A simple and efficient catalytic system for N-arylation of imidazoles in water

Article abstract of DOI:10.1002/chem.200901232

A study was conducted to develop a simple and efficient catalytic system for N-arylation of immidazoles in water. Demonstrations revealed that the catalytic system contained a number of significant advantages. Some of these advantages included the use of water as a green solvent in place of volatile organic solvents and the catalysis was performed without an inert gas atmosphere and with low catalyst loading. Investigations revealed that the presence of catalyst and PTC were essential for the catalysis reaction. The scope of aryl halide substrates was investigated by using the catalytic system under the optimized reaction conditions. It was also demonstrated that the catalytic system tolerated a variety of functionalized aryl halides in the reaction, including nitrile, nitro, acetyl, and ether groups. The new catalytic system was applied to a variety of imidazole derivatives to expand the scope of the methodology.

Full text of DOI:10.1002/chem.200901232

COMMUNICATION
DOI: 10.1002/chem.200901232
A Simple and Efficient Catalytic System for N-Arylation of Imidazoles in
Water
Yi Wang, Zhiqing Wu, Lixia Wang, Zhengkai Li, and Xiangge Zhou*[a]
N-Aryl imidazoles are key structural motifs in a wide
range of agrochemicals, pharmaceuticals, and biologically
active compounds[1] and have been exploited as important
precursors of versatile N-heterocyclic carbenes,[2] a powerful
class of ligands for transition-metal catalysis[3] or room-tem-
perature ionic liquids.[4] A traditional method of introducing
this functionality is nucleophilic aromatic substitution of
imidazole with activated aryl halides (SNAr reactions) or
classic Ullmann-type coupling reactions.[5] However, these
well-known methods suffer from several drawbacks, such as
high reaction temperature, stiochiometric amounts of metal
reagents, and low functional-group tolerance, which has lim-
ited their applications. Recently, Buchwald et al.[6] and Tail-
lefer et al.[7] found several N- and O-based ligands could
greatly facilitate the copper-catalyzed path for the N-aryla-
tion of imidazoles. After the discovery of these ligands,
were directed towards performing the N-arylation reaction
by using water as the sole reaction medium.
To date, salen ligands have been recognized as one of the
most efficient auxiliaries, and many metallosalen complexes
are used as excellent catalysts in various organic transforma-
tions.[10] Herein we report the first example the N-arylation
of imidazoles directly catalyzed by sulfonato–CuACHTUNGTRENNUNG(salen)
complex 1 under mild conditions in water with satisfactory
results. This catalytic system contains several advantages:
1) Water, a green solvent, is used in place of volatile organic
solvents; 2) the catalysis reactions could be performed with-
out an inert gas atmosphere and with low catalyst loading;
3) the work-up procedure is simple with excellent yields;
4) the catalyst could be easily recovered and used again.
As shown in Scheme 1, catalyst 1 could be conveniently
synthesized in 82% yield by a one-pot reaction of three
ACHTUNGTRENNUNGinterest in this field has in-
creased spectacularly in the last
few years[8] and resulted in the
golden age of copper-catalyzed
Ullmann-type coupling reac-
tions. While many important re-
sults have been achieved via
this methodology, it is worth
noting that these protocols are
generally operated in volatile
organic solvents with transition-
Scheme 1. Preparation of catalyst 1.
metal ions. From the standpoint of green chemistry, the de-
velopment of more environmentally benign reaction media,
such as water, in place of organic solvents would be desira-
ble.[9] Henceforth, as part of our endeavors toward the de-
velopment of environmentally friendly protocols, efforts
components, o-phenylenediamine, 5-sulfonatosalicylalde-
hyde, and copper acetate, in methanol/H2O according to a
modified literature method.[11] The complex is remarkably
soluble in water and stable in air and did not decompose
even after several months.
To optimize the reaction conditions, the catalyzed N-aryl-
AHCTUNGTREGaNNNU tion was performed with imidazole (1.1 equiv) and iodo-
[a] Dr. Y. Wang, Z. Wu, L. Wang, Z. Li, Prof. X. Zhou
Institute of Homogeneous Catalysis
College of Chemistry, Sichuan University
Chengdu 610064 (China)
benzene (1 equiv) in the presence of complex 1 (2 mol%), a
base (2 equiv), and (nBu)4NBr as the phase-transfer catalyst
(PTC; 5 mol%) in water. As shown in Table 1, comparison
of the various bases revealed that NaOH and KOH gave the
best yields of around 100% (Table 1, entries 3 and 4),
whereas only a trace amount of product was found when or-
Fax : (+86)28-85412026
E-mail: zhouxiangge@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901232.
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Table 1. Screening reaction conditions for N-arylation of imidazole with
iodobenzene.
Table 2. N-arylation of imidazole with different aryl halides catalyzed by
complex 1.
Entry Catalyst [%] PTC [%] Base
t [h] T [oC] Yield[a] [%]
Entry
1
ArX
Product
Yield[a] [%]
86
1
2
2
2
2
2
2
–
2
2
2
2
5
Cs2CO3
18
18
12
12
24
100
100
100
100
100
100
100
100
25
88
75
2
3
4
5
6
7
8
9
10
11
5
5
5
5
5
–
5
5
5
NaOH
KOH
Et3N
100
100
<1
<1
0
Pyridine 24
NaOH
NaOH
NaOH
NaOH
NaOH
12
12
24
24
18
2
78
32
5
50
23
80
91
3
4
5
93
85
82
[a] Yields were determined by GC/MS with 1,4-dichlrobenzene as inter-
nal standard.
ganic bases, such as triethylamine or pyridine, were used
(Table 1, entries 5 and 6). Therefore, the more inexpensive
