Synthesis of β-hydroxy-1,4-disubstituted-1,2,3-triazoles catalyzed by copper ferrite nanoparticles in tap water using click chemistry

Article abstract of DOI:10.1039/c4ra12061b

A novel one pot synthesis of β-hydroxy-1,4-disubstituted-1,2,3-triazoles has been developed by using CuFe₂O₄ magnetic nanoparticles. This methodology involves additive free, easily recyclable catalyst in water medium and avoids the h

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PAPER
Synthesis of ß-Hydroxy-1,4-disubstituted-1,2,3-triazoles catalyzed by
Copper ferrite nano particles in tap water using Click Chemistry
B. S. P. Anil Kumar, K. Harsha Vardhan Reddy, G. Satish, R. Uday Kumar and Y. V. D. Nageswar*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel one pot synthesis of ß-hydroxy-1,4-disubstituted-1,2,3-triazoles has been developed by using CuFe2O4 magnetic nano
particles. This methodology involves additive free, easily recyclable catalyst in water medium and avoids the handling of organic
azides as they are generated insitu.
Sharpless9 reꢀinvigorated the Huisgen’s 1,3ꢀdipolar
Introduction
50 cycloaddition10 by using a Cu(I) metal source. These copperꢀ
10
Although homogeneous catalysts have several
accelerated 1, 3ꢀ dipolar cycloadditions enabled efficient
advantages like higher selectivity and intense interaction among
preparation of 1, 4ꢀdisubstitutedꢀ1, 2, 3ꢀtriazoles from alkynes
the components in the reaction, the separation of the final product
and azides with excellent selectivity. Recently a few procedures
is difficult after completion of the reaction and trace amounts of
have been reported for the synthesis of βꢀhydroxy triazoles by the
catalyst may remain in the final product. Since metal
55 opening of epoxides in presence of homogeneous catalysts like
15 contamination is highly regulated in the pharmaceutical industry,
11
CuSO4 or CuI12. Francisco Alonso13 and Patrick Pale14 have
it is essential to remove the catalyst from the final compound
even if it is in the ppm level. However, heterogeneous catalysts,
in particular nano catalysts by their particle size having very large
surface area help in enhancing the contact between reactants and
20 catalyst, which can maximize the reaction rates and minimize the
consumption of the catalyst to give excellent yields1. However,
the isolation of these nano particles is not easy through filtration
or centrifugation step. It is beneficial, when these catalysts can be
separated from the reaction mixture with the aid of an external
25 magnet. In this context, magnetic nano particles (MNPs) have
emerged as useful group of heterogeneous catalysts, because of
their insoluble and paramagnetic nature2.
developed separately laboratoryꢀmade copper nano particles on
activated carbon and Cu (I)ꢀzeolite catalytic method to afford 1,
4ꢀdisubstituted βꢀhydroxy triazoles. Since the resulting products
60 possess a 1ꢀ(hydroxyethyl)ꢀ1Hꢀ1,2,3ꢀtriazole moiety which is
present in peptide surrogates of HIVꢀ1 protease inhibitors AB2,
AB3 (Figure 1) and also useful in drugs and pharmaceuticals15,
there is a need to develop a simple and efficient method by using
a readily available and reusable heterogeneous catalyst in green
65 solvent.
1, 2, 3ꢀTriazoles are important in heterocyclic
chemistry because of their unique structure and chemical
30 properties. Many compounds possessing 1,2,3ꢀtriazole structural
scaffold exhibit interesting biological properties such as
antibacterial, antiviral, antiepileptic, and antiꢀallergic activities3,4
.
In particular, 1,4ꢀdisubstituted 1,2,3ꢀtriazoles can be used to
selectively open calcium channels in cells5, to regulate plant
35 growth6, and to inhibit enzymes7, as well as exhibit significant
antiproliferative action against a wide range of human cancer cell
lines8.
40 MCP Division, Indian Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91ꢀ40ꢀ27160512
Eꢀmail: dryvdnageswar@gmail.com
† Electronic Supplementary Information (ESI) available: [details of any
45 supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
Figure 1. AB2 (pdbꢀ1zp8) and AB3 (pdbꢀ1zpA)
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In continuation of our research interest in the synthesis
With the optimal conditions in hand, styrene oxide (1a)
of heterocyclic compounds using green synthetic protocols 35 was treated with sodium azide and phenyl acetylene (2a) in the
involving transition metal catalyst16, a copper ferrite catalyzed
one pot synthesis of 1, 4ꢀdisubstitutedꢀ1, 2, 3ꢀtriazoles from
benzyl halides, sodium azide, and alkynes17 is developed.
Furthermore, in this context, we hereby report copper ferrite
MNPs (Purchased from AldrichꢀCAS No. 12018ꢀ79ꢀ0) catalyzed
oneꢀpot synthesis of βꢀhydroxytriazoles from epoxides, sodium
azide, and alkynes in aqueous medium. The present protocol
presence of 5 mol% of CuFe2O4 in 10 ml of water at 60 oC
(Scheme 2). The reaction proceeded smoothly to give the
corresponding βꢀhydroxyꢀ1, 4ꢀdisubstituted 1, 2, 3ꢀtriazole (3aa)
5
10 satisfies most of the green chemistry principles such as (a) one
pot multi component synthesis, (atom economy) (b) reactions in
water medium, (green solvent) (c) use of easily separable and
recyclable heterogeneous catalyst with the help of an external
magnet, (d) simple workup procedure.
40
45
Scheme 2
Table 2: One pot synthesis of βꢀhydroxy triazoles using CuFe2O4 nano
