried over
MgSO4, and evaporated. The product was separated by silica
gel column chromatography. Yield of 8 was 2.79 g (83%).
1H NMR (CDCl3): 8, δ 1.24 (9H, s), 3.92 (3H, s), 4.49 (2H, d,
J = 5.9 Hz), 5.97 (1H, s), 7.41 (1H, t, J = 7.5 Hz), 7.48 (1H, d,
J = 7.9 Hz), 7.93 (1H, s), 7.95 (1H, d, J = 7.5 Hz).
Reaction of 1 with cyclohexene
Cyclohexene (0.41 g, 5.0 mmol) and 1 (1.74 g, 7.5 mmol, 1.5
equiv.) were stirred in acetic acid (50 mL) at room temperature
for 7 h. The reaction mixture was poured on to ice water
(50 mL), and extracted with ether (50 × 3 mL). The combined
organic extract was washed with 5% Na2S2O3 (10 mL),
10% NaHCO3 (100 × 5 mL) and then with water (100 × 3 mL),
dried over Na2SO4, and evaporated. Yield of trans-1-acetoxy-2-
bromocyclohexane12 17 was 0.77 g (70%). H NMR (CDCl3):
17, δ 1.39 (3H, m), 1.75 (2H, m), 1.87 (1H, m), 2.07 (3H, s), 2.13
(1H, m), 2.36 (1H, m), 3.96 (1H, m), 4.89 (1H, m).
1
Bromination of 8 and moderately electron-deficient aromatics by
means of 1
Bromination of cyclohexanone
Reagent 1 (14 mg, 0.6 mmol, 1.5 equiv.) was added to 8 (0.10 g,
0.4 mmol) dissolved in sulfuric acid (4 mL) and the mixture
was stirred at room temperature for 2 h. It was then poured
onto ice– water (20 mL), and extracted with CHCl3 (50 ×
3 mL). The combined organic extract was washed with 5%
Na2S2O3 (50 mL) and then with water (50 mL), dried over
MgSO4, and evaporated. The product was separated by GPC.
Yield of 9a was 52 mg (40%). 1H NMR (CDCl3): 9a, δ 1.25 (9H,
Cyclohexanone (1.96 g, 20 mmol) and 1 (6.90 g, 30 mmol,
1.5 equiv.) were heated in ether solvent (30 mL) containing
methanesulfonic acid (2.88 g, 30 mmol, 1.5 equiv.) at 40 ЊC for
24 h with stirring. After cooling, the reaction mixture was
poured onto ice–water (20 mL), and extracted with ether (50 ×
3 mL). The combined organic extract was washed with 5%
NaOH (20 mL) and then with water (50 × 3 mL), dried over
Na2SO4, and distilled by a ball distillation apparatus. Yield of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 0 6 – 2 5 1 1
2510

View Article Online
2 R. R. Goehring, Encyclopedia of Reagents for Organic Synthesis,
ed. L. A. Paquette, John Wiley & Sons, New York, 1995, 1,
677.
3 Kokusai Kokai Tokkyo, 1999, WO99/21849.
4 The reagent contained 10% water. It is practically insoluble in
dichloromethane and diethyl ether.
2-bromocyclohexanone was 1.11 g (31%), although gas-
1
chromatographic yield was 72%. H NMR (CDCl3): 2-bromo-
cyclohexanone,20 δ 1.73 (1H, m), 1.81 (1H, m), 1.95 (1H, m),
2.02 (1H, m), 2.24 (1H, m), 2.34 (2H, m), 2.99 (1H, m), 4.45
(1H, m).
5 J. R. Johnson and C. G. Gauerke, Org. Synth., 1941, Coll. Vol. I, 123;
W. A. Wisansky and S. Aasbacher, Org. Synth., 1955, Coll. Vol. III,
138; J. F. Bunnett and M. M. Rauhut, Org. Synth., 1963, Coll. Vol.
IV, 114.
Bingel reaction through bromination of diethyl malonate by 1
Diethyl malonate 18 (32 mg, 0.2 mmol) and 1 (46 mg,
0.2 mmol) were heated to 40 ЊC in o-dichlorobenzene (10 mL)
for 24 h with stirring. After cooling, C60 (72 mg, 0.1 mmol) and
NaH (0.1 g, excess) in o-dichlorobenzene (10 mL) were added
to the reaction mixture. After stirring for 2 h at room temper-
ature, the mixture was evaporated and subjected to column
chromatography (silica gel, toluene). Yield of methanofullerene
6 H. Suzuki and I. Hashiba, 1998, JP10114712.
7 D. H. Derbyshire and W. A. Waters, J. Chem. Soc., 1950, 573.
8 H. Eguchi, H. Kawaguchi, S. Yoshinaga, A. Nishida, T. Nishiguchi
and S. Fujisaki, Bull. Chem. Soc. Jpn., 1994, 67, 1918.
9 D. D. Tanner, J. Am. Chem. Soc., 1964, 86, 4674.
10 (a) S. Skraup and W. Beifuss, Ber., 1927, 60, 1074; (b) D. E. Pearson,
R. D. Wysong and C. V. Breder, J. Org. Chem., 1967, 32, 2358;
(c) K. Kim and Y.-C. Chang, J. Chem. Soc., Chem. Commun., 1986,
1159; (d ) T. Oberhauser, J. Org. Chem., 1997, 62, 4504.
11 H. W. Underwood, Jr. and W. L. Walsh, J. Am. Chem. Soc., 1936, 58,
647.
12 S. Uemura, K. Ohe, S. Fukazawa, S. R. Patil and N. Sugita,
J. Organomet. Chem., 1986, 316, 67.
13 C. Bingel, Chem. Ber., 1993, 126, 1957.
14 A. Groweiss, Org. Process Res. Dev., 2000, 4, 30.
15 G. T. Crisp and P. D. Turner, Tetrahedron, 2000, 56, 407.
16 Commercially available.
1
19 was 43 mg (49%). H NMR (CDCl3): 19,13 δ 1.49 (6H, t,
J = 7.2 Hz), 4.57 (4H, q, J = 7.0 Hz).
Acknowledgements
We gratefully acknowledge the Ministry of Education, Science,
Culture, and Sports and Japan Society for Promotion and
Science for support of this work.
17 B. Plumb, R. Obrycki and C. E. Griffin, J. Org. Chem., 1966, 31,
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18 L. Elion, Rec Trav. Chim., 1923, 42, 145.
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20 M. S. Khrasch and G. Sosnovsky, J. Org. Chem., 1958, 23, 1322.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 5 0 6 – 2 5 1 1
2511