Facile synthesis of 5-substituted-1H-tetrazoles and 1-substituted-1H- tetrazoles catalyzed by recyclable 4′-phenyl-2,2′:6′,2″- terpyridine copper(II) complex immobilized onto activated multi-walled carbon nanotubes

Article abstract of DOI:10.1016/j.jorganchem.2013.04.013

5-Substituted-1H-tetrazoles can conveniently be synthesized from the corresponding nitriles by reaction with NaN₃ using the efficient and recyclable heterogeneous catalyst prepared by immobilization of copper(II) complex of 4′-phenyl-2,2′:6′,2″-terpyridine on activated multi-walled carbon nanotubes [AMWCNTs-O-Cu(II)-PhTPY]. Excellent results were obtained in each case affording the corresponding tetrazole adducts in good to excellent yields. In general, aromatic nitriles with electron-donating group could be accomplished as well as that with electron-withdrawing groups. By leaving out nitrile from the reaction and adding CH(OEt)₃ and amines bearing various substituents, 1-substituted-1H-tetrazoles formed in water in high yields. The reported protocols have the advantages of rapid assembly of a host of heterocyclic systems in high yields with the added advantage of recycling and reuse of the catalyst.

Full text of DOI:10.1016/j.jorganchem.2013.04.013

Journal of Organometallic Chemistry 738 (2013) 41e48
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Facile synthesis of 5-substituted-1H-tetrazoles and 1-substituted-1H-tetrazoles
catalyzed by recyclable 40-phenyl-2,20:60,200-terpyridine copper(II) complex
immobilized onto activated multi-walled carbon nanotubes
*
Hashem Sharghi , Sakineh Ebrahimpourmoghaddam, Mohammad Mahdi Doroodmand
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Substituted-1H-tetrazoles can conveniently be synthesized from the corresponding nitriles by reaction
with NaN3 using the efficient and recyclable heterogeneous catalyst prepared by immobilization of
copper(II) complex of 40-phenyl-2,20:60,200-terpyridine on activated multi-walled carbon nanotubes
[AMWCNTs-OeCu(II)ePhTPY]. Excellent results were obtained in each case affording the corresponding
tetrazole adducts in good to excellent yields. In general, aromatic nitriles with electron-donating group
could be accomplished as well as that with electron-withdrawing groups. By leaving out nitrile from the
reaction and adding CH(OEt)3 and amines bearing various substituents, 1-substituted-1H-tetrazoles
formed in water in high yields. The reported protocols have the advantages of rapid assembly of a host of
heterocyclic systems in high yields with the added advantage of recycling and reuse of the catalyst.
Ó 2013 Elsevier B.V. All rights reserved.
Received 9 December 2012
Received in revised form
5 April 2013
Accepted 10 April 2013
Keywords:
Carbon nanotube
Heterogeneous
Recyclable
Terpyridine copper complex
Tetrazole
1. Introduction
individual compounds or generated directly in a reaction medium
[14]. Another method of a tetrazole ring synthesis is based on the
The chemistry of heterocycles has acquired immense impor-
tance in recent years. Tetrazoles which represent an important class
of heterocycles are an increasingly popular functionality with wide
ranging applications [1]. In particular, this functional group have
shown strong activities as sedatives [2], antihypertensive drugs [2],
antiallergic [2], antimicrobial [3], antibacterial [4], antifungal [5],
carboxylic acid isosteres [6], anti-imflammatory [7], hormonal [8],
diuretics activity [9], and herbicides [10]. These nitrogen-rich ring
systems have also applications in material science including pro-
pellants [11], explosives [12] and photography [13]. Furthermore,
tetrazole moieties are important synthons in synthetic organic
chemistry [14]. They form stable complexes with metals [15] and
have been used as ligands for palladium-catalyzed reactions [16].
Because of their potent usefulness, the synthesis of tetrazole
frameworks has received much attention recently, and various
preparative methods have been developed. For tetrazole ring con-
struction the synthetic equivalents of sodium azide or organic
azides and cyanides, isocyanides, isocyanates or isothiocyanates are
used most frequently [17]. They can be brought into the reaction as
reaction of amines with triethyl orthoformate and sodium azide
[18,19]. Whereas the [3 þ 2] cycloaddition of isocyanides with
TMSN3 under the influence of various catalysts reported by
Yamamoto et al. [20] provides access to various 1-substituted tet-
razoles, reaction of primary amines with orthocarboxylic acid ester/
sodium azide reported in several more recent reports is more
practical. The use of In(OTf)3 and Yb(OTf)3 as catalysts for this three
component transformation has been reported utilizing alcoholic
solvents or neat at high temperatures (100 ꢀC) [18,21]. Catalysis by
1-n-butylimidazolium tetrafluoroborate with NaN3/CH(OEt)3 has
also been shown, but it requires high temperatures [22]. Some of
these methods have one or more of the following drawbacks:
expensive and toxic metal catalysts, harsh reaction conditions,
refluxing for a prolonged period of time and tedious work-ups. All
of these approaches reveal that the catalytic formation of these
classes of heterocyclic compounds is still challenging and that the
area demands to be developed further.
