1-Benzyl-4-aza-1-azoniabicyclo[2.2.2] octane tribromide as a highly reactive brominating agent for aniline derivatives

Article abstract of DOI:10.1081/SCC-200043274

Reaction of anilines with 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane tribromide (3) in the presence of CaCO₃ in small amounts of methanol gave brominated aromatic amines in good yields at room temperature. The isolation of products is straightforward.

Full text of DOI:10.1081/SCC-200043274

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1‐Benzyl‐4‐Aza‐1‐Azoniabicyclo[2
Tribromide as a Highly
Reactive Brominating Agent
for Aniline Derivatives
A. R. Hajipour a , H. Imanieh b & S. A.
Pourmousavi a
a Pharmaceutical Research Laboratory, College
of Chemistry , Isfahan University of Technology ,
Isfahan, 84156, IR Iran
b Department of Chemistry, Faculty of Science ,
Imam Khomeini International University , Gazvin,
IR Iran
Published online: 10 Jan 2011.
To cite this article: A. R. Hajipour , H. Imanieh & S. A. Pourmousavi (2004)
1‐Benzyl‐4‐Aza‐1‐Azoniabicyclo[2.2.2]Octane Tribromide as a Highly Reactive
Brominating Agent for Aniline Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:24, 4597-4604, DOI: 10.1081/SCC-200043274
To link to this article: http://dx.doi.org/10.1081/SCC-200043274
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4597–4604, 2004
1-Benzyl-4-Aza-1-Azoniabicyclo[2.2.2]
Octane Tribromide as a Highly Reactive
Brominating Agent for Aniline Derivatives
2
1
A. R. Hajipour,1, H. Imanieh, and S. A. Pourmousavi
*
1Pharmaceutical Research Laboratory, College of Chemistry,
Isfahan University of Technology, Isfahan, IR Iran
2Department of Chemistry, Faculty of Science, Imam Khomeini
International University, Gazvin, IR Iran
ABSTRACT
Reaction of anilines with 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane
tribromide (3) in the presence of CaCO3 in small amounts of methanol
gave brominated aromatic amines in good yields at room temperature.
The isolation of products is straightforward.
Key Words: Aniline; Bromination; Tribromide.
Bromination of organic substrates, particularly aromatic compounds, has
received a significant amount of attention in recent years,[1–4] owing to the
*
Correspondence: A. R. Hajipour, Pharmaceutical Research Laboratory, College
of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran; Fax: þ98-
311-3912350; E-mail: haji@cc.iut.ac.ir.
4597
DOI: 10.1081/SCC-200043274
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4598
Hajipour, Imanieh, and Pourmousavi
considerable commercial importance of such compounds as potent antitumor,
antibacterial, antifungal, antineoplastic, antiviral, and antioxidizing agents[5]
and also as industrial intermediates for the manufacture of pharmaceuticals,
and agrichemicals. Unfortunately, the hazards associated with traditional bro-
mination are not trivial and cannot be ignored. Environmental problems
caused by the use of detrimental chemicals and solvents in classic bromination
are some of the major concerns.[6]
The use of stable solid crystalline brominated complexes have been
reported in several cases,[7–9] but only a few reactions in bromination of aro-
matic amines giving some selective and controlled products in sequential reac-
tions have been reported.[10] The topology of (3) and reactivity of diazonium
ion encouraged us to investigate another brominating complex in order to have
some selective brominated products. In continuation of our research to
develop new reagents for iodination and bromination of aromatic com-
pounds,[11] we wish to report here the preparation of (3) as an inexpensive
starting material. This reagent was prepared straightforward by addition of
an aqueous solution of KBr3 to a solution of 1-benzyl-4-aza-1-azoniabi-
cyclo[2.2.2]octane chloride at room temperature. Stirring the yellowish solu-
tion for 30 min at room temperature resulted in an orange powder that showed
an intense electronic absorbtion at 279 nm typical of tribromide,[12] and this
reagent is soluble in methanol and dichloromethane and insoluble in water
and carbon tetrachloride. Reagent (3) is a very stable compound and can be
stored at bench for months without losing its activity (Sch. 1).
The reagent (3) is an efficient reagent for bromination of aniline deriva-
tives in good to excellent yields. This reagent brominated activated and deac-
tivated aromatic amines (Sch. 2).
We noticed that the presence of methanol markedly facilitated the
bromination of 4. In this case the main active species, which generate Brþ,
Scheme 1.

