Efficient multicomponent synthesis of 1,2,3-triazoles catalyzed by Cu(II) supported on PEI@Fe3O4 MNPs in a water/PEG300 system

Article abstract of DOI:10.3906/kim-1607-40

A highly dispersible and magnetically recoverable Cu-PEI@Fe₃O₄ MNPs catalyst was prepared and success-fully applied in one-pot three-component coupling of terminal alkynes, sodium azide, and alkyl bromides/chlorides in water to give

Full text of DOI:10.3906/kim-1607-40

Turk J Chem
2017) 41: 294 – 307
Turkish Journal of Chemistry
(
http://journals.tubitak.gov.tr/chem/
¨
˙
⃝
c TUBITAK
Research Article
doi:10.3906/kim-1607-40
Efficient multicomponent synthesis of 1,2,3-triazoles catalyzed by Cu(II)
supported on PEI@Fe O MNPs in a water/PEG system
300
3
4
1
2
3
Zeinab HASANPOUR , Aziz MALEKI , Morteza HOSSEINI ,
4
5
1
Lena GORGANNEZHAD , Vajihe NEJADSHAFIEE , Ali RAMAZANI ,
6
5
5,6,∗
Ismaeil HARIRIAN , Abbas SHAFIEE , Mehdi KHOOBI
1
Department of Chemistry, University of Zanjan, Zanjan, Iran
2
Zanjan Pharmaceutical Nanotechnology Research Center (ZPNRC), Zanjan University of Medical Sciences,
Zanjan, Iran
Department of Life Science Engineering, Faculty of New Sciences & Technologies, University of Tehran,
3
Tehran, Iran
4
Department of Biology, Faculty of Science, Payame Noor University, Iran
5
Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
6
Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy,
Tehran University of Medical Sciences, Tehran, Iran
Received: 18.07.2016
•
Accepted/Published Online: 24.10.2016
•
Final Version: 19.04.2017
3 4
Abstract:A highly dispersible and magnetically recoverable Cu-PEI@Fe O MNPs catalyst was prepared and success-
fully applied in one-pot three-component coupling of terminal alkynes, sodium azide, and alkyl bromides/chlorides in
water to give 1,4-disubstituted 1,2,3-triazoles with good to excellent yields. The catalyst was fully characterized with
FT-IR, TGA, TEM, SEM, VSM, EDX, cyclic voltammetry, and ICP-AES spectroscopic techniques. Furthermore, the
catalyst was easily recycled by an external magnet and successfully reused six times in the reaction without significant
loss of its catalytic activity and copper leaching. The large-scale reaction was also carried out in the absence of any base
and reducing agent even with 0.1 mol% of the catalyst in aqueous media, making this protocol a good candidate for
practical applications.
Key words: Magnetic nanoparticles, copper catalyst, synthesis, 1,2,3-triazoles
1. Introduction
Recently, magnetic nanoparticles (MNPs) have attracted a great deal of attention in research activities.1 They
are readily available, robust, and more importantly can be easily modified by organic and inorganic species,
making them resistant against degradation and agglomeration and promising for the immobilization of catalytic
centers. Furthermore, they have high surface area and can easily be recovered and reused by an external
−3
magnetic field.4
−6
This issue overcome the separation problem of conventional nanocatalysts by filtration or
centrifugation; thereby it prevents loss of the catalysts during their separation and recovery.
Huisgen 1,3-dipolar cycloaddition between organic azides and alkynes is well established for the synthesis
of 1,2,3-triazoles,7
−10
receiving considerable attention in various fields of chemistry.
11−13
Cu(I)-catalyzed azide–alkyne cycloaddition, independently reported by Sharpless14 and Meldal,15 opened
∗
Correspondence: m-khoobi@tums.ac.ir
This paper is dedicated to the memory of Prof Abbas Shafiee (1937–2016).
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HASANPOUR et al./Turk J Chem
the door for the preparation of 1,2,3-triazoles with high regioselectivity and broad substrate scope at room tem-
perature. The noncatalyzed version of the reaction gives the products with poor selectivity and low yield.7
−10
Consequently, many methods based on homogeneous copper catalysts have been reported to date. However,
−10
they suffer from the problems of catalyst recycling, product contamination, and use of toxic solvents.7
In comparison with homogeneous catalysts, heterogeneous catalysts can bring the advantages of catalyst
reusability and easier product separation. Therefore, much effort has been made to immobilize copper com-
plexes on suitable supports including carbon, silica, polymer, alumina, zeolite, dendrimer, and charcoal.1
6−21
Although noticeable improvements in terms of reusability, reducing catalyst loading, and working under aerobic
conditions were made, most of them still used organic solvents and organic base to improve catalytic efficiency.
More importantly they used organic azides directly instead of in situ generated counterparts. Since the organic
azides are toxic and their handling is not safe, the development of one-pot Huisgen 1,3-dipolar cycloaddition
based on heterogeneous catalysts is highly desirable. To address this issue, some copper-based catalytic systems
have been reported. These systems include copper nanoparticles on activated carbon,22,23 polymeric cop-
per catalyst,2
4−27
ionic liquid-supported Cu(I),
28−30
alumina-supported copper nanoparticles,31 CuFe2 O4 ,32
silica-supported Cu(I),33 nanoferrite–glutathione–copper,34 nanosilica triazine dendrimer,35 Cu(II) porphyrin-
bridged silsesquioxane PMO,36 Cu@PMO NCs,37 magnetic nanoparticle-supported Cu(II) acetate,38 and silica-
immobilized NHC–Cu(I).39 However, successful examples using this useful strategy are limited and some of
them still use organic solvents, base, and reducing agents. We have recently reported that PEI-grafted Fe3 O4
MNPs (MNPs@PEI) is a very suitable catalyst for one-pot synthesis of 2-amino-3-cyano-4H -pyran derivatives
in water40 and also could be used for physical adsorption or covalent attachment of Thermomyces lanuginosa
lipase (TLL) through different modification.41 Herein, we supported copper onto magnetic nanoparticle with
covalently anchored polyetylimine (PEI) as catalyst for the three-component coupling reaction of sodium azide,
alkyl halides, and different alkynes in the absence of any base and reducing agent in H2 O/PEG300 as a safe,
inexpensive, green, and environmentally benign medium.
2. Results and discussion
The Cu-PEI@Fe3 O4 MNPs catalyst was prepared as presented in the Scheme. Initially, for grafting of PEI
onto Fe3 O4 MNPs, GOPTMS was added to a solution of PEI in toluene. After 24 h the resulting mixture
was allowed for a further 24 h to react with Fe3 O4 MNPs to give PEI functionalized nanomagnets. The
PEI@Fe3 O4 MNPs material was then used for immobilization of Cu(II) and preparation of the corresponding
magnetic nanoparticle-supported copper catalyst (Cu-PEI@Fe3 O4 MNPs).
The catalyst was characterized by FT-IR, TGA, TEM, VSM, EDX, cyclic voltammetry, and ICP-AES.
−1
Anchoring of PEI on the surface of the MNPs was confirmed by FT-IR spectroscopy.. The band at 1457 cm
could be assigned to the stretching vibration of C–N bonds of PEI macromolecular chains and the bands at
−
1
around 2924 and 2831 cm
are attributed to the aliphatic C–H bands. In addition, the characteristic peaks
−
1
−1
of Fe–O at 584 cm
and a strong adsorption band at 1110–1000 cm
of Si–O–Si were also observed. These
suggested that PEI moiety was truly attached on the surface of the MNPs (Figure 1).
The XRD spectra of the MNP showed that the position and relative intensity of all the diffraction peaks
suitably matched those of standard Fe3 O4 .40 In addition, characteristic peaks of Fe3 O4 did not change after
coating the surface with PEI and Cu immobilization, showing that the crystalline structures of the MNPs are
preserved after the modifications (Figure 2). The average crystalline size of the catalyst calculated by the
Debye–Scherrer equation was about 30 nm.
2
95

