CuO nanoparticle-catalyzed diaminations for synthesis of benzimidazole derivatives

Article abstract of DOI:10.1002/aoc.3492

Copper oxide nanoparticles have been applied as an efficient catalyst for the formation of C–N bonds. They can catalyze diaminations for the regiospecific synthesis of 1,2-disubstituted benzimidazoles from 1,2-dihaloarenes and N-arylamidines. The best per

Full text of DOI:10.1002/aoc.3492

Full paper
Received: 24 February 2016
Revised: 22 March 2016
Accepted: 23 March 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3492
CuO nanoparticle-catalyzed diaminations for
synthesis of benzimidazole derivatives
Dan Yu, Qing You, Xinming Zhang, Guide Tao and Wu Zhang*
Copper oxide nanoparticles have been applied as an efficient catalyst for the formation of C–N bonds. They can catalyze
diaminations for the regiospecific synthesis of 1,2-disubstituted benzimidazoles from 1,2-dihaloarenes and N-arylamidines. The
best performance has been achieved using CuO nanoparticles with average diameter of 6.5 nm. In addition, the catalyst can be
recycled and reused without any significant decrease in catalytic activity. Copyright © 2016 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: CuO nanoparticles; heterogeneous catalyst; benzimidazoles; amidine
substituted benzimidazoles via CuO nanoparticle-catalyzed intra-
Introduction
molecular C–N coupling.[35] Previously we have reported the prep-
Benzimidazoles, an important class of nitrogen-containing hetero-
cycles, show a wide range of biological activities such as antitumor,
antiparasitic, antiviral and antimicrobial. In addition, this motif is the
core structure of some marketed drugs such as esomeprazole,
telmisartan, candesartan and bilastine.[1–4] Therefore, the design
of a mild, original and sustainable method for the synthesis of the
benzimidazole skeleton is of great importance in synthetic organic
chemistry (Scheme 1). The classical synthesis methodology is the
condensation of 1,2-diaminoarenes with either carboxylic acid
derivatives or aldehydes.[5–8] Recently, transition-metal-catalyzed
C–N cross-coupling reaction for the formation of benzimidazole de-
rivatives has been developed.[9–17] For example, Evindar and
Batey[18] reported an intramolecular aryl guanidinylation to give
benzimidazoles with palladium or copper as catalyst. Ma and co-
workers[19] and Buchwald and co-workers[20] demonstrated the
synthesis of 1,2-disubstituted benzimidazoles via a palladium- or
copper-catalyzed aryl amination/condensation process, respec-
tively. Brasche and Buchwald also reported the Cu(OAc)2-catalyzed
synthesis of benzimidazoles from amidines in a process involving
C–H functionalization/C–N bond formation.[21] Shortly afterwards,
Shi and co-workers reported the formation of benzimidazoles
through C–H activation catalyzed by palladium.[22] Later on, Deng
and co-workers described the CuI/N,N′-dimethylethylenediamine
(DMEDA)-catalyzed regiospecific reaction of 1,2-dihaloarenes with
N-substituted amidines or guanidines.[23,24] You and co-workers
also reported the regiospecific synthesis of 1,2-disubstituted
(hetero)arylimidazoles.[25] However, the separation and recycling
of the catalyst remains a problem in the aforementioned
approaches. Considering the preference of modern green chemis-
try for more environmentally friendly methods, the development
of an efficient reaction system with recyclable catalysts in the
presence of mild inorganic base is highly desirable.
aration of CuO nanoparticles with average diameter of 6.5 nm and
their application as a highly efficient catalyst for arylations of
heterocycle C–H bonds and oxidative coupling of amidines and
benzyl alcohols.[36–38] As part of our ongoing research in develop-
ing CuO nanoparticle-catalyzed coupling reactions for the synthesis
of heterocycles, we demonstrate herein an efficient, environmen-
tally friendly and recyclable CuO nano-catalyst in the synthesis of
benzimidazole derivatives via 1,2-dihaloarenes with N-substituted
amidines.
Experimental
General
All reactions were carried out in flame-dried reaction vessels. Reac-
tion temperatures are reported as the temperature of the bath sur-
rounding the reaction vessel. Commercially available chemicals
were used without further purification. All the N-arylamidines[39,40]
and CuO and Cu2O nanoparticles[41–46] were prepared according
to literature procedures.
The prepared nanometric catalyst was characterized using
powder X-ray diffraction with graphite-monochromatized Cu Kα
radiation (λ = 0.154060 nm) in the 2θ range from 10° to 80°. Field-
emission scanning electron microscopy (FESEM) images were
obtained using an S-4800 instrument with an accelerating voltage
of 5 kV. Transmission electron microscopy (TEM) images were
recorded with a FEI Tecnai G2 20 high-resolution microscope at
an acceleration voltage of 200 kV. All new compounds were fully
*
Correspondence to: Wu Zhang, Key Laboratory of Functional Molecular Solids,
Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of
Chemistry and Materials Science, Anhui Normal University, Wuhu 241000,
People’s Republic of China. E-mail: zhangwu@mail.ahnu.edu.cn
Nanoparticles have emerged as robust and high-surface-area
heterogeneous catalysts, which serve as sustainable alternatives
to conventional materials.[26–30] CuO nanoparticles have drawn at-
tention due to their stability and availability.[31–34] For example,
Punniyamurthy and co-workers reported the synthesis of
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui
Laboratory of Molecule-Based Materials, College of Chemistry and Materials
Science, Anhui Normal University, Wuhu 241000, People’s Republic of China
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

