Regioselective bromination of organic substrates by tetrabutylammonium bromide promoted by V2O5-H2O2: An environmentally favorable synthetic protocol

Article abstract of DOI:10.1021/ol9902935

(matrix presented) Vanadium pentoxide very effectively promotes the bromination of organic substrates, including selective bromination of some aromatics, by tetrabutylammonium bromide in the presence of hydrogen peroxide; mild conditions, high selectivity, yield, and reaction rate, and redundancy of bromine and hydrobromic acid are some of the major advantages of the synthetic protocol.

Full text of DOI:10.1021/ol9902935

ORGANIC
LETTERS
2
000
Vol. 2, No. 3
47-249
Regioselective Bromination of Organic
Substrates by Tetrabutylammonium
Bromide Promoted by V O −H O :
2
2
5
2 2
An Environmentally Favorable Synthetic
Protocol
Upasana Bora, Gopal Bose, Mihir K. Chaudhuri,* Siddhartha S. Dhar,
Rangam Gopinath, Abu T. Khan,* and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology, Guwahati-781 001, India
mkc@iitg.ernet.in
Received September 20, 1999
ABSTRACT
Vanadium pentoxide very effectively promotes the bromination of organic substrates, including selective bromination of some aromatics, by
tetrabutylammonium bromide in the presence of hydrogen peroxide; mild conditions, high selectivity, yield, and reaction rate, and redundancy
of bromine and hydrobromic acid are some of the major advantages of the synthetic protocol.
Bromination of organic substrates, particularly aromatics, has
garnered a significant amount of attention in recent years
chemicals, pharmaceuticals, and agrochemicals. Unfortu-
nately, the hazards associated with traditional bromination
are not trivial and cannot be ignored. Environmental
1
-8
7
owing to the considerable commercial importance of such
compounds as potent antitumor, antibacterial, antifungal,
problems caused by the use of detrimental chemicals and
9
10
antineoplastic, antiviral, and antioxidizing agents and also
solvents in classical bromination and the anticipated
as industrial intermediates for the manufacture of speciality
legislations against their use are some of the major concerns.
Consequently, what is needed is a methodology that would
be environmentally friendly and clean and yet efficient, site-
selective, operationally simple, and cost-effective. Selective
bromination of aromatics, which is of great commercial
importance, has also been a case in point.
1) Muathen, H. A. J. Org. Chem. 1992, 57, 2740.
Int. 1994, 26, 439.
(
(
3) Conte, V.; DiFuria, F.; Moro, S. Tetrahedron Lett. 1994, 35, 7429.
4) Dinesh, C. U.; Kumar, R.; Pandey, B.; Kumar, P. J. Chem. Soc., Chem.
Commun. 1995, 611.
(
5) Smith, K.; Bahzad, D. Chem. Commun. 1996, 467.
Taking cues from the knowledge of the activity of
(6) Srivastava, S. K.; Chauhan, P. M. S.; Bhaduri, A. P. Chem. Commun.
1
1
vanadium bromoperoxidase (VBrPO), which catalyses
bromination of marine natural products, as well as our earlier
1
996, 2679.
7) Clark, J. H.; Ross, J. C.; Macquarrie, D. J.; Barlow, S. J.; Bastock, T.
W. Chem. Commun. 1997, 1203.
8) Barhata, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. B.
Tetrahedron Lett. 1998, 39, 6349.
9) Butler, A.; Walker, J. V. Chem. ReV. 1993, 93, 1937.
(
(
(10) Clark, J. H., Ed. Chemistry of Waste Minimisation; Chapman and
Hall: London, 1995.
(
1
0.1021/ol9902935 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/13/2000

