A concise and simple click reaction catalyzed by immobilized Cu(I) in an ionic liquid leading to the synthesis of β-hydroxy triazoles

Article abstract of DOI:10.1016/j.crci.2015.07.006

This study describes an ecocompatible, concise, and practically reliable approach for the regioselective synthesis of β-hydroxy triazoles via Huisgen's click coupling reaction among varied epoxides, NaN₃, and suitable acetylenes catalysed by im

Full text of DOI:10.1016/j.crci.2015.07.006

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CRAS2C-4126; No. of Pages 7
C. R. Chimie xxx (2015) xxx–xxx
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Preliminary communication/Communication
A concise and simple click reaction catalyzed by immobilized
Cu(I) in an ionic liquid leading to the synthesis of
triazoles
b-hydroxy
Nasseb Singh
Synthetic organic chemistry laboratory, faculty of sciences, Shri Mata Vaishno Devi university, Katra, 182 320 Jammu & Kashmir, India
A R T I C L E I N F O
A B S T R A C T
Article history:
This study describes an ecocompatible, concise, and practically reliable approach for the
Received 13 March 2015
Accepted after revision 21 July 2015
Available online xxx
regioselective synthesis of
b-hydroxy triazoles via Huisgen’s click coupling reaction
among varied epoxides, NaN3, and suitable acetylenes catalysed by immobilized Cu(I) in
ionic liquid (IL). This one-pot, atom-economic, efficient, and highly regioselective green
protocol ensures higher yield of
b-hydroxy triazole scaffolds (85–95%). To make the
Keywords:
process ecofriendly, this study emphasizes on the catalyst immobilization technique along
with its possible recycling that gave a high reaction yield in up to three runs. The structures
of all synthesized compounds have been characterized by comparing 1H nuclear magnetic
resonance (NMR), 13C NMR, and mass spectroscopic data with those reported in the
literature.
Epoxide
Click chemistry
b-Hydroxy triazoles
Ionic liquid
Catalyst immobilization
´
ß 2015 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
(I)-catalysed Huisgen’s click coupling reaction (CuAAC) is a
well-known MCR that can be used in highly efficient bond-
The development of new synthetic routes for certain
compounds that are not easily accessible in an ecocompa-
tible manner is quite a challenging objective in the field of
contemporary synthetic chemistry. The regular and
unavoidable induction of chemical wastes from various
chemical transformations in chemical laboratories, bulk
chemical synthesizing industries, and pharmaceuticals
have greatly degraded the global environment. Hence, it is
necessary to develop sustainable methods for compounds
of synthetic interest. Multicomponent reactions (MCRs)
have played a vital role in organic synthesis [1] and are
considered as one of the premiere methods for rapid
building of novel and complex molecular structures
[2,3]. MCRs have also emerged as a powerful route for
the synthesis of diverse biologically active heterocyclic
scaffolds [4] and also in combinatorial synthesis [5]. Copper
forming processes such as diverse chemical synthesis [6],
combinatorial chemistry in drug discovery [7], bioconju-
gation [8], and materials and surface science [9]. On the
other hand, 1,2,3-triazolic systems serve as powerful
pharmacophores [10] and potential targets in drug
discovery due to their broad biological spectrum [11].
Apart from the pharmacophoric values, triazoles also act as
corrosion-control agents, light stabilizers, fluorescent whi-
teners, and opticalbrighteners[12]. AccordingtoWongetal.
[13], the
b-hydroxy 1,2,3-triazole can replace the peptide
group in HIV-1 protease inhibitors. Most of these scaffolds
have been synthesized by the reactions among epoxides,
azides, and suitable terminal alkynes using the click
chemistry approach, which is a 1,3-cycloaddition process
[14]. Such strategies for the
b-hydroxy triazoles have
resulted in minimal by-product expulsions in the consecu-
tive reaction steps. However, its requirement of additives,
insignificant reactivity behaviour, and formation of unde-
sirable side products by self-condensation of reactants were
Email address: nassebsinghsmvdu@gmail.com.
http://dx.doi.org/10.1016/j.crci.2015.07.006
1631-0748/ß 2015 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Singh, N., A concise and simple click reaction catalyzed by immobilized Cu(I) in an
ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/