Heterogeneous-reagent systems have many advantages such as
simple experimental procedures, mild reaction conditions and the
minimization of chemical wastes as compared to their liquid phase
counterparts [23]. Catalysis is currently recognized as a potential
field of application for carbon nanotubes (CNTs), and throughout
the past decade the number of publications and patents on this
subject has been increasing exponentially [23].
* Corresponding author. Fax: þ98 711 2280926.
E-mail addresses: hashemsharghi@gmail.com, shashem@chem.susc.ac.ir
(H. Sharghi).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.04.013

42
H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
In continuation of our work on synthesis of biologically active
231(61.3), 209(41.0), 176(12.1), 106(38.7), 78(97.1). C21 H15 N3
(309.360): C 81.53, H 4.89; found C 81.37, H 4.74.
heterocyclic scaffolds [23], we report here on the use of immobi-
lized 40-phenyl-2,20:60,200-terpyridine copper(II) complex onto
activated multi-walled carbon nanotubes for facile construction of
5-substituted-1H-tetrazoles, and 1-substituted-1H-tetrazole ring
systems in high yields under very mild conditions with recycling
and reuse of the heterogeneous catalyst (Scheme 1).
2.2.2. Preparation of 40-phenyl-2,20:60,200-terpyridine copper (II)
complex
The compound 40-phenyl-2,20:60,200-terpyridine (6.18 mg,
0.02 mmol) was added to solution of Cu(CH3COO)2.H2O (4 mg,
0.02 mmol) in water (2 mL). Stirring for 0.5 h at room temperature
resulted in a clear blueegreen solution. This solution was used as
homogeneous catalyst.
2. Experimental section
2.1. Instrumentation, analysis, materials and general experimental
details
2.2.3. Synthesis of multi-walled carbon nanotubes
MWCNTs were synthesized by the chemical vapor deposition
(CVD) process using acetylene as the source of carbon and ferro-
cene as the source of iron nanoparticles at temperature to
w1300 ꢀC in an inert atmosphere of argon. Trace flow of oxygen in
argon was introduced to the CVD production line for purification of
MWCNTs from any amorphous carbon or bulky nanomaterials such
as fullerene, opening the CNT bundles, and activation of the carbon
nanostructures to form hydroxyl functional groups. To synthesize
MWCNTs, briefly, 5% molar percentage of ferrocene solution in
benzene was used for production of Fe nanoparticles (diameter 2e
10 nm), followed by decomposition of acetylene, generation of
carbon vapors and finally deposition onto the metal nanoparticles.
The synthesized MWCNT bundles were then directly purified by
purging with oxygen and nitric acid vapors. In accordance with the
TG analysis and Raman spectroscopy, the purity of the MWCNT
bundles was estimated to w99%.
NMR spectra were recorded on a Bruker Avance DPX-250 (1H
NMR 250 MHz and 13C NMR 62.9 MHz) in pure deuterated solvents
with tetramethylsilane (TMS) as internal standards. Scanning elec-
tron micrographs were obtained by SEM instrumentation (SEM, XL-
30 FEG SEM, Philips, at 20 kV). An atomic forced microscopy (AFM,
DME-SPM, version 2.0.0.9) was also used for AFM images. FT-IR
spectroscopy (Shimadzu FT-IR 8300 spectrophotometer) were
employed for characterization of the heterogeneous catalyst. The
TG analysis of the samples was carried out using a labmade TG
analyzer instrument. Metal contents were obtained by an ICP
analyzer (Varian, vista-pro). Mass spectra were determined on a
Shimadzu GCMS-QP 1000 EX instrument at 70 or 20 eV. Melting
points determined in open capillary tubes in a Buchi-535 circu-
lating oil melting point apparatus. UV/Vis spectra was obtained
with an Ultrospec 3000 UV/Visible spectrometer. Elemental ana-
lyses were performed on a Thermo Finnigan CHNS-O analyzer, 1112
series. The purity determination of the substrates and reaction
monitoring were accomplished by TLC on silica gel PolyGram SILG/
UV254 plates or by a Shimadzu Gas Chromatograph (GC-10 A) in-
strument with a flame-ionization detector using a column of 15%
carbowax 20 M chromosorb-w acid washed 60e80 mesh. Column
chromatography was carried out on short columns of silica gel 60
(70e230 mesh) in glass columns (2e3 cm diameter) using 15e30 g
of silica gel per 1 g of crude mixture. Chemical materials were either
prepared in our laboratories or were purchased from Fluka, Aldrich
and Merck Companies.
2.2.4. Activation of multi-walled carbon nanotubes
In order to develop hydroxyl groups on the surface for better
anchoring the metal complex, high temperature air activation
method was utilized. A tubing resistance furnace with 150 mm
diameter and w1.0 m length, with the two ports open, was initially
set to 700 ꢀC. The purification step was achieved in an on-line pro-
cess, followed by the synthesis of MWCNTs by CVD method. The
quartz tube carrying the MWCNTs by the flow of argon was placed in
the center of the furnace tube. Temperature was maintained at
700 ꢀC, while the argon was flown with w200 mL minꢁ1 flow rate. So
that MWCNTs were mixed with air to produce the desired AMWCNTs.