HASANPOUR et al./Turk J Chem
3 4
Scheme. Synthesis of Cu-Fe O -PEI MNPs catalyst.
3 4 3 4 3 4
Figure 1. FT-IR spectra of a) Fe O , b) PEI@Fe O MNPs, c) Cu-PEI@Fe O MNPs.
The structure of the prepared MNPs was further verified using transmission electron microscopy (TEM)
images. PEI@Fe3 O4 MNPs were spherical with relatively narrow size distribution (Figure 3a). A magnified
TEM image of single PEI@Fe3 O4 MNPs indicated that the diameter of the MNPs is about 20 nm. The
structure of the MNPs was maintained after copper supporting (Figure 3b). On the other hand, Figure 3c
shows a TEM image of the Cu-PEI@Fe3 O4 MNPs after recovery from the first cycle of the reaction.
By comparing these two sets of TEM images before and after the first reaction cycle, we can see that the
nanoarchitecture of the catalyst survived. The selected area electron diffraction (SAED) pattern taken from
296

HASANPOUR et al./Turk J Chem
the Cu-PEI@Fe3 O4 MNPs revealed that copper on the PEI@Fe3 O4 MNPs was polycrystalline (Figure 3d).
All of these observations confirmed the successful preparation and stability of the catalyst.
.
3 4 3 4 3 4
Figure 2. XRD spectra of a) Fe O , b) PEI@Fe O MNPs, and c) Cu-PEI@Fe O MNPs.
Figure 3. TEM image of a) PEI@Fe
3 4 3 4 3 4
O MNPs, b) Cu-PEI@Fe O MNPs c) recycled Cu-PEI@Fe O MNPs, and
d) SAED pattern of Cu-PEI@Fe MNPs.
3
O
4
TGA analysis was used to determine the amount of ligand incorporated on Fe3 O4 . There are two weight
◦
loss steps in the TGA curve of Cu-PEI@Fe3 O4 MNPs catalyst. The first weight loss between 60 to 250 C may
be due to removal of surface adsorbed water from the catalyst. The weight loss at temperatures higher than
◦
2
50 C could be attributed to the slow decomposition of the higher-molecular-weight species present in the
2
97

HASANPOUR et al./Turk J Chem
magnetic nanospheres (EPO and PEI groups). The loading amount of organic moiety anchored on the surface
Cu-PEI@Fe3 O4 MNPs catalyst was found to be about 20% (Figure 4).
3 4 3 4 3 4
Figure 4. TGA spectra of a) Fe O MNPs, b) PEI@Fe O MNPs, and c) Cu- PEI@Fe O MNPs.
The magnetization curve of the Fe3 O4 MNPs, PEI@Fe3 O4 MNPs, and Cu-PEI@Fe3 O4 MNPs are
shown in Figure 5. It can be seen that the magnetic saturation (MS) of the nanoparticles is 35.0, 32.4, and 30.0
−
1
emu g , respectively. The decrease in mass saturation magnetization can be ascribed to the contribution of
the nonmagnetic silica and PEI shell. Although the MS values of the PEI@Fe3 O4 MNPs decreased, they still
could be efficiently separated from the solution with a permanent magnet (Figure 5).
Figure 5. VSM spectra of a) Fe
3 4 3 4 3 4
O MNPs, b) PEI@Fe O MNPs, and c) Cu-PEI@Fe O MNPs; d) catalyst ability
for easy recovery in the presence of large-scale amount of the reactants (50 mmol).
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HASANPOUR et al./Turk J Chem
The loading of copper catalyst was determined using ICP-AES and the results showed loading at 0.22
−1
mmol g . After each run, the catalyst was removed by permanent magnet and the solution was concentrated
and checked for determination of the leached copper ion by ICP analysis and the isolated catalyst was also
applied for the next runs. According to the results obtained by ICP analysis, the amount of leached copper
from the catalyst was less than 0.11 ppm for the first run and less than 0.021 ppm for the next runs. Energy-
dispersive X-ray (EDX) analysis on various regions with energy bands of 8.05 keV (K lines) and 0.93 keV (L
line) confirmed the presence of copper on the support (Figure 6).23
3 4 3 4
Figure 6. EDX spectra of a) Cu-PEI@Fe O MNPs and b) PEI@Fe O MNPs.
Anchoring of Cu on the solid surface can be followed by DRUV-vis spectroscopy of the resulting catalysts.
The spectrum showed a broad absorption band in the region of 600–900 nm that could be attributed to the d–d
transition of Cu(II) ion in the octahedral ligand field generated by oxygen ions. The band at ca. 250 nm may
be related to the silica matrix (Figure 7a).
Moreover, the oxidation state of copper supported on PEI@Fe3 O4 MNPs was confirmed using the electro-
chemical properties of Cu(OAc)2 and Cu-PEI@Fe3 O4 MNPs. In this experiment, the cyclic voltammograms
of Cu(OAc)2 and Cu-PEI@Fe3 O4 MNPs in 0.1 M KCl as supporting electrolyte was recorded with the scan
−1
rate of 100 mV s
using a glassy carbon as working electrode. One milligram of Cu-PEI@Fe3 O4 MNPs was
dispersed into water (100 µL) to provide a suspension. Next, 5 µL of suspension was dropped on the cleaned
GCE and allowed to dry at room temperature. Cyclic voltammograms of 0.1 µM Cu(OAc)2 were also obtained
in supporting electrolyte. The curve of Cu(OAc)2 exhibited one peak (Ec = –0.45 V vs. Ag/AgCl) corre-
sponding to the electron reductions of Cu(II) and formation of Cu(I) species. Furthermore, in accordance with
the curve of Cu-PEI@Fe3 O4 MNPs, the reduction of Cu(II) supported on PEI@Fe3 O4 MNPs was negatively
shifted (Ec = –0.52 V vs. Ag/AgCl) compared with those related to the Cu (OAc)2 . These results revealed
that Cu(OAc)2 and Cu-PEI@Fe3 O4 MNPs show partially cathodic shifts (Figure 7b).
2
99

