Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)–2-imino-1,2-diphenylethan-1-ol Complex

Article abstract of DOI:10.1007/s10562-017-2173-7

Abstract: In this study, a new amino functionalized nano silica was synthesized using 2-hydroxy-1,2-diphenylethan-1-one. The new 2-hydroxy-1,2-diphenylethan-1-one@amino functionalized nano-silica was used as a support material for copper(II) catalyst. This composite was characterized by various techniques such as transmission electron microscopy, field emission scanning electron microscope, X-ray powder diffraction, inductively coupled plasma, energy dispersive X-ray spectroscopy, thermal gravimetric and FT-IR analysis and its particles size was estimated to be between 20 and 30?nm. The catalyst was tested in the N-heterocycles synthesis via C–N bond forming reactions. The catalyst displayed outstanding catalytic activity for all reactions under mild conditions. Finally, the nano heterogeneous copper catalyst is recoverable up to 12 times without any significant leaching which indicated that the heterogeneous catalyst is stable and very active under the applied conditions. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-017-2173-7

Catal Lett
DOI 10.1007/s10562-017-2173-7
Five-membered N-Heterocycles Synthesis Catalyzed by Nano-
silica Supported Copper(II)–2-imino-1,2-diphenylethan-1-ol
Complex
1
1
1
Hashem Sharghi · Pezhman Shiri · Mahdi Aberi
Received: 3 June 2017 / Accepted: 21 August 2017
©
Springer Science+Business Media, LLC 2017
Abstract In this study, a new amino functionalized nano
and its particles size was estimated to be between 20 and
30 nm. The catalyst was tested in the N-heterocycles synthe-
sis via C–N bond forming reactions. The catalyst displayed
outstanding catalytic activity for all reactions under mild
conditions. Finally, the nano heterogeneous copper catalyst
is recoverable up to 12 times without any significant leach-
ing which indicated that the heterogeneous catalyst is stable
and very active under the applied conditions.
silica was synthesized using 2-hydroxy-1,2-diphenylethan-
1
-one. The new 2-hydroxy-1,2-diphenylethan-1-one@amino
functionalized nano-silica was used as a support material for
copper(II) catalyst. This composite was characterized by var-
ious techniques such as transmission electron microscopy,
field emission scanning electron microscope, X-ray powder
diffraction, inductively coupled plasma, energy dispersive
X-ray spectroscopy, thermal gravimetric and FT-IR analysis
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-017-2173-7) contains supplementary
material, which is available to authorized users.
*
Hashem Sharghi
shashem@susc.ac.ir
1
Department of Chemistry, Shiraz University, Shiraz 71454,
Islamic Republic of Iran
Vol.:(0
1
123456789)
3

H. Sharghi et al.
Graphical Abstract
N N
N
N
Ar (HetAr)
Ar
X
N
N
N
Ar
H
OH
N
N
Ar (R)
N
N
N R
Ar (R)
N
N
N
N
Ar
N
N
X
N
N
S
Ar
O
R
N
N
N
N
Ph
Ph
O
N
O
N
Ph
Ph
O
N
Cu
Cu(II)@Silica
O
R
Si
Si
EtO
OEt
OO OO
good to excellent yields
Cu(II)@Silica
Keywords Amino functionalized nano silica supported
Cu(II) catalyst · Triazole · Tetrazole · Benzimidazole ·
Hybrid molecules
To the best of our knowledge, although there are many
methods for forming N-heterocycles, most of them produce
one type of N-heterocycles using a catalyst [38–42]. Regard-
ing the available procedures for forming azole derivatives,
different copper sources (including copper nanoparticles,
nano-CuI [43–45], copper on charcoal [46, 47], copper and
ligated copper [48–50]) have been introduced. Despite the
significant improvements made in the above transforma-
tions, there is still a need to use more efficient, air stable
and inexpensive complexes and catalysts without difficulties
to recover and reuse for successive reaction cycles.
1
Introduction
Five-membered heterocycles bearing nitrogen [1–3] are
important blocks, on account of a wide range of applica-
tions in biological systems. This type of molecules with high
chemical stability to oxidation, reduction and hydrolysis has
constituted one of the fascinating areas of research for pro-
ducing drugs, fluorescence chemosensors, and etc [4–10]. In
addition, heterocyclic rings bearing nitrogen considered as
corrosion inhibitors [11, 12], agrochemicals [13], industrial
dyes [14], optical brighteners [15], and photostabilizers [16].
Among the N-heterocycle derivatives, triazoles, tetrazoles
and imidazoles are pivotal building scaffolds; they show
a broad spectrum of biological activities, including use as
pharmaceuticals [17, 18], antifungal [19–21], anti-bacterial
In continuation of our interest in exploring efficient and
diverse copper catalysts for organic processes [39, 51–54],
we wish herein to report full details of the utilization of
homogeneous copper(II)–2-imino-1,2-diphenylethan-1-ol
Cu(OAc)2
Ph
Ph
O
N
O
N
Ph
Ph
Ph
Ph
OH
O
Absolute Ethanol
Reflux
Cu
NH2
[
22], anti-HIV [23, 24], anticancer [25–28], anti-inflamma-
tory [29, 30], and antituberculosis agents [31, 32].