G Model
CRAS2C-4126; No. of Pages 7
2
N. Singh / C. R. Chimie xxx (2015) xxx–xxx
some of its drawbacks. Hence, ionic liquids (IL), both as
greensolvents and basement for manycatalysts, canbeused
for catalyst recycling in many organic transformations [15].
Therefore, in order to devise an ecocompatible synthet-
ic strategy for the synthesis of
b-hydroxy triazoles, this
Scheme 1. Synthesis of
b-hydroxy triazole scaffold.
study uses immobilized Cu(I) in IL to synthesize these
potent pharmacophores. Thus, the IL-supported catalyst,
along with the IL, was recycled for the synthesis of target
products without much decrease in the corresponding
yield percent. Subsequently, this resulted in a concise and
Table 1
Click reaction of styrene epoxide, NaN3 and phenylacetylene under
different conditionsa.
simple method for the synthesis of
b-hydroxy triazole
Entry
Catalyst
(mol %)
Solvent
Temp.
Time
(in hr)b
% of yield
(3a)c
scaffolds using catalyst loading at 5 mol% Cu(I)/g of the IL.
It is pertinent to mention that the present investigation is
an outcome of continuous efforts for the synthesis of
bioactive molecules using ecocompatible methods [16].
˚
(C)
1.
Cu(I) (0)
Cu(I) (2.5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (7.5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I) (5)
Cu(I)(5)
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]BF4
[bmIm]PF6
[bmim]OH
DMF, ACN
Toluene
80
80
80
90
80
80
80
80
80
80
80
80
80
80
50
20
10
15
15
15
15
20
30
30
20
30
40
35
0
75
90
90
90
90
90
0
2.
3.
4.
2. Results and discussion
5
6.
7.
A preliminary experimentation was undertaken for the
8.
synthesis of
b-hydroxy triazoles in which styrene oxide
9.
25
27
85
15
20
0
(1a) was treated with sodium azide and phenylacetylene
(2a) in the presence of 5 mol% of Cu(I)/g of [bmim]Br. The
reaction reached its completion at 80 8C, and the product,
10.
11.
12.
13.
14.
PEG-200
CH3CN
H2O
b-hydroxytriazole (3a), was obtained in 95% yield (Scheme
CuCl2 (10)
[bmim]Br
1). Further increment in the mole percentage of Cu(I) under
the same conditions did not show any improvement in the
yield of 3a. Hence, 5 mol% of Cu(I) loaded in 1 g of [bmim]Br
a
Molar ratios: 1:1:1 equivalents of 1a, sodium azide, phenylacetylene.
Time required to complete the reaction (TLC).
b
c
Yield of isolated and purified products.
was found to be sufficient for the synthesis of
b-hydroxy
triazole scaffolds, starting from ꢀ1 milimolar concentra-
tion of the reactant species in moderate temperature
conditions (Table 1). In addition, epoxides and terminal
alkynes were used to get better results from the reaction
conditions mentioned above. Other ILs, such as [bmim]BF4,
[bmim]PF6, [bmim]OH, and some common solvents such
as toluene, PEG-200, DMF, CH3CN (ACN), and water were
also tested as reaction media for carrying out the synthesis.
Out of these, [bmim]OH did not yield the reaction product;
instead, the initial reactant species were recovered after a
reasonableperiodof time. Itmight be duetothedeactivation
of the catalyst as a result of the acid–base reaction between
the Lewis acid and the basic IL. Thus, this combinationfor the
transformation of reactants to products was ruled out. PEG-
200 (Table 1, entry 11), like PEG-400 used in some protocols
[18], has been also observed to carry out the click reaction
smoothly, even in the absence of an argon atmosphere, but
the possibility of catalyst recycling was the major issue
associated with polyethylene glycols. Moreover, other
organic solvents (Table 1) were not promising enough for
the reaction under consideration. Water, the cheapest
universal solvent for click reactions [19], also resulted in
poor yield, which is due to oxidation of Cu(I) to Cu(II) during
the reaction, thereby decreasing the overall yield towards
minima (Table 1, entry 13). However, by using some suitable
additive or stabilizer, it might also be possible to get these
privileged structures under aqueous conditions.
reaction conditions to produce b-hydroxytriazoles in high
yield (Table 2, entries 14, 15,19). The formation of product
3a was mediated through the in situ preferential SN2 attack
at the benzylic position by the azide in a regioselective
manner. Cyclohexene oxide has also shown equal pace in
coupling with sodium azide and phenylacetylene, 1-
ethynyl-4-methylbenzene and 1-ethynyl-3-methylben-
zene, leading to the formation of N-cyclohexyltriazoles
in excellent yield (entries 20,23,24). Further, the stereo-
chemistry of the collected product 3t was exactly in trans
as seen in literature records observed from the coupling
constants of the ring hydrogens [20].
Synthetic strategy was further extended to varied
epoxides such as propylene oxide, epichlorohydrin, 2-
(but-3-en-1-yl) oxirane, 2-(p-tolyl) oxirane, 2-([benzy-
loxy] methyl) oxirane 2-butyloxirane, and various aryloxy-
1, 2-epoxy propane and different types of terminal alkynes
such as 1-ethynyl methylbenzenes, ethynylcyclohexane,
prop-2-yn-1-ylbenzene, tert-butyl 2-ethynylcyclopenta-
necarboxylate, tert-butyl (2-methylbut-3-yn-2-yl) carba-
mate and 2-ethynylpyridine under similar reaction
conditions to deliver corresponding
b-hydroxytriazoles
scaffolds in excellent yields (Table 2). Moreover, the
formation of the major regiomers depends on the type of
the terminal epoxide used (Scheme 2), and the structures
of all the major regiomers were confirmed by comparing
the spectral data with that reported in the literature
[17,18,21,22].
Finally, the study focuses on the recycling of the IL
containing catalyst for the consecutive reaction runs.
Hence, after the work-up, the IL phase that contained Cu(I)
was recovered and subjected to the same reaction after
A
variety of terminal alkynes were chosen and
subjected to Huisgen’s 1,3-cycloaddition process at 80 8C
in IL containing 5 mol% of Cu(I) in 1 g of [bmim]Br. It was
found that aliphatic terminal alkynes, such as 1-hexyne, 1-
octyne, trimethylsilylacetylene, etc., reacted reasonably
with styrene oxide and sodium azide under subjected
Please cite this article in press as: Singh, N., A concise and simple click reaction catalyzed by immobilized Cu(I) in an
ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/

