Mild Benzylic Monobromination of Methyl Toluates in Aqueous CTAB

Article abstract of DOI:10.1055/s-0034-1379005

A strategy has been developed for the regioselective monobromination of methyl toluates by using tert-butylhydrogen peroxide and potassium bromide (TBHP/KBr) in a cetyltrimethylammonium bromide (CTAB) micellar medium. Ultrasonic and microwave-assisted protocols recorded increased rates and product yields under mild reaction conditions, coupled with a straightforward isolation procedure.

Full text of DOI:10.1055/s-0034-1379005

LETTER
▌2485
letter
Mild Benzylic Monobromination of Methyl Toluates in Aqueous CTAB
Mild Benzylic Monobromination of Methyl Toluates
Kancharla Rajendar Reddy, Kamatala C. Rajanna,* Marri Venkateswarlu, P. K. Saiprakash
Department of Chemistry, Osmania University (O.U), Hyderabad-500 007, A.P., India
Fax +91(40)27090020; E-mail: kcrajannaou@yahoo.com
Received: 26.06.2014; Accepted after revision: 26.07.2014
In order to demonstrate the effect and role of CTAB in mi-
celle-mediated reactions, initial bromination reactions
were carried out with methyl 2-chlorotoluate in the pres-
Abstract: A strategy has been developed for the regioselective
monobromination of methyl toluates by using tert-butylhydrogen
peroxide and potassium bromide (TBHP/KBr) in a cetyltrimeth-
ylammonium bromide (CTAB) micellar medium. Ultrasonic and ence and absence of CTAB. In the absence of CTAB, re-
microwave-assisted protocols recorded increased rates and product action did not proceed even under forcing conditions.
yields under mild reaction conditions, coupled with a straightfor-
ward isolation procedure.
However, in the presence of CTAB, reaction occurred
smoothly. The optimum reaction conditions of substrate
Key words: bromination, monobromo methyl toluates, cetyltrime- (1.0 mmol), TBHP (0.4 mL), KBr (1.1 mmol), and aque-
thylammonium bromide, microwaves, ultrasound
ous CTAB solution (5 mL) were used for benzylic bromi-
nation of various methyl toluate derivatives and, on
completion of reaction, the organic products could be ob-
Bromoarenes, bromoalkylbenzenes, and bromoalkylben- tained by simple phase separation, while in small-scale
1
zoates are widely used synthetic intemediates. Apart experiments extraction with an appropriate organic sol-
from their use in C–C coupling reactions, they are used as vent was applied (Table 1).
precursors to organometallic species and in nucleophilic
Table 1 Effects of Catalyst System on the Reaction and Activity of
Bromination Reactions with Methyl 2-Chlorotoluate
substitutions. They are also useful in the synthesis of phar-
maceuticals, agrochemicals, antitumor, antifungal, anti-
1
,2
bacterial, antineoplastic, and antiviral compounds.
Br
KBr (1.1 equiv)
aq CTAB (x equiv)
TBHP
However, the use of molecular bromine has drawbacks
arising from its toxic and corrosive nature, difficulty in
handling, and its high reactivity; the latter often resulting
in exothermic and nonselective reactions. Additional
problems arise from the generation of hydrogen bromide
as a byproduct. Reports have shown that N-bromoimides
are useful for benzyl bromination and for electrophilic ar-
omatic ring bromination, although electron-rich sub-
8 h
Cl
Cl
O
OMe
O
OMe
Yield (%)a
CTAB (x equiv)
0
0
68
72
83
88
88
3
–14
strates are usually required for the latter reaction.
Alternatively, oxidative bromination of arenes has been
0
.0001
developed using in situ generated bromonium species by 0.00025
oxidation of potassium bromide with hydrogen peroxide
0
.0005
or sodium perborate in the presence of sodium tungstate
1
5
or ammonium molybdate as catalysts. In another proto- 0.001
col,16 a combination of NaClO , NaBr, and Mn(acac)
2
3
0
.005
supported on montmorillonite K10 or silica gel has been
used for regioselective monobromination of aromatic
ethers. As part of our ongoing study on micellar surfac-
a
Isolated yields.
1
7
tants as catalysts, we have undertaken a study of the se-
lective bromination of methyl 2-chlorotoluate with tert-
butylhydrogen peroxide (TBHP)/potassium bromide
A range of variously substituted methyl toluates were ef-
ficiently brominated at the benzylic position in this aque-
ous micellar medium at ambient temperature under acid-
free conditions; while such reactions did not proceed un-
der standard conditions (Table 2). Methyl 2-methyltoluate
underwent bromination more effectively than methyl 3-
methyltoluate, which could be due to the steric hindrance
of the adjacent methyl group present in the meta position.
This TBHP/KBr/CTAB bromination protocol appears to
(
KBr) in the presence of aqueous cationic micelles using
cetyltrimethylammonium bromide (CTAB). In addition to
the use of micelles, we also focused our attention on the
use of nonconventional energy sources such as ultra-
18
19
sound and microwaves to initiate and enhance the re-
actions.
2
0
be superior to NBS bromination, affording higher
yields. The mild reaction conditions, straightforward iso-
lation procedure, and use of inexpensive reagents make
SYNLETT 210 014, 25 17, 2485–2487
Advanced online publication: 26.08.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379005; Art ID: st-2014-d0547-l
Georg Thieme Verlag Stuttgart · New York
©