2.2. Synthesis of catalyst
2.2.5. Preparation of AMWCNTs-ONa
2.2.1. Preparation of 40-phenyl-2,20:60,200-terpyridine
Suspension of AMWCNTs with hydroxyl functional group (1 g)
in an alkaline solution of NaOH (10 N, 30 mL) was refluxed for 2 h.
The resulting black precipitate was filtered through a celite pad,
washed with water until PH received 8e9. The black solid was dried
in vacuo to afford the MWCNTs-ONa (1 g).
The ligand 40-phenyl-2,20:60,200-terpyridine was synthesized
according to the literature method and characterized by NMR, IR,
Mass and elemental analysis [23]. Pale yellow crystals; 0.15 g, 47%
yield. M.p. ¼ 122e125 ꢀC. IR (KBr): 682(m), 893(m), 1041(m),
1267(m), 1465(s), 1583(s) cmꢁ1 1H NMR (CDCl3, 250 MHz):
.
d
¼ 7.07e7.42(m, 5H), 7.71e7.81(m, 4H), 8.53e8.67(d, J ¼ 7.5 Hz,
2.2.6. Immobilization of 40-phenyl-2,20:60,200-terpyridine copper(II)
complex onto AMWCNTs
AMWCNTs-ONa (0.5 g) was added to a freshly prepared aqueous
[Cu(II)ePhTPY] (0.5 mmol, 20 mL) solution, the mixture was sonicated
2H), 8.59e8.62(d, J ¼ 7.5 Hz, 2H), 8.63(s, 2H) ppm. 13C NMR (CDCl3,
62.9 MHz):
d
¼ 118, 121, 123, 127, 128, 129, 136, 138, 149, 150, 155,
156 ppm. MS: m/z (%) ¼ 310(66.5) [M þ 1]þ, 309(98.8) [M]þ,
R1
R1
N
NaN3
N
N
N
NH
NH4OAc
N
Cu
N
N
Cu
N
O
O
O
N
N
OAc
R2
NH2
R2
NaN3
N
N
N
N
CH(OEt)3
Scheme 1.

H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
43
for 1 h and stirred at room temperature for 24 h. The resulting black
precipitate was filtered through a celite pad, washed with water
(25 mL), MeOH (25 mL), and ether (25 mL), dried in vacuum to
afford the [AMWCNTs-OeCu(II)ePhTPY] as a black solid.
silica gel using hexane/ethyl acetate as the eluent afforded the pure
products.
2.4. General procedure for the synthesis of 1-substituted-1H-
tetrazoles derivatives in the presence of a catalytic amount of the
[AMWCNTs-OeCu(II)ePhTPY]
2.3. General procedure for the synthesis of 5-substituted-1H-tetrazoles
derivatives in the presence of a catalytic amount of the [AMWCNTs-
OeCu(II)ePhTPY] and recycling of the heterogeneous catalyst
Amine (1.0 mmol), HC(OEt)3 (1.0 mmol) and NaN3 (1.3 mmol)
were mixed and stirred in water (2 mL) in the presence of 4 mol-%
of [AMWCNTs-OeCu(II)ePhTPY] at 70 ꢀC in an uncapped vial. After
the completion of the reaction, as monitored by TLC using n-hex-
ane/ethyl acetate, the mixture was diluted by H2O (5 mL), then the
mixture was vacuum-filtered onto a sintered-glass funnel, and the
residue was consecutively washed with ethyl acetate (30 mL), water
(5 mL). The combined supernatant and organic washings were
extracted with ethyl acetate (3 ꢂ 10 mL), the combined organic layer
was dried over anhydrous Na2SO4. Removal of the solvent under
vacuum, followed by purification on silica gel using hexane/ethyl
acetate as the eluent afforded the pure products.
The [AMWCNTs-OeCu(II)ePhTPY] heterogeneous catalyst was
subjected to 5 successive reuses under the reaction conditions: For
each reaction, nitrile (1.0 mmol), NaN3 (1.3 mmol) and NH4OAc
(1.0 mmol) were mixed and stirred in DMF (1 mL) in the presence of
4 mol-% of [AMWCNTs-OeCu(II)ePhTPY] at 70 ꢀC in an uncapped
vial. After the completion of the reaction, as monitored by TLC using
n-hexane/ethyl acetate, the mixture was diluted by H2O (5 mL),
then the mixture was vacuum-filtered onto a sintered-glass fun-
nel, and the residue was consecutively washed with ethyl acetate
(30 mL), water (5 mL). The heterogeneous catalyst was recharged
for another reaction run. The combined supernatant and organic
washings were extracted with ethyl acetate (3 ꢂ 10 mL), the
combined organic layer was dried over anhydrous Na2SO4.