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N. Singh / C. R. Chimie xxx (2015) xxx–xxx
3
Table 2
Synthesis of
b
-hydroxy triazole scaffolds by click reaction of varied epoxides, NaN3 and terminal alkynesa.
Entry
Epoxide
Alkyne
Product
Timeb
(in hr)
Yieldc,d
(%)
Reference
[17]
O
HO
3a
N
N
1a
1
10
12
95
93
2a
Ph
Ph
Ph
Ph
N
O
OH
N
N
N
O
O
Ph
2
[18]
2a
1b
3b
OMe
N
OMe
NO2
OH
OH
N
N
O
O
Ph
O
3
4
5
O
O
12
12
8
92
93
94
[18]
[18]
[18]
1c
3c
2a
2a
2a
Ph
Ph
Ph
NO2
N
N
N
Ph
O
1d
1e
3d
O
N
N
N
OH
O
Ph
O
3e
F
F
OH
N
O
N
N
1f Cl
6
7
9
8
85 (8:2)
[21]
[17]
2a
2a
3f Cl
Ph
Ph
Ph
O
OH
1g
93
Ph
3g
N
N
N
O
N
OH
N
N
1h PhO
8
9
8
6
95
92
[17]
[18]
3h PhO
3i BnO
2a
2a
Ph
Ph
Ph
OH
N
O
N
1i
N
BnO
Ph
O
OH
N
O
N
O
N
Ph
1j
3j
10
9
93
[18]
2a
Ph
Ph
O
OH
1k
11
12
11
10
92
93
[18]
[18]
2a
2b
Ph
3k
N
N
N
O
OH N N
N
1i
NHBoc
BnO
3l
BnO
NHBoc
Please cite this article in press as: Singh, N., A concise and simple click reaction catalyzed by immobilized Cu(I) in an
ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/