NaOH was chosen for further catalysis reactions. Mean-
while, the control experiments showed that the presence of
catalyst and PTC was crucial for the catalysis. No product
was detected in the absence of catalyst, and only a 32%
yield was obtained in the absence of the PTC (Table 1, en-
tries 7 and 8). In addition, low temperatures decelerated the
reaction rate and led to lower yields (Table 1, entries 9–11).
The scope of aryl halide substrates was then investigated
by using the catalytic system under the optimized reaction
conditions. As shown in Table 2, most of the substituted aryl
iodides and electron-deficient aryl bromides afforded N-aryl
imidazole products 2–12 in water with excellent yields
ranged from 78 to 93%. However, the arylation of electron-
rich aryl bromides resulted in lower yields (41–64%) even
with a longer reaction time of 24 h (Table 2, entries 10–13).
Furthermore, the catalytic system could tolerate a variety of
functionalized aryl halides in the reaction, including nitrile,
nitro, acetyl, and ether groups (Table 2, entries 5–7, 10). On
the other hand, imidazole could be selectively arylated by
aryl halides with hydroxyl or amino group in good yields
without formation of diaryl ether or diaryl amine (Table 2,
entries 12 and 13); usually these functional groups should be
protected before catalysis, as reported previously.[12]
6
85
7
79
8
81
9
88
10
41[b]
11
12
13
47[b]
58[b]
64[b]
In an endeavor to expand the scope of the methodology,
this new catalytic system was applied to a variety of imida-
zole derivatives (see Table 3). To our delight, most of the
imidazole derivatives and indole exclusively afforded the
corresponding products in good to excellent yields (73–
97%) under the optimized reaction conditions. Note that
the sterically hindered 2-methylimidazole could undergo se-
lective N-arylation with 4-nitrobromobenzene and 2-bromo-
pyridine to give yields of 82 and 80%, respectively (Table 3,
entries 6 and 7). The more sterically hindered 2-ethyl-4-
methylimidazole was also coupled with 2-bromopyridine to
[a] Isolated yields. [b] Reaction time: 24 h.
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N-Arylation of Imidazoles in Water
COMMUNICATION
Table 3. Sulfonato–CuACHTUNGTRENNUNG(salen)-catalyzed N-arylation of aryl halides with
In summary, we have developed a simple, highly efficient,
and environmentally friendly protocol of sulfonato–Cu-
other imidazoles.[a]
AHCTUNGTREG(NNUN salen)-catalyzed N-arylation of imidazoles in water with a
low catalyst loading (2%) and cheap base. This method
avoids the use of stringent inert conditions. In addition, the
catalyst can be easily recovered and reused. Overall, we be-
lieve that this catalyst system could provide an important
complement to the Pd- or Cu-catalyzed methods that have
already been used in a number of applications.
Entry Het-NH
ArX
Product
Yield[b] [%]
1
81
Experimental Section
2
3
4
97
92
88
Preparation of catalyst 1: CuACTHNUTRGNE(NUG OAc)2 (0.012 mol, 2.18 g) was added to a
solution of o-phenylenediamine (0.01 mol, 1.08 g) and 5-sulfonatosalicy-
laldehyde (0.02 mol, 4.5 g) in methanol/H2O (10:1, 30 mL). The mixture
was stirred at 608C for 6 h and then filtered. After filtration, the precipi-
tate was washed with dichloromethane to remove unreacted CuACHTUNGTRENNUNG(OAc)2.
The solid product was collected and dried under vacuum to afford the de-
sired complex 1 (4.7 g; 82% yield). IR (Nujol): n˜ =1610 (C=N); 1036,
1116 (SO3); 443 cmÀ1
ACTHNUGRTENUNG(Cu-N); MS (negative): m/z (%): 536 (100%?)
[MÀ2Na]+; elemental analysis calcd (%) for C20H12N2O8S2Na2Cu: C
41.28, H 2.08, N 4.81; found: C 41.35, H 2.21, N 4.80.
Typical procedure for the catalysis: Imidazole (1.1 mmol), catalyst
(12 mg, 0.02 mmol), (nBu)4NBr (16 mg, 0.05 mmol), aryl halide (1 mmol),
NaOH (80 mg, 2 mmol), and water (3 mL) were added to a sealed tube.
The reaction mixture was stirred at 1008C for 12 h and then cooled to
room temperature and extracted with ethyl acetate. The organic layer
was then dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure. The N-arylated product was finally obtained by
column chromatography on silica gel. All the products were confirmed
by 1H and 13C NMR spectroscopic analysis. See the Supporting Informa-
tion for full details.
5
6
7
94
82
80
Acknowledgements
This project was sponsored by Natural Science Foundation of China (nos.
20672075 and 20771076) and the Sichuan Provincial Foundation
(08ZQ026-041).
8
73
[a] The reactions were carried out by using the general procedure (see
the Experimental Section). [b] Isolated yields.
Keywords: copper · cross-coupling · homogeneous catalysis ·
sulfonates · water chemistry
give 1-phenyl-2-ethyl-4-methylimidazole 20 in 73% yield
(Table 3, entry 8), which is the first example of the copper-
catalyzed N-arylation of a substituted imidazole in water.
Furthermore, the catalyst could be easily recovered and
reused. For example, after the first coupling reaction be-
tween 4-trifluoromethylbromobenzene and imidazole, which
gave a yield of 88%, the product could be easily separated
from the reaction mixture by extraction with ethyl acetate.
Substrates, PTC, and base were then added to the remaining
aqueous solution that contained the catalyst for the next re-
action. The recycled catalyst could be reused at least three
times and gave quite stable yields of 87, 85, and 84%. The
reusability study of the catalyst indeed constitutes a chal-
lenge of considerable economic and environmental impor-
tance.
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Received: May 9, 2009
Published online: July 8, 2009
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