Efficient and reusable catalytic system of Cul-PEG for n-arylation of imidazoles

Article abstract of DOI:10.1080/00397911.2010.523149

A simple, efficient, and recyclable catalytic system of CuI-poly(ethylene glycol) (PEG) was developed for the N-arylation of imidazoles with aryl halides to afford corresponding N-arylimidazoles in good to excellent yields under mild conditions and free of any additional ligands and solvents. The isolation of the products was readily performed by simple extraction with ether, and the catalytic system could be reused without remarkable loss of activity even after six runs.

Full text of DOI:10.1080/00397911.2010.523149

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Efficient and Reusable Catalytic System
of CuI-PEG for N-Arylation of Imidazoles
Qiang Zhang a , Jun Luo a & Yunyang Wei a
a School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing, China
Accepted author version posted online: 30 Jun 2011.Published
online: 14 Sep 2011.
To cite this article: Qiang Zhang , Jun Luo & Yunyang Wei (2012) Efficient and Reusable
Catalytic System of CuI-PEG for N-Arylation of Imidazoles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:1, 114-121, DOI:
10.1080/00397911.2010.523149
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Synthetic Communications1, 42: 114–121, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523149
EFFICIENT AND REUSABLE CATALYTIC SYSTEM
OF CuI-PEG FOR N-ARYLATION OF IMIDAZOLES
Qiang Zhang, Jun Luo, and Yunyang Wei
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing, China
GRAPHICAL ABSTRACT
Abstract A simple, efficient, and recyclable catalytic system of CuI–poly(ethylene glycol)
(PEG) was developed for the N-arylation of imidazoles with aryl halides to afford corre-
sponding N-arylimidazoles in good to excellent yields under mild conditions and free of any
additional ligands and solvents. The isolation of the products was readily performed by
simple extraction with ether, and the catalytic system could be reused without remarkable
loss of activity even after six runs.
Keywords Copper; N-arylimidazoles; PEG; Ullmann-type coupling
INTRODUCTION
Nitrogen-containing heterocycles such as N-arylimidazoles play an important
role in a wide range of pharmaceuticals,[1] biologicals,[2] natural products,[3] and
N-heterocyclic carbene chemistry.[4] Traditionally, these N-arylimidazoles have been
prepared by nucleophilic substitution of imidazoles with electron-deficient aryl
halides or the classical Ullmann-type coupling.[5] However, these well-known meth-
ods generally suffer from several drawbacks, such as reaction temperature as high
as 200 ꢀC, use of stoichiometric amounts of copper reagents, moderate yields, and
poor substrate scope. In some instances, palladium catalysts assisted by some phos-
phine ligands have been employed to make the reaction take place under mild
conditions.[6] Recently, Buchwald et al.[7] and Taillefer et al.[8] have discovered and
developed copper catalytic paths for the N-arylation of nitrogen-containing herero-
cycles with aryl halides in the presence of N- and O-based ligands under relatively
mild conditions. From then on, a number of copper-catalyzed coupling reactions with
various ligands have been reported.[9] Nevertheless, these methods are generally
Received January 14, 2010.
Address correspondence to Jun Luo, School of Chemical Engineering, Nanjing University of
Science and Technology, Nanjing 210094, China. E-mail: luojun@mail.njust.edu.cn
114

CuI-PEG FOR N-ARYLATION OF IMIDAZOLES
115
performed in volatile organic solvents and in nonrecyclable catalytic systems. Hence,
the development of simple and green methods for the C-N coupling reaction is of
particular value.
Poly(ethylene glycol) (PEG) has been successfully used as a reaction medium
for metal-catalyzed reactions with easy recycling of solvents and catalysts.[10] In
addition, because PEG is inexpensive, readily available, easily degradable, and less
toxic, many studies have also covered PEG chemistry.[11] Herein, we report a simple
and efficient N-arylation of imidazoles with aryl halides in a recyclable catalytic
system of CuI-PEG.
RESULTS AND DISCUSSION
The N-arylation of imidazole and bromobenzene was selected as the model
reaction to optimize the reaction conditions, and the results are shown in Table 1.
Some readily available copper sources were investigated, and it was found that CuI
sources were more favored (entries 1–5), which is in agreement with the previous
reports.[9a,9b,12] As CuI turned out to give the best result, it was chosen as the standard
Cu source for the following experiments. Subsequently, various bases were screened.
Cs2CO3, K2CO3, K3PO4 ꢁ 3H2O, and KOH were found to be highly effective (entries
2, 8–10). Other inorganic bases such as KF, Na2CO3, and NaOAc led to moderate
yields (entries 11–13), while NEt3 and dimethylaminopyridine (DMAP) proved to
be inefficient bases (entries 14 and 15). Therefore, the cheap and mild base K2CO3
was chosen as the standard base. Moreover, all the PEGs tested afford similar results
(entries 2 and 18–20). Because PEG200 had less viscosity, it was chosen as the medium.
The control experiments showed that the presence of catalyst, base, and PEG was
crucial for the reaction. No product was detected in the absence of copper salt, while
only 31% yield was obtained in the absence of base (entries 6 and 7), and 52% yield
was obtained in the absence of PEG (entry 16). In addition, the catalytic reactions
performed in air afforded the product with 82% yield (entry 22), and at lower
temperature (90 ꢀC) only moderate yield was obtained (entry 23).
With the optimal conditions in hand, different aryl halides were used for
N-arylation of imidazole in the presence of 10 mol% CuI and 2 equiv of K2CO3 in
PEG200 at 110 ꢀC under N2, and the results are listed in Table 2. The results indicated
clearly that this method was applicable for N-arylation of imidazole with a variety of
aryl bromides, and the yields were also good (64–96%) (entries 1–10). In general, sub-
strates possessing electron-withdrawing groups (such as p-NO2, p-CF3, and m-CF3
groups) proceeded quickly to give excellent yields (entries 1–3). Bromoarenes bearing
electron-donating groups (such as p-CH3, p-OH, p-OMe, and o-OMe) afforded coup-
ling products with moderate to excellent yields ranging from 64% to 90% with longer
reaction time (up to 48 h) (entries 5–8). It is noteworthy that the reaction was highly
chemoselective; for example, the coupling reaction between 1-bromo-4-chloroben-
zene and imidazole gave N-(4-chlorophenyl) imidazole as the sole product (Table 2,
entry 9). In particular, imidazole could be selectively arylated by 4-bromophenol in
satisfactory yields without formation of diaryl ether (entry 8). As usual, free hydroxyl
should be protected before N-arylation.[13] Attempts to use chlorobenzene as aryl
source failed; however, the employment of several aryl chloride possessing
electron-withdrawing groups (such as p-NO2, o-NO2, and p-CF3 groups) led to the

