Copper supported on the SiO2 nanoparticle in click chemistry: An alternative catalytic system for regioselective and one-pot synthesis of 1,2,3-triazoles and β-hydroxytriazoles

Article abstract of DOI:10.1002/cjoc.201100231

In this work, readily prepared copper supported on the SiO₂ nanoparticles has been found to effectively catalyze the 1,3-dipolar cycloaddition of a variety of azides, alkynes, epoxides and sodium azide, furnishing the corresponding 1,2,3-triazo

Full text of DOI:10.1002/cjoc.201100231

COMMUNICATION
DOI: 10.1002/cjoc.201100231
Copper Supported on the SiO2 Nanoparticle in Click Chemistry:
An Alternative Catalytic System for Regioselective and
One-Pot Synthesis of 1,2,3-Triazoles and β-Hydroxytriazoles
Ciyabi Hashjin, Maryam*
Ciyabi, Roghayeh
Baharloui, Maryam
Hosseini, Ghaffar
Tavakoli, Hamed
Department of Chemistry, Faculty of Science, Islamic Azad University, Karaj Branch, P.O. Box 31485-313, Karaj,
Iran
In this work, readily prepared copper supported on the SiO2 nanoparticles has been found to effectively catalyze
the 1,3-dipolar cycloaddition of a variety of azides, alkynes, epoxides and sodium azide, furnishing the correspond-
ing 1,2,3-triazoles and β-hydroxytriazoles. Click reaction proceeds in short reaction times and under mild reaction
conditions, and the resulting products are obtained in good yields at ambient temperature.
Keywords nanoparticle, 1,3-dipolar cycloaddition, 1,2,3-triazole, β-hydroxytriazole
Introduction
these methods are, in general, excellent. There are,
however, some issues that should be addressed in order
to further improve the efficiency of the reaction and to
fulfill the requirements of a truly click reaction. The
addition of some copper complexes[11] or ligands[4,12]
was found to enhance the reaction rate, but it was with
the application of microwave chemistry (75—140 ℃)
that reaction times were dramatically reduced to less
than 1 h.[4a,13] New and interesting advances in the title
reaction involve heterogeneous catalysis.[14] In recent
times, our group developed new protocols using
SiO2/CuSO4 as solid-supported catalyst to prepare
1,2,3-triazoles and β-hydroxytriazoles.[15]
Few reactions in organic chemistry have experienced
the revival and great splendour achieved by the Huisgen
1,3-dipolar cycloaddition reaction of organic azides and
alkynes[1] in the dawn of the 21st century. The enor-
mous attention recently gained by this reaction began
with the pivotal discovery by the groups of Meldal[2]
and Sharpless,[3] in which copper(I) catalysis was found
to dramatically accelerate the reaction under mild con-
ditions at the same time a high regioselectivity was
achieved towards the 1,4-regioisomer of the triazole
product.[4] This powerful, highly reliable and selective
reaction is the paradigm of a click reaction, as it meets
the set of stringent criteria required in click chemistry as
defined by Sharpless et al.[5] Consequently, this protocol
has found increasing application in a variety of disci-
plines[4b,6] such as organic chemistry,[4] drug discovery
and medicinal chemistry,[7] polymer and materials sci-
ence,[8] or bioconjugation.[7a,9]
In spite of the fact that some copper-free
azide-alkyne cycloaddition strategies have been recently
reported, the kinetics is rather low and the regioselectiv-
ity unpredictable.[10] Therefore, the copper(I)-catalyzed
process is still the preferred choice. The sources of
copper(I) include: (a) copper(I) salts (normally in the
presence of a base and/or a ligand), (b) in-situ reduction
of copper(II) salts (e.g., copper sulfate with sodium
ascorbate) and (c) comproportionation of copper(0) and
copper(II), generally limited to special applications (e.g.,
biological systems).[4] The results obtained by any of
Experimental
General experimental considerations
Melting points were measured on an Electrothermal
9100 apparatus and uncorrected. The chemicals used
were purchased from Merck and Fluka Chemical Com-
panies.
General procedure for the synthesis of 1,2,3-triazole
4a—4k
To a mixture of azides (1 mmol) and alkynes (1
mmol) was added 10 mg of SiO2/CuSO4 and ascorbic
acid (10 mol%) in 2 mL of water and 2 mL of ethanol
and the whole mixture was stirred at room temperature.
After stirring for 3 h, ethyl acetate (10 mL) was added,
and the organic solution was separated from
SiO2/CuSO4 by filtration. The solvent was evaporated
*
E-mail: mciyabi@gmail.com; Fax: 0098-21-22431661
Received August 13, 2011; accepted September 29, 2011.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100231 or from the author.
Chin. J. Chem. 2012, 30, 223—227 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
223