a
Table 1. Bromination of Aromatics and Some Other Substrates with Tetrabutylammonium bromide (TBAB) and V
2
5 2 2
O -H O
yield
(%)b
substrate
t/h
product
aniline (1)
acetanilide (2)
o-cresol (3)
m-cresol (4)
phenol (5)
â-naphthol (6)
anthracene (7)
cyclohexene (8)
crotyl alcohol (9)
0.5
2
1.5
0.5
1
1
1
2
2
1.5
2
1
1
1
4-bromoanilinec
4-bromoacetanilide
4-bromo-o-cresol
82
92
92
60
98
76
93
70
60
46
52
55
72
70
4-bromo-m-cresol
2,4,6-tribromophenold
1-bromo-â-naphthol
9,10-dibromoanthracened
1,2-dibromocyclohexane
2,3-dibromo-1-butanol
2
-butyne-1,4-diol (10)
2,3-dibromo-2-butene-1,4-diol
2-bromocyclohexanone
R,R-dibromo-o-hydroxy acetophenone (15)
4-benzyloxy-3′-bromo-4′,6′-dimethoxy-2′-hydroxychalcone (16)
3′-bromo-4,4′,6′-trimethoxy-2′-hydroxy-chalcone (17)
cyclohexanone (11)
4
4
2
-hydroxycoumarin (12)
-benzyloxy-4′,6′-dimethoxy-2′-hydroxychalcone (13)
′-hydroxy-4,4′,6′-trimethoxy-chalcone (14)
a
Reactions were monitored by TLC and GC. b Isolated yields. c Isolated as an acetyl or a benzoyl derivative. d Using substrate:TBAB at 1:1, p-bromophenol
and 9-bromoanthracene are obtained as ca. 20% and ca. 30% yields, respectively.
experience of the reactivity of peroxovanadium systems,12
conversion to products with high yields) and that CH
2
H O (1:1, 8 mL/mmol of TBAB) solvent gave very good
yields. The bromination reaction was conducted at ca. 5 °C
with stirring for the time period shown for each substrate in
Table 1. The desired products have been obtained in high to
very high yields as reported (Table 1). Notably, the reaction
3
CN/
we have now developed an environmentally acceptable
bromination protocol involving V as a promoter and
O
2 5
hydrogen peroxide and tetrabutylammonium bromide (TBAB)
as the sources of active oxygen and bromide, respectively.
The solvent of choice is CH
3
2 2 5
CN/H O. The promoter (V O )
and the oxidant (H
chemicals.
The methodology is based on (i) activation of dioxygen
by the interaction of H with vanadium(V) leading to the
formation of peroxovanadium(V) species (λ ) 430 nm) in
solution followed by (ii) oxidation of bromide by the
2
O
2
) are both environmentally acceptable
2 5
may be conducted using a substrate:V O molar ratio of 1:0.1
or 0.2; however, conversion to product is rather slow.
Importantly, no extra addition of acid is required by this
method. The reaction pH was, however, found to be ca. 2.1.
Incidentally, the intrinsic acidity of the reaction originating
2 2
O
2 5
from dissolution of V O in hydrogen peroxide solution not
peroxovanadium(V) intermediate ultimately leading to the
only neutralizes the hydroxide in Figure 1 but also maintains
the acidic reaction medium. The pH values recorded at the
beginning and after completion of the reaction were ca. 2.0
and ca. 2.2, respectively. It appears that sufficient acid could
be generated in the process from the use of 0.5 molar equiv
-
formation of Br
3
( λ˜ ) 266 nm) as the active brominating
agent, and finally (iii) bromination of organic substrates to
afford bromoorganics (Figure 1). The wavelengths listed in
2 5
of V O to allow for bromide oxidation by the peroxovana-
dium(V) species formed in the reaction. The methodology
is capable of being made catalytic with KBr as the consum-
able source.
Quite intriguing is the regioselective bromination of
activated aromatics such as aniline (1), acetanilide (2),
o-cresol (3), and m-cresol (4) exclusively to the correspond-
ing p-bromo derivatives. In the latter two cases the -OH
group seems to have a stronger influence than the -CH
3
group. Under similar experimental conditions, phenol (5) and
â-naphthol (6) produced 2,4,6-tribromophenol and 1-bromo-
Figure 1. Generation of TBATB and bromination of organic
substrates.
(11) (a) Waver, R.; Krenn, M. B. E. Vanadium in Biological System;
Chasteen, N. D., Ed.; Kluwer Academic Publishers: Dordrecht, The
Netherlands, 1990; p 81. (b) de la Rosa, R. I.; Clague, M. J.; Butler, A. J.
Am. Chem. Soc. 1992, 114, 760. Clague, M. J.; Keder, N. L.; Butler, A.
Inorg. Chem. 1993, 32, 4754. Coplas, G. J.; Hamstra, B. J.; Kamf, J. W.;
Pecoraro, V. L. J. Am. Chem. Soc. 1994, 116, 3627; 1996, 118, 3469.
Clague, M. J.; Butler, A. J. Am. Chem. Soc. 1995, 117, 3475. Sheng, D.;
Gold, M. H. Arch. Biochem. Biophys. 1997, 345, 126.
parentheses were used experimentally to characterize the
species present in the methodology, lending credence to the
contention.
Various conditions were sampled, with the result that a
(12) Bhattacharjee, M. N.; Chaudhuri, M. K.; Islam, N. S. Inorg. Chem.
989, 28, 2420. Chaudhuri, M. K.; Chettri, S. K.; Mandal, G. C.; Paul, P.
C.; Paul, S. B.; Srinivasan, P. Proc. Indian Acad. Sci. (Chem. Sci.) 1995,
107, 305.
1
1
:3:0.5:16 substrate to tetrabutylammonium bromide to V
2 5
O
to H stoichiometry appeared optimal (ostensibly to speed
2 2
O
248
Org. Lett., Vol. 2, No. 3, 2000

