A recyclable/reusable hydrotalcite supported copper nano catalyst for 1,4-disubstituted-1,2,3-triazole synthesis via click chemistry approach

Article abstract of DOI:10.1016/j.tetlet.2017.12.051

Using hydrotalcite as solid support, copper nano particles were synthesized and used in azide-alkyne cycloaddition reaction en route to the synthesis of 1,4-disubstituted-1,2,3-triazoles. The catalyst is heterogeneous and can be recycled and reused easily

Full text of DOI:10.1016/j.tetlet.2017.12.051

Accepted Manuscript
A recyclable/reusable hydrotalcite supported copper nano catalyst for 1,4-dis-
ubstituted-1,2,3-triazole synthesis via click chemistry approach
Mitali Chetia, Praveen Singh Gehlot, Arvind Kumar, Diganta Sarma
PII:
S0040-4039(17)31557-5
https://doi.org/10.1016/j.tetlet.2017.12.051
TETL 49553
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 November 2017
14 December 2017
15 December 2017
Please cite this article as: Chetia, M., Singh Gehlot, P., Kumar, A., Sarma, D., A recyclable/reusable hydrotalcite
supported copper nano catalyst for 1,4-disubstituted-1,2,3-triazole synthesis via click chemistry approach,
Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.051
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A recyclable/reusable hydrotalcite supported
copper nano catalyst for 1,4-disubstituted-
Leave this area blank for abstract info.
1,2,3-triazole synthesis via click chemistry
approach
a
Mitali Chetia , Praveen Singh Gehlot , Arvind Kumar , and Diganta Sarma *
b
b
a,

1
Tetrahedron Letters
journal homepage: www.els evier.com
A recyclable/reusable hydrotalcite supported copper nano catalyst for 1,4-
disubstituted-1,2,3-triazole synthesis via click chemistry approach
a
Mitali Chetia , Praveen Singh Gehlot , Arvind Kumar , and Diganta Sarma *
b
b
a,
a
Department of Chemistry, Dibrugarh University, Dibrugarh-786004, Assam, India, dsarma22@gmail.com
b
Academy of Scientific and Innovative Research (AcSIR)-Salt and Marine Chemicals Discipline, Central Salt and Marine Chemicals Research Institute, Council
of Scientific and Industrial Research (CSIR), G. B. Marg, Bhavnagar, 364002, Gujarat, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Using hydrotalcite as solid support, copper nano particles were synthesized and used in azide-
alkyne cycloaddition reaction en route to the synthesis of 1,4-disubstituted-1,2,3-triazoles. The
catalyst is heterogeneous and can be recycled and reused easily. Room temperature reaction
condition and the use of ethylene glycol as solvent make it an environment friendly system.
Received in revised form
Accepted
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Click Chemistry
Cycloaddition
Hydrotalcite
Nano Particles
Triazole
6
chemistry” which satisfies almost all the requirements of green
Introduction
2
chemistry. Various copper forms were applied in the
The syntheses of biologically active compounds are greatly
important for the society and the scientists are continuously
trying to develop new and efficient methodologies to produce
such compounds. Compounds containing 1,2,3-triazole moiety
have important biological activities and pharmaceutical
properties and are potent agents for treating different diseases and
cycloaddition reaction in order to find different convenient routes
to form1,2,3-triazole. Starting from using copper (II) salts in
presence of reducing agents to directly copper (I) sources with
stabilizing ligands and various solid supported copper catalysts
to nano copper were reported for the regioselective synthesis of
7,8
1
,2,3-triazole. Nowadays, heterogeneous catalysis for 1,4-
1
disorders. Triazoles possess inherent properties of high stability,
non harmfulness due to which they could be extensively used in
disubstituted-1,2,3-triazole synthesis is of more interest and area
of study as from the point of green chemistry view and the
advantages of heterogeneous system over homogeneous system
are encouraging the scientists to develop new methodologies
using various heterogeneous catalysts. Heterogeneous catalysis
eliminates the drawbacks of production of bistriazoles and
diacetylene as by products in azide-alkyne cycloaddition
reactions. It is also noteworthy that heterogeneous catalysis
minimizes the amount of metal used in the reaction by
immobilisation and recyclability and reusability of the catalyst,
besides their properties of easy handling and simple separation,
2
the field of drug discovery. Because of such utmost importance
of 1,2,3-triazoles, 1,3-dipolar cycloaddition of azides and alkynes
to produce triazole had acquired the attraction of the scientific
society immensely. The pioneering work which can be
considered as the landmark on synthesis of 1,2,3-triazole was
3
4
reported independently by Sharpless and Mendal in 2002.
Earlier, it was Rolf Huisgen who for the first time studied deeply
and put forward the thermally induced classical reaction of azide
and alkynes to produce 1,4 and 1,5 regioisomers of 1,2,3-
5
triazoles. But this conventional method has the drawback of use
9
make them more advantageous.
of high temperature and production of both the 1,4 and 1,5
regioisomers. Sharpless and Meldal eliminated these drawbacks
of Huisgen 1,3-dipolar cycloaddition in their work on azide-
alkyne cycloaddition forming regioselectively only 1,4-
disubstituted 1,2,3-triazole at room temperature by using copper
sulphate as catalyst with sodium ascorbate as reducing agent.
This work on 1,3-dipolar cycloaddition can be considered as the
milestone of regioselective triazole synthesis which draws
attraction of the scientific community towards it and afterwards a
handful of works have been done on it. This copper catalysed
azide-alkyne cycloaddition is the cream of the crop in “click
Keeping in mind the importance of triazoles and advantages
of heterogeneous system, in this study we have synthesised
triazole derivatives using new solid supported Cu based
heterogeneous catalyst. Continuing our previous works on
triazole synthesis, here we have developed hydrotalcite supported
copper nano particles as heterogeneous catalyst for azide-alkyne
1
0
cycloaddition reaction. Hydrotalcite is
hydroxide useful as solid support for metals in various
a layered double
11,12
reactions.