Certainly, one-pot multicomponent coupling and domino
reactions (MCRs) [33–37], combining at least three simple
building blocks in one pot, have proved to be a powerful
tool in organic chemistry especially in the sustainable and
diversity-oriented synthesis of heterocycles.
Si
Si
EtO
Si
OEt
EtO OEt EtO OEt
EtO
EtO OEt
Scheme 1 Synthetic route for copper(II)–2-imino-1,2-diphenylethan-
-ol complex [Cu(II)–ID]
1
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
complex [Cu(II)–ID] [55] and also heterogeneous silica sup-
ported copper(II)–2-imino-1,2-diphenylethan-1-ol complex
X-ray (EDS) analysis was done using SIRIUS SD EDX ana-
lyzer. TGA of the sample was performed under a nitrogen
atmosphere with a Netzsch STA 409 PC/PG instrument. The
X-ray diffraction (XRD, D8, Advance, Bruker, axs) data was
used to characterize the heterogeneous catalyst. Copper con-
tent was obtained with an ICP analyzer (Varian, vista-pro).
Column chromatography was carried out on short columns
of silica gel 60 (70–230 mesh) in glass columns.
[
Cu(II)–ID@silica] as a novel, convenient, stable and reus-
able catalyst for the efficient synthesis of azole compounds
under mild conditions.
2
Experimental Section
Chemical materials and solvents were purchased from
Aldrich, Fluka and Merck Companies. IR spectra were
obtained using a Shimadzu FT-IR 8300 spectrophotometer.
NMR spectra were recorded on a Bruker Avance DPX-250
2.1 General Procedure for the Click Synthesis
of 1,2,3-Triazoles
A mixture of organic halide or organic epoxide (1.0 mmol),
sodium azide (1.2 mmol), and alkyne (1.0 mol) was stirred
in the presence of water (1.0 mL) as solvent and homogene-
ous or heterogeneous catalytic system (1.0 mol%) at room
temperature. Upon completion, ethyl acetate (30 mL) was
added to the reaction mixture and then nano-silica supported
copper(II) complex was centrifuged. After separation of the
catalyst, the organic layer was washed with deionized water
1
13
(
H-NMR 250 MHz and C NMR 62.9 MHz) spectrom-
eter in pure deuterated solvents with tetramethylsilane as
an internal standard. Melting points determined in open
capillary tubes in a Büchi-535 circulating oil melting point
apparatus. Morphology of the nano-catalyst was conducted
with a MIRA3 TESCAN SEM, operating at 20.0 kV. TEM
images were obtained with a transmission electron micros-
copy (TEM, Zeiss-EM10C, 80 kV). The energy dispersive
Scheme 2 Synthetic route for
Ph
Ph
OH
O
silica supported copper(II)–
Cu(OAc)2
NH2
2
-imino-1,2-diphenylethan-1-ol
Ph
Ph
O
N
O
N
Ph
Ph
complex [Cu(II)–ID@silica]
Cu
NH2
Absolute Ethanol
Reflux
Si
O O
Si
O O
Si
O O
Si
O O
EtO
EtO
OEt
OEt
1
00.0
100.0
95
9
9
8
8
7
7
6
6
5
5
0
5
0
5
0
5
0
5
5
46.05
1921.22
535.91
90
525.86
4
492.26
85
84.09
80
75
70
3
080.95 2932.79
1317.99
339.31
3029.27
65
1
1028.33
774.87
3058.45
1394.18
307.50
60
1
1003.89
928.97
855.90
643.73
55
3257.66
3062.18
832.74
%T
50
%T 50
2
888.28
4
4
3
3
2
2
1
1
5
0
5
0
5
0
5
0
45
40
35
30
25
20
15
10
5.0
1339.92
2
931.35
719.02
686.74
1
541.95
621.91
611.30
596.92
1
179.82
1
092.52
1213.24
9
77.44
512.20
6
82.06
1068.50
7
55.45
1667.86
1406.07
1262.94
207.28
704.91
695.98
1
3419.52
1578.89
3
379.70
1
683.43
1119.55
1200
5
.0
000.0
4
3600
3200
2800
2400
2000
1800
CM-1
1600
1400
1200
1000
800
600
470.0
4000.0
3600
3200
2800
2400
2000
1800
cm-1
1600
1400
1000
800
600
470.0
Fig. 1 IR spectroscopy of 2-hydroxy-1,2-diphenylethan-1-one (at left) and copper(II)–2-imino-1,2-diphenylethan-1-ol complex [Cu(II)–ID] (at
right)
1
3

H. Sharghi et al.
(
3×30 mL) which was purified by silica gel column chroma-
was purified by silica gel column chromatography employ-
tography employing n-hexane/ethyl acetate as eluent.
ing n-hexane/ethyl acetate as eluent.
2
.2 General Procedure for the Three Component
Synthesis of Tetrazoles
2.3 General Procedure for the Synthesis
of 2-Aryl-1H-benzo[d]imidazole
A mixture of amine (1.0 mmol), triethyl orthoformate
1.0 mmol) and sodium azide (1.3 mmol) was stirred in the
A mixture of aldehyde (1.0 mmol) and diamine (1.2 mmol)
was stirred in the presence of ethanol (5.0 mL) as solvent and
homogeneous or heterogeneous catalytic system (5.0 mol%)
at 50 °C. Upon completion, nano-silica supported copper(II)
complex was centrifuged. After separation of the catalyst,
the organic layer was evaporated and then purified by silica
gel column chromatography employing n-hexane/ethyl ace-
tate as eluent.
