Copper(II) Nitrate Catalyzed Azide–Alkyne Cycloaddition Reaction: Study the Effect of Counter Ion, Role of Ligands and Catalyst Structure

Article abstract of DOI:10.1007/s10562-018-2357-9

Abstract: For the first time, CuAAC reaction catalyzed by copper(II) nitrate and counter ion effect of various copper(II) salts are reported. Use of a novel copper complex 1, derived from the reaction of copper(II) nitrate with 5-acetyl-2-amino-6-methyl-4

Full text of DOI:10.1007/s10562-018-2357-9

Catalysis Letters
https://doi.org/10.1007/s10562-018-2357-9
Copper(II) Nitrate Catalyzed Azide–Alkyne Cycloaddition Reaction:
Study the Effect of Counter Ion, Role of Ligands and Catalyst Structure
Manisha Bihani1 · Bala G. Pasupuleti1 · Pranjal P. Bora1 · Ghanashyam Bez1 · Ram A. Lal1
Received: 9 January 2018 / Accepted: 10 March 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
For the first time, CuAAC reaction catalyzed by copper(II) nitrate and counter ion effect of various copper(II) salts are
reported. Use of a novel copper complex 1, derived from the reaction of copper(II) nitrate with 5-acetyl-2-amino-6-methyl-
4-(pyridin-3-yl)-4H-pyran-3-carbonitrile, facilitated the CuAAC reaction at room temperature with a catalyst loading as low
as 1 mol% within a very short reaction time.
Graphical Abstract
Keywords Click reaction · Copper nitrate · 5-Acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-4H-pyran-3-carbonitrile ·
Copper(II) nitrate pyridine complex · Counter ion effect
1 Introduction
amides, it is not susceptible to cleavage. Additionally, it is
nearly impossible to oxidize or reduce triazoles and are inert
towards biological molecules and aqueous environments
which allows the use of the Huisgen 1,3-dipolar cycload-
dition in target guided synthesis and activity-based protein
profiling [1, 2].
Compounds containing the triazole functionality have been
known to exhibit a range of biological functions including
antitumor, antibacterial, antiparasitic and antiviral activ-
ity. Interestingly, triazole moiety has similarities with the
ubiquitous amide moiety found in nature, but unlike the
The application of copper catalysts in click reactions
stands out as a latest success of organometallic chemistry
for the synthesis of 1,4-disubstituted triazoles in contrast to
the uncatalyzed reaction via Huisgen reaction which pro-
vides both 1,4 and 1,5-regio-isomers at a very slow rate. The
use of copper catalysts accelerates the rate of the reaction
by 107 times and enables the reaction to perform in aque-
ous media with high yield and regioselectivity [3, 4]. The
fact that Cu(I) is the active form of the catalytic systems, a
range of catalytic systems [5–8] including the photochemical
routes [9–12] have been developed over the last decade to tie
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-018-2357-9) contains
supplementary material, which is available to authorized users.
* Ghanashyam Bez
ghanashyambez@yahoo.com
1
Department of Chemistry, North Eastern Hill University,
Shillong 793022, India
Vol.:(0123456789)
1 3

M. Bihani et al.
over the instability of the catalyst. As a result, the emphasis
has shifted to Cu(II) catalysts which can be converted to
Cu(I) systems in the presence of a sacrificial reducing agent
such as sodium ascorbate. However, most of Cu(II)–sodium
ascorbate systems require various additives such as N-con-
taining ligands [13], phase transfer catalysts [1], and acids
[14]. Additionally, the use of copper(II) salts directly in the
reaction creates the chance of metal contamination with
the end triazole product to lower the yield. Nevertheless,
the mechanism of click reaction involves multiple revers-
ible steps involving coordination complexes of copper(I)
acetylides of varying nuclearity. Therefore, a proper under-
standing on controlling the reaction dynamics is of para-
mount importance to achieve a productive catalytic cycle.
Therefore, ligand designing is an important part for subtle
control of the ligands over the metal centres to which they
are coordinated.
