Magnetically separable CuFe2O4 nano particles catalyzed multicomponent synthesis of 1,4-disubstituted 1,2,3-triazoles in tap water using 'click chemistry'

Article abstract of DOI:10.1016/j.tetlet.2012.06.077

The synthesis of 1,4-disubstituted 1,2,3-triazoles is attempted using magnetically separable and reusable copper ferrite nano particles in a one pot reaction, in tap water.

Full text of DOI:10.1016/j.tetlet.2012.06.077

Tetrahedron Letters 53 (2012) 4595–4599
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Tetrahedron Letters
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Magnetically separable CuFe2O4 nano particles catalyzed multicomponent
synthesis of 1,4-disubstituted 1,2,3-triazoles in tap water using ‘click chemistry’
⇑
B. S. P. Anil Kumar, K. Harsha Vardhan Reddy, B. Madhav, K. Ramesh, Y. V. D. Nageswar
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1,4-disubstituted 1,2,3-triazoles is attempted using magnetically separable and reusable
copper ferrite nano particles in a one pot reaction, in tap water.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 15 May 2012
Revised 12 June 2012
Accepted 15 June 2012
Available online 20 June 2012
Keywords:
Triazoles
Copper ferrite nano particles
Terminal alkynes
Azides
Click reaction
Green chemistry relates to the design of a process that mini-
mizes the use and generation of hazardous substances. Green
catalysis is one of the key areas of green chemistry. The use of be-
nign solvents (e.g., water, ionic liquids) as well as efficient and
cleanly reusable catalytic materials is significant in the practice
of green chemistry. Nano catalysts enjoy several advantages over
the conventional catalyst systems. Although, a significant enhance-
ment of catalytic activity can be achieved by synthesizing a cata-
lyst in nanometer dimensions, recovery of these tiny nano
catalysts from the reaction mixture is not easy and most of the het-
erogeneous systems require a filtration or centrifugation step and/
or a tedious work-up of the final reaction mixture to recover the
catalyst. Conventional techniques (such as filtration) are not effi-
cient because of the nano size of the catalyst particles. This limita-
tion hampers the economics and sustainability of these nano
catalytic protocols. To overcome the separation problems of the
nano catalysts, magnetically active nano particles have recently
emerged as viable alternatives to conventional materials for cata-
lyst supports.1
applications.2 The use of magnetic nano particles has been studied
extensively for various biological applications such as magnetic
resonance imaging, drug delivery, and bio molecular sensors.3
On the other hand, the catalysis of organic reactions in aqueous
medium has received much attention in recent years, since the
studies on Diels alder reactions by Breslow.4 Water is a preferred
solvent medium compared to the other organic solvents because
water is the most abundant, safe, nontoxic, inexpensive, and envi-
ron-friendly solvent.
1,2,3-Triazoles have attracted interest over the past few years as
their moieties have been widely used in pharmaceuticals, agro
chemicals, dyes, photographic materials, corrosion inhibition5 etc.
1,2,3-Triazoles are also associated with a wide range of biological
properties such as antiviral, antiepileptic, antiallergic,6 anticancer,7
anti HIV,8 and antimicrobial activities against gram positive bacte-
ria.9 In general, these compounds are prepared through the
coupling reaction between alkynes and azides at high tempera-
tures,10 and by using solid supports.11 Sharpless et al. used Cu (I)
salts to promote the reaction of azide with terminal alkynes to af-
ford 1,4-disubstituted products.12 Fokin and co-workers have
developed the reaction under microwave conditions. In the micro-
Magnetic separation is an attractive alternative to filtration or
centrifugation as it prevents loss of the catalyst and increases reus-
ability. Their insoluble and paramagnetic nature enables easy and
efficient separation of the catalysts from the reaction mixture with
an external magnet. The paramagnetic character, results in
remarkable catalyst recovery, without the need for filtration step.
This makes the catalyst cost-effective and promising for industrial
NaN3
Ar1
N
N
Ar
N
Ar
X
CuFe2O4
Ar1
70 oC,
H2O
⇑
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.077