(
presence of water (1.0 mL) as solvent and homogeneous or
heterogeneous catalytic system (1.0 mol%) at 65 °C. Upon
completion, ethyl acetate (30 mL) was added to the reaction
mixture and then nano-silica supported copper(II) complex
was centrifuged. After separation of the catalyst, the organic
layer was washed with deionized water (3×30 mL) which
Fig. 2 a EDS spectrum of
a
Cu(II)-ID@silica nanoparticles.
b XRD spectrum of Cu(II)–
ID@silica nanoparticles
b
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
3
Results and Discussion
complex [Cu(II)–HD]. Next, this complex was immediately
reacted with 3-(triethoxysilyl)propan-1-amine to form
[Cu(II)–ID]. The solvent was evaporated and the copper
complex was washed with ether. The resulting complex was
3
.1 Preparation of Homogeneous [Cu(II)–ID]
and heterogeneous [Cu(II)–ID@silica]
−
1
characterized by IR. The peaks at 1119 and 774 cm are
ascribable asymmetric and symmetric stretching vibration
The synthetic route for homogeneous [Cu(II)–ID] and het-
erogeneous [Cu(II)–ID@silica] is demonstrated in Schemes
−1
of Si–O groups. The peak at 1667 cm is attributed to C=N
(Fig. 1).
1
and 2 [55–57]. First, 2-hydroxy-1,2-diphenylethan-1-one
was reacted with Cu(OAc) in absolute ethanol at reflux con-
Immobilization of metal complex on solid support
appears to be a good way to render it practicable and to
2
dition to produce Cu(II)–2-hydroxy-1,2-diphenylethan-1-one
Fig. 3 FESEM images for sup-
ported catalyst
Fig. 4 TEM images for sup-
ported nanocatalyst
1
3

H. Sharghi et al.
improve their stability. In line with current challenges to
improve industrial and laboratorial catalysts, solid catalysts
should be tolerant, easily accessible, and highly reusable
[Cu(II)–ID@silica]. Since the IR spectroscopy showed weak
peaks, the catalyst was characterized by using other analysts
such as XRD, EDS, ICP, CHN, and TG analysis. The XRD
pattern of the Cu(II)–ID@silica nanocatalyst is indicated in
Fig. 2. The obtained XRD pattern matches well with the nor-
mal characteristic diffractions of both amino functionalized
silica and copper, and the diffraction peaks at 2θ around 29°,
38°, 56°, and 79° are related to the different copper phases
[
58–60]. Functionalized silica materials have been used as
suitable solid supports for many metallic catalysts. With this
regard, after stirring 2-hydroxy-1,2-diphenylethan-1-one and
Cu(OAc) in absolute ethanol at reflux condition, amino
2
functionalized silica was added at reflux condition to create
Fig. 5 TG analysis of sup-
ported nanocatalyst
N
N
OH
N
N
X
Ar (HetAr)
N
Ar (R)
N
H
N
N
Ar
Ar (R)
Ar
a
e
b
Ph
Ph
O
N
O
N
Ph
Ph
Cu
Ar
X
N N
N
N
Ar (R)
OH
d
c
N
N
N
N
N
Si
O O
Si
O O
EtO
Ar
OEt
Nano-SiO2
Conditions:
b, c, d, and e: water, 1.0 mol % catalyst, good to exellent yield.
a: ethanol, 5.0 mol % catalyst, good to exellent yield.
Fig. 6 Catalytic activity of heterogeneous silica supported copper(II)–2-imino-1,2-diphenylethan-1-ol complex [Cu(II)–ID@silica] in azole for-
mation reactions
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
of Cu(111), Cu(110), Cu (222), and Cu(220), respectively.
FESEM was also used to investigate the surface morphology
of the Cu(II)–ID@silica nanocatalyst, displaying a homoge-
neous structure. As shown in Fig. 3, the average size of this
heterogeneous nano-catalyst was calculated to be between
[Cu(II)–ID@silica] (Fig. 5). The CHN analysis data proved
the structure of the heterogeneous [Cu(II)–ID@silica].
The catalytic activity of homogeneous [Cu(II)–ID] and
heterogeneous [Cu(II)–ID@silica] was evaluated in azole
formation reactions (Fig. 6).
2
0 and 30 nm. Further characterization of nanocatalyst was
achieved using EDS spectrum. The EDS analysis of Cu(II)-
ID@silica nanocatalyst indicates peaks for Si, N, O, C, and
Cu elements in the catalyst that confirms the major constitu-
ents of silica supported Cu(II) nanocatalyst (Fig. 2). Also,
TEM images were used to further characterization of the
structure and morphology of Cu(II)–ID@silica nanoparti-
cles; this analysis confirms the FESEM data (Fig. 4). The
ICP analysis revealed that 0.05 mmol of copper source is on
3.2 Synthesis of Triazoles and β-Hydroxy-triazoles
Initial experiments were performed to examine homoge-
neous [Cu(II)–ID] and heterogeneous [Cu(II)–ID@silica]
via triazole formation reaction of different benzyl halides
or epoxides, alkynes, and sodium azide. The reaction of
phenyl acetylene, benzyl bromide, and sodium azide was
selected as a model reaction to optimize the reaction con-
ditions. According to the green chemistry, the choice of
green solvent is crucial, so different solvents were screened.