HASANPOUR et al./Turk J Chem
10
Cu-PEI@Fe O MNPs
(b)
8
8
8
7
7
7
7
7
4
2
0
8
6
4
2
0
(a)
3
4
Cu(OAc)2
8
6
4
2
0
-
2
200
400
600
800
-
0.2
-0.4
-0.6
-0.8
-1.0
Wavelength (nm)
E (V)
3 4
MNPs, b) cyclic voltammograms of Cu-PEI@Fe O MNPs,
Figure 7. a) DRUV-vis spectra of Cu-PEI@Fe
Cu(OAc)
3
O
4
2
.
Table 1. Optimization study for the three-component coupling of sodium azide, benzyl bromide, and phenyl acetylene
under various conditions.
Entry[a] Catalyst (mol%)
Solvent (additive) Yield (%) TON /TOF
[b]
[c]
1
Cu-PEI@Fe3O4 MNPs (0.3) H2O
0
0
2[d]
3[e]
4[f]
5[f]
6[f]
7[f]
8
Cu-PEI@Fe3O4 MNPs (0.3) H2O
70
70
98
30
30
233/77
233/77
326/108
100/33
100/33
313/104
970/323
233/77
266/88
316/105
0
Cu-PEI@Fe3O4 MNPs (0.3) H2O
Cu-PEI@Fe3O4 MNPs (0.3) H2O (PEG300)
Cu-PEI@Fe3O4 MNPs (0.3) H2O (CTMBr)
Cu-PEI@Fe3O4 MNPs (0.3) H2O (TBAB)
Cu-PEI@Fe3O4 MNPs (0.3) H2O (ADOGEN) 94
Cu-PEI@Fe3O4 MNPs (0.1) H2O (PEG300)
Cu-PEI@Fe3O4 MNPs (0.3) 1,4-Dioxane
Cu-PEI@Fe3O4 MNPs (0.3) CH3CN
Cu-PEI@Fe3O4 MNPs (0.3) DMF
97
70
80
95
35
88
55
50
9
1
1
1
1
1 [
1 [
0
1
2
3
No. Cat.
H2O (PEG300)
H2O (PEG300)
H2O (PEG300)
H2O (PEG300)
Cu(OAc)2 (3)
Fe3O4 MNPs
Fe3O4@SiO2 MNPs
29/9
g]
g]
4
-
5
-
[
a] Reaction conditions: sodium azide (1 mmol), benzyl bromide (1 mmol), and phenyl acetylene (1 mmol), rt, 3 h. [b]
TON is mole of the formed 1,4-disubstituted 1,2,3-triazole per mole of the catalyst. [c] TOF is TON per time. [d] The
◦
◦
reaction was performed at 70 C. [e] The reaction was performed at 100 C. [f] PEG and the other surfactants were
added in 20% w/w H O. [g] The reaction was carried out in the presence of 5 mg of catalyst.
2
After full characterization of the prepared catalyst, three-component Huisgen 1,3-dipolar cycloaddition
between sodium azide, benzyl bromide, and phenyl acetylene was evaluated as a model reaction in water at 25
◦
C and in the presence of the catalyst. Only a trace amount of the corresponding triazole 4 was produced at
◦
ambient temperature (Table 1, entry 1). Raising the reaction temperature to 70 C increased the yield to 70%
(
Table 1, entry 2). Further increasing the reaction temperature not only did not lead to any improvement in
catalytic activity but also some by-products were formed (Table 1, entry 3). Interestingly, when the reaction
300

HASANPOUR et al./Turk J Chem
carried out in the presence of water/PEG300 , the yield of the product 4 was further increased (Table 1, entry
4
). On the other hand, other additives based on tetra alkyl ammonium bromides such as tetra-butyl ammonium
bromide (TBAB) and cetyltrimethylammonium bromide (CTMBr) gave poor results and the expected triazole
was obtained in 30% yield in both cases (Table 1, entries 5 and 6). It is worth mentioning that the three-
4
component coupling reaction was conducted in water/ADOGEN with high yield of 94% (Table 1, entry 7).
Importantly, the catalyst loading could be lowered from 5 to 0.1 mol% Cu without any significant decrease
in product yield (Table 1, entry 8). Among the different solvents tested, DMF gave good results but the
water/PEG300 system was chosen as medium for environmental concerns (Table 1, entries 9–11). It should
be pointed out that in the absence of any catalyst the reaction proceeded to give product 4 with much lower
yield (35%) and the regioselectivity of the reaction was lost (Table 1, entry 12). These results clearly confirmed
that copper is crucial for achieving high activity and selectivity. Our studies on optimization of the reaction
conditions revealed that Fe3 O4 or Fe3 O4 @SiO2 could also catalyze the reaction but the coupling product was
obtained in low yield and regioselectivity (Table 1, entries 14, 15). After optimization of the model reaction,
we next investigated the scope of the 3+2 cycloaddition (Table 2). Benzyl bromides/chlorides bearing both
electron-donating and electron-withdrawing groups with phenyl acetylene gave the corresponding alkynes in
good to excellent yields (Table 2, entries 1–15). These results showed that the nature of substitution did
not have a significant impact on the outcome of the reaction. It was found that cyclization of the dibenzyl
chloride with phenyl acetylene provided bistriazole in high yield (Table 2, entry 15). Encouraged by these
results, we then managed to employ aliphatic alkynes with various types of benzyl bromides/chlorides. The
corresponding three-component coupling product was obtained in high yield (Table 2, entries 16–20). However,
a longer reaction time (12 h) was required for the formation of triazoles bearing an aliphatic substituent. It
is worth mentioning that various bromoalkanes participated in the 3+2 cycloaddition, producing the expected
1,4-disubstituted triazoles with good yields (Table 2, entries 22 and 23). It should be noted that the nitrile
functional group is also well tolerated, which could be useful for further functionalization (Table 2, entries 21).
Moreover, this protocol worked well in the case of more complex structures containing coumarin, isatin,
and steroid groups and provided the corresponding 1,4-triazoles in good yield (Table 2, entry 23–28). It is also
interesting to note that in all tested examples in this protocol, only 1,4-disubstituted triazoles were obtained.
The catalytic activity of the catalyst for the reaction of benzyl halide, phenylacetylene, and sodium azide
was compared with that of other previously reported heterogeneous catalysts as depicted in Table 3. Recently,
a variety of copper catalysts were prepared via addition of prepared copper particles to different supports. As
indicated in Table 3, the Cu-PEI@Fe3 O4 MNPs showed proper activity with low copper loading in comparison
with the other catalysts (Table 3, entries 5 vs. 1–4). In addition, some of them suffer from disadvantages such
as the necessity to apply azide derivatives instead of in situ formation of counterparts and the inability of the
catalyst to catalyze the reaction of aliphatic or complex substrate as well as large-scale reactions.
Interestingly, when the above-mentioned reaction was conducted in the presence of a large amount of the
reactants (50 mmol), the corresponding coupling product was obtained in 90% isolated yield. Since recycling
and lifetime of heterogeneous catalysts are two important issues for practical applications, the recycling of
Cu-PEI@Fe3 O4 MNPs was also investigated in the three-component coupling of benzyl bromide, NaN3 , and
phenyl acetylene as a model reaction. After completion of the first run, the catalyst was separated by external
magnet (Figure 5d) and then washed with ethanol and the recycled catalyst was successfully applied in five
successive reaction runs without significant decrease in its catalytic activity (about 90% conversion after the
3
01