Removal of the solvent under vacuum, followed by purification on
3. Results and discussion
In chemical and pharmaceutical industries, recycling of homo-
geneous catalysts has great economic and environmental importance.
a)
O
O
N
N
N
EtOH/H2O/NaOH
r.t/Overnight
H
O
O
2
N
N
H2O/Cu(OAc)2
r.t/1h
N
N
N
N
Cu
AcO
OAc
b)
OH
HO
N
1) NaOH(aq)/reflux
2)
N
N
Cu
O
O
N
N
N
OH
N
N
Cu
O
O
Cu
HO
O
OAc
N
N
N
N
Cu
AcO
OH
HO
OAc
Scheme 2. a) Synthesis of 40-phenyl-2,20:60,200-terpyridine copper(II) complex, b) Immobilized 40-phenyl-2,20:60,200-terpyridine copper(II) complex onto activated multi-walled
carbon nanotubes [AMWCNTs-OeCu(II)ePhTPY].

44
H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
3.1. Characterization of heterogeneous catalyst
We have recently reported the use of activated multi-walled
carbon nanotubes as a feasible support for 40-Phenyl-2,20:60,200-
terpyridine copper(II) complex [AMWCNTs-OeCu(II)ePhTPY] [23],
which has been applied as the catalyst for Huisgen’s [3 þ 2] azide-
alkyne cycloaddition, a three-component click reaction in water.
Now in this report, we have presented another highly useful cata-
lytic application of this catalyst for synthesis of tetrazole systems.
The catalyst was prepared and characterized according to our
previously reported protocol (Scheme 2) [23]. 40-Phenyl-2,20:60,200-
terpyridine was synthesized according to a modified Krönke pro-
cedure. The copper complex was obtained by adding 40-phenyl-
2,20:60,200-terpyridine to an aqueous solution of copper(II) acetate
monohydrate, and the mixture was stirred for 1 h, resulting in a
blueegreen solution. Before direct use of the MWCNTs, their surface
was activated via introduction hydroxy (OH) groups by means of
gas phase oxidation under air. This modification booms the reac-
tivity of CNTs and allows for easier deposition of the metal pre-
cursors at the nucleating sites; thus, higher catalyst dispersions are
to be expected. Firstly, AMWCNTs-ONa was obtained via refluxing
of AMWCNTs in an alkaline solution. Then, it was added in to a
freshly prepared aqueous solution of [Cu(II)ePhTPY]. Finally, the
mixture was sonicated for 1 h and stirred at room temperature for
24 h. The resulting black precipitate was filtered through a celite
pad, washed with water, MeOH and ether, dried in vacuum to afford
the [AMWCNTs-OeCu(II)ePhTPY] as a black solid.
The resulting immobilized copper complex on AMWCNTs were
characterized by UVeVis spectroscopy. In Fig. 1 the absorption
spectra of free [Cu(II)ePhTPY], AMWCNTs, and [AMWCNTs-Oe
Cu(II)ePhTPY] in ethanol are compared. [Cu(II)ePhTPY] absorbs light
at 288 nm and 320e350 nm showing sharp bands with fine struc-
tures. The spectrum of AMWCNTs does not show any fine structure;
however, a continuous absorption is evident. According to Fig.1, the
spectrum of [AMWCNTs-OeCu(II)ePhTPY] reveals that the char-
acteristic absorption bands of [Cu(II)ePhTPY] in the [AMWCNTs-Oe
Cu(II)ePhTPY] are evidently broaden as compared with the free
[Cu(II)ePhTPY], although the exact comparison at the same [Cu(II)e
PhTPY] concentration is impossible due to the masking effect from
AMWCNTs [27]. These observations verify efficient complex for-
mation between [Cu(II)ePhTPY] and AMWCNTs. Treatment of
[AMWCNTs-OeCu(II)ePhTPY] with EDTA solution resulted in the
disappearance of the characteristic absorptions due to [Cu(II)ePhTPY],
indicating that EDTA dissociate the [Cu(II)ePhTPY] by liberating tpy
ligand absorbing at 235e290 nm (see Supporting Information,
Figure S1).
Fig. 1. UV/Vis. spectra of AMWCNTs (——), [AMWCNTs-OeCu(II)ePhTPY] (▬) and
[Cu(II)ePhTPY] (..), obtained in ethanol.
Homogeneous catalysts immobilization on various insoluble solid
supports with high surface areas is usually the method of choice,
since the immobilized catalysts can be facilely recovered via a
simple filtration process after reactions [24]. Catalysis is currently
recognized as a potential field of application for carbon nanotubes
(CNTs), and throughout the past decade, the number of publications
and patents on this subject has been increasing exponentially [25].
In the most cases, the use of these nanomaterials as solid supports
have better performances than conventional supports. Indeed,
CNTs represent an interesting alternative to conventional support
structures because of their high purity that eliminates self-
poisoning, high electrical conductivity and thermal stability,
impressive mechanical properties, high accessibility of the active
phase, absence of any microporosity, eliminating diffusion and
intraparticle mass transfer in the reactions medium, the possibility
for macroscopic shaping of the support, the possibility of tuning the
specific metalesupport interactions, which can directly affect the
catalytic activity and selectivity; and finally the possibility of
confinement effects in their inner cavity. Additionally, compared to
conventional supports, CNTs have a high flexibility for the dispersion
of the active phase, since it is possible to modulate their specific
surface area (50e500 m2 gꢁ1 for multi-walled carbon nanotubes
(MWCNTs)) or their internal diameter (5e100 nm for MWCNTs),
ease of chemical functionalization of their surfaces, change their
chemical composition (nitrogen- or boron-doped CNTs), and de-
posit lots of catalytic phase either on their external surface or in
their inner cavity [26].