D. Yu et al.
Figure 1. (a) TEM image of CuO nanoparticles. FESEM images of (b) CuO
nanoparticles, (c) CuO nanospindles, (d) CuO nanoplates, (e) CuO
nanoflowers and (f) Cu2O nanocubes.
Scheme 1. Efficient syntheses of benzimidazoles.
characterized. Melting points were determined with melting point
1
apparatus in open capillaries and are uncorrected. H NMR and
13C NMR spectra were recorded with 300 MHz NMR spectrometers
using CDCl3 as solvent and tetramethylsilane as an internal stan-
dard. High-resolution mass spectral data were obtained with ioniza-
tion mode of ESI using an Agilent 6200 LC/MS TOF.
effective catalyst. No product is formed in the absence of any cata-
lyst, and all starting materials are recovered from the reaction
system. Solvent effect studies show that diglyme is the best (entries
9–12). A series of bases were also investigated to reveal that
K3PO4Á3H2O gives the highest yield (entries 13–17). It is observed
that the product yield is decreased to 43% on decreasing the cata-
lyst loading from 10 to 5 mol%, whereas no significant increase is
observed when using 20 mol% of catalyst (entries 18 and 19). Other
factors such as ligand, temperature and reaction time with preset
optimized reaction conditions were screened for the reaction. It is
interesting to find that the reaction does not proceed well without
ligand, and phen is the best ligand (entries 20–24). The temperature
also has a significant effect on this reaction: the yield is dramatically
increased from 35% at 120 °C to 64% at 130 °C and 82% yield is
achieved at 150 °C (entries 25–27). Lower yield is obtained when
the reaction time is changed from 24 to 12 h; however, no signifi-
cant increase in yield is observed when the reaction time is
extended to 48 h (entries 28 and 29). Based on all the results
discussed above, the optimized reaction conditions are: 10 mol%
CuO nanoparticles in the presence of 4 equiv. of K3PO4Á3H2O in
refluxing diglyme for 24 h. Under the optimized conditions, the
desired benzimidazole product is obtained in 90% yield.
General procedures for 1,2-Disubstituted Benzimidazoles
The reactions were typically carried out using 1,2-diiodobenzene
(0.50 mmol), amidine (0.60 mmol), CuO (0.050 mmol), base
(2.0 mmol) and ligand (0.050 mmol) in diglyme (2 ml) under reflux
in argon for 24 h. After cooling to room temperature, the reaction
mixture was extracted with ethyl acetate (3 × 5 ml). The combined
organic layer was dried over Na2SO4, filtered and concentrated. The
crude products were purified by column chromatography on silica
gel (300–400 mesh) with petroleum ether–ethyl acetate as eluent.
Recycling of the catalysts
The separated precipitates in the procedure described above were
washed sufficiently with deionized water and ethanol three times
each and then dried under vacuum at 50 °C for 8 h. The CuO nano-
particles were then recovered.
With the optimized reaction conditions in hand, we then turned
our attention to the scope of the reaction. The results are shown
in Scheme 2. It is found that moderate to good yields are achieved
for amidines with both electron-withdrawing and electron-donating
substituents on the arene ring. The influence of the electronic varia-
tion of amidines on the yield is negligible. Then, we discovered that
the steric hindrance has an important effect on the reaction,
amidine with bulky substituents affording lower yields. For example,
only 51% yield is obtained when amidine with n-dodecyl substituent
is used and no product is detected when 2,6-diisopropyl-substituted
benzimidamide is employed as substrate. Also various substituents
on o-dihalobenzenes were studied: CH3, CF3 and Cl could be toler-
ated. It is found that o-dihalobenzenes with electron-donating
substituents can lead to higher yields than those with electron-
withdrawing substituents. When o-diiodobenzene is changed to
o-bromoiodobenzene, almost identical results are obtained. How-
ever, o-dibromobenzene and o-dichlorobenzene under the same
conditions lead to only 51 and 30% yield of products, respectively.
The reusability of the CuO nanoparticles was investigated. As
evident from Table 2, no significant decrease in the catalytic
Results and discussion
The synthesized CuO and Cu2O were characterized using TEM and
FESEM (Fig. 1). Our initial investigations were focused on CuO
nanoparticle-catalyzed diamination for the synthesis of benzimid-
azoles. When N-phenylbenzimidamide (1a) derived from the
addition of aniline to benzonitrile was refluxed with 1,2-
diiodobenzene (2a) in diglyme in the presence of 10 mol% of
CuO nanoparticles and 10 mol% of 1,10-phenanthroline (phen),
benzimidazole (3a) was obtained in 66% yield (Table 1, entry 1).
Among the various copper sources employed (entries 2–8), it is
observed that nanoparticles are better catalysts than non-
nanoparticles. Low yields are obtained for two conventional cata-
lysts, Cu(OAc)2ÁH2O (25%) and commercial CuO powder (about
200 mesh, 30%), while nano-catalysts such as CuO nanospindles,
CuO nanoplates, CuO nanoflowers and Cu2O nanocubes give the
desired products in higher yields, among which CuO nanoparticles
with average diameter of 6.5 nm were found to be the most
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Copyright © 2016 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2016)