HASANPOUR et al./Turk J Chem
Table 2. Synthesis of different 1,4-disubstituted 1,2,3-triazoles catalyzed in water.
Y!eld
Ref
Entry Organ!c hal!de
Alkyne
Tr!azole
t(h)
3
M.P
(
%)
1
6-21
1
Ph
96
90
112 115 °C
F
4
3
2
Cl
Ph
7
108-111 °C
F
Cl
4
3
3
4
5
6
Ph
Ph
Ph
Ph
7
88
93
90
93
88-92 °C
Cl
4
3
7
112-115 °C
F
Br
Br
1
6-21
3.5
3.5
88-92 °C
Br
°
136-139 C
16-21
Br
O N
2
Br
1
1
6-21
6-21
7
8
Ph
Ph
3.5
7
83
88
148-152 °C
112-116 °C
H3CO
Cl
CH3
1
6-21
9
1
1
1
Cl
Ph
Ph
Ph
Ph
7
7
7
7
92
91
90
93
102-105 °C
H3C
Cl
1
6-21
0
1
2
96-100 °C
Cl
Cl
1
6-21
Cl
Cl
113-117 °C
137-141°C
Cl
Cl
1
6-21
302

HASANPOUR et al./Turk J Chem
Table 2. Continued.
1
6-21
1
1
3
4
Ph
7
7
88
90
150-154°C
Cl
4
1
3
Cl
Ph
Ph
159-162 °C
111-114 °C
F
Cl
Cl
6-21
1
1
5
6
7
88
80
4
4
4
4
12
70-72 °C
58-60 °C
Cl
1
7
Cl
12
80
Br
4
4
4
4
1
1
8
9
12
12
12
80
80
80
76-78 °C
62-64 °C
Br
4
4
2
2
9
1
99-100 °C
85-87 °C
Br
Br
CN
Ph
3
3
70
92
4
5,46
2
2
2
3
Ph
57-58 °C
O
O
4
7
3
90
150-152 °C
O
3
03

HASANPOUR et al./Turk J Chem
Table 2. Continued.
O
F
O
2
4
3
74
130-132 °C
O
Cl
O
O
4
8
2
5
N
3
94
112-114 °C
Br
2
2
2
6
7
8
3
95
207-210 °C
101-104 °C
108-112 °C
Br
HO
Br
H
H
H
H
24
70
Br
O
HO
Br
H
H
H
H
24
70
Br
O
304

HASANPOUR et al./Turk J Chem
Table 3. The comparison between the prepared catalyst and previously reported heterogeneous catalytic systems.
◦
Entry Catalyzer
Catalyst amount Temp. ( C) Time
Yield (%) Ref.
a
49
1
2
3
4
Cu(0)Fe3O4@SiO2/NH2cel
0.05 g
60
50
5 h
2 h
97
96
b
50
MNP@PDMA -Cu
MNPs-CuBr
Cu2O/Casein@Fe3O4NPs
0.3 mol %
1.46 mol%
0.43 mol%,
0.1 mol%
5
5
1
2
80/MW
55
70
20 min 96
2 h
3 h
100
96
5
Cu-PEI@Fe3O4 MNPs
a
b
cel: cellulose PDMA: poly(2-dimethylaminoethyl acrylamide)
fifth run). The rapid and efficient recycling method prevents the loss of the catalyst in each run and makes it
a promising option for practical applications.
Furthermore, the leaching test after each catalytic run in the model reaction revealed that the amount
of the copper leached from the heterogeneous catalyst was negligible as determined by ICP-AES. This result
confirmed that there are no contributions from homogeneous catalysis of active species leached into the reaction
solution (see Table S1).
3. Conclusion
We developed a recoverable Cu(II)-based heterogeneous catalytic system for one-pot Huisgen 1,3-dipolar cy-
cloaddition in water. The catalyst was prepared by covalent attachment of PEI on the surface of Fe3 O4 MNPs
and subsequent incorporation of Cu(II) on the support. Our studies revealed that several types of alkynes
and alkyl bromides/chlorides could participate in the reaction in the presence of a low loading amount of the
catalyst under base-free and reducing agent conditions to give 1,4-disubstituted 1,2,3-triazoles in good to excel-
lent yields. Furthermore, this novel catalytic system can be rapidly isolated from the reaction mixture by an
external magnet and successfully reused five times in reactions. Besides its efficient and easy recyclability, the
use of the catalyst in large-scale reactions makes this system a valuable candidate for practical applications.
4
4
. Experimental
.1. Synthesis of the catalyst
Fe3 O4 MNPs were synthesized using co-precipitation.42 For PEI grafting onto the Fe3 O4 MNPs (PEI@Fe3 O4
MNPs), (3-glycidyloxypropyl)-trimethoxysilane (GOPTMS, 1 mmol) was added to a stirred solution of 150 mL
◦
of dry toluene containing 3 mmol of PEI. The resultant mixture was allowed to react at 80 C for 24 h. To this
◦
solution, 2.5 g of Fe3 O4 MNPs and 25 mL of ethanol were added, and the solution was stirred at 80 C for 24
h. PEI@ Fe3 O4 MNPs were magnetically isolated by an external magnet and repeatedly washed with methanol
and ethanol to obtain the product. Subsequently, it was soxhleted with ethanol for 24 h to remove unreacted
◦
substrates and by-products, and dried at 40 C. For incorporation of copper into the nanocomposite matrix,
300 mg of PEI@Fe3 O4 MNPs was charged into a round-bottomed flask containing an acetonitrile solution (25
mL) of copper acetate (0.6 mmol) and stirred under nitrogen atmosphere for 48 h. The resultant catalyst was
isolated by an external magnet and washed with acetonitrile followed by acetone. The residue was dried in air
for 24 h. The copper content in PEI@Fe3 O4 MNPs was analyzed by the ICP-AES technique (0.22 mmol g 1).
−
3
05

HASANPOUR et al./Turk J Chem
4.2. General process for the synthesis of different 1,4-disubstituted 1,2,3-triazoles
A mixture of sodium azide (1 mmol), benzyl or alkyl halide (1 mmol), and corresponding acetylene (1 mmol
of phenyl acetylene or 2 mmol of alkyl acetylene) and catalyst (5 mg of catalyst equal to 0.1 mol % of copper)
◦
was taken in a round bottomed flask containing 1 mL of H2 O and 0.2 mL of PEG300 and heated at 70 C for
3
h under vigorous stirring. After completion of the reaction (monitored by TLC), the catalyst was removed
by external magnet, washed with EtOH, and dried under vacuum. The collected solvent was concentrated
under vacuum and the product was allowed to crystalize, which did not require any further purification.
The obtained products were confirmed and completely characterized by physical and spectral data (see the
Supporting Information).
Acknowledgments
This work was supported by grants from the research council of Tehran University of Medical Sciences and from
the Iran National Science Foundation (INSF).
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3
07

