Highly efficient and reusable copper-catalyzed N-arylation of nitrogen-containing heterocycles with aryl halides

Article abstract of DOI:10.3390/molecules14125169

CuO/AB was found to be a simple and efficient catalyst for the N-arylation of a variety of nitrogen-containing heterocycles, giving the products in excellent yields.

Full text of DOI:10.3390/molecules14125169

Molecules 2009, 14, 5169-5178; doi:10.3390/molecules14125169
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Highly Efficient and Reusable Copper-Catalyzed N-Arylation of
Nitrogen-Containing Heterocycles with Aryl Halides
A Young Kim 1, Hyun Ju Lee 1, Ji Chan Park 2, Hyunju Kang 1, Haesik Yang 1, Hyunjoon Song 2
and Kang Hyun Park 1,*
1
Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National
University, Busan 609-735, Korea; E-Mails: cuteangel02@hanmail.net (AY.K.);
hjloveth486@naver.com (H.J.L.); asteria818@hanmail.net (H.K.); hyang@pusan.ac.kr (H.Y.)
2
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, Korea;
E-Mails: whiteprince@kaist.ac.kr (J.C.P.); hsong@kaist.ac.kr (H.S.)
* Author to whom correspondence should be addressed; E-Mail: chemistry@pusan.ac.kr.
Received: 10 November 2009; in revised form: 4 December 2009 / Accepted: 9 December 2009 /
Published: 10 December 2009
Abstract: CuO/AB was found to be a simple and efficient catalyst for the N-arylation of a
variety of nitrogen-containing heterocycles, giving the products in excellent yields.
Keywords: N-arylation; copper; heterocycles; heterogeneous catalyst; acetylene black
1. Introduction
The copper-mediated C-heteroatom (C-N, C-O, C-S, C-P, C-Se), C-C, and C-metal bonds
formations are pivotal transformations that have been developed to include a wide range of substrates.
Specifically, the N-arylation of nitrogen-containing heterocycles is of particular interest as the resulting
products represent important structural motifs of numerous natural products and biologically active
compounds. N-Arylimidazoles, N-arylpyrroles, N-arylpyrazoles, N-arylindoles, and N-aryl-triazoles
have received substantial attention in a variety of fields throughout the chemical, pharmaceutical, and
material sciences [1–6]. Despite the significant progress made in the development of copper catalyzed
coupling reactions of this type, there still exists a need for new methods that involve cheap and
`environmentally sound catalysts [7–9]. Classical Ullmann chemistry, along with closely related
methods, have been known for a full century. This copper-mediated synthesis of biaryl is known as the

Molecules 2009, 14
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Ullmann condensation (synthesis of diaryl ethers, diaryl amines, or diaryl thioethers). (Scheme 1).
During the first 70 years of the 20th century, copper was nearly the only metal usable for aryl-aryl bond
formation, finding initial in the reductive symmetrical coupling of aryl halides, corresponding aromatic
compounds, aryl halides, diaryl ether, N-containing reactants, phenols, and related nucleophilic agents
[10–18]. Relatively mild and highly efficient CuI-catalyzed N-arylation procedures for nitrogen-
containing heterocycles (imidazoles, benzimidazoles, pyrroles, pyrazoles, indoles, triazoles) with aryl
and heteroaryl halides have also been developed [19–22]. In this paper, the CuO hollow nanospheres
were used to catalyze the N-arylation of nitrogen-containing heterocycles with aryl halides.
Scheme 1. Ullmann condensation.
Ullmann
1903
HNu
Nu
X
+
HNu = NHRR', HOAr, HSR
2. Results and Discussion
In the present study, an approach for gram-scale synthesis of uniform Cu2O nanocubes by a one-pot
polyol process was developed [23]. The CuO hollow nanospheres were prepared by adding an aqueous
ammonia solution to the Cu2O nanocube colloidal solution. The CuO hollow nanospheres were then
immobilized onto acetylene black (AB) or charcoal. Thus, these immobilized CuO hollow nanospheres
overcome the issue of reuse [24].
2.1. Catalyst characterization
The Cu2O nanocubes prepared by a polyol process were transformed into CuO hollow nanospheres
by a controlled oxidation reaction using an aqueous ammonia solution. Addition of ammonia solution
(2.0 mL, 3.7 M) into a Cu2O colloidal solution gave the CuO hollow nanospheres. The transmission
electron microscopy (TEM) image in Figure 1a shows the regular hollow shape of the CuO particles.
The CuO hollow spheres were obtained as (103 ± 8)-nm-sized, highly monodisperse nanoparticles
(Figure 1d). The crystalline features of the hollow spheres are represented in the XRD data
(Figure 1c). The main peaks at θ = 35o and 39o were assigned to the reflections of the (002)/(11–1)
and (111)/(200) planes in the CuO phase (JCPDS No. 48-1548). The CuO hollow particles were
immobilized on acetylene carbon black through a simple sonication method at room temperature. The
TEM image in Figure 1b shows that the immobilized CuO hollow spheres were well dispersed,
isolated, and maintained their original size and structure with an average diameter of approximately
100 nm. The absolute amount of copper metal on the acetylene black was determined by inductively
coupled plasma-atomic emission spectroscopy (ICP-AES). The CuO hollow spheres on the acetylene
black showed excellent activity towards a wide range of azides and acetylenes.