Transmission electron microscopy (TEM) and scanning electron
microscopy (SEM) images of the catalyst show the morphology of
catalyst, when doped with copper complex (Fig. 2). In order to
obtain more information about the topography of the surface of the
Fig. 2. A) SEM, B) TEM, C) TEM with higher resolution of the immobilized copper complex on AMWCNTs.

H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
45
of the sample at an air flow rate of 2.0 mL minꢁ1 and a temperature
ramp of 2.0 ꢀC minꢁ1. Based on this thermogram, significant change
at w210 ꢀC is related to the decomposition of ligand. Also, a de-
crease enhancement at w400 ꢀC is due to the oxidation of copper
and formation of copper oxide (CuO). Whereas, significant decrease
in the weight percentage of the thermogram at w610 ꢀC is related
to the decomposition of AMWCNTs (see Supporting Information,
Figure S4). In this study, no significant changes were observed in
the active surface area of the copper-doped AMWCNTs, compared
to AMWCNTs as evaluated via following the nitrogen adsorption
capacity of both AMWCNTs and copper-doped AMWCNTs (see
Supporting Information, Figure S5).
The process related to the complex formation of the nano-
catalyst was also evaluated using FT-IR spectrometry. Fig. 3I and II
shows the FT-IR spectra of AMWCNTs and [AMWCNTs-OeCu(II)e
PhTPY], respectively. Based on the FT-IR spectra (Fig. 3II), sharp
peak at 578.6 cmꢁ1 is related to the formation of CueO bond [23].
Whereas, the broad peak positioned around 1616.2 cmꢁ1, is corre-
lated to the C]C bond presented in the CNT matrix overlapped
with the copper complexed moieties [28]. It seems that, low amounts
of copper complex on the CNTs surface lead to the peak broadening
in the [AMWCNTs-OeCu(II)ePhTPY] system. The amounts of hy-
droxyl group were also estimated to 6.11% based on the back titration
process.
Fig. 3. FT-IR spectra of I) AMWCNTs and II) [AMWCNTs-OeCu(II)ePhTPY].
3.2. Synthesis of 5-substituted-1H-tetrazoles
To evaluate the merit of application of this catalytic system in
organic synthesis, we applied it in the [3 þ 2] cycloaddition of ni-
triles and azide. Initial studies were performed upon the reaction of
4-methylbenzonitrile with NaN3 as a model reaction and the effects
of different conditions were studied for this reaction (Table 1). In
order to create a procedure that avoids the use of high amount of
catalyst, ammonium acetate was used as proton source to provide
the pure tetrazoles. Thanks to the low pKa of 1H-tetrazoles (ca. 3e
5) and their highly crystalline nature [29], a simple acidification is
usually sufficient to break the metal-nitrogen bond.
prepared catalyst, we have also presented the AFM image of the
catalyst (see Supporting Information, Figure S2).
The width of the band at half height of the voltage profile peak
reveals the size of copper(II) complexes nanoparticles. From AFM
images, the histogram related to the frequency percentages of the
average of different sizes of copper complexes on AMWCNTs ob-
tained. According to this histogram, the diameter of copper com-
plexes is ranged from 2.5 to 40 nm (see Supporting Information,
Figure S3). The amount of copper complex content supported on
AMWCNTs was determined by ICP analysis techniques to be 4.895%.
The thermal stability of copper-doped AMWCNTs was also investi-
gated using a TG analysis instrumentation system. The thermogram
According to Table 1, when the model reaction was performed
under catalyst-free conditions at 100 ꢀC, the desired product was
obtained in low yield (Table 1, Entry 1). Although, copper acetate
Table 1
Comparison of the conditions used for the reaction of 4-methylbenzonitrile with NaN3..
H
N
N
[AMWCNTs-O-Cu(II)-PhTPY]
N
N
NaN3
H3C
H3C
CN
NH4OAc/Solvent/heat
Entry
Solvent
Temperature (ꢀC)
Catalyst (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
None
DMSO
Dioxane
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
Reflux
80
70
50
30
70
e
5
5
5
5
5
5
5
5
5
5
5
5
4
4
4
30
50
90
100
10
70
60
50
80
80
30
5
100
100
100
(CH3COO)2Cu$H2O (2)
[Cu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (2)
[AMWCNTs-OeCu(II)ePhTPY] (4)
[AMWCNTs-OeCu(II)ePhTPY] (6)
[AMWCNTs-OeCu(II)ePhTPY] (8)
9
10
11
12
13
14
15
70
70
a
Determined by 1H NMR spectroscopy.

46
H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
could accelerate the reaction to produce the target compound, it
could not provide satisfactory yields (Table 1, Entry 2). We observed
an increase in the reaction yield using [Cu(II)ePhTPY] (2.0 mol %) at
100 ꢀC (Table 1, Entry 3).
Table 2
Synthesis of 5-substituted 1H-tetrazoles.