4596
B. S. P. Anil Kumar et al. / Tetrahedron Letters 53 (2012) 4595–4599
wave assisted synthesis, reaction time gets drastically reduced to
15–20 min, the temperature being raised to 125 °C.13 Moreover in
recent years, several methods have been reported for the synthesis
of triazoles.14
Most of the literature methods involve azides, as starting mate-
rials, as well as organic solvents as reaction media. Although, these
organic azides are stable against most reaction conditions, low
molecular weight azides are explosive and difficult to handle.15
A
few procedures have been reported that involve the generation
of azides in situ followed by the addition of alkyne as well as azide
cycloaddition.16 Recently, Francisco Alonso reported a method
using copper on activated carbon, for the synthesis of 1,2,3-tria-
zoles. It involves the in situ generation of azides by using sodium
azide in the presence of alkynes.17 However, most of the above
methods suffer from drawbacks such as the use of organic solvents,
use of metal catalysts with solid supports as well as difficult exper-
imental procedures to separate the catalyst. In view of the above
shortcomings, there is a need to broaden the scope of one pot multi
(a)
(b)
Figure 1. (a) Magnetic separation of CuFe2O4 nano particles and (b) product
floating on water after the reaction.
Table 1
Synthesis of triazoles using CuFe2O4 nano particles in watera
Entry
1
Alkyne 1
Ph
Organic halide 2
Triazole 3
t (h)
Yieldb (%)
X=Br
N
N
3
6
93
80
N
Ph
Br
X
X=Cl
1a
Ph
2a
Ph
3aa
N
N
Br
N
N
2
3
1a
1a
4
4
86
85
Br
3ab
2b
Ph
N
Br
N
3ac
2c
Ph
N
Br
N
N
4
5
6
1a
1a
1a
5
8
4
86
78
83
O2N
O2N
3ad
2d
Ph
O
N
O
N
Ph
Br
Br
N
Ph
Ph
2e
3ae
N
N
N
Br
Br
2f
3af
N
Ph
N
N
Br
7
8
1a
4
4
82
83
2g
3ag
Ph
Br
Br
N
N
Ph
Br
N
2a
Ph
Br
3ba
1b
N
Br
N
N
Br
9
10
11
1b
4
4
5
84
84
80
2b
3bb
N
Br
N
N
N
1b
1b
2c
3bc
Br
N
N
O2N
2d
3bd
O2N

B. S. P. Anil Kumar et al. / Tetrahedron Letters 53 (2012) 4595–4599
4597
Table 1 (continued)
Entry
Alkyne 1
Organic halide 2
Triazole 3
t (h)
Yieldb (%)
N
N
N
Ph
Br
N
N
2a
12
13
4
86
82
N
1c
Ph
3ca
Br
N
N
Br
1c
1c
1c
4
5
4
4
N
2b
3cb
Br
N
Br
N
N
N
MeO
14
15
16
79
83
85
N
2h
3ch
MeO
N
Br
N
N
2c
Br
3cc
N
N
Ph
F
2a
N
Ph
Br
3da
F
1d
N
Br
N
N
Br
17
18
19
20
1d
4
4
6
7
84
82
83
82
2b
F
3db
N
Br
N
N
1d
2c
Br
F
3dc
CF3
Ph
Ph
Ph
F3C
N
N
N
2a
2a
3ea
Ph
Ph
1e
CF3
CF3
MeO
OMe
Br
Br
N
N
N
3fa
1f
4
2a
2a
1g
21
22
9
9
74
75
2
N
N
N
N
N
N
N
N
N
3ga
Ph
Br
Br
Br
5
1h
3
N
N
N
3ha
N
N
N
N
6
6
N
N
2i
23
9
76
F
1i
3ii
F
F
a
Reaction conditions: Alkyne (1 mmol), organic halide (1 mmol), NaN3 (1.1 mmol), CuFe2O4 (12 mg) in H2O (2 mL) at 70 °C.
Isolated yield.
b
step reactions, in combination with ‘click reaction’, without using a
from the reaction mixture and reuse it without any loss. Moreover,
the catalyst is also commercially available. The reaction proceeds
via a three-component reaction between various benzyl bromides,
phenyl acetylenes, and sodium azide in water.
The present methodology (Scheme 1) involves the in situ
preparation of the organic azide and also reduces the number
of steps as well as the time involved in the reaction strategy.
solid support.18
As a part of our continuous research in the field of aqueous
medium organic synthesis19 and copper nano catalysts,20 we inves-
tigated the reaction by using magnetically separable nano copper
ferrite as a catalyst and without using any solid support. Because
of the magnetic property of the catalyst, we can easily separate it

