N-Arylation of nitrogen heterocycles with aryl halides and arylboronic acids catalyzed by cellulose supported copper(0)

Article abstract of DOI:10.1016/j.molcata.2006.02.053

Cellulose supported copper(0) catalyst was prepared and employed for the N-arylation of nitrogen heterocycles with a variety of aryl halides and arylboronic acids to afford the corresponding coupled products in good to excellent yields without using external ligands or additives as promoters. The catalyst was recovered by simple filtration and reused for several cycles.

Full text of DOI:10.1016/j.molcata.2006.02.053

Journal of Molecular Catalysis A: Chemical 252 (2006) 136–141
N-Arylation of nitrogen heterocycles with aryl halides and arylboronic
acids catalyzed by cellulose supported copper(0)
K. Rajender Reddy∗, Nadakuditi S. Kumar, B. Sreedhar, M. Lakshmi Kantam∗
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
Received 21 October 2005; received in revised form 17 February 2006; accepted 20 February 2006
Available online 29 March 2006
Abstract
Cellulose supported copper(0) catalyst was prepared and employed for the N-arylation of nitrogen heterocycles with a variety of aryl halides and
arylboronic acids to afford the corresponding coupled products in good to excellent yields without using external ligands or additives as promoters.
The catalyst was recovered by simple filtration and reused for several cycles.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Copper catalyst; Cellulose support; C–N coupling; Imidazole; Aryl halides; Arylboronic acids
1. Introduction
where recyclability of the catalyst could not be achieved and
moreover additional stabilizing ligand or co-oxidant is required.
We are interested to develop a supported copper catalyst,
particularly utilizing naturally occurring biopolymer, cellulose,
which is bio-degradable, environmentally safe, widely abundant
in nature, inexpensive and easy to handle [21]. Cellulose and
its derivatives are widely used in chemical and bio-chemical
applications and also as supports for the synthesis of organic
molecules [22]. Interestingly, it is also observed that cellulose
fibers act as a nanoreactor for the stabilization of metal nanopar-
ticles[23]. However, itsuseasasupportforcatalyticapplications
is not well explored. Recently, Quignard and Choplin reported
cellulose as the support for water soluble Pd(OAc)2/5TPPTS
system in Trost Tsuji allylic alkylation reaction [24]. Similarly
hydrogenation reactions with cellulose derivatives are reported
[25]. Herein, we report N-arylation of imidazoles with aryl-
boronic acids and aryl halides using cellulose supported Cu(0)
catalyst (CELL-Cu(0)).
The metal mediated N-arylation is an important transforma-
tion in organic synthesis and the resulting arylated products have
wide spread applications in pharmaceutical and agrochemical
industries [1–6]. This reaction is generally achieved by the clas-
sical copper mediated Ullmann reaction under harsh reaction
conditions utilizing stoichiometric quantities of copper salts and
activated aryl halides as aryl donors. There are reports describ-
ing hypervalent iodonium salts [7], aryllead [8], arylbismuth [9],
arylstannane [10] and arylsilane [11] as aryl donors using cop-
per salts and a base. However, significant improvement in copper
catalyzed N-arylations is realized after the introduction of aryl-
boronic acids as the aryl donors, independently by Lam et al.
[11c], Chan et al. [12] and Evans et al. [13] in 1998 utilizing sto-
ichiometric amount of Cu(OAc)2. More recently Collman et al.
[14], Antilla and Buchwald [15] and Lam et al. [16] reported the
catalytic version of N-arylation using arylboronic acids. Sim-
ilarly, several copper catalyzed C–N coupling reactions under
mild conditions have been reported using various ligands such as
aliphatic-diamines [17], diimines [18], amido alcohols [19] and
amino acids [20] as promoters using aryl halides as aryl donors.
Most of the above methodologies are homogeneous in nature,
2. Experimental
2.1. Materials
Microcrystalline cellulose was purchased from S.D. Fine
Chem. Ltd., India, and is used as such. Cu(NO3)2·3H2O was
purchased from LOBA Chemie, India. All the boronic acids,
aryl halides and imidazole are purchased from Aldrich.
∗
Corresponding authors. Tel.: +91 40 271 93510; fax: +91 40 27160921.
E-mail address: mlakshmi@iict.res.in (M.L. Kantam).
1381-1169/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2006.02.053