Entry
Nitrile
Product
Time [h] Yield [%]a
The results showed that among the tested conditions, using
[AMWCNTs-OeCu(II)ePhTPY] as catalyst and DMF as solvent were
more efficient in which the desired product was obtained in higher
yields than the other solvents under study (Table 1, Entry 4). In the
reactions employing DMSO, dioxane and CH3CN as the solvents, the
reactions did not progress efficiently and after 5 h, the desired
product was obtained in 50e70% yields (Table 1, Entries 6e8).
Lowering the temperature to 80 and 70 ꢀC led to decrease in re-
action yields (Table 1, Entry 9 and 10). Reducing the temperature to
50 and 30 ꢀC was accompanied by a considerable drop of yield by
30 and 5%, respectively (Table 1, Entry 11 and 12). We have also
investigated the effect of different amount of catalyst upon the
reaction. By increasing of the catalyst loading to 4.0 mol % the re-
action completed after 4 h at 70 ꢀC. However, using higher amount
of catalyst has no significant effect on reaction rate and isolated
yield of product (Table 1, Entries 14 and 15).
Study for optimization of the reaction with respect to the amounts
of the starting materials and the catalyst, led us to nitrile (1 mmol),
azide (1.3 mmol), DMF (1.0 mL), NH4OAc (1 mmol) and catalyst
(4.0 mol%) at 70 ꢀC (Scheme 3). As a result of these endeavors, we have
found that in the presence of [AMWCNTs-OeCu(II)ePhTPY], tetrazole
formation proceeds with excellent yields and scope in DMF (Table 2).
As shown in Table 2, a range of nitriles reacted with NaN3 to give
the desired products. Employing the optimized catalytic conditions,
nitriles bearing electron-donating groups provided high yields of
the desired products (Table 2, Entries 1e3). Similarly, the reactions
of substrates with electron-withdrawing group as well as hetero-
aryl nitriles with azide were also studied (Table 2, Entries 4e14). As
shown in Table 2, the reaction of nitriles having a NO2, CF3 or CN
functional group in para position went to completion within 1.0, 0.8
and 1.5 h to give tetrazole in excellent yield (Table 2, Entry 4, 5 and
10). It is noticeable that, compared to electron-rich nitriles, elec-
trondeficients furnished the corresponding products in shorter
reaction time and comparatively higher reaction yields. Steric
hindrance also shows its effects upon the rates of the reactions. As
the example, 4-methylbenzonitrile reacted with azide within 4 h
with the isolation of the desired product in 90% (Table 2, Entry 1).
Although, the similar reaction with 2-methylbenzonitrile was
performed in 7 h producing the final product in 75% yield (Table 2,
Entry 2). Similarly, longer reaction time has been observed for the
reaction of phthalonitrile with azide (Table 2, Entry 12).
H
N
N
N
1
4.0
7.0
90
75
H3C
CN
H3C
N
1
H
N
N
N
CN
2
N
CH3
CH3
2
H
N
N
N
N
3
4
5
6
6.0
1.0
0.8
2.5
90
92
98
90
MeO
O2N
F3C
Cl
CN
CN
MeO
O2N
F3C
Cl
3
H
N
N
N
N 4
H
N
N
N
CN
N
5
H
N
N
N
N
CN
6
H
N
N
N
CN
7
2.0
3.0
2.5
1.5
2.0
85
95
90
85
80
N
Cl
Br
Cl
Br
7
H
N
N
N
N
8
CN
8
H
N
N
N
CN
9
N
Br
Br
9
H
N
N
N
N
10
11
NC
CN
NC
10
A plausible mechanism is shown in Scheme 4. Initially, [Cu (II)
TPY] nano-catalyst reacts with azide to produce the [Cu (II) TPY]e
N3 (I) catalytic species. The [3 þ 2] cycloaddition between the CeN
bond of nitrile and (I) takes place to form the intermediate (II).
Precoordination of the nitrogen atom of the CN group of 2 with (I)
to form complex (II) would accelerate this cyclization step. Proto-
nolysis of the intermediate (II) by Hþ of NH4OAc affords the 5-
substituted-1H-tetrazole (III) and copper catalyst.
H
N
N
N
N
CN
NC
NC
11
H
N
N
N
CN
CN
12
13
3.5
80
N
3.3. Activity and reusability of heterogeneous catalyst
CN
12
H
The model reaction (4-methylbenzonitrile, NaN3 in a 1:1.3 M
ratio in DMF at 70 ꢀC) was performed successfully within 4 h in the
N
N
N
N
3.0
4.0
85
85
N
CN
N
13
14
H
[AMWCNTs-O-Cu(II)-PhTPY]
H
N
N
(4 mol%)
N
N
N
CN
14
N
CN
NaN3
N
R
N
N
R
N
DMF/70 °C/NH4OAc
a
Isolated yield.
Scheme 3. Synthesis of 5-substituted 1H-tetrazol.

H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
47
Table 3
R C N
2
Synthesis of 1-substituted-1H-1,2,3,4-tetrazoles from various amines (1.0 mmol),
triethyl orthoformate (1.0 mmol) and sodium azide (1.3 mmol) in the presence of
[AMWCNTs-OeCu(II)ePhTPY] (4.0 mol%).