As shown in Table 1, performing the reaction in the neat
water and in the presence of catalyst (5.0 mol%) resulted
high yield of product at reflux condition. The effect of reac-
tion temperature on this cyclization reaction was investi-
gated in the range of 25 to 100 °C. In all cases, the reac-
tion was performed well, but the increase of temperature
caused forming triazole product in a shorter reaction time.
The room temperature condition was chosen according to
green chemistry concepts. For the purpose of optimization
0
.1 g of the solid support.
To explore the thermal stability of heterogeneous
[
Cu(II)–ID@silica], TG analysis has been carried out under
N flow from 25 to 700 °C temperature range. The TGA
2
profile shows two-stage decomposition. The first decrease in
weight loss corresponds to adsorbed water and organic sol-
vents in the Cu grafted organic functionalized mesoporous
silica material. The second weight loss occurred between
2
80 and 600 °C is due to decomposition of the organic
functionalized part on the surface of silica. The TGA
curve also suggests high thermal stability of heterogeneous
Table 1 Comparison of the conditions used for coupling/cyclization of benzyl bromide, sodium azide, and phenyl acetylene toward triazole
product
Br
N
N
N
+
NaN3
+
Ph
Entry
Solvent
Temperature (˚C)
Catalyst (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
–
25
25
25
25
25
100
70
50
25
25
25
25
5
5
5
5
5
5
5
5
1.0
3.0
3.0
3.0
3.0
0.33
0.5
0.5
0.75
1.0
1.0
4
0 (0)
9 (14)
10 (15)
4 (4)
61 (68)
98 (98)
97 (97)
97 (98)
97 (98)
97 (97)
98 (98)
71 (75)
DMSO
DMF
Toluene
Ethanol
Water
Water
Water
Water
Water
Water
Water
5
2.5
1
10
11
12
0.1
a
Isolated yield of product (the average of at least two runs) using heterogeneous catalyst; the numbers in parentheses is isolated yield (the aver-
age of at least two runs) of product using homogenous catalyst
1
3

H. Sharghi et al.
Table 2 Synthesis of 1,2,3-triazoles by the way of a three-component reaction using 1.0 mol% homogeneous [Cu(II)–ID] and heterogeneous
[
Cu(II)–ID@silica] at room temperature
Entry
Benzyl halides or Alkyne
epoxide
Product
Time (h)
1.0
Yielda
Lit. mp (°C)
1
98 (98)
129.0–129.5 [38]
Br
N
N
N
Ph
2
3
1.0
1.0
97 (97)
98 (98)
129.0–129.5 [38]
110.0 [46]
Cl
N
N
N
Ph
Br
N
N
N
Ph
Me
Me
4
N
1.2
91 (92)
156.0–157.0 [46]
Br
N
N
Ph
NO2
NO2
5
6
0.75
0.75
94 (97)
95 (95)
125.5–126.5 [54, 61]
[61]
7
1.2
91 (93)
179–180 [54, 61]
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
Table 2 (continued)
Entry
Benzyl halides or Alkyne
epoxide
Product
Time (h)
Yielda
Lit. mp (°C)
8
1.5
90 (90)
125–126 [52, 54]
9
1.5
89 (93)
71.5–728 [52, 54]
1
0b
3.0
91 (95)
129.0–129.5 [38]
Reagents and conditions: organic halide or organic epoxide (1.0 mmol), alkyne (1.0 mmol), sodium azide (1.2 mmol), homogeneous or heteroge-
neous catalyst (1.0 mol%)
a
Isolated yield (the average of at least two runs) of product using heterogeneous catalyst; the numbers in parentheses is isolated yield (the aver-
age of at least two runs) of product using homogenous catalyst
b
The reaction was performed on a 5 mmol scale
1
3

H. Sharghi et al.
Scheme 3 A plausible mecha-
nism for the copper(II) complex
catalyzed click reaction
N
R
N
R2
N
Cu(II)
R1
H+
R
H
A
Cu(II)
N
N
R2
N
R1
Cu(II)
H+
E
Cu(II)
R
B
N
N
R1
R2
N
Cu(II)
N
N
N
N
D
R1
N
R1
N
Cu(II)
R
C
Table 3 Effect of reaction medium for the three-component and
cycloaddition reaction of m-toluidine (1.0 mmol), triethyl orthofor-
mate (1.0 mmol) and sodium azide (1.3 mmol) in presence of homo-
geneous [Cu(II)–ID] and heterogeneous [Cu(II)–ID@silica]
of catalyst loading, the reaction was checked using varying
the concentration of the catalyst from 0.1 to 5.0 mol%. By
decreasing the catalyst loading, the conversion of starting
materials to desired product was performed in longer time.
In order to optimize the time and catalyst loading, 1.0 mol%
catalyst was set to perform other reactions. From Table 1,
it was found that 25 °C for 1 h was the best conditions for
coupling/cyclization of benzyl bromide, sodium azide, and
phenyl acetylene in a 1:1.2:1 molar ratio to substituted tria-
zol using 1.0 mol% catalyst.