2
Tetrahedron
Materials and method: Reagents and solvents were obtained
from commercial suppliers namely Spectrochem, Merck and
Sigma Aldrich and used without further purification. All the
reactions were carried out in oven-dried glassware under
atmospheric conditions. All reported yields are isolated yields.
Preparation of the catalyst: In order to prepare the catalyst,
first we have prepared hydrotalcite with formula
Ca
6
Al
2
(CO
3
)(OH)16.4H
2
O
according to earlier reported
procedure. In brief, the hydrotalcites were synthesised by the
1
3
co-precipitation method. Two solutions were prepared, solution 1
contained 2M NaOH and 0.2 M Na
2
CO
with 0.75M concentration, together with
3 2
.25M Al (AlCl .6H O). Solution 2 was added at a steady rate
3
, and solution 2
2+
contained Ca as CaCl
2
3+
0
to solution 1 drop wise, under vigorous stirring. A separating
funnel was used to deliver solution 2 to solution 1. The
precipitated minerals were washed at ambient temperatures
thoroughly with ultra pure water to remove any residual salts and
dried in an oven (85 °C) for 8 h.
Preparation of Cu@HT nanocatalyst: Hydrotalcite was
4 2
dispersed with CuSO ·5H O (0.5g) in water (500 mL) at room
temperature for 30 min. Hydrazine hydrate (50%, 10 mL) was
added drop wise for 30 min and the reaction mixture was stirred
at room temperature for 2 h. The obtained solid was centrifuged
and washed with distilled water and acetone, to remove un-
Figure 2: (A) SEM image of the Cu NPs@HT catalyst (B)
HRTEM at 2nm scale, (C) and (D) are TEM images at 20 and
1
0nm scale and (E) SAED pattern for Cu NPs@HT catalyst.
0
reacted reagents. The product was dried at 100 C for 8 h and
stored in desiccators. The prepared catalyst was then
characterised with different analysis methods.
The intensity weighted size distribution of prepared
nanocatalyst (Fig. 3) also revealing its nano structure. Double
distribution leads to different aggregates at two different radii (10
±0.5 nm and 173 ±1.26 nm). The size distribution (DLS) was
measured by using a NaBiTecSpectro-Size300 light-scattering
instrument (NaBiTec, Germany) with a source of the He−Ne
laser (633 nm, 4 mW) at 298.15 K. The amount of copper
immobilised in the solid support HT was confirmed by ICP- OES
CaCl
2
+ AlCl
3 2
.6H O
(
Perkin Elmer ICP optima 2000 DV ICP-OES, Inductively
solution
Coupled Plasma–Optical Emission Spectroscopy) analysis and it
was found that 1.87 wt % copper metal impregnated in the
catalyst. The XRD and TGA profiles of Cu NPs@HT are given
in supporting information.
added dropwise
White powdery
hydrotalcite
Filtration of
the precipitate
0
0
.20
.15
Cu NPs@HT
1
73 nm
NaOH+Na
2 3
CO
solution
Cu NPs@HT
CuSO
4 2
.5H O
Addition of
Hydrazine Hydrate
0.10
10 nm
Solution
Figure 1: Sequential preparation of HT supported Cu Nps (Cu
NPs@HT) as a catalyst.
0
0
.05
.00
Characterization of the nanocatalyst (Cu NPs@HT):
1
10
100
1000
10000
R (nm)
The prepared catalyst was characterised by TGA, SEM, TEM,
XRD and ICP-AES analysis. We can observe the morphology of
the as-prepared CuNPs@HT nanocatalyst from the SEM image
h
Figure 3: Intensity weighted size distribution of nanocatlyst (Cu
NPs@HT
(Fig. 2 A; JEOL JSM 7100F Scanning Electron Microscope). It
)
can be seen from that the as-prepared nano-catalysts have a plate-
like morphology with some hexagonal structure, which is the
typical morphology of layered double hydroxides. Figures 2B,
General procedure for the synthesis of 1,4-disubstituted-1H-
1,2,3-triazole:
2C and 2D are the TEM ( JEOL JEM-2100 electron microscope
at a working voltage of 200 kV) images of prepared nonocatalyst
taken at various measurement scales where Fig. 2E showed
SAED pattern which explores the amorphous nature of catalyst.
To a mixture of azide 1 (1 mmol, 1 equiv.) and acetylene 2
(1.1 mmol, 1.1 equiv.) in ethylene glycol (3 mL), the catalyst (15
mg, 1.87wt %, 0.4 mol%) was added. The mixture was stirred at

