Immobilized [Cu(cdsalMeen)] on silica gel: a highly efficient heterogeneous catalyst for ‘Click’ [3?+?2] Huisgen cycloaddition

Article abstract of DOI:10.1007/s13738-016-0999-3

Abstract: A facile and simple protocol for the ‘Click’ cycloaddition of organic azides with terminal alkynes catalyzed by immobilized [Cu(cdsalMeen)] on silica as a new and convenient heterogeneous catalyst is described. In this synthetic methodology, [Cu(cdsalMeen)]–SiO₂ catalyzes 1,3-dipolar Huisgen cycloaddition of different functionalized β-azido alcohols and alkynes in the presence of ascorbic acid and a solution of THF/H₂O (2:1, V/V) at room temperature. Good to excellent yields of β-hydroxytriazolylalkyl derivatives were afforded using [Cu(cdsalMeen)]–SiO₂. Immobilization of [Cu(cdsalMeen)] on silica was approved as a chemically and thermally stable catalyst that can be reused for many consecutive trials without a significant decline in its reactivity. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13738-016-0999-3

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0999-3
ORIGINAL PAPER
Immobilized [Cu(cdsalMeen)] on silica gel: a highly efficient
heterogeneous catalyst for ‘Click’ [3 + 2] Huisgen cycloaddition
Elham Zarenezhad1 · Mohammad Navid Soltani Rad2 · Somayeh Behrouz2 ·
Sheida Esmaielzadeh3 · Mojtaba Farjam1
Received: 9 July 2016 / Accepted: 28 October 2016
© Iranian Chemical Society 2016
Abstract A facile and simple protocol for the ‘Click’
cycloaddition of organic azides with terminal alkynes
catalyzed by immobilized [Cu(cdsalMeen)] on silica as a
new and convenient heterogeneous catalyst is described.
In this synthetic methodology, [Cu(cdsalMeen)]–SiO2
catalyzes 1,3-dipolar Huisgen cycloaddition of dif-
ferent functionalized β-azido alcohols and alkynes in
the presence of ascorbic acid and a solution of THF/
H2O (2:1, V/V) at room temperature. Good to excel-
lent yields of β-hydroxytriazolylalkyl derivatives were
afforded using [Cu(cdsalMeen)]–SiO2. Immobilization
of [Cu(cdsalMeen)] on silica was approved as a chemi-
cally and thermally stable catalyst that can be reused for
many consecutive trials without a significant decline in its
reactivity.
Graphical Abstract
R2
N
OH
N
N
[Cu(cdsalMeen)]-SiO2
OH
R1
N3
+
R2
R1
THF/H2O(2:1)/ r.t
Ascorbic acid
R1: alkyl, aryloxy, alkoxy
1a - 1m
R2:
CH2OH,ArOCH2,Ph, (Me)2COH,
Me
H2C
N
Cu(cdsalMeen):
N
N
O
Cu
S
MeS
Keywords Click’ cycloaddition · Heterogeneous
catalyst · β-azido alcohols · Terminal alkynes ·
β-hydroxytriazolylalkyl
Introduction
1,2,3-Triazoles are an attractive class of heterocyclic com-
pounds because of their wide range of applications includ-
ing use as agrochemicals, pharmaceutical agents, industrial
applications as well as in organometallic chemistry [1, 2].
Heterocyclic compounds containing 1,2,3-triazole struc-
ture are known as bioactive compounds, exhibiting a broad
spectrum of biological activities, such as antiviral [3], anti-
cancer [4], anti-HIV [5], antibiotic [6], antibacterial [7]
and antimicrobial [8]. The Huisgen 1,3-dipolar cycloaddi-
tion of azides and alkynes is one of the most widely used
method for the synthesis of 1,2,3-triazoles [9]. This type of
reaction gives poor regiospecificity which normally leads
to a mixture of 1,4- and 1,5-substituted triazoles [10, 11].
Separately, Meldal and Sharpless discovered a modification
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-016-0999-3) contains supplementary
material, which is available to authorized users.
* Elham Zarenezhad
El_Zarenezhad@yahoo.com
1
Non-communicable Diseases Research Center, School
of Medicine, Fasa University of Medical Sciences, Fasa, Iran
2
Medicinal Chemistry Research Laboratory, Department
(I)
of the Huisgen reaction, in which addition of Cu to the
of Chemistry, Shiraz University of Technology,
Shiraz 71555-313, Iran
reaction mixture produced in only 1, 4-substituted triazoles
(I)
3
[12, 13]. Various copper sources were applied as cata-
Department of Chemistry, Darab Branch, Islamic Azad
University, Darab, Iran
lyst such as CuOTf and CuI. Cu (I) can be in situ produced
1 3