Molecules 2009, 14
Figure 1. (a) TEM image, c) XRD pattern, d) size distribution diagrams of the CuO hollow
5171
nanospheres, and (b) TEM image of the CuO hollow nanospheres on acetylene black
(CuO/AB). The scale bars represent 100 nm.
2.2. Reaction test
Prior research studies that have tested catalyst effectiveness have employed iodobenzene and
pyrrole as benchmark substrates (Scheme 2).
Scheme 2. Test reaction.
CuO/AB
I
N
HN
+
Toluene
The N-arylation of iodobenzene (0.17 mL, 1.5 mmol) and pyrrole (0.15 mL, 2.25 mmol) with
CuO/AB in toluene (7.0 mL), afforded 1-phenyl-1H-pyrrole. As shown in Table 1, 3.0 mol% CuO/AB
in toluene at 180 °C for 8 h gave 1-phenyl-1H-pyrrole in 51% yield (entry 1, Table 1). When the
reaction time was increased to 18 h, an 81% conversion was achieved (entry 2, Table 1). The reaction
temperature was increased to 180 °C through use of a stainless steel reactor. Furthermore, when 5.0
mol% of the catalyst was used, a 22% yield was achieved at 150 °C for, 8 h (entry 3, Table 1). In
general, it was found that increasing reaction temperature and time were effective means of increasing
the conversion (59% for 180 °C, 8 h, entry 4, Table 1). Increasing the reaction time and changing the

Molecules 2009, 14
5172
base to KOH, K2CO3, and KOtBu, gave respective, varied yields of 9, 71 and 72% (entries 5, 6, and 7,
Table 1). After that, in order to exploit the thermally stable properties of the CuO/AB catalyst, reaction
temperature was increased. Placing the reaction in a closed system (stainless steel reactor) at 180 °C
and reacting for 18 h achieved a 92% conversion (entry 8, Table 1). Finally, the optimum reaction
conditions were achieved: N-arylation of iodobenzene (0.17 mL, 1.5 mmol) and pyrrole (0.15 mL, 2.25
mmol) with CuO/AB (70 mg, 5.0 mol%) in Toluene (7.0 mL) at 180 °C for 18 h to afford
1-phenyl-1H-pyrrole. In addition, under optimum reaction conditions, no reaction occurred without a
catalyst. It was also observed via NMR, TLC and column chromatography that no side products, such
as Ar-Ar coupling products, were formed. Remarkably, after the reaction, the CuO on AB as separated
by centrifugation and could be reused ten times under the same reaction conditions, without any loss of
catalytic activity; the maximum reusability has not yet been tested. These results confirm that the
catalytic system presented herein satisfies the conditions for heterogeneous catalysts of ease of
separation, recyclability, and persistence.
Table 1. Screening reaction condition for N-arylation of iodobenzene with pyrrole.
Conv.
Entry
Cat (mol %)
Temp (°C) Time (h)
Base
(%)a
51
81
22
59
9
1
2
3
4
5
6
7
8
3 mol%
3 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
recovered from # 8
recovered from # 9
recovered from # 10
recovered from # 11
recovered from # 12
recovered from # 13
recovered from # 14
recovered from # 15
recovered from # 16
180
180
150
180
180
180
180
180
180
180
180
180
180
180
180
180
180
8
18
8
KOtBu
KOtBu
KOtBu
KOtBu
K2CO3
KOH
8
12
12
12
18
18
18
18
18
18
18
18
18
18
71
72
96
94
92
92
90
96
96
94
96
87
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
9
10
11
12
13
14
15
16
17
a Determined by 1H-NMR. Yields are based on the amount of iodobenzene used.
As transmission electron microscope (TEM) and cyclic voltammograms (CVs) studies prove, the
structure of the CuO hollow nanospheres on acetylene black (CuO/AB) remained unchanged after the
reaction, which is demonstrating catalyst recyclability (Figure 2). CV were measured by using CHI
405A (CH Instruments). 70 μL of a CuO in ethanol was dropped to ITO electrode. After 3 h, the signal
of the reduced CuO on ITO was measured via linear sweep voltammetry. The linear sweep was
voltamogram obtained at CuO ITO electrode in 10 mM tris buffer (pH 7.4) at scan rate of 50 mV/s.