K.R. Reddy et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 136–141
137
2.2. Catalyst preparation
Microcrystalline cellulose (5 g) is added to a solution of 0.1 M
(0.604 g) of Cu(NO3)2·3H2O in distilled water (25 mL), and
stirred for 15 min. Then, hydrazine hydrate (80%, 1 mL) is added
drop wise for 15 min to the above reaction mixture and stirred
for 12 h at room temperature. The grey coloured solid formed is
filtered under nitrogen atmosphere, washed several times with
distilled water, finally with acetone and dried under vacuum
resulting cellulose supported Cu(0) catalyst.
2.3. Characterization
X-ray powder diffraction (XRD) data were collected on a
Siemens/D-5000 diffractometer. The copper content in the sup-
ported catalyst was determined by inductively coupled plasma-
atomic emission spectroscopy (ICP-AES) using Thermo elec-
tron corporation make IRIS Intrepid 11 XDL instrument. X-
ray photoelectronic spectrographs (XPS) are recorded on a
KRATOS AXIS 165 instrument. All the products were charac-
terized by 1H NMR using Varian-Unity 400 MHz NMR Spec-
trophotometer.
Fig. 1. X-ray diffraction patterns of: (a) microcrystalline cellulose and (b)
CELL-Cu(0) catalyst.
attributed to Cu(0) (Fig. 1) [28]. Further, the high resolution
XPS narrow scan (Fig. 2(a)) of the fresh CELL-Cu(0) catalyst
shows a peak at 932.72 of Cu 2p3/2, which is attributed to Cu(0)
[29]. ICP-AES analysis of the catalyst shows the presence of
0.368 mmol/g of copper.
Preliminary experiments are carried out by taking phenyl-
boronic acid as a test molecule for the N-arylation of imidazole
(Scheme 1). In order to determine the best reaction medium, we
tested different solvents such as methanol, 1,2-dichloroethane,
acetonitrile, tetrahydrofuran and toluene. Methanol is found to
be the best solvent for the N-arylation of imidazole (98%). On
the other hand, reaction in other solvents gave trace amount
of coupled product under identical conditions. The nature of
base has a pronounced effect in these reactions. Reaction of
imidazole with phenylboronic acid in presence of K2CO3 and
KOtBu gave no coupled product, while triethylamine and pyri-
2.4. Reaction procedures
2.4.1. General procedure for coupling of imidazole with
arylboronic acids
To a mixture of imidazole (1 mmol), CELL-Cu(0) catalyst
(0.025 g), triethylamine (2 mmol), in methanol (5 mL), aryl-
boronic acid (1 mmol) was added and stirred under reflux. After
completion of the reaction, as indicated by TLC, the reaction
mixture was filtered and washed with methanol. The solvent was
evaporated under reduced pressure and followed a conventional
work up with ethyl acetate and water. The organic layer was sep-
arated, dried over Na2SO4 and the solvent was removed under
reduced pressure to get the crude product. The crude product
was purified by column chromatography (ethyl acetate:hexane)
to afford the pure product, which gave satisfactory 1H NMR and
mass spectral data [14a,26].
2.4.2. General procedure for coupling of imidazole with
aryl halides
To a mixture of imidazole (2 mmol), CELL-Cu(0) cata-
lyst (0.05 g), K2CO3 (4 mmol), in DMSO (3 mL), aryl halide
(2 mmol) was added and stirred at 130 ◦C for 24 h. The resulting
reaction mixture was cooled to room temperature, filtered and
followed a conventional work up with ethyl acetate and water.
The organic layer was separated, dried over Na2SO4 and the
solvent was removed under reduced pressure to get the crude
product. The crude product was purified by column chromatog-
raphy (ethyl acetate:hexane) to afford the pure product, which
gave satisfactory 1H NMR and mass spectral data [26,27].
3. Results and discussion
X-raydiffractionpatternofCELL-Cu(0)catalystclearlyindi-
cates the presence of Cu(1 1 1) and Cu(2 0 0) phases which are
Fig. 2. XPS spectra of: (a) fresh and (b) used CELL-Cu(0) catalyst.