2 Experimental Section
2.1 Materials and Instruments
The chemicals and reagents were available commercially
and that were used without further purification. The prod-
ucts were characterized by IR, 1H NMR, 13C NMR, Mass
spectroscopy and elemental analysis. The IR spectra were
1
recorded on a Perkin Elmer spectrophotometer. H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were obtained
on a Bruker AC-400 using CDCl3 as solvent and TMS as
internal standard, unless otherwise stated. The mass spectra
were obtained from Waters ZQ 4000 mass spectrometer by
the ESI method, and the elemental analyses of the complexes
were performed on a Perkin–Elmer-2400 CHN/S analyzer.
Absorption spectra were obtained at room temperature
using a Perkin-Elmer Lambda 25 UV–Vis spectrophotom-
eter. The fluorescence measurement was carried out using
HITACHI F4500 spectrophotometer. X-band EPR spectra at
room temperature and at variable temperature were recorded
from powdered sample and from DMSO solution on a Var-
ian E-112 ESR Spectrometer using TCNE (g=2.0027) as
an internal standard. Room temperature magnetic suscep-
tibility measurements were made on Sherwood Magnetic
Susceptibility Balance MSB-Auto. SEM was carried out
with JEOL JSM-6360 and EDAX was done with Oxford
INCA 350 EDS.
Nature of the copper counter ion has dramatic effect on
the rate and efficiency of the reaction. As Hein and Fokin
[15] noted, the cuprous iodide catalyzed click reaction takes
nearly 100 min for full conversion, while the same reaction
completes within minutes with weakly coordinated copper
tetrafluoroborate. Surprisingly, in spite of being the least
expensive among the copper salts, copper nitrate have not
found application in click reaction. Given the fact that, a
nitrate counterion is more weakly coordinating ion toward
copper(II) than the halide [16] ions, it can in principle work
as better salt for click reaction. Moreover, the molecular
structure of copper nitrate, where the copper ion is sand-
wiched between the planes of nitrate group, tends to reduce
intermolecular forces, a property that may help in avoiding
metal contamination in triazole end products observed in
commonly used copper salts. In order to prove our conten-
tion, we planned to explore copper(II) nitrate as a catalyst
for click reaction and its catalytic behaviour in the presence
of various commonly used ligands. This study led to devel-
opment of a novel Cu(II) nitrate pyridine complex–sodium
ascorbate system for Click reaction which does not require
any additives (Scheme 1).
2.2 Synthesis of Acetyl‑2‑amino‑6‑methyl‑4‑
(pyridin‑3‑yl)‑4H‑pyran‑3‑carbonitrile
To a solution of pyridine-3-carbaldehyde (0.535 g, 5 mmol)
and malononitrile (0.330 g, 5 mmol) in ethanol (50 mL),
were added acetylacetone (0.5 g, 5 mmol) and Amberlyst
A21 (30 mg/mmol). As the reaction progressed, precipi-
tation of the product was observed. Upon stirring at room
temperature for a specified time, the reaction underwent
to completion as supported by TLC study. Warm ethanol
(60 °C) was added to dissolve the solid product and filtered.
The residue of Amberlyst A21 was washed thoroughly with
warm ethanol. The combined ethanolic solution was con-
centrated and allowed to stand in a refrigerator to get pure
crystalline product. Yield: 1.083 g (85%); white crystals;
Scheme 1 Copper(II) nitrate
N
pyridine complex catalysed
click reaction
Complex of copper (II) nitrate
O
R
with pyranopyridine 1
NC
R1 N3
R1
N
+
R
Sodium ascorbate, EtOH-H2O
N
N
H2N
O
1
1 3

Copper(II) Nitrate Catalyzed Azide–Alkyne Cycloaddition Reaction: Study the Effect of Counter…
m. p.: 163–164 °C; IR (KBr): 3356, 2190, 1686 cm−1; 1
H
J=7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 54.2, 119.6,
125.4, 125.7, 128.1, 128.2, 128.3, 128.5, 128.6, 128.8, 128.8,
129.1, 130.5, 134.7, 140.2; ESI–MS (m/z): 236 (M+H)+, 258
(M+Na)+; Elemental Anal. for C15H13N3: Calcd. C 76.57, H
5.57, N 17.86; Observed: C 76.52, H 5.51; N 17.80.