Molecules 2009, 14
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Figure 2. Cyclic voltammograms (CVs) of CuO hollow nanospheres on acetylene black,
before (Dot line) and after the two cycle. (Dash line).
Furthermore, in the case of using various nitrogencontaining heterocycles, good results were
achieved (Table 2). A wide variety of substrates with C-I, C-Br, and C-Cl bonds, as well as
nucleophiles, have been examined. Relative reactivities of halogen-substituted substrates toward the
halophilic attack by a carboanion were also investigated. The following order of relative reactivities
toward the halophilic attack was ascertained: R-I, R-Br or R-Cl, with a bond reactivity order of:
C-I > C-Br > C-Cl (entries 1~3, Table 2). This new catalytic system was also suitable for other
electron-rich nitrogen heterocycles. Experiments on substituted aryl halides were conducted with OH-,
OMe-, and CH3-containing substrates. The results were showing 70% conversion yield in case of
4-bromo-phenol while only a low yield was obtained in case of 1-bromo-4-methoxybenzene. In one
case, the use of 1-chloro-4-methylbenzene resulted in lower obtained yields (entry 6, Table 2).
Unfortunately, no reaction occurred in case of p-chloroacetophenone. It is worth noting that these
optimized conditions could be applied to the N-arylation of other imidazole derivatives. (pyrroles,
pyrazoles, imidazoles; Table 2). For example, the N-arylation of 1H-pyrazole with iodobenzene
afforded the corresponding 1-phenyl-1H-pyrazole in 96% conversion yield (entry 7, Table 2). In
addition, the coupling of 1H-imidazole with iodobenzene affords the 1-phenyl-1H-imidazole. Further
investigation of the reaction of iodobenzene with other heteroarylamines, as well as aniline, under the
optimized conditions was also undertaken. Pyridin-3-amine, and pyrimidin-2-amine heteroarylamines
gave the expected diphenylamine, N-phenylpyridin-3-amine, and N-phenylpyrimidin-2-amine with
good conversion (entries 11 and 12, Table 2). Such a result shows a similar yield albeit with shorter
reaction time (24 h–40 h), compared with known literature [25–28].

Molecules 2009, 14
Table 2. CuO/AB catalyzed N-arylation of various Nitrogen-containing Heterocycles with
5174
Aryl Halides.
R2
R3
R2
R3
5 mol% CuO/AB
N
X
X
HN
+
KOtBu, Toluene
180 oC, 18h
R1
Product
R1
Conv. (%)a
Entry
Aryl Halides
Heterocycles
96 (X = I). 80b
80 (X = Br)
74 (X = Cl)
1
2
3
HN
N
N
4
5
6
7
8
HN
70
34
Br
Br
HO
HO
MeO
HN
HN
N
N
MeO
H3C
H3C
Cl
I
40
N
N
N
N
96
HN
N
N
I
HN
100
H
N
H2N
I
I
I
I
9
26
56
H
N
H2N
H2N
10
11
N
N
H
N
88, 89b
N
N
N
N
H
N
H2N
12
71
N
N
a
1
b
Determined by H-NMR. Yields are based on the amount of aryl halides used; Yields are
isolated yields after column chromatography on silica.