R
N
N
N3
[Cu(II)-TPY]
Entry
Amine
Product
Time [h] Yield [%]a
N
N
[Cu(II)TPY]
N
N
N
II
I
NH2
N
N
1
1.0
1.2
95
89
NaN3
1
15
16
N N
N
N
N
N
R
NH2
N
2
3
[Cu(II)-TPY]
III
[Cu(II)-TPY]
OMe
H+
OMe
N
N
N
NH2
NH2
N
N
N
HN
1.0
94
N
N
OMe
OH
R
OMe
OH
17
3
N
N
N
Scheme 4. A plausible mechanism for the formation of 5-substituted 1H-tetrazol.
4
5
1.0
0.8
95
95
presence of 4.0 mol-% of heterogeneous catalyst in the first run. The
heterogeneous catalyst, which recovered by filtration after each
reaction, can be reused for 5 successive times in the new experi-
ments without dramatic yield loss and generate products with
purities similar to those obtained in the first run (Fig. 4), which
shows that there is no considerable change in the catalytic activity
of the catalysts even after five reaction cycles.
18
N
N
N
NH2
N
Me
Me
19
N
N
N
N
NH2
3.4. Synthesis of 1-substituted-1H-tetrazoles
H3C
6
1.0
90
H3C
Spurred with the success of 5-substituted 1H-tetrazol synthesis,
the formation of 1-substituted-1H-tetrazoles was studied using this
efficient nanocatalyst. Some modifications of the previously opti-
mized experimental protocol (Scheme 5) were required to verify
that, in the presence of copper nano-catalyst (4 mol%), amine, NaN3
and CH(OEt)3 in a 1:1.3:1 M ratio are smoothly converted to 1-
substituted-1H-tetrazoles in satisfactory yield (Scheme 5). Here
the appropriate solvent was water. As previously demonstrated, the
heterogeneous catalyst is recyclable and its activity is retained after
five reaction cycles.
CH3
CH3
20
N
N
N
NH2
N
7
8
9
2.0
2.0
2.5
90
90
88
Cl
Cl
21
N
N
N
N
NH2
Cl
Cl
22
N
N
N
NH2
N
Br
Br
23
N
N
N
NH2
NH2
N
10
11
3.0
4.0
90
80
Br
Br
24
25
Fig. 4. Reusability of catalyst.
N
N
N
N
OEt
OEt
N
[AMWCNTs-O-Cu(II)-PhTPY]
N
N
NH2
N
R
NO2
R
NO2
EtO
°
NaN3/H2O/70 C
(continued on next page)
Scheme 5. One-pot synthesis of 1-substituted 1H-tetrazol with copper nano-catalyst.

48
H. Sharghi et al. / Journal of Organometallic Chemistry 738 (2013) 41e48
Table 3 (continued )
exceptional efficacy of the TPY framework as copper scavenger
guarantees negligible copper leaching. Other significant features of
this method include its ease of operation, high efficiency, and
reusability in the reaction process, which provides an efficient
method for synthesis of different heterocyclic systems.
Entry
Amine
Product
Time [h] Yield [%]a
N
N
N
NH2
N
12
2.5
92
O
Acknowledgments
O
26
a
Isolated yield.
We gratefully acknowledge the support of this work by the
Shiraz University Research Council.
HC(OEt)2
HC(OEt)2
OEt
Appendix A. Supplementary data
OEt
2
N3
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jorganchem.2013.04.013.
[Cu(II)-TPY]
II
N3
[Cu(II)TPY]
I
NaN3
1
RNH2
References
-OEt
NHR
3
[1] R.N. Bulter, in: A.R. Katrizky, C.W. Rees, E.F.V. Scriven (Eds.), Comprehensive
Heterocyclic Chemistry, vol. 4, Pergamon, Oxford, UK, 1996.
[2] E.P. Ellis, G.B. West, Progress in Medicinal Chemistry, vol. 17, Biomedical Press,
1980, p. 151.
[3] S. Narender Rao, T. Ravisankar, J. Latha, K. Sudhakar Babu, Der Pharma Chem. 4
(2012) 1093e1103.
[4] T. Narasaiaha, D. Subba Raoa, S. Rasheeda, G. Madhavaa, D. Srinivasulua,
P. Brahma Naidub, C. Naga Rajua, Der Pharm. Lett. 4 (2012) 854e862.
[5] M. Ahmad Malik, S.A. Al-Thabaiti, M.A. Malik, Int. J. Mol. Sci. 13 (2012) 10880e
10898.
[6] R.N. Butler, Adv. Heterocycl. Chem. 21 (1977) 323.
[7] S. Bepary, B.K. Das, S.C. Bachar, J.K. Kundu, A.S. Shamsur rouf, B.K. Datta, Pak.
J. Pharm. Sci. 21 (2008) 295e298.
[Cu(II)-TPY]
-OEt
N
N
N
N
EtO
OEt
N R
[Cu(II)-TPH2Y]
N
4
R
N
N3
III
-OEt
N
[Cu(II)-TPY]
EtO
IV
Scheme 6. A plausible mechanism for the formation of 1-substituted 1H-tetrazol.