NMR (400 MHz, DMSO-d6): δ 1.93 (s, 3H, H3C–C=C–),
2.10 (s, 3H, H3C–CO–C=C–), 4.36 (s, 1H, –CHC5H4N),
6.38 (s, 2H, NH2), 7.18–7.21 (m, 1H), 7.39 (d, J = 8 Hz,
1H), 8.25–8.28 (m, 2H); 13C NMR (100 MHz, DMSO-
d6): δ 18.7 (H3C–C=C–), 30 (H3C–CO–C=C–), 36.2
(–CHC5H4N), 56.8 (=C–CN), 114.4 (H3C–CO–C=C–),
119.6(CN), 123.9 (C-5 of –C5H4N), 134.8 (C-1 of –C5H4N),
140 (C-6 of –C5H4N), 148.1 (C-4 of –C5H4N), 148.3 (C-2
of –C5H4N), 155.8 (H3C–C=C–), 158.4 (=C–NH2), 197.9
(C=O); ESI–MS (m/z): 256 (M+H)+, 278 (M+Na)+; Ele-
mental Anal. for C14H13N3O2: Calcd. C 65.87, H 5.13, N
16.46 Observed C 65.78, H 5.15, N 16.12.
3 Results and Discussion
Among the amine ligands, diamine ligands are more popular
for Click reaction because they block the copper–triazolyde
species from bonding with starting alkyne again and hence
contribute towards increase of the yield of click reaction.
We strongly believed that if copper(II) nitrate is taken as the
copper source, the planarity of the nitrate counterion might
also block the coordination of copper triazolyde with the
starting alkyne. To test our hypothesis, an equimolar mix-
ture of phenyl acetylene and benzyl azide was stirred with
10 mol% Cu(NO3)2 and 10 mol% diisopropylethylamine
in a 1:1 EtOH–H2O mixture for 12 h at room temperature.
Ironically, no conversion was observed. We then decided to
screen some monodentate and bidentate ligands such as pyri-
dine, 3-methylpyridine, 2,6-lutidine, 4-DMAP, 2,2′-bipyri-
dine, 1,10-phenanthroline, 8-hydroxyquinoline, 5-acetyl-2-
amino-6-methyl-4-(pyridin-3-yl)-4H-pyran-3-carbonitrile,
and 5-acetyl-2-amino-6-methyl-4-(pyridin-2-yl)-4H-pyran-
3-carbonitrile under similar reaction conditions (Table 1).
Interestingly, 5-acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-
4H-pyran-3-carbonitrile gave the highest yield (67%) in
12 h, while many other pyridine-based ligands were found to
be catalytically much inferior under the reaction conditions.
Increase of 5-acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-4H-
pyran-3-carbonitrile (20 mol%, entry 13–14) and reaction
time (24 h, entry 14) showed only marginal increase in yield
of the reaction. We carried out the same click reaction with
other commonly used copper salts to see the counter ion
effect on the reaction in the presence of 5-acetyl-2-amino-
6-methyl-4-(pyridin-3-yl)-4H-pyran-3-carbonitrile. To our
surprise, the commonly used counterion such as −I, Cl−, Br−,
AcO− and SO42− gave inferior yields within similar reaction
time under our reaction conditions (Table 1, entries 15–19).
The fact that Cu(NO3)2 is not reported in the literature
and its catalytic activity in the presence of 5-acetyl-2-amino-
6-methyl-4-(pyridin-3-yl)-4H-pyran-3-carbonitrile for the
Click reaction can be termed as moderate to good under
in-situ conditions, we decided to explore if the reactivity
can be increased by pre-forming the copper(II) complex with
5-acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-4H-pyran-3-
carbonitrile. For that purpose, a mixture of readily acces-
sible 5-acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-4H-pyran-
3-carbonitrile [17, 18] and Cu(NO3)2·3H2O was ground in
2:1 molar ratio in a mortar with a pestle with 0.5 mmol of
triethylamine at room temperature. Within 20 min, formation
2.3 Synthesis of the Copper(II) Nitrate Pyridine
Complex (1)
A mixture of 5-acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-
4H-pyran-3-carbonitrile (0.255 g, 1 mmol), Cu(NO3)2·3H2O
(0.5 equiv.) and Et3N (0.5 mmol) was ground in mortar with
pestle at room temperature. Within 20 min of grinding, for-
mation of a melt was observed which got converted to a red-
dish brown colored solid mass after another 10 min. The
solid mass was heated at 60 °C for 2 h and washed with 30%
ethyl acetate–hexane mixture and finally dried over anhy-
drous CaCl2 in a desiccator. Finally it was characterized by
IR, UV–Vis spectroscopy, Fluorescence spectroscopy, EPR
spectroscopy, ESI–MS analysis, magnetic susceptibility
measurement, SEM, energy dispersive X-ray (EDX) and ele-
mental analyses. M. p.: 298–299 °C; IR (KBr): 3250, 2196,
1675, 1634, 1482, 1432, 1297, 1113, 486 cm−1; ESI–MS
(m/z): 698 (M+H)+, UV/Vis (MeOH) λmax/nm: 260, 301,
359, 510. Magnetic Moment (B.M): 1.79. Elemental analysis
for C28H26N8O10Cu: Calculated C 48.17, H 3.75, N 16.05;
Observed C 48.21, H 3.68, N 16.15.