Ciyabi Hashjin et al.
COMMUNICATION
under reduced pressure, and the residue was purified by
column chromatography over silica gel eluting with
hexanes/AcOEt (V∶V＝9∶1) to give the 1,2,3-tri-
azoles 4a—4k.
thesis.
Table 1 Effects of solvents on the synthesis of 3aa
Entry
Solvent
Time/h Yield/%
General procedure for the synthesis of β-hydroxy-
triazoles 5a—5f
1
2
3
4
5
6
PhCH3
3
3
3
3
3
3
3
25
32
25
60
60
80
85
CH2Cl2
CH3CN
To a suspension of epoxides (1.0 mmol) and sodium
azide (1.2 mmol) in water (3.0 mL) were added
SiO2/CuSO4 (10 mg) and sodium ascorbate (20 mol%).
The resulting solution was stirred for 2 h at room tem-
perature. After completion indicated by TLC, acetylenes
(1 mmol) was added to the reaction mixture, and the
solution was stirred for another 4 h. The reaction mix-
ture was extracted with ethyl acetate. The combined
organic layers were dried over anhydrous Na2SO4, and
concentrated in vacuum. The resulting residue was puri-
fied by column chromatography (hexane/EtOAc, V∶V
＝3∶1) to give the β-hydroxytriazoles 5a—5f.
EtOH
H2O
H2O/EtOH (V∶V＝1∶2)
H2O/EtOH (V∶V＝1∶1)
7
a
Benzyl azide (1 mmol), phenylacetylene (1 mmol) in the pres-
ence of SiO2/CuSO4 (10 mg) and ascorbic acid (10 mol%) under
ambient temperature in the presence of different solvents.
To study the effect of amount of the catalyst on this
reaction, the synthesis of 1,2,3-triazoles 3a was selected
as model reaction. To illustrate the need of catalyst for
these reactions an experiment was conducted in the ab-
sence of catalyst and the yield in this case was trace af-
ter 3 h. Obviously, catalyst is an important component
of the reaction. To determine the optimum amount of
catalyst, the reaction was investigated using 10, 20, 30,
40 and 50 mg of SiO2/CuSO4. The results are shown in
Table 2. It is clear that the yields depend on the amount
of catalyst, and the optimum amount was 10 mg for all
derivatives.
Results and Discussion
As a continuation, we report herein the results of
new and cleaner methods for classical synthesis of the
1,2,3-triazoles and β-hydroxytriazoles by a two-com-
ponent one-pot condensation of an azides 1, an alkynes
2 and a three-component one-pot condensation of al-
kynes 2, epoxides 4, sodium azide in the presence of a
catalytic amounts of SiO2/CuSO4 and ascorbic acid at
ambient temperature in good yields with rather short
reaction times (Scheme 1).
Table 2 Effects of amounts of SiO2/CuSO4 on the synthesis of
3aa
Scheme 1 Synthesis of 1,2,3-triazoles 3a—3k and and β-hydro-
xytriazoles 5a—5f
Entry
Catalyst amount/mg
Time/h
Yield/%
85
1
2
3
4
5
6
10
20
30
40
50
—
3
3
3
3
3
3
SiO2/CuSO4 (10 mg)/
N
86
ascorbic acid (10 mol%)
N
R1
R1 N3 R2
+
1
N
H2O/EtOH (V : V = 1 : 1), r.t.
85
R2
2
84
3a － 3k
OH
85
N
Trace
SiO2/CuSO4/NaN3
ascorbic acid
N
N
R3
O
a
R2
Benzyl azide (1 mmol), phenylacetylene (1 mmol) in the pres-
ence of SiO2/CuSO4 and ascorbic acid (10 mol%) under ambient
temperature in H2O/ EtOH (V∶V＝1∶1).
+
R3
R2
5a － 5f
H2O, 6 h, r.t.
2
4
The catalyst is very active, stable to air and moisture,
nontoxic and inexpensive. In addition, it can be quanti-
tatively recovered by filtration and reused. In a pilot
experiment, azides and alkynes were stirred in water
and ethanol in the presence of catalytic amounts of
SiO2/CuSO4 and ascorbic acid. The progress of the re-
action was monitored by TLC. After completion of the
reaction, an aqueous workup afforded 1,2,3-triazoles
3a─3k in 80%—85% yields. To evaluate the use of this
approach, several azides and alkynes were condensed
under similar circumstances. The results shown in Table
3 clearly indicate the efficient scope and limitations of
this reaction. This reaction proceeded very cleanly un-
First, we prepared SiO2/CuSO4 as a catalyst with
Jacob’s method.[15] To a 100 mL beaker was added
nano-SiO2 (Aerosil 200) which was supplied by De-
gussa Co., Germany, with an average size of 12 nm and
a specific surface area of 200 m2/g (5.0 g), CuSO4•5H2O
(2.0 g) and water (4.0 mL). The suspension was stirred
for 5 h at room temperature, dried at 80 ℃ for 12 h and
for an additional 24 h at 150 ℃ in an oven and then
cooled in a desiccator.
The effect of solvent on the reaction has been inves-
tigated. As indicated in Table 1, the reaction could be
progressed very efficiently in H2O/EtOH (V∶V＝1∶1).
This solvent was chosen as a green solvent for the syn-
224
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Chin. J. Chem. 2012, 30, 223—227