particles in water from various epoxides, sodium azide and alkynesa
15 Results and Discussion
Scheme 1
Initially, CuFe2O4 catalyzed reaction between styrene
20 oxide 1a (1 mmol) and phenyl acetylene 2a (1 mmol) was
investigated to optimise the reaction conditions in various
solvents (Scheme 1). Among different solvents examined (Table
1), water yielded the best results (entry 2), where as MeOH and
MeOH:H2O (1:1) gave the products in moderate yields (entries 1
25 and 7). Solvents such as DMSO, DMF, THF and toluene were
ineffective (entries 3,4,6 and 8). The influence of the amount of
catalyst and sodium azide was also evaluated. It was observed
that the best yield was obtained using 5 mol% of catalyst and 1.1
mmol of NaN3 (entries 9, 10, 11, 12 and 13).
30 Table 1: Optimization studies for the synthesis of ßꢀhydroxyꢀ1,4ꢀ
disubstitutedꢀ1,2,3ꢀtriazoles
2
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25
Scheme 3
The reactivity of glycidyl phenyl ether (entries 7 to 12)
and aryl substituted glycidyl phenyl ethers was further explored
and examined (Scheme 3). These epoxides gave a single
30 regioisomer (3ba) with preferential attack at the less hindered
terminal carbon atom which was confirmed by the reported
literature12, 13
.
Both para methoxy as well as ortho methyl substituted
glycidyl phenyl ethers also reacted effectively (entries 13 to 22).
35 The reaction between glycidyl phenyl ether and aliphatic 1ꢀ
octyne (entry 12) resulted in the product in an encouraging yield.
It was observed that 1, 4ꢀbis oxirane also reacted with two
equivalents of phenyl acetylene providing bis triazole product
(entry 22).
40
Recycling
Table 3: Recyclability of nano CuFe2O4 catalyst
45
Reaction conditions: phenyl acetylene (1 mmol), styrene oxide (1 mmol),
NaN3 (1.1 mmol), CuFe2O4 (5 mol%) in H2O (10 mL) at 60O C
a. Reaction conditions: Alkyne (1 mmol), Epoxide (1 mmol), NaN3 (1.1
mmol), CuFe2O4 (5 mol%) in H2O (10 mL) at 60O C.
b. Isolated yield.
CuFe2O4 catalyst was easily separated by using an
50 external magnet from the reaction mixture (Figure 2), washed
with acetone and dried under vacuum. The air dried catalyst was
used directly for the next cycles without further purification. As
shown in Table 3, catalyst could be reused four times without
significant changes.
5
c. Phenyl acetylene (2 mmol)
in high yield. Based on the literature reports,12,13 among the two
possible regional isomers, it was observed that the present
product was exclusively primary βꢀhydroxy triazole (3aa) which
10 was obtained from the styrene oxide by benzylic position
opening.
55
The scope of this copper ferrite catalyzed click reaction
was further expanded with a variety of oxiranes and alkynes and
these results were summarized in Table 2. The reactions
15 proceeded well to obtain products in encouraging yields. Electron
donating substituents like tertiary butyl, as well as methyl group
at para position (entries 3 and 4) and electron withdrawing
fluorine atom at meta position of phenyl acetylene (entry 5) did
not induce appreciable changes in the reaction efficiency. The
20 presence of heterocyclic moiety in the alkynes was equally
effective towards the opening of epoxide, followed by 1, 3ꢀ
dipolar cycloaddition (entry 2).
Figure 2. Separation of CuFe2O4 nano particles by using an
external magnet
60
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Experimental Section
General Experimental Procedure: Styrene Oxide (1 mmol),
phenyl acetylene (1 mmol) and NaN3 (72 mg, 1.1 mmol) were
35 placed in a 25 ml roundꢀbottomed flask in H2O (10 mL), to which
CuFe2O4 (5 mol %) was added. The reaction mixture was
0
warmed to 60 C and monitored by TLC until total conversion of
the starting materials. After completion of the reaction, the
catalyst was separated with the aid of a magnet. The separated
40 catalyst was washed several times with acetone, dried under
vacuum. The reaction mixture was extracted with EtOAc (4x10
mL), the collected organic phases were dried with Na2SO4 and the
solvent was removed under vacuum to give the corresponding
triazole derivative. Further, products were purified by column
45 chromatography using hexane and ethyl acetate.
Figure 3. (a) SEMꢀanalysis of native CuFe2O4 catalyst. (b) SEMꢀ
analysis of reused CuFe2O4 catalyst after 4th cycle
5
The SEM images of the catalyst exhibited identical
shape and size (Figure 3) and the XRD analysis also indicated
similar peaks for both native and recycled catalyst (Figure 4).
These results clearly support nearly unaltered efficiency of the
10 catalyst.
Acknowledgments
The authors thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for financial assistance.
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20 sodium azide and alkynes in aqueous medium. The advantages of
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Synthesis of ß-Hydroxy-1,4-disubstituted-1,2,3-triazoles catalyzed
by Copper ferrite nano particles in tap water using Click Chemistry
B. S. P. Anil Kumar, K. Harsha Vardhan Reddy, G. Satish, R. Uday Kumar and Y. V. D.
Nageswar*
A novel one pot synthesis of ß-hydroxy-1,4-disubstituted-1,2,3-triazoles has been developed by
using CuFe2O4 magnetic nano particles. This methodology involves additive free, easily
recyclable catalyst in water medium and avoids the handling of organic azides as they are
generated insitu.