Entry
Solvent
Tempera- Catalyst
Time (h)
Yield (%)a
ture (˚C)
(mol%)
1
2
3
5
6
7
8
9
-
120
100
100
100
100
80
65
65
65
65
5
5
5
5
5
5
5
3
2
1
3.0
3.0
3.0
3.0
0.5
0.5
0.5
0.75
1.0
1.0
47 (49)
69 (74)
74 (77)
69 (73)
96 (98)
96 (98)
96 (98)
95 (98)
95 (98)
94 (95)
DMSO
DMF
Ethanol
Water
Water
Water
Water
Water
Water
With the optimal conditions in hand, we demonstrated the
generality of our protocol through the reaction of a variety of
benzyl halides or epoxides, sodium azide, and alkynes. We
were pleased to find that different benzyl halides with both
electron-withdrawing and electron donating groups can be
transformed to desired triazole products in good to excellent
yields. Various epoxides were also subjected to the same
reaction conditions to produce the desired β-hydroxy-1,4-
disubstituted-1,2,3-triazole derivatives. Using heterogeneous
catalysts instead of homogeneous ones is preferred owing
to easy and quick isolation of products and cleaner reaction
profile (Table 2).
1
1
0
1
a
Isolated yield (the average of at least two runs) of product using het-
erogeneous catalyst; the numbers in parentheses is isolated yield (the
average of at least two runs) of product using homogenous catalyst
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
Table 4 Three component
Yield (%)a
Entry Aniline derivative
1
Product
Time (h)
1.0
Lit. mp (°C)
[48]
synthesis of 1-substituted-1H-
1
,2,3,4-tetrazoles from various
94 (95)
amines (1.0 mmol), triethyl
orthoformate (1.0 mmol) and
sodium azide (1.3 mmol) in
the presence of 1.0 mol%
homogeneous [Cu(II)–ID] and
heterogeneous [Cu(II)–ID@
silica]
2
3
4
1.0
1.0
1.2
97 (97)
95 (97)
89 (93)
92 [48, 64]
153 [48, 64]
90–93 [48]
5
1.5
85 (88)
101–102 [48]
6
1.0
3.5
94 (95)
86 (89)
162–164 [48]
[48]
7b
a
Isolated yield (the average of at least two runs) of product using heterogeneous catalyst; the numbers in
parentheses is isolated yield (the average of at least two runs) of product using homogenous catalyst
The reaction was performed on a 5-mmol scale
b
According to the literature focusing on copper(II)
complexes with a variety of ligands, we propose a simi-
1H-tetrazoles. Herein, the initial experiment was performed
by stirring a mixture of m-toluidine (1.0 mmol), triethyl
orthoformate (1.0 mmol) and sodium azide (1.3 mmol) in
presence of 1.0 mol% catalyst in water at reflux condition.
After 60 min, the desired product (1-(m-tolyl)-1H-tetra-
zole) could be isolated in high yield. We also evaluated
the amount of catalyst and temperature for this three com-
ponent cyclization reaction. The best result was obtained
using 1.0 mol% catalyst at 65 °C. The effect of different
solvents was also studied by carrying out the model reaction.
A useful conversion is not observed by using other solvents
including DMSO, DMF, and ethanol. However the produc-
tivity increases by using water as a safe solvent (Table 3).
Aiming to extend the scope of our protocol, different ani-
lines with both electron-withdrawing and electron donating
groups as the substrates was applied for this reaction. The
results showed that an electron donating group or an elec-
tron withdrawing group on aniline derivatives does not have
a notable effect on the reaction yield and gives excellent
2
+
lar reaction pathway involving Cu . In the first step, the
π-interaction may be formed between the copper(II) com-
plex and acetylene to produce intermediate (A). Next,
deprotonation of the π-complex alkyne may create copper
acetylide intermediate (B). The azide intermediate binds to
the copper(II) catalyst to generate intermediate (C). Subse-
quently, previously proposed six-membered-ring intermedi-
ate (D) is expected to give intermediate E. Finally, dissocia-
tion and protonation of the intermediate E probably occur to
complete the reaction and regenerate the Cu(II)-catalyst
(
Scheme 3) [49, 62, 63].
3
.3 Synthesis of Tetrazoles
Also, the catalytic activity of homogeneous [Cu(II)–ID]
and heterogeneous [Cu(II)–ID@silica] was screened in
order to optimize the protocol for formation of 1-substituted
1
3

