Regioselective bromination of aromatic amines and phenols using N-benzyl-DABCO tribromide

Article abstract of DOI:10.1080/00397910902898569

N-Benzyl-DABCO tribromide, a stable, solid organic ammonium tribromide, has been used as a bromine source for the regioselective and high-yielding bromination of aromatic amines and phenols. Mono-bromination proceeds well in the presence of a stoichiometric amount of bromine source at room temperature.

Full text of DOI:10.1080/00397910902898569

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Regioselective Bromination
of Aromatic Amines and
Phenols Using N-Benzyl-DABCO
Tribromide
Firouz Matloubi Moghaddam a & Dordaneh Zargarani
a
a Laboratory of Organic Synthesis and Natural
Products, Department of Chemistry, Sharif University
of Technology, Tehran, Iran
Published online: 29 Oct 2009.
To cite this article: Firouz Matloubi Moghaddam & Dordaneh Zargarani (2009):
Regioselective Bromination of Aromatic Amines and Phenols Using N-Benzyl-
DABCO Tribromide, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:23, 4212-4220
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Synthetic Communications1, 39: 4212–4220, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902898569
Regioselective Bromination of Aromatic
Amines and Phenols Using N-Benzyl-DABCO
Tribromide
Firouz Matloubi Moghaddam and Dordaneh Zargarani
Laboratory of Organic Synthesis and Natural Products,
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Abstract: N-Benzyl-DABCO tribromide, a stable, solid organic ammonium
tribromide, has been used as a bromine source for the regioselective and
high-yielding bromination of aromatic amines and phenols. Mono-bromination
proceeds well in the presence of a stoichiometric amount of bromine source at
room temperature.
Keywords: N-Benzyl-DABCO tribromide, bromination, mono-bromoarenes,
organic ammonium tribromides
INTRODUCTION
Bromoaromatics are widely used in the synthesis of a variety of
biologically active compounds, and they are the key intermediates in
the preparation of organometallic reagents. Also, they play significant
roles in organic syntheses by functionalization through carbon–carbon
bond and transition metal–mediated coupling reactions such as Heck,
Stille, Sonogashira, and Suzuki reactions and formation of diarenes,
ethylenic, or actylenic condensation.[1–4]
Received November 1, 2008.
Address correspondence to Firouz Matloubi Moghaddam, Laboratory of
Organic Synthesis and Natural Products, Department of Chemistry, Sharif
University of Technology, P. O. Box 11155-9516, Tehran, Iran. E-mail:
matloubi@sharif.edu
4212

Regioselective Bromination
4213
The traditional electrophilic bromination reaction involves toxic
elemental bromine in the presence of a metal catalyst under harsh
reaction conditions with generation of corrosive hydrobromic acid.
Moreover, handling of hazardous liquid bromine, difficulties in
separation, the production of by-products from side reactions, and the
lack of regioselectivity are disadvantages of classical bromination meth-
ods. To overcome the problems in this context, numerous attempts
at bromoaromatic synthesis have been developed, and several methods
have been reported.[5–11] A variety of brominating agents under various
reaction conditions have been used, which include Br2–Lewis acids,[12]
Br2–zeolite or clay-supported ZnBr2,[13,14] BDMS (bromodimethylsulfo-
nium bromide),[15] NBS (N-bromosuccinimide),[16] Br2–heteropolyacid
cesium salt,[17] Br2=SO2Cl2,[18] hexamethylenetetramine–bromine,[19] and
organic ammonium tribromides (OATBs).[7,20,21]
[21a]
Solid OATBs such as Bu4NBr3
have good stability, ease of
handling, and ability to maintain the desired stoichiometry and thus
are finding increasing applications as an alternative to molecular bromine
in various organic reactions.
Over the past few years, we have synthesized N-benzyl-DABCO-
tribromide (NBDTB) as a new, solid OATB, and we have applied it
for the synthesis of benzothiazols,[22] deprotection of dithioacetals,[23]
and oxidative coupling of benzyl cyanides.[24]
Following our continued interest in NBDTB, herein we report a new
and useful application of NBDTB as a reagent for easier, inexpensive,
high-yielding, and highly regioselective bromination of aromatic
compounds within a short reaction time (Scheme 1).
NBDTB[22] is an efficient, stable, and cheap solid-form reagent,
which is quite soluble in methanol, dichloromethane, and dimethylsulfox-
ide but insoluble in most nonpolar or less-polar solvents such as n-hexane
and diethyl ether. A series of aromatic compounds was subjected to
bromination to furnish the corresponding bromoarenes (Table 1).
Scheme 1. Regioselecive mono-bromination of aromatic compounds using
NBDTB. R: OH, NMe2, NH2, OMe; G: H, electron-releasing or -withdrawing
substituent.