Synthesis of benzimidazoles by CuO nanoparticle-catalyzed diamination
Table 1. Optimization of nano-CuO-catalyzed cascade reaction of N-
phenylbenzimidamidea
Entry Catalyst (10 mol%) Base
Ligand
Solvent Yield (%)b
1
CuO nanoparticles K2CO3
CuO (200 mesh) K2CO3
CuO nanospindles K2CO3
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Toluene
DMSO
66
30
2
3
46
4
CuO nanoplates
CuO nanoflowers
Cu2O nanocubes
Cu(OAc)2ÁH2O
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
50
5
58
6
20
7
25
8
—
9
CuO nanoparticles K2CO3
CuO nanoparticles K2CO3
CuO nanoparticles K2CO3
CuO nanoparticles K2CO3
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
—
DMF
Trace
—
Xylene
CuO nanoparticles Cs2CO3 Phen
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
56
CuO nanoparticles NEt3
CuO nanoparticles K3PO4
Phen
Phen
45
90
CuO nanoparticles Na2CO3 Phen
CuO nanoparticles NaOAc Phen
51
33
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
CuO nanoparticles K3PO4
Phen
Phen
43c
91d
33
DMEDA Diglyme
L-Proline Diglyme
51
dppm
—
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
46
—
H2acac
Phen
Phen
Phen
Phen
Phen
Trace
35e
64f
82g
51h
93i
aReaction conditions: 1,2-diiodobenzene (0.50 mmol), N-
phenylbenzimidamide (1.2 equiv.), base (4 equiv.), catalyst (10 mol
%), ligand (10 mol%), solvent (2 ml), under reflux in argon for 24
bIsolated yields
cCuO (5 mol%)
dCuO (20 mol%)
e120°C
f130°C
g150°C
h12 h.
i48 h
Scheme 2. Synthesis of benzimidazole derivatives catalyzed by CuO
nanoparticles.
activity for the diamination of 1,2-diiodobenzene with N-
phenylbenzimidamide is observed when recovered CuO nanoparti-
cles are used. To examine whether the observed catalysis was
derived from CuO nanoparticles or leached copper species, the
diamination of 1,2-diiodobenzene was carried out under the
optimized conditions and the catalyst was removed from the mix-
ture by centrifugation after 6 h. The leaching of copper from the
CuO nanoparticles during the reaction was examined using atomic
absorption spectroscopic analysis, and a slight leaching (< 1 ppm)
is observed. However, no further progress of reaction is observed
for the ‘catalyst-free’ solution under the same conditions even after
18 h. We thus believe that the reaction may proceed through an
oxidative addition, anion substitution,[47] then by a reductive elimi-
nation process on the surface of the CuO nanoparticles which are
stabilized by phen via a heterogeneous process.[36]
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
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D. Yu et al.
Table 2. Successive reactions using recycled CuO nanoparticlesa
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2
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90
86
83
aReaction conditions: 1,2-diiodobenzene (0.50 mmol), N-
phenylbenzimidamide (1.2 equiv.), CuO nanoparticles (10 mol%), phen
(10 mol%), K3PO4 (4 equiv.), diglyme (2 ml), under reflux in argon for 24 h
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We have developed a practical and efficient CuO nanoparticle-
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We are grateful to the National Natural Science Foundation of China
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Supporting Information
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web site.
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Copyright © 2016 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2016)