H. Sharghi et al.
Scheme 4 A plausible mecha-
nism for the copper(II) complex
catalyzed formation of 1-substi-
tuted-1H-1,2,3,4-tetrazole
N
R
N
N
N
NaN3
Cu(II)
N3
N
R
N
N
N
Cu(II)
EtO
Cu(II)
EtO
OEt
CH
EtO
N3
N3
EtO
OEt
ArHN
OEt
CH
EtO
Cu(II)
CH
EtO
Cu(II)
EtOH
ArNH2
Table 5 Effect of reaction medium for the one step reaction of p-chlorobenzaldehyde with o-phenylenediamine in a 1:1.2 ratio in presence of
homogeneous [Cu(II)–ID] and heterogeneous [Cu(II)–ID@silica]
Entry
Solvent
Temperature (°C)
Catalyst (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
EtOH
EtOH
50
50
80
Reflux
Reflux
Reflux
R.t
70
50
–
5
5
5
5
5
5
5
7
3
4.0
3.0
4.0
3.0
3.0
3.0
7.0
3.0
3.0
3.0
<15
81 (84)
30 (30)
10 (17)
60 (63)
20 (24)
50 (58)
84 (88)
80 (82)
70 (76)
Dioxane
CH Cl
2
2
CH CN
3
Water
EtOH
EtOH
EtOH
EtOH
1
0
50
a
Isolated yield (the average of at least two runs) of product using heterogeneous catalyst; the numbers in parentheses is isolated yield (the aver-
age of at least two runs) of product using homogenous catalyst
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
Table 6 One step synthesis of a series of benzimidazoles from different benzaldehydes and o-phenylenediamine in a 1:1.2 ratio in the presence
of 5.0 mol% homogeneous [Cu(II)–ID] and heterogeneous [Cu(II)–ID@silica]
Entry
1
Aldehyde derivative
o-phenylenediamine derivative
Product
Yielda
Ref.
81 (80)
290–92 [42]
2
3
4
5
6
7
82 (83)
80 (80)
79 (79)
81 (84)
84 (88)
84 (85)
270–272 [42]
226 [42]
287–289 [42]
292–293 [40, 42]
329–331 [40]
218 [40]
8
9
81 (81)
70 (71)
242–243 [42]
221–222 [42]
1
0b
73 (74)
290−92 [42]
All reactions was completed for 3.0 h
a
Isolated yield (the average of at least two runs) of product using heterogeneous catalyst; the numbers in parentheses is isolated yield (the aver-
age of at least two runs) of product using homogenous catalyst
b
The reaction was performed on a 5-mmol scale for 7 h
1
3

H. Sharghi et al.
Scheme 5 A plausible mecha-
nism for the copper(II) complex
catalyzed arylbenzimidazoles
synthesis
O
H
N
NH2
NH2
H
N
R
R
Cu(II)
-
H O
Air
oxidation
Cu(II)
2
H
N
N
H
R
N
H
NH2
A
B
R
yields, but electron donating groups reacted faster than elec-
tron withdrawing ones (Table 4).
5.0 mol% catalyst was the most efficient in which structur-
ally diverse benzimidazoles were formed in short reaction
times (Table 5, entries 1, 2, 9 and 10). The temperature effect
on the model reaction was also checked and the best result
was obtained at 50 °C as a mild reaction conditions (Table 5,
entries 2, 7 and 8).
Herein, the plausible mechanistic pathways for the syn-
thesis of 1-substituted-1H-1,2,3,4-tetrazoles with homoge-
neous [Cu(II)–ID] and heterogeneous [Cu(II)–ID@silica]
catalyst are shown in Scheme 4. Lewis acid property of the
Cu(II) catalyst probably has an important role in the pro-
After optimization of the model reaction, the efficiency
and scope of the catalytic system was studied. The method
was subjected to the one step reaction to obtain benzimi-
dazole derivatives. Different aryl and heteroaryl aldehydes
were also well tolerated to form benzimidazole products and
the results are shown in Table 6. During our investigations,
it was found that electron-donating aromatic aldehydes as
well as electron-withdrawing aromatic aldehydes could
be accomplished the reaction. The reaction profiles were
so cleaned and desired azole derivatives were isolated by
column chromatography. The results are shown in Table 6.
Finally, the feasibility of all the processes on a prepara-
tive scale was also screened. In this case, the model reac-
tions were performed on a 5-mmol scale in the presence of
the Cu(II)-catalyst. As expected, the large scale reactions
proceeded similarly to the experiment on a smaller scale
(Tables 2, 4, 6).
motion of the complexation of NaN with Cu(II) catalyst,
3
activation of ethoxy group and cleavage of C–O bond. Ini-
tially, carbocations stabilized by neighboring heteroatom are
created followed by the cleavage of ethoxy group of triethyl
orthoformate. In the next step, sequence of nucleophilic dis-
placements by amine and azide are occurred. Finally, cycli-
zation with azide produces tetrazole product [48].
3
.4 Synthesis of Benzimidazoles
To optimize the one step synthesis of benzimidazoles using
homogeneous [Cu(II)-ID] and heterogeneous [Cu(II)–ID@
silica], the reaction of p-chlorobenzaldehyde with o-phe-
nylenediamine in a 1:1.2 ratio was studied as a model reac-
tion under different parameters including solvents, catalyst
loadings, and temperature. At the onset of our studies, we
decided to investigate the effect of solvents on the one step
synthesis of benzimidazoles as the key chemical transfor-
mation. Among the various solvents tested in Table 5, the
reaction in ethanol stands out as the best choice according to
high fast reaction, high yield, and environmental acceptabil-
ity. Different catalytic amounts of homogenous and hetero-
geneous catalyst were screened in one step benzimidazoles
synthesis using the model reaction. The results showed that
Herein, we propose a mechanism for the Cu(II) complex
catalyzed 2-arylbenzimidazoles synthesis (Scheme 5), which
is in analogy to the established mechanism as reported in
the literature. We believe that the synthesis of 2-arylben-
zimidazoles under these conditions follows through the
known imine (A). The Cu(II) complex probably facilitates
the formation of A by increasing the electrophilicity of the
carbonyl group. Imine intermediate may exist in equilibrium
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
Table 7 Substrate scope
for synthesis of hybride
Yielda
Entry
1
Epoxide
Alkyne
Product
Time (h)
4.0
molecules by the way of a
three-component reaction
using 1.0 mol% homogeneous
81 (85)
[
[
Cu(II)–ID] and heterogeneous
Cu(II)–ID@silica] at room
temperature
2
3
5.5
5.5
80 (85)
81 (84)
4
4.0
79 (85)
1
3