4598
B. S. P. Anil Kumar et al. / Tetrahedron Letters 53 (2012) 4595–4599
Table 2
Based on the preliminary results, various benzyl bromides and
Recyclability of nano-CuFe2O4 catalysta
alkynes were subjected to the present reaction conditions to inves-
tigate the scope and limitation of the reaction. These results are
presented in Table 1. Electron donating substituents like methyl,
methoxy (entries 3, 10, 14, 15, and 18), and electron withdrawing
substituents such as bromo, nitro groups at para position of benzyl
bromide (entries 2, 4, 9, 11, 13, and 17) were equally effective to-
ward the nucleophilic substitution of azide, followed by 1,3-dipo-
lar cycloaddition.
When the heterocyclic compound such as 2-ethynylpyridine
was used as the alkyne, the reaction proceeded smoothly and the
products were isolated in high yields (entries 12–15). In the case
of ortho, meta, and para bromo benzyl bromides, all these reacted
well to give the corresponding triazoles in near quantitative yields
(entries 2, 6, and 7) (steric hindrance has not affected the reaction).
However in the case of activated functionalized organic halides
such as phenacyl bromide (entry 5), a little low yield of the desired
triazole was obtained.
In view of the interesting results obtained with benzyl bro-
mides, the scope of the inexpensive magnetically separable nano
copper ferrite catalyzed reaction was extended further to dibromo
aliphatic alkanes and aliphatic diacetylenes. The reactions pro-
ceeded well to obtain encouraging yields. It was found that termi-
nal dibromoalkane reacts with 2 equiv of alkynes to give
bistriazole products (entry 23). Similarly 1,7-octadiyne and 1,8-
nonadiyne with 2 equiv of benzyl bromide provided the corre-
sponding bis triazoles (entries 21 and 22).
CuFe2O4
N
nano particles Ph
N
N
Ph
+
NaN3
+
Ph
X
70 oC
H2O
Ph
3
1
2
Cycle
Isolated product yield (%)
Catalyst recovery (%)
Native
93
90
88
84
92
89
85
82
1
2
3
a
Reaction conditions: Benzyl bromide (1 mmol), phenyl acetylene (1 mmol),
NaN3 (72 mg, 1.1 mmol) and CuFe2O4 (5 mol %, 12 mg) in H2O (2 mL) at 70 °C and
3 h.
The advantages of the present protocol are short reaction path-
way and the use of aqueous medium at moderate temperatures
for the conduct of the reaction. It also reduces and minimizes
the hazards derived from the isolation and handling of the
azides. This one pot procedure21 exhibits higher atom-economy,
deliver fewer by-products compared to the classical stepwise
synthetic routes. The synthetic utility of this protocol is further
made more attractive, as the reactions are carried out in tap
water, with magnetically separable nano copper ferrite as
catalyst.
In the initial studies, we selected the reaction between ben-
zylbromide, sodium azide, and phenyl acetylene in the presence
of copper ferrite nano catalyst in water at 70 °C and as expected,
the cyclo addition reaction proceeded well. The azide was gener-
ated in situ from the nucleophilic substitution reaction of organic
halide with sodium azide. The azide generated in situ in this reac-
tion reacted with the terminal alkyne to give 1,4-disubstituted
1,2,3-triazole. The progress of the reaction is monitored by TLC.
Most importantly, the product phase separated out from the aque-
ous medium after completion of the reaction, which in turn en-
abled the isolation of the final product by simple decantation (
Fig. 1). Furthermore, there is no need for column chromatography
to separate the products from the reaction mixture except in the
bistriazole products (entries 21–23). By comparing the 1H NMR
data, with the literature reports, the product was confirmed as
1,4-disubstituted 1,2,3-triazole but not as 1,5-disubstituted 1,2,3-
triazole.17,22 On completion of the reaction, the catalyst was mag-
netically separated from the reaction mixture, using an external
magnet. The separated catalyst was then washed several times
with diethyl ether and water, dried under vacuum, and subse-
quently reused directly for further catalytic reactions. No signifi-
cant loss of catalyst (CuFe2O4) activity was observed up to four
cycles.
The reusability of the nano-CuFe2O4 catalyst was examined and
the results are summarized in Table 2. The SEM-analysis of Cu-
Fe2O4 nano particles before and after the reaction showed identical
shape and size (Fig. 2).
In conclusion we have developed magnetically separable copper
ferrite nanoparticles as a catalyst for the synthesis of 1,2,3-tria-
zoles. This one pot preparation of 1,2,3-triazoles involves initial
substitution of benzyl halides with sodium azide to generate
in situ benzyl azides which is followed by copper ferrite catalyzed
cycloaddition reaction with alkynes in water at 70 °C. The present
method described here is simple, facile and can be applicable to a
wide range of substrates with high functional group tolerance. The
method circumvents the problems encountered with the isolation
of organic azides.
The high activity, easy separation, commercial availability, and
reusability are the salient features of the catalyst that make this as
a competitive catalyst. The operational simplicity of this method
makes it more attractive for preparative applications.
Acknowledgement
We thank CSIR, New Delhi, India, for fellowships to B.S.P.A.K.,
K.H.V.R., B.M. and UGC for fellowship to K.R.
(a)
(b)
Figure 2. (a) SEM-analysis of native CuFe2O4 catalyst. (b) SEM-analysis of reused CuFe2O4 catalyst after 4th cycle.