3
room temperature till the completion of the reaction which was
confirmed by TLC. After completion of the reaction, it was
extracted with EtOAc (2x20 mL), washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed under
reduced pressure to give the crude product which was purified
through silica gel column chromatography (10–20%
EtOAc/hexanes) to get the desired product. The products are
aromatic alkynes very effectively (Table 2, entries 1-13) under
this catalytic condition.
Table 2. Scope of cycloaddition reaction of different azides and
a
alkynes
CuNPs-HT catalyst
1,4-disubstituted-1H-triazole
Azide
1
Alkyne
2
+
Ethylene glycol, 1-3 hr,r.t.
1
13
3a-m
characterized by H and C NMR spectroscopic data.
Produ
ct
Ent
ry
Time
(min)
Yield
b
(%)
Results and discussion:
Azides
Alkynes
Triazoles
Code
To check the effectiveness of our prepared catalyst, the
reaction between benzyl azide and phenyl acetylene was taken as
the model reaction. To 1 mmol of the azide, 1.1 mmol of phenyl
acetylene was added in presence of 15 mg (0.004 mmol Cu) of
the catalyst in ethylene glycol at room temperature. A very good
product yield (97%) was obtained after performing the reaction
for 1 hr (Table 1, entry 2). Lowering the catalyst quantity to 5
mg afforded reasonably good yields (62% yields) of the triazoles
N3
N
N
N
3a
1
2
60
45
90
97
98
85
N3
N
N
N
N
3
b
c
(
Table 1, entry 3). The reaction of benzyl azide and phenyl
N3
N
N
acetylene was further carried out with 10 mg and 20 mg of the
catalyst affording 73% and 97% yields of the desired triazoles
respectively (Table 1, entries 4,5). Therefore, 15 mg of the
catalyst was considered as the optimized amount for AAC
reaction. The reaction between benzyl azide and phenyl acetylene
was carried out in ethylene glycol without adding catalyst (Table
3
4
3
Cl
Cl
N3
N
N
N
90
75
89
90
80
3d
Cl
1
, entry 1). No required product was observed in absence of
Cl
catalyst indicating the necessity of copper for AAC reaction. The
reaction between benzyl azide and phenyl acetylene was then
carried out with 15 mg of the catalyst at room temperature in
different solvents (Table 1, entry 6-13). With ethylene glycol the
reaction gave best result of 97% yields (Table 1, entry 2)
N3
N
N
N
5
6
3e
3f
NC
CN
N3
N
N
N
N
N
a
Table 1. Solvent optimization study
120
CuNPs-HT catalyst
N
N
3
N
N
+
N3
Solvent, r.t.
N
1a
2a
3a
3
3
g
h
7
8
9
120
OH 105
105
82
71
89
Catalyst loading
b
Entry
1
Solvent
Yield (%)
N3
(
mg)
N
N
N
Ethylene Glycol
-
No Product
HO
HO
2
3
Ethylene Glycol
Ethylene Glycol
15
5
97
62
N3
N
N
N
3i
OH
4
Ethylene Glycol
10
73
N
N3
N
N
5
6
Ethylene Glycol
20
15
97
O2N
1
1
0
1
120
120
82
78
3j
-
trace
t
Water- Butanol
NO2
7
15
55
N3
N
(
1:1)
N
N
8
9
Water
DMSO
15
15
15
15
15
15
50
<10
40
MeO
3k
1
1
1
1
0
1
2
3
THF
OMe
N3
Water-THF
Glycerol
Acetonitrile
66
72
N
N
N
45
3l
1
2
120
76
89
OMe
a
Reagents and reaction conditions: benzyl azide (1 mmol), phenyl
acetylene (1.1 mmol), catalyst in the given solvent (3 mL) was
MeO
b
stirred at room temperature for 1 h in open air. Isolated yields.
O
N
N
H3CO
H3CO
N3
N
O
180
The excellent results inspired us to carry out further
experiments with electronically diverged azides and alkynes.
Various benzyl and phenyl azides reacted with aliphatic and
3m
1
3
H3CO
O
H3CO
O