H. Sharghi et al.
Table 7 (continued)
Yielda
Entry
5
Epoxide
Alkyne
Product
Time (h)
5.3
77 (78)
6
5.5
80 (80)
Reagents and conditions: organic epoxide (1.0 mmol), alkyne (1.0 mmol), sodium azide (1.2 mmol), homo-
geneous or heterogeneous catalyst (1.0 mol%)
a
Isolated yield (the average of at least two runs) of product using heterogeneous catalyst; the numbers in
parentheses is isolated yield (the average of at least two runs) of product using homogenous catalyst
with the cyclic hydrobenzimidazoles (B). Subsequently, in
the presence of Cu(II) complex and air, B probably oxidize
the synthesis of a series of hybrid molecules. These hybrid
molecules, which are displaying pharmacological activities,
are well documented in the literature. Triazoles and benzi-
midazoles have individually found extensive applications in
agrochemicals, industries, photostabilizers, pharmaceuticals,
and medicals. In this aspect, no modifications to the triazole
experimental procedure were required to verify that organic
epoxides and sodium azide can react with nonactivated
by O to give 2-arylbenzimidazoles [65–67].
2
3
.5 Synthesis of Hybrid Molecules
In continuation of our research work to establish the five-
membered heterocycles bearing nitrogen, we herein report
1
3

Five-membered N-Heterocycles Synthesis Catalyzed by Nano-silica Supported Copper(II)…
Fig. 7 The catalytic activity of
the heterogeneous [Cu(II)–ID@
silica] in 12 cycles for the reac-
tion of phenyl acetylene, benzyl
bromide, and sodium azide in
water at room temperature
terminal alkynes based on 1H-benzo[d]imidazole, benzo[d]
thiazole, or benzo[d] oxazole in a 1:1:1.2 molar ratio to form
β-hydroxy 1,2,3-triazoles in good yields (Table 7).
Finally, a comparison with other copper catalysts is made
for these C–N bond forming reactions to reveal some advan-
tages of the present catalytic system over most others in
terms of higher yield and shorter reaction time (Table 8).
3
.6 Investigation of Catalyst Recycling
Recycling of the heterogeneous [Cu(II)–ID@silica] was also
checked through the reaction of phenyl acetylene, benzyl
bromide, and sodium azide as a model reaction for twelves
runs (Fig. 7). The yields of desired functionalized triazole in
further runs were almost the same as the first run. In every
case, the heterogeneous [Cu(II)–ID@silica] was reused by
simple centrifugation from the reaction mixture by washing
with ethyl acetate. This organic phase was also washed with
water, and purified by silica gel column chromatography
employing n-hexane/ethyl acetate as eluent.
4 Conclusion
In conclusion, homogeneous and heterogeneous catalysts
were successfully synthesized. The heterogeneous catalyst
was characterized by TEM, FESEM, XRD, TG, FT-IR,
ICP and CHN analysis. The homogeneous Cu(II) catalyst
and nano sized heterogeneous catalyst exhibited excellent
activity for the library of azole products. In general, this
protocol provides novel, efficient, and one-pot catalytic
processes that enables the three-component synthetic route
to triazols, β-hydroxy-triazoles, tetrazols, and hybrid mol-
ecules. A series of substituted benzimidazole products was
also prepared via one step process under mild reaction con-
ditions. This operationally simple protocol does not require
the using toxic organic solvents and reagents. In addition,
this novel catalyst could be simply centrifuged and reused
for 12 times and could proceed the C-N bond forming reac-
tions in a suitable times and yields without expensive and
toxic metal and ligand. Therefore, the present methodology
To determine the amount of the catalyst leaching, the
reaction of phenyl acetylene (1.0 mmol), benzyl bromide
(
1.0 mmol), and sodium azide (1.2 mmol) in water at room
temperature was stirred in the presence of the nano-hetero-
geneous Cu(II) catalyst (1.0 mol%). After twelves runs, ICP
results showed 86.5% recovery for this anchoring procedure.
Also, heterogeneous [Cu(II)–ID@silica] was stirred for 2 h
in water at 80 °C. The catalyst was separated and the cop-
per content in water was investigated by ICP analysis; only
negligible copper was found.
1
3

H. Sharghi et al.
Table 8 Comparison of the catalytic efficiency of heterogeneous [Cu(II)-ID@silica] with the previously reported catalytic systems in the azole
products synthesis
The method
Starting materials, catalyst and conditions
Refs.