Regioselective and One-Pot Synthesis of 1,2,3-Triazoles and β-Hydroxytriazoles
der mild conditions at ambient temperature and no un-
desirable side reactions were observed.
Recyclability of the catalyst was examined too. For
this reason, catalyst was recovered from reaction be-
tween benzyl azide and phenylacetylene by filtration;
after drying the catalyst in oven (150 ℃, 24 h), it was
used again. This procedure was carried out for four
times. Results of these successive reactions are shown
Table 3 Synthesis of 1,2,3-triazoles 3a—3k
m.p./℃
Reported
Compd.
Azide
Alkyne
Time/h
Triazole
Yielda/%
85
Found
N
N
N
N3
3
128—130 128—129[16c]
3a
N
N
N
N3
3
82
85
83
155—157 154—156[16c]
3b
3c
3d
I
I
N
N
N
N3
3.5
3.5
150—151 150—152[16c]
141—143 140—142[16c]
Br
Br
N
N
N
N3
O2N
O2N
N
N
N
N3
3
4
80
80
81
85
135—136 135—136[16e]
46—48 46—49[16e]
199—200 198—200[16b]
236—238 236—238[16c]
3f
3g
3h
3j
HO
O2N
OH
O2N
N
N
N3
N
OH
OH
O2N
N3
N
N
N
4
NO2
N
N
N3
O2N
N
N
3.5
O2N
N
N
N3
3
3
85
84
164—166 164—165[16e]
3i
N
N
N
N3
HO
75—77 76—77[16d]
OH
3k
a Isolated yield.
Chin. J. Chem. 2012, 30, 223—227
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www.cjc.wiley-vch.de
225