SUPPORTING INFORMATION
Efficient multicomponent synthesis of 1,2,3-triazoles catalyzed by Cu(II) supported on
PEI@Fe
3 4
O MNPs in a water/PEG300 system
Contents
1
. General methods and materials
All commercially available reagents were used without further purification. All reagents were
purchased from Merck and Acros Organics. Column chromatography was carried out on silica
1
gel. TLC was conducted on silica gel 250 micron, F254 plates. H NMR spectra were recorded at
3
room temperature on 500 MHz spectrometers, using CDCl as the NMR solvent. Chemical shifts
1
3
are reported in ppm with TMS as an internal standard (TMS: δ 0.0 ppm). C NMR spectra are
referenced from the solvent central peak (77.23 ppm). Chemical shifts are given in ppm.
2
. Experimental procedures
Synthesis of different 1,4-disubstituted 1,2,3-triazoles with Cu-PEI@Fe
catalyst in water
3 4
O MNPs as
A mixture of sodium azide (1 mmol), benzyl or alkyl halide (1 mmol), and corresponding
acetylene (1 mmol of phenyl acetylene and 2 mmol of alkyl acetylene) and catalyst (5 mg of
catalyst equal to 0.1 mol% of copper) was taken in a round bottomed flask containing 1 mL of
2
H O and 0.2 mmol PEG 300 and heated at 70 °C for 3 h under vigorous stirring. After
completion of the reaction (monitored by TLC), the catalyst was removed by external magnet.
The catalyst was washed several times with ether followed by water and dried under vacuum.
The resulting reaction mixture was extracted with EtOAc. The collected organic phases were
1

dried with Na
2 4
SO and the solvent was concentrated under vacuum and the product was allowed
to be crystalized with the aid of slow evaporation, which did not require any further purification.
3
. Leaching test
The model reaction was used to study the amount of leached copper from the catalyst. After each
run, the catalyst was removed by permanent magnet and the solution was concentrated and
checked for determination of the leached copper ion by ICP analysis and the isolated catalyst
was also applied for the next runs. The results are presented in Table S1.
Table S1. Amount of leached copper in solution after each catalytic run.
Entry
Run 1
Run 2
Run 3
Run 4
Run 5
Cu (ppm)
0.010
Yield of the reaction after each run
94
90
93
85
90
0.088
0.088
0.113
0.070
2

4
1
. Characterization data
1
-benzyl-4-phenyl-1H-1,2,3-triazole (4). Yield: 96%; white solid; mp: 112–115 °C; H NMR
) δ: 5.58 (s, 2H, CH ), 7.27–7.41 (m, 8H, CH Arom), 7.69 (s, 1H, CH triazole),
.81 (d, 2H, J = 7.2); C NMR (500 MHz, CDCl ) δ 53.8, 119.1, 125.2, 127.5, 127.7, 128.3,
28.7, 129, 130.2, 134.2, 147.8. IR (KBr): v = 3141 (=C–H), 1494, 1469, 1449 (aromatic cycle),
(500 MHz, CDCl
3
2
1
3
7
1
1
7
3
359, 1224 (C–N). Anal. Calcd for C15
6.61; H, 5.43; N, 17.93.
13 3
H N (235.28): C, 76.57; H, 5.57; N, 17.86. Found: C,
1
-(2-fluorobenzyl)-4-phenyl-1H-1,2,3-triazole (5). Yield: 90%; white solid; mp: 108–111 °C;
1
3 2
H NMR (500 MHz, CDCl ): 5.65 (s, 2H, CH ), 7.13–7.43 (m, 7H, CH Arom), 7.78 (s, 1H, CH
triazole), 7.82 (d, 2H, J = 7.3, CH). IR (KBr): v = 3121 (=C–H), 1494, 1462, 1650 (aromatic
cycle), 1356, 1230 (C–N), 1610 (C=C). Anal. Calcd for C15
N, 16.59. Found: C, 71.21; H, 4.73; N, 17.03.
H
12FN
3
(253.27): C, 71.13; H, 4.78;
1
1
-(3-fluorobenzyl)-4-phenyl-1H-1,2,3-triazole (6). Yield: 88%; white solid; mp: 88–92 °C; H
NMR (500 MHz, CDCl
CH Arom), 7.74 (s, 1H, CH triazole), 7.81 (d, 2H, J = 6.6, CH). IR (KBr): v = 3108 (=C–H),
591, 1483, 1453 (aromatic cycle), 1342, 1248 (C–N), 1600 (C=C). Anal. Calcd for C15
253.27): C, 71.13; H, 4.78; N, 16.59. Found: C, 71.04; H, 4.93; N, 17.12.
3 2
): 5.57 (s, 2H, CH ), 7.01–7.09 (m, 3H, CH Arom), 7.33–7.41 (m, 4H,
1
H12FN
3
(
1
-(4-fluorobenzyl)-4-phenyl-1H-1,2,3-triazole (7). Yield: 93%; pale yellow solid; mp: 112–115
1
°
C; H NMR (500 MHz, CDCl
3
): 5.56 (s, 2H, CH
2
), 7.09–7.42 (m, 7H, CH Arom), 7.69 (s, 1H,
): 53.1, 115.6, 115.7, 118.8,
25.2, 125.8, 127.7, 128.3, 129.4, 129.4, 129.8, 129.9, 163.3. IR (KBr): v = 3124 (=C–H), 1605,
1
3
CH triazole), 7.81 (2H, d, J = 7.0, CH). C NMR (500 MHz, CDCl
3
1
3