2.4 Typical Procedure for CuAAC
A 20-mL round-bottomed flask equipped with a magnetic stir-
rer was charged with benzyl azide (0.133 g, 1 mmol), phenyl
acetylene (102 g, 1 mmol), and the copper(II) nitrate pyrano-
pyridine complex 1 (1 mol%). A solution of sodium ascor-
bate (0.5 equiv.) in 1:1 ethanol–water mixture (6 mL) was
added into it and stirred at room temperature for 10 min. After
completion of the reaction, as evident from TLC, ethanol was
removed in a rotavapor under reduced pressure and the aque-
ous solution was extracted with ethyl acetate (3×10 mL).
The organic part was dried over Na2SO4 and the solvent
was removed under reduced pressure to obtain the triazole
derivative 3a in 94% yield (0.221 g) as white solid with excel-
lent purity. m.p.: 122–123 °C; IR (KBr): 3322, 3093, 3056,
1613, 1478, 1101 cm−1; 1H NMR (400 MHz, CDCl3): δ 5.47
(s, 2H, –CH2–), 7.22–7.31 (m, 8H), 7.58 (s, 1H), 7.71 (d,
1 3

M. Bihani et al.
Table 1 Screening of ligands
Sl no.
Ligands
Cu salt
Loading (mol%)
Time (h)
% Yielda
and counter ion effect
1
2
3
4
5
6
7
8
9
10
None
DIPEA
Pyridine
3-Methyl pyridine
4-DMAP
2,6-Lutidine
2,2′-Bipyridine
1,10-Phenanthroline
8-Hydroxyquinoline
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
None
10
10
10
10
10
10
10
10
12
12
12
12
12
12
12
12
12
12
NR
NR
37
35
41
44
24
39
24
10
NR
11
Cu(NO3)2
10
10
12
42
67
12
Cu(NO3)2
12
13
14
15
16
17
18
19
Cu(NO3)2
Cu(NO3)2
CuI2
CuCl2
CuBr2
Cu(AcO)2
Cu(SO4)2
20
20
20
20
20
20
20
12
24
24
24
24
24
24
71
73
53
41
47
21
38
All the reactions were carried out at room temperature with EtOH–H2O as solvent
aYield of purified product
of a melt was observed which subsequently got converted
to a reddish brown solid mass. TLC of the reaction mix-
ture showed disappearance of starting 5-acetyl-2-amino-
6-methyl-4-(pyridin-3-yl)-4H-pyran-3-carbonitrile and the
formation of a highly polar compound. The reddish brown
solid was heated at 60 °C for 2 h, washed with 30% ethyl
acetate in petroleum ether, and dried over anhydrous CaCl2
in a desiccator.
H2N
NC
O
O
H2N
O
ONO2
O
NC
N
Cu
N
O2NO
1
3.1 Catalyst Characterization
The structure of the copper(II) complex 1 (Fig. 1) was con-
firmed by IR, UV–Vis spectroscopy, Fluorescence spec-
troscopy, EPR spectroscopy, ESI–MS analysis, magnetic
susceptibility measurements, SEM, EDAX, and elemental
analyses. In spite of our repeated efforts, single crystal for
the copper(II) complex 1 could not be obtained. The IR
spectra of the complex showed shifting of band for C=N
(aromatic) (Table S1, Supplementary materials) along with
bands at 1432, 1297 cm−1 to indicate that nitrate group is
Fig. 1 Structure of the complex, 1
bound to the metal center in monodentate fashion [19, 20].