4214
F. M. Moghaddam and D. Zargarani
Table 1. Results of bromination of phenols and amines using NBDTB
T
Yield Mp=bp Mp=bp
(%)a
Entry Substrate (ꢀC) Time (min)
Product
(ꢀC)
(ꢀC)[lit.]
1
2
rt Immediately
rt Immediately
98
53–54
55–56[9]
90
47–50
48–51[19]
3
4
5
rt
rt
45
5
91 102–104 104.5[19]
77
82
63–66
61–63
63[25]
rt Immediately
61–64[19]
6
7
rt
30
80
96
32–34
82–84
33–34[9]
rt Immediately
84[9]
8
40
10
85
223
223[7]
(Continued )

Regioselective Bromination
4215
Table 1. Continued
T
Yield Mp=bp Mp=bp
(%)a
Entry Substrate (ꢀC) Time (min)
Product
(ꢀC)
(ꢀC)[lit.]
9
rt Immediately
63
99–101 100–102[9]
10
rt
30
80 102–104 105[25]
aYields refer to the isolated products.
Our method is based on the in situ generation of Brþ using NBDTB.
Simply by adding NBDTB to a solution of aromatic amines and phenols,
rapid complete conversion and regioselective mono-bromination was
delivered.
Initially, bromination of N,N-dimethylanilin as a model compound
using NBDTB in various solvents was examined. The solvents examined
were dichloromethane, chloroform, and methanol. Chloroform was an
inferior solvent compared to dichloromethane and methanol. Next, the
effect of the amount of the NBDTB was examined in a mixture of
dichloromethane and methanol. The optimum molar ratio of N,N-
dimethylanilin to NBDTB (1:1) in dichloromethane and methanol
(50:50 v=v) was found to be ideal for complete conversion.
In our investigation, electron-rich aromatics such as substituted ani-
lines, phenols, and b-naphthol were found to be the most reactive, and in
those examples where both ortho- and para-substitution was possible,
bromination occur only in para-position and the para-substituted pro-
duct was the only isomer isolated. The para-substituted aromatics were
brominated in the ortho-position (Table 1, Entries 3 and 6).
According to our investigation on the series of aromatics in Table 1,
the best results in terms of good yield and short reaction time were
N,N-dimethylanilin (Entry 1) and b-naphthol (Entry 7). However, pyri-
dine, indole, quinoline, and coumarins could not be brominated by
NBDTB at ambient temperature or even after a prolonged reaction time.
To demonstrate the advantage of this reagent, its activity was com-
pared with different OATBs[7,20b,21] in the bromination reaction. Table 2
shows the results, and it was found that compound NBDTB as

4216

Regioselective Bromination
4217
brominating reagent for anisole, phenol, and b-naphthol gives the best
yield in shorter reaction time under mild reaction conditions.
In conclusion, we have developed a novel and efficient brominating
reagent using NBDTB as an interesting alternative to liquid brominating
reagents for mono-bromination of phenols and substituted anilines at
room temperature with good yield. The mild reaction conditions, rapid
conversion, excellent yields, and high regioselectivity are the impressive
advantages of the present protocol.
EXPERIMENTAL
The compounds all gave satisfactory spectroscopic data. A Bruker
1
(DRX-500 Avance) NMR instrument was used to record the H NMR
spectra. All NMR spectra were determined in CDCl3 at ambient
temperature. Melting points were determined on a Buchi B540
apparatus.
Procedure for Bromination of Aromatic Compounds
NBDTB[22–24] (0.44 g, 1 mmol) was added to a stirred solution of phenol
or amine (1 mmol) in CH3OH–CH2Cl2 (50:50, 6 mL), and the reaction
mixture was stirred at room temperature for the required time (see
Table 1). Upon the completion of reaction (monitored by thin-layer chro-
matography), the reaction mixture was washed with two portions of
water (15 mL). The organic layer was separated and dried over MgSO4.
Evaporation of the solvent gave the desired pure product.
Spectral Data of the Selected Products
N,N-Dimethyl-4-bromoaniline (Entry 1, Table 1)
1H NMR (CDC13, 500 MHz) d (ppm): 2.98 (s, 6H), 6.66 (d, J ¼ 8.9 Hz,
2H), 7.37 (d, J ¼ 8.9 Hz, 2H); 13C NMR (CDC13, 125 MHz) d (ppm):
149.8, 132.1, 114.6, 109.1, 41.0.
2-Bromo-4-nitroaniline (Entry 3, Table 1)
1H NMR (CDC13, 500 MHz) d (ppm): 4.88 (s, 2H), 6.78 (d, J ¼ 8.9 Hz,
1H), 8.07 (dd, J ¼ 6.5 Hz, 2.5 Hz, 1H), 8.41 (d, J ¼ 2.5 Hz, 1H).

4218
F. M. Moghaddam and D. Zargarani
4-Bromophenol (Entry 5, Table 1)
1H NMR (CDC13, 500 MHz) d (ppm): 5.45, (s, 1H), 6.77 (d, J ¼ 8.9 Hz,
2H), 7.38 (d, J ¼ 8.9 Hz, 2H).
1-Bromo-2-naphthol (Entry 7, Table 1)
1H NMR (CDC13, 500 MHz) d (ppm): 5.96 (s, 1H), 7.31 (d, J ¼ 8.8 Hz,
1H), 7.45 (t, J ¼ 7.5 Hz, 1H), 7.62 (t, J ¼ 7.7 Hz, 1H), 7.79 (d, J ¼ 8.8 Hz,
Hz, 1H), 7.83 (d, J ¼ 8.1 Hz, 1H), 8.08 (d, J ¼ 8.5 Hz, 1H); 13C NMR
(CDC13, 125 MHz) d (ppm): 106.5, 117.5, 124.5, 125.7, 128.2, 128.6,
129.7, 130.1, 132.7, 151.0.
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