4a
Tetrahedron
All reactions were carried out using azide (1 mmol), alkynes
1.1 mmol), catalyst (15 mg, 1.87 wt%), in ethylene glycol (3 ml)
Conclusions: In conclusion, we have developed a highly
efficient recyclable and reusable heterogeneous catalyst for the
very important synthesis of 1,4-disubstituted 1,2,3-triazole from
the cycloaddition of azides and alkynes. A wide range of azides
and alkynes can be combined to form the pharmaceutically
important 1,2,3-triazoles. The use of benign ethylene glycol as
solvent and room temperature reaction condition makes it an
environmental friendly system.
(
at room temperature; Isolated yields.
b
The efficiency of a heterogeneous catalyst is tested with
recyclability and reusability of the catalytic system. The reaction
of benzyl azide and phenyl acetylene was carried out using the
th
same catalytic system up to 5 time without substantial loss of
the catalytic activity (Fig. 4). AAC reactions were carried out in
ethylene glycol at room temperature with 15 mg catalyst. After
each run, the products were extracted with ethyl acetate from
ethylene glycol and recovered the catalyst by centrifugation. The
leaching test was done in order to check if leaching of copper
metal occurs from the support. But no significant leaching of
copper from the catalyst was observed. Thus the catalyst has been
proved to be an effective heterogeneous catalyst for azide-alkyne
cycloaddition reaction to form 1,2,3-triazoles.
Acknowledgement: MC is thankful to UGC, New Delhi for
UGC-BSR-RFSMS. We gratefully acknowledge the Special
Assistance Programme (UGC-SAP) by UGC to the Department
of Chemistry, Dibrugarh University. DS is thankful to DST, New
Delhi, for a research grant [No. EMR/2016/002345].
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830–9837

6
Tetrahedron
HIGHLIGHTS
ꢀ
ꢀ
Impregnation of Cu nanoparticles over
hydrotalcite was very easy and simple
Hydrotalcite as solid surface has certain
advantages over other solid surfaces
ꢀ
ꢀ
Substrate scope for click reaction is wide
The catalyst is heterogeneous and can be
recycled/ reused easily
ꢀ
Environment friendly protocol