The band occurring in the far IR region at 486 cm− 1 is
assigned to ν(Cu–N). These observations clearly pointed
towards the involvement of the aromatic C=N group of
5-acetyl-2-amino-6-methyl-4-(pyridin-3-yl)-4H-pyran-3-
carbonitrile and nitrate in complexation.
1 3

Copper(II) Nitrate Catalyzed Azide–Alkyne Cycloaddition Reaction: Study the Effect of Counter…
In the electronic spectra of the 5-acetyl-2-amino-6-
methyl-4-(pyridin-3-yl)-4H-pyran-3-carbonitrile and the
copper(II) complex (1) in a 10−5 M methanolic solution,
the ligand showed two strong absorptions bands at 240 and
307 nm which were attributed to intraligand π–π* and n–π*
transitions, respectively. On the other hand, the complex 1
showed absorption bands at 260, 301 and 359 nm due to the
intraligand π–π*, π–π* and n–π* transitions, respectively.
The absorption peak at 510 nm indicated d–d transition
responsible for co-ordination of the ligand to the metal cen-
tre (Fig. 2) [21]. This indicated that the ligand is coordinated
to the metal centre forming the copper complex.
The synthesized Cu(II) complex, 1 was also characterized
by EPR spectroscopy, recorded for powder and solution sam-
ple at RT and LNT (Table S3, Supplementary Materials).
The EPR spectra of the Cu(II) complex was anisotropic in
solid state both at RT and LNT. The EPR spectrum showed
hyperfine splitting in DMSO at LNT with three lines in the
g║ region. The g║ and g⊥ values for the complex 1 in poly-
crystalline state at RT were 2.462 and 2.115, while those
at LNT were 2.501 and 2.111. The hyperfine splitting in
g║ region was observed due to intermolecular interaction
of unpaired electron spin of copper(II) with nuclear spin
(I=3/2). Although four hyperfine lines should be observed,
only three components were visible in the g║ region which
might be due to overlap of last line of split component with
the strong signal in the g║ region. The observed Hamilto-
nian parameters are g║ =2.231, g⊥ =2.071, gav =2.124, and
A║ =150 G at LNT in DMSO. Although not well resolved,
the LNT spectra of the complex in solution showed addi-
tional three small lines with A║ = 75 G which are indica-
tive of a pattern typical of a dimer structure involving weak
Cu–Cu interaction. This observation suggests that there
might be a small percentage of dimer species in solution in
equilibrium with the monomeric copper(II) complex. The
dimeric species might arise due to solvation of the mono-
meric complex in DMSO solution. The g values for the com-
plex which are in the order of g║ >g⊥ >2.0023 indicated a
The magnetic moment value for the copper(II) complex
1 was found to be 1.79 B.M at room temperature which is
close to the magnetic moment obtained from spin only for-
mula (1.73 B.M). This result suggested a square planner
geometry of the complex and no M–M interaction in the
structural unit [22].
Fluorescence studies were carried out to gather additional
evidences of complexation between the ligand and the metal
ion. The emission spectra of the ligand and complex were
measured in the methanolic solution at room temperature.
The ligand displayed a photoluminescence with emission
maxima at 303 and 392 nm on excitation at 260 nm, whereas
the copper(II) complex 1 showed photoluminescence with
an emission maximum at 304 and 432 nm on excitation at
260 nm (Table S2, in Supplementary Materials).
2
2
dx −y ground state. The nature of the ligand forming the
complex was evaluated by using the equation [G=(g║−2)/
(g⊥−2)]. The G value obtained for the complex are in the
region 3.25–4.51 to suggest a moderately strong field ligand
character in the complex and the local tetragonal axes are
misaligned. The ratio of g║/A║, which is used to find the
distortion in the equatorial plane of the coordination com-
plex, was found to be 148 cm−1 for the copper(II) complex.
This data suggested a plausible square planar geometry of
the complex [24].