138
K.R. Reddy et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 136–141
Scheme 1.
dine provided good yield. However, we continued the reac-
tions in triethylamine instead of pyridine because of toxicity
reasons.
The reaction temperature plays an important role, the reaction
at room temperature afforded 80% of the coupled product after
18 h (87%, 24 h), while the duration of the reaction is drastically
decreased to 2.5 h under reflux conditions to provide quantitative
yields (Table 1, entry 1).
After optimizing the reaction conditions, different aryl-
boronic acids were coupled with imidazole using CELL-Cu(0)
catalyst, triethylamine as base and methanol as solvent under
refluxing conditions and the results are summarized in Table 1.
Various structurally and electronically diverse arylboronic acids
gave the corresponding N-arylated products in high yields. How-
ever, methyl, acetyl and methoxy substituted boronic acids
required longer reaction times (Table 1, entries 5, 6 and 8) com-
Table 1
N-Arylation of imidazole with various arylboronic acids using CELL-Cu(0) catalysta
Entry
1
Substrate
Product
Time (h)
2.5
Yield (%)b
98
87c
80d
2
3
2.5
2.5
82
87
83c
4
5
6
2.5
4.0
5.0
93
95
80
77c
7
5.0
5.0
83
86
8
a
Reaction conditions: imidazole (1 mmol), triethylamine (2 mmol), CELL-Cu(0) catalyst (0.025 g), phenylboronic acid (1 mmol), methanol (5 ml), reflux.
Isolated yields.
Yield after fourth cycle.
Reaction performed at room temperature for 18 h.
b
c
d

K.R. Reddy et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 136–141
139
Scheme 2.
pared to chloro, fluoro and trifluoromethyl substituted boronic
acids (Table 1, entries 2–4). o- and p-substituted arylboronic
acids were equally effective for the coupling with imidazoles
(Table 1, entries 7 and 8).
To explore further the applicability of this supported copper
catalyst for C–N coupling reactions, we tested the N-arylation
of imidazole with various aryl halides as aryl donors, which
are less expensive than arylboronic acids using K2CO3 as base
(Scheme 2).
In order to determine the best reaction medium, we tested
different solvents such as methanol, 1,2-dichloroethane, toluene,
DMF and DMSO for the N-arylation of imidazole with iodoben-
zene. DMSO is found to be the best solvent for the N-arylation
of imidazole (95%) while DMF provided lower yield (15%).
On the other hand, reaction in other solvents gave no coupled
product under identical conditions. Temperature is proved to
be very crucial, when the reaction is carried out at lower tem-
perature (70 ◦C), <10% product formation was observed, by
Table 2
N-Arylation of nitrogen heterocycles with aryl halides using CELL-Cu(0) catalysta
Entry
Aryl halide
Product
Time (h)
12
Yield (%)
1
95, 90b, <10c
2
3
12
12
89(85)b
40
4
24
70
5
6
24
24
70
95(91)b
7
8
24
48
50
20d
9
24
24
24
40
60
85
10
11
a
Reaction conditions: 2 mmol of aryl halide, 2 mmol of imidazole, 4 mmol of K2CO3, CELL-Cu(0) catalyst (0.05 g), DMSO, 130 ◦C.
Yield after fourth cycle.
Reaction temperature: 80 ◦C.
b
c
d
Reaction with 0.1 g of CELL-Cu(0) catalyst.