Highly Reactive Brominating Agent for Aniline Derivatives
4599
Scheme 2.
is probably methyl hypobromite, which was produced from the reaction of (3)
with methanol, which can be employed repeatedly. The generated hydrogen
bromide should be neutralized by additional calcium carbonate.[9] The
probable mechanism is shown in Sch. 3.
The reaction occurs under mild conditions in a few minutes. Interestingly,
in the case of 2-aminobenzoic acid, we obtained 2,4,6-tribromoaniline instead
of 2-amino-3,5-dibromobenzoic acid. This product showed that a carboxylic
acid group can be replaced by bromine in good yield (Sch. 4, Table 1).
The tribromide (3), having advantages of stable solid crystalline, can be
easily handled because of its solid character and availability to be treated
quantitatively as compared with the commonly used liquid bromine. It is
important that this reagent can be reproduced. After extraction of the bro-
moaromatic compounds, the aqueous layer was treated with a fresh bath of
the aqueous Br2 to regenerate the reagent 3 in quantitave yield. This means
that the complex can be considered to be a Br2 transfer agent.
In summary it is interesting to mention that this reaction needs only a
few milliliters of inexpensive methanol, and the end-point of the reaction
can be easily confirmed by decolorization of the orange-colored solution.
Other advantages of this reaction are straightforward work-up of product by
evaporation of methanol under vacuum and washing the residue with small
Scheme 3.

4600
Hajipour, Imanieh, and Pourmousavi
Scheme 4.
amounts of warm ether to isolate the pure products. Finally, we believe that
the procedure for bromination of aromatic amines using Br23 is a highly
useful method owing to its cost-effectiveness, simplicity, mildness, and
good yields.
EXPERIMENTAL
All yields refer to isolated products after purification. All the products
were confirmed by comparison with authentic samples (mp, TLC, and
1H-NMR).[13–21] All melting points were taken on a Gallenkamp melting
1
apparatus and are uncorrected. H-NMR spectra were recorded on a Varian
EM-390 NMR spectrometer operating at 90 or 300 MHz. The spectra were
measured in CDCl3 (unless otherwise stated) relative to TMS.
Preparation of 1-Benzyl-4-Aza-1-Azoniabicyclo[2.2.2]Octane
Tribromide (3)
To a stirring solution of KBr (11.9g, 0.1 mol) in water (200mL) was added
bromine dropwise (16.0 g, 0.1 mol) at room temperature. After 30min the
bromine color disappeared and KBr3 was formed. To a solution of 1-benzyl-4-
aza-1-azoniabicyclo[2.2.2]octane chloride (2)[22] (24.8 g, 0.1 mol) in water
(200 mL) was added the KBr3 solution dropwise until a yellow precipitate was
formed. After stirring 30min, the reaction mixture was filtered and washed
with water (3 ꢀ 30mL). The filtered cake was dried under vacuum and resulted
in yellow crystals (40.0g, 90% yield), which decomposed at 181–1838C to a
dark-brown material. IR (KBr): y ¼ 3050 (m), 1600 (s) 1460 (s), 1360 (s),
1
1040(m), 1210 (s), 840 (m), 800 (m) cm21, H-NMR: d 3.52–3.57 (t, 6H),
3.68–3.72 (t, 6H), 4.73 (s, 2H), 7.57 (s, 5H), 13CNMR: d 131.1, 128.9, 127.5,
124.7, 112.4, 48.8, 42.1. UV (CH2Cl2) lmax: 279 nm, Anal. Calc. for
C13H19N2Br3: C, 35.24; H, 4.32; N, 6.32%. Found: C, 35.55; H, 4.21; N, 6.53%.