1
513, 1462, 1439 (aromatic cycle), 1351, 1227 (C–N), 1650 (C=C). Anal. Calcd for C15
H12FN
3
(253.27): C, 71.13; H, 4.78; N, 16.59. Found: C, 71.25; H, 4.96; N, 16.45.
1
-(3-bromobenzyl)-4-phenyl-1H-1,2,3-triazole (8). Yield: 90%; pale yellow solid; mp: 88–92
1
°
C; H NMR (500 MHz, CDCl
3
): 5.55 (s, 2H, CH
2
), 7.24–7.51 (m, 7H, CH Arom), 7.70 (s, 1H,
CH triazole), 7.82 (d, 2H, J = 7.3, CH). IR (KBr): v = 3084 (=C–H), 1426 (aromatic cycle),
1
5
1
1
7
345, 1221 (C–N).; Anal. Calcd for C15
7.28; H, 3.96; N, 13.45.
3
H12BrN (314.18): C, 57.34; H, 3.85; N, 13.37. Found: C,
-(4-bromobenzyl)-4-phenyl-1H-1,2,3-triazole (9). Yield: 93%; pale yellow solid; mp: 136–
1
39 °C; H NMR (500 MHz, CDCl
3
): 5.55 (s, 2H, CH
2
), 7.21 (d, 2H, J = 8.2), 7.35 (t, 1H, J =
.4), 7.42 (t, 2H, J = 7.4), 7.53 (d, 2H, J = 8.5), 7.70 (s, 1H, CH triazole), 7.82 (d, 2H, J = 7.9).
IR (KBr): v = 3100 (=C–H), 1462 (aromatic cycle), 1377, 1224 (C–N). Anal. Calcd for
(314.18): C, 57.34; H, 3.85; N, 13.37. Found: C, 57.28; H, 3.76; N, 13.45.
15 3
C H12BrN
1
-(3-nitrobenzyl)-4-phenyl-1H-1,2,3-triazole (10). Yield: 83%; pale yellow solid; mp: 148–152
1
°
C; H NMR (500 MHz, CDCl
3
): 6.01 (s, 2H, CH
2
), 7.10–7.63 (m, 6H), 7.86 (d, 2H, J = 6.5),
7
1
.95 (s, 1H, CH triazole), 8.21 (d, 1H, J = 6.8). IR (KBr): v = 3088 (=C–H), 1608 (C=C), 1524,
330 (NO ), 1462, 1406 (aromatic cycle), 1304, 1204 (C–N). Anal. Calcd for C15
2
12 4 2
H N O
(280.28): C, 64.28; H, 4.32; N, 19.99. Found: C, 64.39; H, 4.16; N, 19.45.
1
-(3-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole (11). Yield: 88%; yellow solid; mp: 112–116
1
°
C; H NMR (500 MHz, CDCl
3
): 3.80 (s, 3H, CH
3
), 5.57 (s, 2H, CH
2
), 6.80 (s, 1H, CH), 6.91 (d,
2
7
H, J = 7.8), 7.30–7.34 (m, 2H), 7.41 (t, 2H, J = 7.4), 7.70 (s, 1H, CH triazole), 7.81 (d, 2H, J =
.6). IR (KBr): v = 3010 (=C–H), 1485, 1434 (aromatic cycle), 1263 (C–N), 1157 (C–O). Anal.
15 3
Calcd for C16H N O (265.31): C, 72.43; H, 5.70; N, 15.84. Found: C, 72.36; H, 5.93; N, 15.95.
4

1
-(2-methylbenzyl)-4-phenyl-1H-1,2,3-triazole (12). Yield: 91%; yellow solid; mp: 102–105
1
°
C; H NMR (500 MHz, CDCl
3
): 2.30 (s, 3H, CH
3
), 5.59 (s, 2H, CH
2
), 7.2–7.4 (m, 8H, CH
): 18.5, 51.9,
18.8, 125.1, 126.2, 127.6, 128.3, 128.7, 128.9, 130.1, 130.6, 132.1, 136.5, 147.5. IR (KBr): v =
143 (=C–H), 1603 (C=C), 1441 (aromatic cycle), 1346 (C–N). Anal. Calcd for C16
1
3
Arom), 7.56 (s, 1H, CH triazole), 7.80 (d, 2H, J = 7.3). C NMR (500 MHz, CDCl
3
1
3
15 3
H N
(249.31): C, 77.08; H, 6.06; N, 16.85. Found: C, 77.27; H, 5.95; N, 16.92.
1
1
-(3-methylbenzyl)-4-phenyl-1H-1,2,3-triazole (13). Yield: 92%; pale yellow solid; mp: 96–
1
00 °C; H NMR (500 MHz, CDCl
3
): 2.35 (s, 3H, CH
3
), 5.53 (s, 2H, CH
2
), 7.13–7.41 (m, 7H,
CH Arom), 7.71 (s, 1H, CH triazole), 7.82 (d, 2H, J = 6.2). IR (KBr): v = 3087 (=C–H), 1614
C=C), 1460, 1435 (aromatic cycle), 1343, 1216 (C–N). Anal. Calcd for C16 (249.31): C,
(
15 3
H N
7
7.08; H, 6.06; N, 16.85. Found: C, 77.30; H, 6.15; N, 16.98.
1
1
7
-(2,3-dichlorobenzyl)-4-phenyl-1H-1,2,3-triazole (14). Yield: 90%; yellow solid; mp: 113–
1
17 °C; H NMR (500 MHz, CDCl
3
): 5.75 (s, 2H, CH
2
), 7.00 (d, 1H, J = 7.8), 7.20 (t, 1H, J =
.9), 7.32 (t, 1H, J = 7.8), 7.43 (t, 2H, J = 7.8), 7.5 (d, 1H, J = 7.8), 7.8 (s, 1H, CH triazole), 7.83
(
d, 2H, J = 7.7). IR (KBr): v = 3113 (=C–H), 1458, 1421 (aromatic cycle), 1357, 1225 (C–N).
Anal. Calcd for C15 (304.17): C, 59.23; H, 3.65; N, 13.81. Found: C, 59.31; H, 3.45; N,
11 l2 3
H C N
1
3.66.
1
-(3,4-dichlorobenzyl)-4-phenyl-1H-1,2,3-triazole (15). Yield: 93%; yellow solid; mp: 137–
1
1
41 °C; H NMR (500 MHz, CDCl
3
): 55.50 (s, 2H, CH
2
), 7.26–7.47 (m, 7H), 7.72–7.47 (s, 1H,
CH triazole), 7.81–7.83 (d, 2H, J = 7.8). IR (KBr): v = 3088 (=C–H), 1485 (aromatic cycle),
1
5
214 (C–N). Anal. Calcd for C15
9.02; H, 3.51; N, 13.93.
11 l2 3
H C N (304.17): C, 59.23; H, 3.65; N, 13.81. Found: C,
5

1
1
7
-(2,6-dichlorobenzyl)-4-phenyl-1H-1,2,3-triazole (16). Yield: 88%; yellow solid; mp: 150–
1
54 °C; H NMR (500 MHz, CDCl
3
): 5.92 (s, 2H, CH
2
), 7.30–7.34 (m, 2H), 7.39–7.44 (m, 3H),
.72 (s, 1H, CH triazole), 7.81 (d, 2H, J = 7.7). IR (KBr): v = 3128 (=C–H), 1481, 1480
(304.17): C, 59.23; H, 3.65; N,
(aromatic cycle), 1216 (C–N). Anal. Calcd for C15
H
11Cl
2
N
3
1
3.81. Found: C, 59.12; H, 3.79; N, 13.95.
1
1
5
1
3
-(2-chloro-6-fluorobenzyl)-4-phenyl-1H-1,2,3-triazole (17). Yield: 90%; yellow solid; mp:
1
59–162 °C; H NMR (500 MHz, CDCl
3
): 5.80 (s, 2H, CH
2
), 7.13 (t, 1H, J = 8.8), 7.27–7.43 (m,
H), 7.80 (s, 1H, CH triazole), 7.81 (d, 2H, J = 7.3). IR (KBr): v = 3128 (=C–H), 1605 (C=C),
459, 1433 (aromatic cycle), 1245 (C–N). Anal. Calcd for C15
.85; N, 14.60. Found: C, 62.77; H, 3.75; N, 11.90.
3
H11ClFN (304.17): C, 62.62; H,
1
,3-bis((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)benzene (18). Yield: 88%; yellow solid; mp:
1
1
11–114 °C; H NMR (500 MHz, CDCl
3
): 5.58 (s, 4H, CH
2
), 7.27–7.41 (m, 10H), 7.70 (s, 2H,
+
CH triazole), 7.80 (d, 4H, J = 7.3). MS (EI) (70 eV): m/z (%) 392 (9) (M ), 364 (20), 335 (3),
2
90 (5), 248 (23), 219 (21), 178 (6), 146 (3), 116 (100), 89 (34), 63 (12). Anal. Calcd for
(392.46): C, 73.45; H, 5.14; N, 21.41. Found: C, 73.22; H, 5.09; N, 21.54.
24 20 6
C H N
1
1
-benzyl-4-hexyl-1H-1,2,3-triazole (19). Yield: 86%; yellow solid; mp: 70–72 °C; H NMR
300 MHz, CDCl ): 0.80 (t, 3H, J = 7.0, CH ), 1.17–1.30 (m, 6H), 1.43–1.56 (m, 2H), 2.59–2.64
t, 2H, J = 7.5), 5.39 (s, 2H, CH ), 7.00–7.52 (6H, m, CH). C NMR (300 MHz, CDCl
4.1, 21.1, 22.4, 25.5, 28.8, 29.2, 31.4, 53.8, 120.7, 127.8, 128.1, 128.4, 128.9, 134.9. IR (KBr):
v = 3113 (=C–H), 2924 (–C–H), 1459 (aromatic cycle), 1323, 1212 (C–N). Anal. Calcd for
(243.35): C, 74.03; H, 8.70; N, 17.27. Found: C, 74.16; H, 8.51; N, 17.38.
(
(
3
3
1
3
2
3
) = 13.9,
1
15 21 3
C H N
6

