J . Org. Chem. 1998, 63, 6023-6026
6023
Ta ble 1. Br om in a tion of Tolu en e w ith Na Br O3/Na HSO3
Rea gen t u n d er Sever a l Con d ition sa
An Alter n a tive Meth od for th e Selective
Br om in a tion of Alk ylben zen es Usin g
Na Br O3/Na HSO3 Rea gen t
Daisuke Kikuchi, Satoshi Sakaguchi, and
Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering
and High Technology Research Center, Kansai University,
Suita, Osaka 564-8680, J apan
Received December 15, 1997
R-Brominated alkylbenzenes are a valuable class of
compounds in organic synthesis, since they are frequently
used as the starting materials for synthesis of a wide
variety of important compounds. R-Bromination of alkyl-
benzenes is usually performed by the use of bromine,1
NBS,2 CBrCl3,3 CuBr2,4 and Br-/CAN5 under heating or
irradiation of light. To achieve the bromination by these
reagents in satisfactory yields, the reaction must be
carried out in halogenated solvents such as CCl4, CHCl3,
and CH2ClCH2Cl. However, these solvents will become
difficult to use from an environmental point of view. In
this respect, Shaw et al. have recently demonstrated the
free-radical bromination of toluene and xylenes with
bromine in water under irradiation of a mercury lamp.6
In previous papers, we showed that NaBrO3 combined
with a reducing reagent such as NaHSO3 (NaBrO3/
NaHSO3) generates in situ hypobromous acid (HOBr) and
serves as an effective bromohydroxylation reagent of
olefins,7 alkynes, and allylic alcohols8 and an oxidizing
agent of primary alcohols,9 diols, and ethers.10 In the
course of our study to extend the scope of the NaBrO3/
NaHSO3 reagent in organic synthesis, we have found that
this reagent facilitates the R-bromination of alkylben-
zenes under a two-phase system using ethyl acetate as
solvent under ambient conditions. In this paper, we wish
a
To a solution of alkylbenzene (3 mmol) in organic solvent (6
mL) and NaBrO3 (9 mmol) in water (4.5 mL) was added dropwise
NaHSO3 (9 mmol) in H2O (9 mL) during a period of 15 min at
room temperature. NaBrO3/NaHSO3 (3/3 mmol) was used. c A
b
small amount of aromatic bromination products derived from 2
and 4 were formed. Ratio of o-4/p-4.
d
to report the selective side chain and ring brominations11
of alkylbenzenes with the NaBrO3/NaHSO3 reagent.
The bromination of toluene (1) by the NaBrO3/NaHSO3
reagent was chosen as a model reaction and carried out
under various reaction conditions. Representative re-
sults are shown in Table 1.
To a two-phase system comprised of ethyl acetate
involving 1 and aqueous NaBrO3 (3 equiv) was added
dropwise aqueous NaHSO3 (3 equiv) over a period of
about 15 min under stirring and the mixture was allowed
to react at room temperature for 4 h. The reaction
produced R-bromotoluene (2) in 72% yield along with R,R′-
dibromo toluene (3) (22%) (run 1). When 1 was allowed
to react with a stoichiometric amount of NaBrO3/NaHSO3
(1 equiv), 2 was formed in unsatisfactory yield (47%) (run
2). Hence, the reaction was carried out by the use of 3
equiv of NaBrO3/NaHSO3. Similarly, the reaction of 1
using cyclohexane as solvent in place of ethyl acetate
produced 2 as the major product (run 3). No bromination
of the cyclohexane used as the solvent was observed. It
is important to note that the side bromination of 1 can
be successfully carried out using NaBrO3/NaHSO3 re-
agent in ethyl acetate or cyclohexane as the solvent, since
the conventional bromination of alkylbenzenes under
irradiation is usually conducted in environmentally
unfavorable halogenated hydrocarbon. The reaction in
a mixed solvent of diisopropyl ether and water led to 2
in low conversion (30%) and yield (20%) (run 4). This is
because the diisopropyl ether itself was oxidized by this
(1) (a) Snell, J . M.; Weissherger, A. Organic Synthesis; J ohn Wiley:
New York, 1955; Collect. Vol. III, p 788. (b) Stephenson, E. F. M.