The SEM image (Fig. S1, Supplementary materials)
revealed the surface morphology of Cu(II) complex. The
particles were agglomerated and were present as small
grains of non-uniform size. Furthermore, EDX (Fig. 2S,
Supporting Information) indicated that presence of Cu with
energy bands of 8.01, 9.01 keV (K lines) and 0.93 keV (L
line) [23]. The ESI–MS analysis of the copper(II) complex 1
gave prominent band at m/z 698 corresponding to [M+H]+
supported the proposed structure of the complex, 1.
3.2 Catalytic Studies
The catalytic activity of the newly prepared copper(II)
complex 1 was investigated for the synthesis of 1, 2, 3-tria-
zoles employing the Click reaction. For this purpose, we
carried out the reaction of benzyl azide with phenyl acety-
lene at room temperature with 10 mol% of the synthesized
catalyst 1 in THF in the presence of sodium ascorbate as
a sacrificial reducing agent. To our pleasure, the reaction
led to complete conversion of the starting azide and phenyl
acetylene within 30 min of vigorous stirring leading to the
formation of a more polar white solid product. The product
was found to be pure without further chromatographic puri-
fication with a yield of 78%. Interestingly, almost similar
yield was achieved when the catalyst loading was reduced
to 1 mol%. Inspired by the huge improvement in comparison
Fig. 2 UV–Vis spectra of the ligand (red) and the complex 1 (black)
1 3

M. Bihani et al.
to our in-situ observations, we decided to screen the effect
of solvent and catalyst loading on efficiency of the reaction
(Table 2).
stearyl azide (entries 10 and 11, Table 3) also yielded the
corresponding triazoles in excellent yield within 20 min.
In a bid to diversify the protocol, we employed different
alkynes such as propargyl alcohol, 2-ethynyl pyridine and
(4-pentyl phenyl)-acetylene with benzyl azide under the
optimized reaction conditions to achieve the desired tria-
zoles in excellent yields.
It was found that 1:1 mixture of ethanol and water is the
optimum solvent system for the pilot reaction. A series of
experiments for the pilot reaction was carried out with vary-
ing catalyst loading viz. no catalyst, 0.5, 1, 2 and 5 mol% of
the complex 1. It was found that 1 mol% of catalyst in 1:1
ethanol–water system is the optimum for the said synthesis
with respect to both time and yield (entry 9, Table 2). Effi-
cient cycloaddition was also realized with significantly lower
catalyst loading although it required a longer reaction time
(entry 10, Table 2).
The fact that the click reactions have found applications
in labeling of biomolecules, we tested our catalytic system
for the synthesis of triazole derived from biomolecules
such as cholesterol. For the purpose, we carried out the
reaction of cholesterol derived azide with phenyl acety-
lene under our optimized reaction conditions (entry 12,
Table 3). To our pleasure, in this case also we achieved
the desired 1-cholesteryl 4-phenyl-1H-1,2,3-triazole in
93% isolated yield by simple aqueous work-up without
any column chromatographic purification within 20 min.
The catalytic efficiency was explored for synthesis of bis-
and tris-1,2,3-triazoles (Fig. 3) and excellent results were
achieved.
3.3 Substrate Scope
With the optimized reaction conditions in place, the sub-
strate scope of the reaction was explored by varying both
azido compounds and the terminal alkynes (Table 3). A
variety of triazoles could be isolated in excellent yields
and in high purity without employing any column chro-
matographic purification. All the benzyl azides (entries
1–3, Table 3) and secondary azides (entries 7–9, Table 3)
reacted with phenyl acetylene to generate the correspond-
ing triazoles with excellent isolated yield. It is important
to note that under our optimized reaction conditions,
straight chain aliphatic azide such as hexyl azide and
To establish the catalytic efficiency of our system, we
selected some commonly used copper salts for click reac-
tion that work at room temperature in the presence of vari-
ous ligands (Table 4). In comparison to these methods, our
method employs a readily accessible ligand, takes shorter
reaction time and works at mild reaction conditions.