1
-(2-chlorobenzyl)-4-hexyl-1H-1,2,3-triazole (20). Yield: 78%; pale yellow solid; mp: 58– 60
1
°
C; H NMR (300 MHz, CDCl
3
): 0.78 (t, 3H, J = 6.8, CH
), 2.59–2.64 (t, 2H, J = 7.3), 5.52 (s, 2H, CH ), 7.00 (d, 2H, J = 6.7, CH), 7.10–7.31
) = 13.9, 22.4, 25.6, 29.3, 31.4, 51.2, 120.9, 127.4,
29.7, 129.9, 132.8, 133.1, 148.6. IR (KBr): v = 3113 (=C–H), 2923 (–C–H), 1469, 1444
aromatic cycle), 1330, 1215 (C–N). Anal. Calcd for C15 (277.79): C, 64.85; H, 7.26; N,
3 2
), 1.10–1.30 (m, 6H, CH ), 1.55–1.60
(
m, 2H, CH
2
2
1
3
(
m, 5H, CH). C NMR (300 MHz, CDCl
3
1
(
H20ClN
3
1
7.26. Found: C, 64.64; H, 7.31; N, 17.34.
1
-(4-bromobenzyl)-4-hexyl-1H-1,2,3-triazole (21). Yield: 76%; yellow solid; mp: 76–78 °C;
1
H NMR (300 MHz, CDCl
3
): 0.77 (t, 3H, J = 7.0, CH
), 7.03–7.05 (d, 2H, J = 8.2, CH), 7.21 (s, 1H, CH triazole), 7.37–7.39 (d,
H, J = 8.2, CH). C NMR (300 MHz, CDCl ) = 14.1, 22.4, 25.6, 28.8, 29.2, 31.4, 53.1, 120.6,
22.5, 12.4, 132.1, 134.1, 148.9. IR (KBr): v = 3110 (=C–H), 2930 (–C–H), 1655 (C=C), 1463
(322.24): C, 55.91; H, 6.26; N,
3 2
), 1.15–1.28 (m, 6H, CH ), 1.51–1.58 (m,
2
2
1
H), 5.36 (s, 2H, CH
2
1
3
3
(
aromatic cycle), 1323, 1212 (C–N). Anal. Calcd for C15
H
20BrN
3
1
3.04. Found: C, 55.74; H, 6.31; N, 13.00.
4
-hexyl-1-(4-methylbenzyl)-1H-1,2,3-triazole) (22). Yield: 83%; yellow solid; mp: 62–64 °C;
1
H NMR (300 MHz, CDCl
H), 2.30 (s, 3H, CH ), 2.63 (t, 2H, J = 7.7), 5.40 (s, 2H, CH
CH triazole). C NMR (300 MHz, CDCl ) = 14.1, 21.1, 22.5, 25.6, 25.8, 29.3, 31.5, 35.6, 120.4,
26.9, 127.9, 128.9, 129.6, 132.0, 138.3, 148.7. IR (KBr): v = 3116 (=C–H), 2930 (–C–H), 1466
aromatic cycle), 1215 (C–N). Anal. Calcd for C16 (257.37): C, 74.67; H, 9.01; N, 16.33.
Found: C, 74.58; H, 9.22; N, 16.18.
3
): 0.81 (t, 3H, J = 6.8, CH
3
CH
2
), 1.24–134 (m, 6H), 1.54–1.64 (m,
2
3
2
), 7.12 (d, 4H, J = 7), 7.16 (s, 1H,
1
3
3
1
(
23 3
H N
7

1
4
-hexyl-1-(2-nitrobenzyl)-1H-1,2,3-triazole (23). Yield: 86%; yellow solid; mp: 99–100 °C; H
NMR (300 MHz, CDCl ): 0.80 (t, 3H, J = 6.2, CH ), 1.23–1.32 (m, 6H, CH CH ), 1.66–1.56 (m,
H), 1.97 (t, 2H, J = 7.4), 5.85 (s, 2H, CH ), 6.90 (d, 1H, J = 7.6), 7.48 (s, 1H, CH triazole),
3
3
2
2
2
7
2
2
1
3
.56–7.46 (m, 2H), 8.00 (d, 2H, J = 7.9). C NMR (300 MHz, CDCl
8.6, 29.2, 48.2, 121.7, 125.4, 128.2, 129.3, 129.8, 129.8, 134.2, 147.1. IR (KBr): v = 3116 (=C–
), 1466 (aromatic cycle), 1348 (C–N). Anal. Calcd for
(288.34): C, 62.48; H, 6.99; N, 19.43. Found: C, 62.36; H, 6.72; N, 19.48.
3
) = 13.9, 22.8, 25.6, 27.7,
H), 2927 (–C–H), 1608, 1524 (NO
2
15 20 4 2
C H N O
4
-(4-phenyl-1H-1,2,3-triazol-1-yl)butanenitrile (24). Yield: 86%; yellow solid; mp: 85–87 °C;
1
H NMR (300 MHz, CDCl
3
): 2.24–2.37 (m, 4H), 4.45 (t, 2H, J = 8.1), 7.73–7.82 (m, 6H, CH
) = 14.5, 25.8, 48.3, 118.4, 120.3, 125.6, 128.3, 128.9, 130.2,
47.8. IR (KBr): v = 3124 (=C–H), 2924 (–C–H), 2247 (cyanide), 1458, 1448 (aromatic cycle),
1
3
Arom). C NMR (300 MHz, CDCl
3
1
1
6
354, 1222 (C–N). Anal. Calcd for C12
7.96; H, 5.52; N, 26.49.
H
22
N
4
(288.34): C, 67.90; H, 5.70; N, 26.40. Found: C,
1
4
-phenyl-1-propyl-1H-1,2,3-triazole (25). Yield: 92%; yellow solid; mp: 57–58 °C; H NMR
(
300 MHz, CDCl
m, 6H, CH Arom). C NMR (300 MHz, CDCl
30.6, 147.6. IR (KBr): v = 3131 (=C–H), 2923 (–C–H), 1463 (aromatic cycle), 1330, 1217 (C–
N). Anal. Calcd for C11 (187.24): C, 70.56; H, 7.00; N, 22.44. Found: C, 70.69; H, 7.08; N,
3
): 1.00 (t, 3H, J = 7.3, CH
3
CH
2
), 2.01 (m, 2H), 4.37 (t, 2H, J = 7.0), 7.2–7.83
1
3
(
3
) = 11.1, 23.7, 51.9, 119.4, 125.6, 128.1, 128.8,
1
13 3
H N
2
2.29.
7
-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (26). Yield: 94%; yellow
1
solid; mp: 150–152 °C; H NMR (500 MHz, CDCl
3
): 5.52 (s, 2H, OCH
2
), 5.56 (s, 2H, CH
2
),
6
.26 (d, 1H, J = 9.4), 6.91–6.93 (m, 2H), 7.27–7.39 (m, 5H), 7.60 (s, 1H, CH triazole), 7.63 (m,
8