Ciyabi Hashjin et al.
COMMUNICATION
in Table 4. It is clear that by successive use of catalyst
no decrease in reactivity or performance can be seen.
dium azide and acetylenes 2 in the presence of catalytic
amounts of SiO2/CuSO4 and 20 mol% of sodium ascor-
bate in water. The reactions went to completion at am-
bient temperature and the products, β-hydroxytriazoles
5a—5f were obtained in 70%—75% yields (Scheme 2).
Table 4 Recycle of the catalysta
Cycle
Amount of (SiO2/CuSO4)/mg
Yield/%
85
1
2
3
4
10
9
Scheme 2 Synthesis of β-hydroxytriazoles 5a—5f
84
OH
9
85
SiO2/CuSO4/NaN3
N
ascorbic acid (20 mol%)
N
N
R3
O
8
82
R2
+
R3
a
H2O, 6 h, r.t.
R2
5a － 5f
Benzyl azide (1 mmol), phenylacetylene (1 mmol) in the pres-
2
4
ence of SiO2/CuSO4 and ascorbic acid (10 mol%) under ambient
temperature in H2O/EtOH (V∶V＝1∶1).
Various other alkynes reacted readily with various
epoxides and sodium azide under these reaction condi-
tions to produce β-hydroxytriazoles in good yields (Ta-
ble 5).
In Table 6 we have compared the results of our
investigations with previous report with CuSO4•5H2O.
The results show that SiO2/CuSO4 is a best catalytic
system in times, amount of catalyst and yields for syn-
thesis of the 1,2,3-triazole 3a and β-hydroxytriazole 5a.
To check the generality of this catalyst, we report an
efficient approach for the one-pot synthesis of
β-hydroxytriazoles from epoxides, sodium azide, and
alkynes by way of a three-component reaction, pro-
ceeding via the formation of 2-azidoalcohols from ep-
oxides and sodium azide in the presence of catalytic
amounts of SiO2/CuSO4 and ascorbic acid. In a pre-
liminary experiment, epoxides 4 were treated with so-
Table 5 One-pot synthesis of β-hydroxytriazoles from various epoxides, sodium azide and alkynes
m.p./℃
Reported
Compd.
Epoxide
Alkyne
Time/h
Triazole
Yielda/%
Found
130
OH
N
O
N
N
6
75
130—132[17]
5a
OH
N
O
N
109—111 110—112[15d]
N
6
6
75
74
5b
5c
5d
OH
N
O
N
N
108[18]
F3C
108—110
CF3
OH
N
N
O
N
6
6
70
70
65—66
64[18]
HO
N N
N
5f
O
180—182 182—184[17]
a Isolated yield
226
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Chin. J. Chem. 2012, 30, 223—227

Regioselective and One-Pot Synthesis of 1,2,3-Triazoles and β-Hydroxytriazoles
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Table 6 Comparison of the results of SiO2/CuSO4 with
CuSO4•5H2O
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Dosage of
Entry
Catalyst
Yield Time
88% 30 h
Ref.
catalyst
CuSO4•5H2O 1 mol%
CuSO4•5H2O 16 mg
[19]
3a
5a
3a
5a
92%
85%
75%
4 h
3 h
6 h
[17]
10 mg
This work
This work
SiO2/CuSO4
10 mg
SiO2/CuSO4
This results show that amount, time and recyclability
of SiO2/CuSO4 in these reactions is good. For this rea-
son, we believe that this is one of the fastest and better
catalyst system procedures for synthesis of 1,2,3-tri-
azoles and β-hydroxytriazoles in good yields.
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Petersen, J. L.; Berteina-Raboin, S.; Nolan, S. P.; Agrofolio, L. A.
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Conclusions
In conclusion, we have introduced a catalytic system
based on SiO2/CuSO4, can catalyze the 1,3-dipolar
cycloaddition of azides and terminal alkynes. The
SiO2/CuSO4 is quickly prepared from commercially
available reagents under mild conditions. We believe
that the herein described methodology fulfils the re-
quirements of a true click reaction, namely: (a) wide
scope, (b) simple reaction conditions, (c) readily avail-
able starting materials and reagents, (d) easily removed
solvent and (e) simple removal of by-products and prod-
uct isolation. In view of the results presented above, we
also believe that this is one of the fastest procedures
ever reported for the title reaction, but involving milder
conditions and without the inherent limitations and at
ambient temperature in good yields. Further research to
extend the substrate scope and on the reaction mecha-
nism is underway and will be reported in due course.
The operational simplicity of this method makes it at-
tractive for preparative applications as well as for the
synthesis of screening libraries for drug discovery.
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Acknowledgement
We gratefully acknowledge financial support from
the Research Council of Islamic Azad University of
Karaj.
[17] Yadav, J. S.; Reddy, B. V. S.; Reddy, G. M.; Chary, D. N.
Tetrahedron Lett. 2007, 48, 8773.
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