Table 2 Screening of solvent and catalyst loading
Entry
Solvent(s)
Catalyst (mol%)
Time (min)
% Yield
1
2
3
4
5
6
7
8
H2O:EtOH (1:2)
H2O:EtOH (1:1)
1
1
0.5
2
5
1
1
1
10
1
30
10
30
10
10
45
45
60
30
30
30
40
88
94
87
92
95
75
68
72
78
76
64
78
EtOH
MeOH
H2O
THF
9
10
11
12
THF
CH3CN
H2O: CH3CN (1:1)
1
1
Reaction condition: reaction of benzyl azide with phenyl acetylene in water at room temperature with 1 mol% of the copper(II) complex 1 in
presence of sodium ascorbate
Isolated yield
1 3

Copper(II) Nitrate Catalyzed Azide–Alkyne Cycloaddition Reaction: Study the Effect of Counter…
Table 3 Synthesis of 1, 2,
3-triazoles
Entry
1
Azide
Product
t (min)
10
%Yielda
94
2
10
92
3
10
15
91
96
4
5
10
15
95
94
6
7
8
9
15
15
15
90
88
90
10
11
12
Hexyl azide
Stearyl azide
15
20
20
93
92
93
Cholestrol azide
Reaction conditions: reaction of azide (1 mmol) with phenyl acetylene (1 equiv.) at room temperature
with the copper(II) complex 1 (1 mol%) in ethanol–water mixture (1:1) in the presence of sodium ascor-
bate
aIsolated yield
by various spectroscopic studies and its catalytic activ-
ity was evaluated for azide alkyne cycloaddition reaction
4 Conclusion
under click conditions to synthesize a number of 1,4-dis-
ubstituted triazoles. Very low catalyst loading (1 mol%),
short reaction time (10–20 min), room temperature reac-
tion conditions, use of environmentally benign solvents,
chromatography-free purification, readily available and
cost-effective copper(II) nitrate as catalyst for click reac-
tion are some important features of our protocol.
For the first time, we have established copper(II) nitrate
as a catalyst for click reaction in the presence of 5-acetyl-
2-amino-6-methyl-4-(pyridin-3-yl)-4H-pyran-3-carboni-
trile, a readily available ligand synthesized from pyridine-
3-carboxaldehyde, acetylacetone and malononitrile by
MCR. The structure of the active catalyst was confirmed
1 3

M. Bihani et al.
Fig. 3 Synthesis of bis- and tris-1,2,3-triazoles
Table 4 Comparative studies with reported methods
S. no.
1
Reaction conditions
% Yield
99
Ref.
[25]
CuBr2, Cu(CH3CN)4PF6, NaASc, N-((1H-pyrazol-3yl)methyl-1-(pyridine-2-yl) –N-(pyridine-
2-ylmethyl))methanamine, NEt3, N2 atmosphere, 16 h
2
3
4
5
6
7
8
CuSO4 in NaOH, sodium potassium tartrate, DIPEA, Hydrazine, 15 min
CuCl2 or CuCl, 1,3-bis(2,6-dimethylphenyl)thiourea, 1.5 h
CuSO4.5H2O, NaASc, urea, water, 1 h
Chitosan-stabilised copper–iron oxide nanocomposite, DCM, 12 h
CuSO4, (1-(4-methoxybenzyl)-1-H-1,2,3-triazol-4-yl)methanol, NaASc, PEG-H2O, 6 h
CuSO4·5H2O, Betaine, NaAsc, water, 30 °C, 24 h
98
99
99
92
96
95
94
[26]
[27]
[28]
[29]
[30]
[31]
This work, 10 min
10. Dadashi-Silab S, Kiskan B, Antonietti M, Yagci Y (2014) RSC
Adv 4:52170
Acknowledgements Thanks are due to University Grant Commission,
Centre for Advanced Studies grant (F.540/21/CAS/2013) (SAP-I) for
providing partial financial support. The analytical services provided by
Spohisticated Analytical Instrumentation Facility, North Eastern Hill
University, Shillong, India are highly appreciated.
11. Taskin O, Yilmaz G, Yagci Y (2016) ACS Macro Lett 5:103
12. Kumar P, Joshi C, Srivastava AK, Gupta P, Boukherroub R, Jain
SL (2016) ACS Sustain Chem Eng 4:69–75
13. Chan TR, Hilgraf R, Sharpless KB, Fokin VV (2004) Org Lett
6:2853
14. Shao C, Wang X, Xu J, Zhao J, Zhang Q, Hu Y (2010) J Org
Chem 75:7002
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