â-naphthol, respectively, in very high yields. A polycyclic
aromatic, anthracene (7), is capable of being brominated to
2 4 2 5 2 2
H SO , separately without involving either V O or H O ,
did not bring about any change in the substrates so far
examined.
9
,10-dibromoanthracene. Notable in this context is that by
setting the molar ratio between the substrate and TBAB at
:1, phenol (5) and antharacene (7) can be brominated to
yield p-bromophenol (ca. 20%) and 9-bromoanthracene (ca.
0%) in addition to the tribromo and dibromo derivatives,
In summary, we have shown that various brominated
organic compounds can be prepared via the treatment of
organic substrates including aromatics typically with tet-
rabutylammonium bromide promoted by hydrogen peroxide
1
3
respectively, if desired.
2 5
and V O . We have evidence showing that the methodology
The efficacy of the methodology lies also in the bromi-
nation of alkene and alkyne systems as exemplified by the
facile bromination of cyclohexene (8), crotyl alcohol (9), and
may work as well with other organic bromides such as
tetraethylammonium bromide, cetyltrimethylammonium bro-
mide, and pyridinium bromide, for instance. This methodol-
ogy represents an efficient, straightforward, and safer
alternative to the rather hazardous classical bromination
protocols, opening an opportunity to gain easy access to a
variety of bromoorganics. Its synthetic applications as well
as the reaction mechanism are currently under investigation.
2-butyne-1,4-diol (10), respectively. The conversion of
cyclohexanone (11) to the corresponding 2-bromocyclohex-
anone in high yield might be a paradigm for the synthesis
of R-bromoketone. Quite interesting is the transformation
of 4-hydroxycoumarin (12) to R,R-dibromo-o-hydroxy-
acetophenone (15).13 Indeed R,R-dibromination of the enol
form of â-ketolactone (cf. 12) is, to the best of our
knowledge, unprecedented. Also important is the selective
bromination of the activated aromatic ring in the presence
of an enone by the present methodology. Thus, for instance,
the activated aromatic ring of 4-benzyloxy-4′,6′-dimethoxy-
Acknowledgment. The authors thank CSIR, New Delhi
(S.S.D.), and the institute (U.B., G. B., and R.G.) for research
fellowships, one of the referees for helpful comments, and
Drs. N. C. Barua and M. J. Bordoloi of RRL Johrat for some
NMR spectra.
2′-hydroxychalcone (13) and 2′-hydroxy-4,4′,6′-trimethoxy-
chalcone (14) were selectively brominated, in the presence
of an enone, to produce 4-benzyloxy-3′-bromo-4′,6′-dimeth-
oxy-2′-hydroxychalcone (16) and 3′-bromo-4,4′,6′-trimethoxy-
Supporting Information Available: Detailed experi-
mental procedures for bromination of o-cresol (3) to 4-bromo-
o-cresol and 4-benzyloxy-4′,6′-dimethoxy-2′-hydroxychal-
cone (13) to 4-benzyloxy-3′-bromo-4′,6′-dimethoxy-2′-
hydroxychalcone (16) and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
14
2′-hydroxychalcone (17), respectively, in very high yields.
OL9902935
(13) Selected data for 15: δH (CDCl3) 6.78 (s, 1H, -CH Br2), 6.95 (t,
J ) 6 Hz, 1H, ArH), 7.50 (d, J ) 9 Hz, 1H, ArH), 7.56 (t, J ) 6 Hz, 1H,
ArH), 7.84 (d, J ) 9 Hz, 1H, ArH), 11.46 (s, 1H, OH, D2O exchangeable);
δC(CDCl3) 38.59, 114.21, 119.74 (2C), 130.38, 138.54, 164.43, 191.39.
(
14) Selected data for 17: δH (CDCl3) 3.84 (s, 3H, OCH3), 3.97 (s, 3H,
OCH3), 3.98 (s, 3H, OCH3), 6.03 (s, 1H, 5′H), 6.92 (d, J ) 9 Hz, 2H,
ArH), 7.54 (d, J ) 12 Hz, 2H, ArH), 7.74 (d, J ) 15 Hz, 1H, olefinic H),
.83 (d, J ) 15 Hz, 1H, olefinic H), 14.98 (s, 1H, OH, D2O exchangeable),
7
δC (CDCl3) 55.82, 56.50, 56.72, 87.61, 92.42, 114.83, 122.05, 124.91,
28.47, 130.68, 143.91, 162.03, 162.17, 162.61, 163.63, 193.08.
15) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: London,
1995, pp 297-300.
The products (16 and 17) are important precursors for the
synthesis of the flavonoids (cf. vitexin).15 Control experi-
ments conducted by adjusting the pH to 2.1 with 0.01 M
1
(
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