Triazole formation reaction
phenylacetylene (1.0 mmol), benzyl bromide (1.0 mmol), NaN (1.2 mmol), γ-Fe O @TiO -EG- [49]
3
2
3
2
Cu(II), (4.0 mol%), water (5.0 mL), 50 °C, 5 min, 94%
phenylacetylene (1.2 mmol), benzyl azide (1.0 mmol), copper(II) acetate (20 mol%), H O
[68]
[46]
[69]
2
(
3.0 mL), r.t., 20 h, 77%
phenylacetylene (1.0 mmol), benzyl bromide (1.0 mmol), NaN (1.1 mmol), copper nanoparti-
3
cles on charcoal (1.0 mol%), H O (1.0 mL), 100 °C, 0.6 h, 91%
2
phenylacetylene (1.0 mmol), p-bromobenzyl bromide (1.0 mmol), sodium azide (1.2 mmol),
SNIL-Cu(II) (0.05 mol%), Na-ascorbate (2.0 mol%), PEG-400/H O (1:1) (2.0 mL), r.t.,
2
1
5 min, 99%
phenylacetylene (1.0 mmol), benzyl chloride (1.0 mmol), sodium azide (1.1 mmol), [bis-(MIM)] [70]
(
CuBr )] (5.0 mol%), ethanol/water (60: 40%), 80 °C, 2–3 h, 91%
2
phenylacetylene (1.2 mmol), benzyl azide (1.0 mmol), [Cu(im) ] (0.1 mol%), ethanol (6.0 mL), [71]
2
7
0 °C, N atmospheric pressure, 1 h, >99%
2
phenylacetylene (1.0 mmol), benzyl bromide (1.0 mmol), sodium azide (1.2 mmol), [Cu(II)-
This work
[72]
ID@silica] (1.0 mol%), water (1.0 mL) r.t., 1 h, 98%
Tetrazole formation reaction
aniline (2.0 mmol), NaN (2.0 mmol), triethyl orthoformate (2.4 mmol), Cu NPs/bentonite
3
(
0.05 g), 120 °C, 3 h, 93%
aniline (1.0 mmol), NaN (1.0 mmol), triethyl orthoformate (1.2 mmol), ZnS nanoparti-
[73]
3
cles (50 mol%), 130 °C, 4.5 h, 78%
+
−
aniline (5.3 mmol), NaN (5.3 mmol), triethyl orthoformate (6.4 mmol), [bbim] Br /DMSO
[74]
3
(
0.1/1), 20 min, 86%
aniline (1.0 mmol), NaN (1.0 mmol), triethyl ortho-formate (1.2 mmol), CSMIL (2.5 mol%),
[64]
3
7
0 °C, 2.5 h, 86%
aniline (1.0 mmol), NaN (1.3 mmol), triethyl orthoformate (1.0 mmol), [AMWCNTs-O–
[48]
3
Cu(II)–PhTPY] (4.0 mol%), water (2.0 mL), 70 °C, 1.0 h, 95%
m-toluidine (1.0 mmol), NaN (1.3 mmol), triethyl orthoformate (1.0 mmol), [Cu(II)–ID@silica] This work
3
(
1.0 mol%), water (1.0 mL), 65 °C, 1.0 h, 94%
Benzimidazole formation reaction benzaldehyde (1.0 mmol), o-phenylenediamine (1.1 mmol), Fe O @SiO @(NH ) Mo O nano- [75]
3
4
2
4 6
7
24
composites (0.04 mmol), H O (0.2 mL), EtOH (5.0 mL), 30 min, r.t., 90.3%
2
2
benzaldehyde (1.0 mmol), o-phenylenediamine (1.2 mmol), nano-MoO (2.0 mol%, 0.002 g),
[76]
3
TBHP (2.0 mmol), 50 °C, 30 min, 93%
benzaldehyde (0.5 mmol), o-phenylenediamine (0.5 mmol), DBSA (0.05 mmol), iodine
[77]
(
0.05 mmol), H O (2.0 mL), r.t., 2 h, 92%
2
benzaldehyde (1.0 mmol), o-phenylenediamine (1.0 mmol), supported-Co(salen) (5.0 mol%),
[42]
ethanol (2.0 mL), r.t., 25 min, 96%
benzaldehyde (1.0 mmol), o-phenylenediamine (1.2 mmol), [Cu(II)–ID@silica] (5.0 mol%),
This work
ethanol (5.0 mL) 50 °C, 3 h, 81%
has potential versatile applications in the fields of chemistry,
biology, and medicine.
5. Dabak K, Sezer Ö, Akar A, Anaç O (2003) Eur J Med Chem
3
8:215
6
7
.
.
Horne WS, Yadav MK, Stout CD, Ghadiri MR (2004) J Am Chem
Soc 126:15366
Acknowledgements We gratefully acknowledge the financial support
of this work by the Shiraz University Research Council and the Iran
National Elite Foundation.
Moorhouse AD, Santos AM, Gunaratnam M, Moore M, Neidle S,
Moses JE (2006) J Am Chem Soc 128:15972
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Moorhouse AD, Moses JE (2008), ChemMedChem 3:715–723
Mamat C, Ramenda T, Wuest FR (2009) Mini Rev Org Chem 6:21
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0. Best MD (2009) BioChemistry 48:6571
1. Zheludkevich ML, Yasakau KA, Poznyak SK, Ferreira MGS
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