116
Q. ZHANG, J. LUO, AND Y. WEI
Table 1. N-Arylation of imidazole with bromobenzene under different reaction conditionsa
Entry
Cu cat.
Base
PEG
Yield (%)b
1
2
Cu(OAc)2 ꢁ H2O
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
PEG200
—
89
97
93
87
85
0
3
CuBr
CuCl
Cu
4
5
6
—
CuI
7
31
98
95
97
82
65
70
28
24
52c
95d
97
96
95
85e
82f
61g
8
CuI
CuI
Cs2CO3
K3PO4 ꢁ 3H2O
KOH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuI
CuI
KF
CuI
CuI
Na2CO3
NaOAc
NEt3
CuI
CuI
DMAP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CuI
CuI
—
CuI
CuI
PEG600
PEG1000
PEG2000
PEG200
PEG200
PEG200
CuI
CuI
CuI
CuI
aReaction conditions: bromobenzene (2.0 mmol), imidazole (2.4 mmol), and base (4.2 mmol) in the
presence of 10 mol% of Cu catalyst in 3 mL of PEG at 110 ꢀC for 24 h under N2.
bDetermined by GC-MS.
cPure DMSO (3 mL) was used instead of PEG.
d10 mol% PEG200-DMSO (3 mL) was used.
eThe amount of catalyst is 5 mol%.
fThe catalytic reaction was performed in air.
gThe catalytic reaction was performed at 90 ꢀC.
corresponding coupling product in good to excellent yields (70–95%) (entries 11–13).
Actually, only a few articles have described copper-catalyzed N-arylation of
imidaolze with aryl chlorides.[14]
In an endeavor to expand the scope of the methodology, other p-electron-rich
nitrogen heterocycles such as benzimidazole, 2-methylimidazole, indole, and pyrrole
were coupled with aryl halides to give the corresponding N-arylated products in good
to excellent yields (Table 3). For example, the coupling reaction of 1H-benzimidazole
with bromobenzene afforded the corresponding product in 73% yield (entry 2). The
sterically hindered 2-methylimidazole could also undergo efficient N-arylation with
4-nitrochlorobenzene and 4-bromobenzotrifluoride to give the corresponding pro-
ducts in good yields (entries 4 and 5). Moreover, the N-arylation of indole and pyrrole

CuI-PEG FOR N-ARYLATION OF IMIDAZOLES
117
Table 2. N-Arylation of imidazole with different aryl halides catalyzed by CuI-PEG systema
Entry
Aryl halide
Product
Time (h)
Yield (%)b
1
2
18
18
96
95
3
18
91
4
5
6
24
24
24
93
90
80
7
48
64c
8
9
24
24
36
24
82
86
85
95
10
11
12
13
14
24
36
48
88
70
35
aGeneral reaction conditions: aryl halide (2.0 mmol), imidazole (2.4 mmol), and K2CO3 (4.2 mmol) in
the presence of 10 mol% of CuI in 3 mL of PEG200 at 110 ꢀC under N2.
bIsolated yield.
c20 mol% of CuI.