Organic Synthesis; J ohn Wiley: New York, 1963; Collect. Vol. III, p
984. (c) Quertani, M.; Girard, P.; Kagan, H. B. Bull. Chem. Soc. Chim.
Fr. II, 1982, 327. (d) Sket, B.; Zupen, M. J . Org. Chem. 1986, 51, 929.
(e) Venkatachalapathy, C.; Pitchumani, K. Tetrahedron 1997, 53, 2581.
(2) (a) Djerassi, C. Chem. Rev. 1948, 43, 271. (b) Wenner, W. J . Org.
Chem. 1952, 17, 523. (c) Wenner, W. Angew. Chem. 1959, 71, 349. (d)
Andrews, L. J .; Keefer, R. M. J . Org. Chem. 1969, 34, 944. (e) Lind, J .
J onsson, M.; Xinhua, S.; Eriksen, T. E.; Eberson, L. J . Am. Chem. Soc.
1993, 115, 3503. (f) Carreno, M. C.; Ruano, J . L. G. J . Org. Chem. 1995,
60, 5328.
(3) (a) Huyser, E. S. J . Chem. Soc. 1960, 391. (b) Hori, Y.; Nagano,
Y.; Uchiyama, H.; Yamada, Y.; Taniguchi, H. Chem. Lett. 1978, 73. (c)
J on, A. O. J . Org. Chem. 1966, 31, 4933.
(4) Chaintreau, A.; Adrian, G.; Couturier, D. Synth. Commun. 1981,
669.
(5) Baciocchi, E.; Rol, C.; Sebstiani, G.; Serena, B. J . Chem. Res.
1984, 24.
(6) Show, H.; Perlmutter, H. D.; Gu, C. J . Org. Chem. 1997, 62, 236.
(7) Previously, an appropriate method for generating HOBr or HOI
equivalents from NaBrO3 or NaIO4 combined with various reducing
agents (NaHSO3, Na2SO3, Na2S2O3, Na2HPO3, FeSO4, and H2C2O4 etc.)
was examined, and the NaHSO3 was found to be the best reducing
reagent employed: Ohta, H.; Sakata, Y.; Takeuchi, T.; Ishii, Y. Chem.
Lett. 1990, 733.
(8) Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyama,
Y.; Sakaguchi, S.; Ishii, Y. J . Org. Chem. 1994, 59, 5550.
(9) Takase, K.; Masuda, H.; Kai, O.; Nishiyama, Y.; Sakaguchi, S.;
Ishii, Y. Chem. Lett. 1995, 871.
(11) For ring brominations, various papers have appeared: (a)
Mckillop, A.; Bromley, D. J . Org. Chem. 1972, 37, 88. (b) Mitchell, R.
H.; Williams, R. V. J . Org. Chem. 1979, 44, 4733. (c) Bovonsombat, P.;
Mcnelis, E. Synthesis 1993, 237. (d) Srivastava, S. K.; Bhaduri, A. P.;
Man, D.; Chanhan, S. J . Chem. Soc., Chem. Commun. 1996, 2679. (e)
Bezodis, P.; Hanson, J . R.; Philippe, P. J . Chem. Res. 1996, 334.(f)
Clark, J . H.; Ross, J . C.; Macquarrie, D. J .; Barlow, S. J .; Bastock, T.
W. J . Chem. Soc., Chem. Commun. 1997, 1203. (g) Vega, F.; Sasson,
Y. J . Chem. Soc., Chem. Commun. 1989, 653. (h) Smith, K.; Bahzad,
D. J . Chem. Soc., Chem. Commun. 1996, 467.
(10) Sakaguchi, S.; Kikuchi, D.; Ishii, Y. Bull. Chem. Soc. J pn. 1997,
70, 2561.
S0022-3263(97)02263-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/31/1998