Molecules 2009, 14
3. Experimental
5175
3.1. General remarks
Reagents were purchased from Aldrich Chemical Co. and Strem Chemical Co. and used as
1
1
received. Reaction products were analyzed by H-NMR. H-NMR spectroscopy obtained on a Varian
Mercury Plus (300 MHz). Chemical shift values were recorded as parts per million relative to a
tetramethylsilane internal standard, unless otherwise indicated, and coupling constants in Hertz.
Reaction products were assigned by comparison with the literature value of known compounds. The
CuO and CuO nanoparticles immobilized on acetylene black were characterized by TEM (Philips F20
Tecnai operated at 200 kV, KAIST). Samples were prepared by placing a few drops of the
corresponding colloidal solution on carbon-coated copper grids (Ted Pellar, Inc.). The X-ray powder
diffraction (XRD) patterns were recorded on a Rigaku D/MAX-RB (12 kW) diffractometer. The
copper loading amounts were measured by inductively coupled plasma-atomic emission spectrometry
(ICP-AES).
3.2. General procedure for catalytic N-arylation of nitrogen-containing heterocycles with aryl halides
In a 25 mL stainless steel reactor, CuO hollow nanospheres on acetylene black (CuO/AB) (70 mg,
5.0 mol% with respect to the substrate concentration), iodobenzene (0.17 mL, 1.5 mmol), pyrrole
(0.15 mL, 2.25 mmol), KOtBu (0.34 g, 3.0 mmol), and toluene (7.0 mL) were added. The mixture was
stirred for 18 h at 180 °C. After the reaction, the nanoparticles were separated from the clean solution
by centrifugation and the clean solution analyzed by 300 MHz NMR.
3.3. Synthesis of CuO hollow nanospheres
The CuO hollow nanospheres were synthesized by a controlled oxidation reaction of Cu2O
nanocubes. Typically, Cu2O nanocubes were prepared by a polyol process in 1,5-pentanediol (PD,
Aldrich, 96%) in the presence of poly(vinyl pyrrolidone) (PVP, Aldrich, Mw = 55,000). The PVP
(5.3 g) dissolved in 45.0 mL of 1,5-pentanediol (PD, Aldrich, 96%), was slowly heated to 240 °C
under a nitrogen atmosphere. Then, 4.0 mmol of Cu(acac)2 (Strem, 98%), dissolved in 15 mL of PD,
was injected into the hot PVP solution at 240 °C and the mixture allowed to stir for 15 min at the same
temperature. The yellowish colloidal dispersion was cooled to room temperature and precipitated by
adding acetone followed by centrifugation at 8,000 rpm for 20 min. The precipitated Cu2O particles
were washed with ethanol several times and re-dispersed in ethanol. To obtain the CuO hollow
nanospheres, an aqueous ammonia solution (2.0 mL, 3.7 M) was added into 25.0 mL of the Cu2O cube
dispersion in ethanol (16.0 mM with respect to the precursor concentration). The mixture was then
stirred at room temperature for 2 h. After the reaction, the final products were collected by
centrifugation at 6,000 rpm for 20 min.

Molecules 2009, 14
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3.4. Immobilization of CuO hollow nanospheres on acetylene carbon black (CuO/AB) and charcoal
(CuO/C)
The acetylene carbon black (Strem, 99.99%, 1.2 g) was mixed with the CuO hollow nanosphere
dispersion in ethanol (100 mL, 17.0 mM), and the reaction mixture sonicated for 1 h at room
temperature. After 1 h, the product CuO/AB was washed with ethanol several times and vacuum dried
at room temperature. For the synthesis of CuO/C, the mixture solution of charcoal (0.8 g) and CuO
hollow nanosphere dispersion in ethanol (50.0 mL, 50.0 mM) was refluxed for 4 h. After 4 h, the black
suspension was cooled to room temperature and precipitated by centrifugation. The product CuO/C
was washed with ethanol thoroughly and dried in a vacuum oven at room temperature.
4. Conclusions
In conclusion, an environmentally sound process for CuO/AB catalyzed N-arylation has been
developed, for a variety of nitrogen-containing heterocycles with aryl halides. In addition, the CuO/AB
was readily separated by centrifugation and could be reused ten times under the present reaction
conditions without any loss of catalytic activity. Transition metals loaded on acetylene black were
useful reagents for a wide variety of organic transformations. Moreover, these heterogeneous systems
are promising industrial catalysts with the concept of chemical economy. Further studies to expand the
applications of the catalytic system are underway in this laboratory.
Acknowledgements
This research was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-
0070926) and by the Korean Research Foundation Grant (KRF-2006-312-C00565).
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Sample Availability: Samples of the compounds are available from the authors.
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