118
Q. ZHANG, J. LUO, AND Y. WEI
Table 3. N-Arylation of imidazoles with aryl halides catalyzed by CuI-PEG systema
Entry
1
Het-NH
ArX
Product
Yield (%)b
90
2
3
73c
82c
4
5
81
72
6
63
7
8
94
91
aGeneral reaction conditions: aryl halide (2.0 mmol), N-heterocycle (2.4 mmol), K2CO3 (4.2 mmol) in
the presence of 10 mol % of CuI in 3 mL of PEG200 at 110 ꢀC for 24 h under N2.
bIsolated yield.
c36 h at 110 ꢀC.
with iodobenzene could also be conducted smoothly to give excellent yields in 94%
and 91%, respectively (entries 7 and 8).
The recyclability experiment was performed on the coupling of imidazole and
bromobenzene in the CuI-PEG200 system. Notably, isolation of the product and
catalytic system was very simple and convenient. When the final reaction mixture
was cooled to room temperature, diethyl ether was added, and the upper layer of
ether containing product was separated by decantion. The lower layer containing
PEG and Cu catalyst was subjected to a second run of the N-arylation by charging
it with fresh imidazole, bromobenzene, and potassium carbonate. The procedure was
repeated six times, and the results indicated that the CuI-PEG200 system could be
recycled without apparent loss of catalytic activity (Fig. 1).
In summary, we have developed a simple, highly efficient, and environmentally
friendly method for the N-arylation of imidazoles with aryl halides catalyzed by CuI
in PEG without any additional ligand. Particularly noteworthy are the facts that this
method avoids the use of volatile organic solvents and that the catalytic system can

CuI-PEG FOR N-ARYLATION OF IMIDAZOLES
119
Figure 1. Recycling experiment of the CuI-PEG200 system.
be easily recycled. In addition, this method can be performed simply and tolerates a
variety of functional groups, such as aldehyde, nitro, ether, and free hydroxyl.
Thus, we believe that this method may provide wide application in preparation of
N-arylated products.
EXPERIMENTAL
1H NMR spectra were recorded on Bruker DRX300 (300 MHz). Mass
spectra were obtained with automated Fininigan Trace Ultra-Trace DSQ gas
chromatography–mass spectrometry (GC=MS) spectrometer. All chemicals (analyti-
cal reagent) were commercially available and used without further purification.
General Procedure for the Coupling Reaction
A Schlenk tube with a magnetic stirring bar was charged with imidazole
(2.4 mmol), K2CO3 (4.2 mmol), CuI (0.16 mmol, 10 mol%), aryl halide (2.0 mmol),
and PEG (3 mL). The tube was sealed after being evacuated twice and back filled
with N2. The mixture was stirred at 110 ꢀC for 24 h, cooled to room temperature,
and extracted with diethyl ether (5 ꢂ 10 mL). The upper layers were decanted, com-
bined, and concentrated to the crude product, which was analyzed by GC-MS. The
PEG phase of the lower layer was subjected to a second run with the same substrates.
Further purification of the product was achieved by flash chromatography on a
silica-gel column. All the products, which are known compounds, were
characterized and compared with authentic compounds previously reported in the
literatures.[9a,9b,12,15] Some typical data of products was provided as follows.
Selected Data
1-(4-Trifluoromethylphenyl)-1H-imidazole (Table 2, Entry 2). 1H NMR
(300 MHz, CDCl3) d 7.94 (s, 1H), 7.76 (d, 2H, J ¼ 9.0 Hz), 7.54 (d, 2H, J ¼ 9.0 Hz),
7.34 (s, 1H), 7.25 (s, 1H). GC-MS (EI, m=z): 211.9 [Mþ].

120
Q. ZHANG, J. LUO, AND Y. WEI
1-(3-Trifluoromethylphenyl)-1H-imidazole (Table 2, Entry 3). 1H NMR
(300 MHz, CDCl3) d 7.92 (s, 1H), 7.67–7.61 (m, 4H), 7.34 (s, 1H), 7.26 (s, 1H).
GC-MS (EI, m=z): 211.9 [Mþ].
1-Phenyl-1H-imidazole (Table 2, Entry 4). 1H NMR (300 MHz, CDCl3) d
7.85 (s, 1H), 7.50–7.45 (m, 2H), 7.40–7.34 (m, 3H), 7.27 (s, 1H), 7.20 (s, 1H). GC-MS
(EI, m=z): 144.0 [Mþ].
1-(4-Methoxyphenyl)-1H-imidazole (Table 2, Entry 6). 1H NMR
(300 MHz, CDCl3) d 7.78 (s, 1H), 7.34–7.31 (m, 2H), 7.22 (s, 1H), 7.20 (s, 1H),
7.02–6.99 (m, 2H), 3.87 (s, 3H). GC-MS (EI, m=z): 173.9 [Mþ].
1-(4-Nitrophenyl)-1H-imidazole (Table 2, Entry 11). 1H NMR (300 MHz,
CDCl3) d 8.38 (d, 2H, J ¼ 9.0 Hz), 8.01 (s, 1H), 7.60 (d, 2H, J ¼ 9.0 Hz), 7.41 (s,
1H), 7.31 (s, 1H). GC-MS (EI, m=z): 188.9 [Mþ].
ACKNOWLEDGMENTS
We are grateful for the financial support of the Doctoral Fund of Ministry of
Education of China for New Teachers (No. 200802881029) and the Science and
Technology Development Fund of Nanjing University of Science and Technology
(No. XKF09066).
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