140
K.R. Reddy et al. / Journal of Molecular Catalysis A: Chemical 252 (2006) 136–141
raising the temperature to 130 ◦C quantitative (95%) yield of
coupled product is achieved (Table 2, entry 1). Further experi-
ments with different aryl halides were carried out under these
optimized conditions and results are summarized in Table 2.
Very good yield (89%) was observed for the reaction of imida-
zole with 4-iodoanisole (Table 2, entry 2). On the other hand,
2-iodoanisole resulted in lower yields, which may be because of
steric factors (Table 2, entry 3). In the case of bromo-derivatives,
4-bromoacetophenone and bromobenzene afforded 70% of the
coupled product (Table 2, entries 4 and 5). Further we have
screened the chloro-derivatives (Table 2, entries 6–8) for the N-
arylation of imidazole. Among them p-nitrochlorobenzene with
a strong electron-withdrawing group resulted in quantitative
yield (Table 2, entry 6), whereas 4-chloroacetophenone resulted
in lower yield (Table 2, entry 7). N-Arylation of imidazole with
chlorobenzene gave no coupled product under the above con-
ditions. However, an increase of catalyst loading (0.1 g) with
longer reaction time provided 20% yield of the coupled prod-
uct (Table 2, entry 8). To test further the scope of this catalyst,
reactions with benzimidazole and indole are conducted, which
resulted in a very good yield (Table 2, entries 9–11).
935.25 of Cu 2p3/2, which are attributed to Cu(0) and Cu(II),
respectively. ICP-AES results of the used CELL-Cu(0) catalyst
indicate leaching of 0.8% of copper in the N-arylation reaction
of imidazole with iodobenzene after the first cycle and 3.5%
after the fourth cycle. In the reaction of imidazole with phenyl-
boronic acid, leaching of 1.1% of copper after the first cycle and
5% after the fourth cycle are observed.
Hyeon and co-workers reported N-arylation of imidazoles
witharylchloridesusingCu2Ocoatedcoppernanoparticles[28].
Rothenberg and co-workers described the synthesis of triazoles
using copper nanoclusters and they reasoned that the surface of
copper metal is usually coated by a monolayer of Cu(I) oxide, a
dark red powder when in bulk, but virtually unnoticeable when
on the metal, which may serve as the source of Cu(I) [30]. We
assume that the present supported catalyst also contains Cu2O
coated copper nanoparticles. However, we could not see Cu2O
either in XRD or XPS because of low concentration of Cu2O.
4. Conclusions
In conclusion, cellulose supported copper catalyst was pre-
pared and employed for the N-arylation of nitrogen heterocycles
with a variety of aryl halides and arylboronic acids to afford cor-
responding coupled products in good to excellent yields without
using any external ligands or additives as promoters. The cat-
alyst was recovered by simple filtration and reused for several
cycles.
We followed the N-arylation of imidazole with iodobenzene
by GC at regular intervals of time during the reaction and the
reaction profile is shown in Fig. 3. The conversion gradually
increases with increase of time without the formation of any
by-products.
3.1. Reusability of the catalyst
Acknowledgements
The catalyst was recovered by simple filtration and washed
with acetone and oven dried. The recovered catalyst was
reused for N-arylation of imidazole with different boronic acids
(Table 1, entries 1, 3 and 6) and aryl halide (Table 2, entries 1, 2
and 6) derivatives. These results indicate that the CELL-Cu(0)
catalyst can be used for several cycles successfully with minimal
loss of activity. The high resolution XPS narrow scan (Fig. 2(b))
of the used CELL-Cu(0) catalyst shows two peaks at 932.72 and
We wish to thank the CSIR for financial support under the
Task Force Project COR-0003 and N.S.K. thanks the CSIR,
India, for the award of research fellowship.
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