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N. Singh / C. R. Chimie xxx (2015) xxx–xxx
Table 2 (Continued )
Entry
Epoxide
Alkyne
Product
Timeb
(in hr)
Yieldc,d
(%)
Reference
OH
O
13
13
93
[21]
1l
N
3m
3n
3o
2c
N
Ph
N
Me
Ph
Me
OH
N
O
N
1a
14
13
87
[21]
2d
SiMe3
N
SiMe3
OH
O
O
N
2e
1a
1a
N
15
10
92
[21]
N
OH
N
3p
3q
N
2c
2a
16
11
94
[21]
N
Ph
Ph
Ph
H3C
N
N
O
N
17
18
19
20
14
14
90 (8:2)
92 (9:1)
[21]
[21]
OH
1m
H3C
Ph
N
Me
HO
N
O
N
1n Me
3r
3s
OH
2a
2f
Ph
Ph
O
10
91
[17]
N
N
1a
Ph
N
Ph
N
10
95
89
[17]
[17]
1o
1a
2a
2g
2h
Ph
N
3t
N
O
N
OH
O
O
21
22
8
N
3u
HO
N
N
N
Ph
1a
8
89
[17]
3v HO
N
N
N
Ph
Please cite this article in press as: Singh, N., A concise and simple click reaction catalyzed by immobilized Cu(I) in an
ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/

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5
Table 2 (Continued )
Entry
Epoxide
Alkyne
Product
Timeb
(in hr)
Yieldc,d
(%)
Reference
[22]
23
1o
O
O
2i
N
N
Me
10
10
95
95
3w
N
OH
24
[22]
1o
2j
3x
N
N
N
OH
a
1:1:1 equivalents of reactants 1, NaN3 and 2 was taken with 5 mol% of Cu(I) catalyst loaded in [bmim]Br.
Time taken for completion of reaction (TLC).
b
c
Yield of isolated and purified products.
All compounds gave C, H and N analysis within Æ0.04 and satisfactory spectral (IR, 1H NMR 13C NMR and ESI-MS) data.
d
Scheme 2. Differentiation of products depending on the nature of epoxides.
Table 3
3. Conclusion
Effectiveness of recycled Cu(I) immobilized in [bmim]Br for click
reactiona.
This study presents a facile, efficient, and an ecocom-
patible method for the regioselective synthesis of
Entry
Cycle
Temp. (8C)
Time (in hr)b
% of yield (3a)c
b
-hydroxy triazoles using the click chemistry approach.
1.
2.
3.
4.
5.
6.
1st run
2nd run
3rd run
4th run
5th run
6th run
80
80
80
80
80
80
11
11
11
15
20
25
95
93
90
86
80
70
Operational simplicity, complete regioselectivity, reuse of
supported catalyst, excellent reaction output, and moder-
ate reaction conditions are some of the notable features of
the envisaged protocol. In addition, this protocol is only
limited to terminal alkynes and epoxides. Products with a
modest yield were also obtained using internal alkynes and
alkynes bearing electron withdrawal functionality (such as
acetylene dicarboxylic acid), but it lacked appreciable
regioselectivity.
a
Reaction conditions: 1:1:1 equivalents of 1a, sodium azide, 2a and
recycled [bmim]Br containing Cu(I) at 80 8C.
b
Time required to complete the reaction (TLC).
c
Yield of isolated and purified products.
drying in a hot air oven at 100 8C for about 20–30 min. It
was expectedly found that the isolated yields obtained
after the second (93% yield) and third (90% yield) cycles
were not much lower than that of the first run (Table 3).
However, a decrease in the corresponding percentage yield
in case of second and third reaction runs may be observed
due to in situ accumulation of Na+ (probably NaOH) during
work-up, which tends to deactivate the catalyst. Thus,
1–2 drops of dilute HCl should be added to the IL phase
before reducing under vacuum evaporation. Further,
successive decreases in the percentage yield in case of
fourth, fifth, and sixth runs may be because the regular
contact of catalyst with water during the operation might
have led to irreversible oxidation of Cu from +1 to +2
oxidation state in the presence of excess chloride ions.
4. Experimental
The chemicals used in the experiments were purchased
from Sigma-Aldrich, Himedia and SDFCL and were used as
received without any further purification. The melting
points were recorded in open capillaries using the ANALAB
Melting Point Apparatus. The IR spectra were recorded as
KBr discs or as neat, using PerkinElmer FT-IR spectrometer.
1H (400 MHz) and 13C (100 MHz) NMR spectra were
recorded as CDCl3/DMSO-d6 solutions with tetramethylsi-
lane (TMS) as an internal standard on a Bruker AVANCE III
HD spectrometer. Mass analysis was carried out using
Nexera UHPLC @ 130 Mpa with SIL-30AC Nexera auto
sampler coupled with an LC-MS 8030 tandem mass
spectrometer (Shimadzu Corporation, Tokyo, Japan). All
Please cite this article in press as: Singh, N., A concise and simple click reaction catalyzed by immobilized Cu(I) in an
ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/