Highly Reactive Brominating Agent for Aniline Derivatives
4601
Table 1. Bromination of anilines (4) by reagent (3).
mp 8C or
bp 8C/
mmHg
(lit.)[13–21]
Molar
ratio
(3/4)
Compounds
(4)
Time
(min)
Yield
(%)b
Entry
Product (5)a
4a
3/1
2/1
10
94
121
(112)
4b
4c
4d
10
95
121
(122)
2/1
2/1
15
15
90
92
101–102
(103–104)
94–95
(95.5)
4e
4f
2/1
2/1
2/1
5
5
90
95
90
38–40
(39–40)
38–40
(39–40)
4g
25
77–78
(79)
4h
4i
3/1
2/1
30
45
85
80
127
(127)
119–121
(120.5)
(continued)

4602
Hajipour, Imanieh, and Pourmousavi
Table 1. Continued.
mp 8C or
bp 8C/
mmHg
(lit.)[13–21]
Molar
ratio
(3/4)
Compounds
(4)
Time
(min)
Yield
(%)b
Entry
Product (5)a
4j
2/1
2/1
2/1
40
15
25
85
85
80
204–206
(206–207)
4k
4l
48–49
(48–49)
276/740
(275/740)
4m
4n
3/1
3/1
60
25
80
90
178–179
(180)
120–122
(122)
4o
4p
4q
2/1
4/1
4/1
15
20
20
90
90
85
116–117
(118–119)
120–122
162–165
aAll isolated products are known and their spectra and physical data have been reported
in literature.
bPure product.
Bromination of Aniline Derivatives (4a–q)
A typical procedure: To a solution of aniline (4a) (0.19 g, 2 mmol) in
methanol (10 mL) was added (3) (2.66 g, 6 mmol) and CaCO3 (0.6 g, 6 mmol).

Highly Reactive Brominating Agent for Aniline Derivatives
4603
The reaction mixture was stirred for 10 min at room temperature; meanwhile,
decolorization of orange solution took place. When TLC showed complete dis-
appearance of aniline, the solvent was evaporated and the solid residue was
washed with ether (4 ꢀ 40 mL) and filtered off. The combined organic layers
were dried on MgSO4 and evaporated under vacuum to give 2,4,6-tribromoani-
line(5a),whichwasrecrystallizedinmethanol/water(1 : 3)ascolorlessneedles
in 94% yield (0.62 g).
4,40-diamino-3,5,3050-tetrabromo-diphenylether (4p): m.p. 120–122,
1H-NMR: d 3.7–3.9 (broad, 4H), 4.1(s-2H), 7.5 (s-4H).
4,40-diamino-3,5,3050-tetrabromo-diphenylmethane (4q): m.p. 162–165,
1H-NMR: d 4.2–4.6 (broad, 4H), 7.3 (s, 4H).
Regeneration of Reagent (3)
After the residue was washed with ether and filtrated, the filtered cake was
washed with water (3 ꢀ 20) to dissolve the 1-benzyl-4-aza-1-azoniabicyclo
[2.2.2]octane bromide and separate the inorganic salt that is insoluble in
water (CaCO3) by filtration. Then, to the combined aqueous solution was
added a batch of bromine solution (0.96 gr 6 mmol in 50 mL water) during
30 min to obtain (3) as yellow crystals (2.32 gr 90% yield).
ACKNOWLEDGMENT
Partial support of this work by the Isfahan University of Technology
(IUT), Research Council is gratefully acknowledged. Further financial
support from the Center of Excellency in Chemistry Research (IUT) is grate-
fully acknowledged.
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Received in UK August 7, 2004