[8] J. Li, S.Y. Chen, J.A. Tino, Bioorg. Med. Chem. Lett. 18 (6) (2008) 5. PMID
18295486.
[9] R.J. Nachman, G.M. Coast, K. Kaczmarek, H.J. Williams, J. Zabrocki, Acta Bio-
chim. Pol. 51 (2004) 121e127.
[10] P. Camilleri, M.W. Kerr, T.W. Newton, J.R. Bowyer, J. Agric. Food Chem. 37
(1989) 196e200.
[11] R. Damavarapu, T.M. Klapötke, J. Stierstorfer, K.R. Tarantik, Propellants Explos.
Pyrotech. 35 (2010) 395e406.
[12] C. Zhaoxu, X. Heming, Propellants Explos. Pyrotech. 24 (1999) 319e324.
[13] L. Miguel Teodoro Frija, A. Ismael, M. Lurdes Santos Cristiano, Molecules 15
(2010) 3757e3774.
[14] G.I. Koldobskii, Russ. J. Org. Chem. 42 (2006) 469e486.
[15] A. Palazzi, S. Stagni, S. Selva, M. Monari, J. Organomet. Chem. 669 (2003) 135.
[16] K. Gupta, C.Y. Rim, C.H. Oh, Synlett (2004) 2227.
[17] N.T. Pokhodylo, V.S. Matiychuk, M.D. Obushak, Tetrahedron 64 (2008) 1430e
1434.
[18] D. Kundu, A. Majee, A. Hajra, Tetrahedron Lett. 50 (2009) 2668e2670.
[19] Y. Boland, P. Hertsens, J. Marchand-Brynaert, Y. Garcia, Synthesis (2006) 1504.
[20] T. Jin, S. Kamijo, Y. Yamamoto, Tetrahedron Lett. 45 (2004) 9435e9437.
[21] W.-K. Su, Z. Hong, W.-G. Shan, X.-X. Zhang, Eur. J. Org. Chem. (2006) 2723e
2726.
[22] T.M. Potewar, S.A. Siddiqui, R.J. Lahoti, K.V. Srinivasan, Tetrahedron Lett. 48
(2007) 1721e1724.
[23] H. Sharghi, S. Ebrahimpourmoghaddam, M.M. Doroodmand, A. Purkhosrow,
Asian J. Org. Chem. 1 (4) (2012) 377e388.
[24] P.D. Stevens, J. Fan, H.M.R. Gardimalla, M. Yen, Y. Gao, Org. Lett. 7 (11) (2005)
2085e2088.
[25] P. Serp, in: P. Serp, J.L. Figueiredo (Eds.), Carbon Materials for Catalysis, John
Wiley & Sons, Inc., Hoboken, NJ, 2009, pp. 309e372.
As shown in Table 3, aniline and a series of its substituted de-
rivatives, bearing a variety substituents (and their isomers), con-
taining electron-withdrawing or electron-donating groups such as
chloro, bromo, nitro, acetyl, alkoxy and alkyl underwent condensa-
tion in reasonable reaction times with excellent isolated yields
(Table 3, Entry 2e12). However, applying nitro aniline as an elec-
trondeficient amine was accompanied by the elongation of the re-
action times to 4 h with the production of the desired product in 80%
yields (Table 3, Entry 11).
A proposed mechanism for the 1-substituted tetrazole-forming
reaction is shown in Scheme 6. It is clear from the sequence of steps
that the role of [AMWCNTs-OeCu(II)ePhTPY] is complexation of
NaN3 with [Cu(II)eTPY] complexes, activation of ethoxy groups and
cleavage of CeO bonds. It can generate carbenium ions that are
resonance stabilized by neighboring hetero atom O/N or readily
facilitate sequential nucleophilic displacements by amine and
cyclization with azide. This would explain the formation of in-
termediates (II)e(IV). [Cu(II)eTPY] nano-catalyst-assisted elimi-
nation of ethanol from (IV) leads to the final heterocycle 4.
[26] M. Monthioux, P. Serp, E. Flahaut, C. Laurent, A. Peigney, M. Razafinimanana,
W. Bacsa, J.-M. Broto, in: B. Bhushan (Ed.), Springer Handbook of Nanotech-
nology, second revised and extended ed., Springer-Verlag, Heidelberg, Ger-
many, 2007, pp. 43e112.
[27] G. Rotas, A.S.D. Sandanayaka, N. Tagmatarchis, T. Ichihashi, M. Yudasaka,
S. Iijima, Osamu Ito, J. Am. Chem. Soc. 130 (2008) 4725e4731.
[28] C.N. Moorefield, S. Li, S.-H. Hwang, C.D. Shreimer, G.R. Newkome, Chem.
Commun. (2006) 1091.
4. Conclusions
In summary, we have reported the use of robust and recyclable
heterogeneous catalysts that provide efficient access to one-pot
synthesis of various 5-substituted-1H-tetrazoles and 1-substituted-
1H-tetrazoles. The use of these catalysts facilitates the imple-
mentation of high-throughput synthetic methodologies, while the
[29] Z. achary, P. Demko, K.B. Sharpless, J. Org. Chem. 66 (2001) 7945e7950.