B. S. P. Anil Kumar et al. / Tetrahedron Letters 53 (2012) 4595–4599
4599
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.077.
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21. Representative procedure: Benzyl bromide (1 mmol), phenyl acetylene (1 mmol)
and NaN3 (72 mg, 1.1 mmol) were placed in a 10 ml round-bottomed flask in
H2O (2 mL). Sequentially CuFe2O4 (5 mol %, 12 mg) was added. The reaction
mixture was warmed to 70 °C and monitored by TLC until conversion of the
starting materials is satisfactory. After completion of the reaction, the reaction
mixture was magnetically concentrated with the aid of a magnet to separate
the catalyst. Catalyst was separated and washed several times with ether
followed by water, dried under vacuum. Water (30 mL) was added to the
resulting reaction mixture followed by extraction with EtOAc (4 Â 10 mL). The
collected organic phases were dried with Na2SO4 and the solvent was removed
under vacuum to give the corresponding triazole, which did not require any
further purification (except compounds 3ga, 3ha and 3ii).
22. Data of representative example: 1-Benzyl-4-phenyl-1H-1, 2,3-triazole (Table 1,
entry 1): 1H NMR (300 MHz, CDCl3): d 5.55 (2H, s), 7.22–7.41 (8H, m), 7.58 (1H,
s), 7.75 (2H, d, J = 6.79 Hz). ESI-MS: m/z 236 (M+H)+. HRMS for C15H13N3 Calcd.
236.1187 (M+H)+. Found, 236.1190.