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N. Singh / C. R. Chimie xxx (2015) xxx–xxx
the compounds were analysed in the full scan mode with
nitrogen as the interface gas.
(t, J = 7.7, 2H, Ar–H), 7.30–7.37(m, 1H, Ar–H), 4.70–4.77(brd.
s, 1H, exchanges with D2O), 4.25–4.30 (m, 1H), 3.80–3.68 (m,
1H), 2.20–2.14 (m, 8H) ppm. 13C NMR (100 MHz, DMSO-d6):
4.1. General experimental procedure1 for the synthesis of
beta-hydroxy triazoles 3
d
= 149, 132.1, 129.5, 128.1, 123.2, 121.9, 72.1, 66.3, 35.2,
32.2, 25.5, 24 ppm. ESI-MS m/z: 244 [M + H]+. Anal. calcd for
C14H17N3O: C, 69.11; H, 7.04; N, 17.27%. Found: C, 69.13; H,
An equimolar mixture of epoxides 1 and NaN3 was
stirred for 10 min in 1 g of IL i.e. [bmim]Br, loaded with
Cu(I) at 5 mol% w.r.t. reactant concentration. To the
resultant, were added an equimolar ratio of terminal
alkynes 2 via a syringe and the reaction was further
maintained under stirring at 80 8C for a specified period of
time. After completion of the reaction (as indicated by
TLC), 10 mL of distilled water were added under continu-
ous stirring, and solid crude product obtained was simply
collected by filtration. Purification of crude products was
carried out by recrystallization from ethanol. The filtrate
containing IL and the Cu(I) catalyst was immediately
reduced under low pressure and further dried at 100 8C for
20–30 min in a hot air oven, for the consecutive reaction
runs. Physical data of some representative compounds are
given below.
7.06; N, 17.25%.
Acknowledgements
I heartily thank IIIM Jammu, SAIF, and Punjab Universi-
ty, Chandigarh, for providing microanalyses and spectra. I
also express my deepest gratitude to Dr. Anil Kumar (Ph. D
supervisor) and Dr. Vijai Kumar Rai, for giving me an
opportunity to work on MRPs from time to time,
sanctioned vide F. No. 39-788/2010 (SR) and F. No. 39-
764/2010 (SR) respectively, by UGC – New Delhi.
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C16H15N3O: C, 72.43; H, 5.70; N, 15.84%. Found: C,
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4.1.2. Compound 3s
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(m, 2H), 1.65–1.55 (m, 2H), 1.35–1.25 (m, 6H), 0.92 (t, 3H)
ppm. 13C NMR (100 MHz, CDCl3):
d = 155, 140, 129, 128.5,
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ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/

G Model
CRAS2C-4126; No. of Pages 7
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Please cite this article in press as: Singh, N., A concise and simple click reaction catalyzed by immobilized Cu(I) in an
ionic liquid leading to the synthesis of
j.crci.2015.07.006
b-hydroxy triazoles. C. R. Chimie (2015), http://dx.doi.org/10.1016/