2
H). IR (KBr): v = 3066 (=C–H), 1711 (C=O), 1491, 1402 (aromatic cycle), 1346, 1275 (C–N).
Anal. Calcd for C19 (333.34): C, 68.64; H, 4.54; N, 12.61. Found: C, 67.63; H, 4.69; N,
15 3 3
H N O
1
2.49.
7
-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (27). Yield: 95%;
1
yellow solid; mp: 130–132 °C; H NMR (500 MHz, CDCl
3
): 5.24 (s, 2H, OCH
2
), 5.55 (s, 2H,
CH
2
), 6.28 (d, 1H, J = 8.5), 6.90 (m, 2H), 7.01–7.39 (m, 4H), 7.64 (m, 2H), 7.76 (d, 1H, J = 8.5).
1
3
3
C NMR (300 MHz, CDCl ) = 53.8, 62.2, 102.1, 112.7, 113.0, 113.5, 116.1, 116.2, 128.8,
1
1
30.0, 130.1, 143.2, 155.7, 160.9, 161.2, 161.9, 163.9. IR (KBr): v = 3102 (=C–H), 1705 (C=O),
614 (C=C), 1348, 1280 (C–N), 1128 (C–O). Anal. Calcd for C19 (351.33): C, 64.95;
H
3 3
11FN O
H, 4.02; N, 11.96. Found: C, 64.73; H, 4.09; N, 11.68.
1
-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)indoline-2,3-dione (28). Yield: 70%; orange solid;
1
mp: 112–114 °C; H NMR (500 MHz, CDCl
3
): 5.00 (s, 2H, CH
2
-C triazole), 5.50 (s, 2H, CH
2
-N
triazole), 7.12 (d, 2H, J = 7.0), 7.28–7.37 (m, 5H), 7.54–7.58 (m, 3H). Anal. Calcd for C18
(318.33): C, 67.91; H, 4.43; N, 17.60. Found: C, 67.99; H, 4.51; N, 17.52.
H
14
4 2
N O
1
-((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(piperidin-1-ylsulfonyl)indoline-2,3-
1
dione (29). Yield: 50%; orange solid; mp: 207–210 °C; H NMR (500 MHz, CDCl
3
): 0.89–1.66
1
3
(
m, 6H), 3.10 (m, 4H), 5.10 (s, 2H), 5.46 (s, 2H), 7.16–8.00 (m, 8H). C NMR (300 MHz,
CDCl ) = 23.4, 25.1, 29.6, 35.5, 46.9, 53.7, 111.9, 117.2, 123.0, 124.5, 129.9, 132.4, 132.9,
37.7, 141.6, 152.8, 157.4, 181.6. IR (KBr): v = 3128 (=C–H), 1750, 1612 (C=O), 1474, 1448
3
1
(
aromatic cycle), 1362 (S=O), 1333, 1277 (C–N), 1155 (C–O). Anal. Calcd for C23
544.42): C, 67.91; H, 4.43; N, 17.60. Found: C, 67.99; H, 4.51; N, 17.52.
H
22
N
5
O
4
S
(
9

(8R,9S,10R,13S,14S,17S)-17-(1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)-17-hydroxy-13-
methyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-
1
one (30). Yield: 70%; orange solid; mp: 101–104 °C; H NMR (500 MHz, CDCl
3
): 0.51–2.97
1
3
(
m, 23H), 5.70 (s, 2H, CH
CDCl ) = 26.2, 29.4, 30.5, 32.4, 35.3, 36.2, 37.6, 40.8, 42.3, 46.9, 48.0, 48.7, 53.2, 82.0, 121.2,
22.6, 124.2, 129.4, 132.0, 133.5, 154.1, 167.0, 200.0. IR (KBr): v = 3411 (O–H), 3063 (=C–H),
661 (C=O), 1449 (aromatic cycle), 1359, 1260 (C–N), 1132 (C–O). Anal. Calcd for C27
(466.01): C, 69.59; H, 6.92; N, 9.02. Found: C, 69.72; H, 6.99; N, 9.15.
2
), 5.81 (s, 1H, OH), 7.16–7.145 (m, 5H). C NMR (300 MHz,
3
1
1
H
32
3 2
ClN O
(8R,9S,10R,13S,14S,17S)-17-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)-17-hydroxy-13-
methyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-
1
one (31). Yield: 70%; yellow solid; mp: 108–112 °C; H NMR (500 MHz, CDCl
3
): 0.48–2.47
(m, 23H), 5.45 (s, 2H, CH
2
), 5.46 (s, 1H, OH), 5.78 (s, 1H), 7.12 (d, 2H, J = 8.2), 7.30 (s, 1H,
1
3
CH triazole), 7.48 (d, 2H, J = 8.2). C NMR (300 MHz, CDCl
3
) = 26.5, 29.6, 30.7, 32.6, 35.4,
6.4, 37.8, 41.1, 42.5, 47.1, 48.2, 49.0, 51.5, 82.1, 121.4, 124.5, 127.5, 129.9, 130.2, 153.6,
66.6, 199.9. IR (KBr): v = 3444 (O–H), 3139 (=C–H), 1661 (C=O), 1488, 1452 (aromatic
(510.47): C, 63.53; H, 6.32; N,
3
1
cycle), 1261 (C–N), 1131 (C–O). Anal. Calcd for C27
.23 Found: C, 69.45; H, 6.29; N, 8.37.
3 2
H32 BrN O
8
1
0

1
13
5
. Copy of H NMR & C NMR spectra of the synthesized compounds:
1
1

1
2

1
3

1
4

1
5

1
6