2486
K. R Reddy et al.
LETTER
Table 2 Selective Benzylic Monobromination of Methyl Toluates
necessary. Column chromatography can then be used
with KBr in Aqueous CTAB Mediuma
(SiO , hexane–EtOAc) to give the pure monobromo meth-
2
yl toluates.
Br
It is proposed that the surfactant forms micelles with the
organic substrate concentrated in the interior of spherical
aggregates, which act as hydrophobic reaction sites. Thus
the hydrophobic interior of the micelles acts to shift the
equilibrium towards the desired product. This explanation
is schematically presented in Scheme 1.
R2
R1
TBHP, KBr
CTAB (aq)
R2
R1
O
OMe
O
OMe
Yield (%)b
Entry Product R1
R2
Conventional MW
US
Reaction times were further reduced from eight hours to
2
1
about 40–50 minutes under sonication and 7–10 minutes
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Cl
H
88
87
85
64
83
86
82
83
85
87
81
83
81
84
82
81
93
94
93
72
91
91
93
90
91
94
93
92
90
94
93
94
90
90
89
69
89
88
88
89
89
91
87
87
88
90
91
91
22
under microwave irradiation.
Br
Me
H
H
In summary, we have developed a mild and simple practi-
cal method for the selective benzylic bromination of
methyl toluates in the presence of aqueous cationic mi-
celles under conventional, as well as sonication and mi-
crowave conditions. The reactions afford very good yields
at room temperature.
H
Me
H
Et
OMe
t-Bu
i-Pr
CN
CF3
H
H
2g
2h
2i
H
Acknowledgment
H
The authors are indebted to Professor T. Navaneeth Rao (Former
Vice-Chancellor, O.U), Principal, Nizam College and Head, De-
partment of Chemistry, O.U) for constant encouragement and pro-
vision of facilities.
H
1
1
1
1
1
1
2j
H
2k
2l
F
Supporting Information for this article is available online
H
Cl
Et
OMe
CN
CF3
at
http://www.thieme-connect.com/products/ejournals/journal/
1
0.1055/s-00000083. SunogIpimirf antoSuIpg
n
ori
m
2m
2n
2o
2p
H
H
References and Notes
H
(
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Scheme 1 Bromination of methyl-4-methylbenzoates in the presence of micellar media
Synlett 2014, 25, 2485–2487
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mild Benzylic Monobromination of Methyl Toluates
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