J IRAN CHEM SOC
by using CuSO4·5H2O and sodium ascorbate as a reducing
agent [14]. Whereas, enriching the metal core with elec-
trons can accelerate the investigated reaction, a stable cop-
per (II) complex with an electron-donating ligand is a useful
surrogate for copper (I) systems [15].
easily visualized as structure (I). Various aryloxypropanol
amines have been synthesized so far, and many of them
are now clinically approved drugs that used as cardiovas-
cular agents [34]. Many approved drugs with cardiovas-
cular property including propranolol (II), alprenolol (III),
metoprolol (IV) and carazolol (V) having aryloxypropanol
amine framework (Fig. 1).
Since the considerable therapeutic activities of triazole
derivatives [35], we incorporated the triazole cores instead
of amine-derived moieties in compounds (I) to obtain
β-hydroxytriazoles (VI), (Fig. 1). Herein, we report a new
and reusable catalyst system based on Cu(II) on silica gel
and ascorbic acid as reducing agent. This heterogeneous
catalyst system exhibits a potent catalytic activity for regi-
oselective 1,3-dipolar Huisgen cycloaddition reaction to
access diverse 1,2,3-triazole cores.
Immobilization of organometallic complexes on inor-
ganic supports appears to be a good way to render them
practicable and to improve their stability, selectivity and
the control of their reactivity through the microenviron-
ment created by the support [16–22]. For these reasons, a
common progress in catalysis is the transformation of suc-
cessful homogeneous catalysts into recoverable catalytic
systems that can easily be separated from the reaction mix-
ture by simple filtration and reused multiple times without
the loss of the activity and selectivity characteristic of the
original catalyst. The development of complex supported
on silica gel has attracted attention in recent years because
industry seeks more environmentally friendly chemical
manufacturing processes. Silica gel as an inorganic support
has a high surface area (5–800 m2 kg−1) compared with
other inorganic supports, ranking these materials at the top
of the list of high surface area solids [23–25].
Experimental
General Remarks: All preliminary chemicals were pur-
chased from either Fluka or Merck. Solvents were puri-
fied by standard procedures, and stored over 3 Å molecular
sieves. The catalyst was prepared due to reported procedure
[36]. Reactions were followed by TLC using SILG/UV 254
silica gel plates. Column chromatography was performed
on silica gel 60 (0.063–0.200 mm, 70–230 mesh; ASTM).
IR spectra were obtained using a Shimadzu FT-IR-8300
spectrophotometer. 1H-, and 13C-NMR spectra were
obtained using a Brüker Avance-DPX-400 spectrometer
operating at 400/100 MHz also, using a Brüker Avance-
DPX-250 spectrometer operating at 250/62.5 MHz, respec-
tively (δ in ppm, J in Hz). GC/MS were performed on a
Shimadzu GC/MS-QP 1000-EX apparatus (m/z; rel. %).
Elemental analyses were performed on a Perkin–Elmer
240-B microanalyzer.
Silica-based supports have been widely utilized for pre-
paring heterogeneous Cu catalysts, which opens up new
opportunities for the environmentally benign synthesis
(I)
of clicked compounds. Wang’s group immobilized Cu
catalyst on primary amine-modified silica gel and utilized
this Cu(I) complex as the promoter for the three-compo-
nent reactions between alkyl halides, sodium azide and
terminal alkynes [26]. Li and coworkers also employed
N-heterocyclic carbene (NHC)-modified silica particles as
efficient and recyclable ligands for the Huisgen cycloaddi-
tion [27]. Shamim and Paul found that the silica modified
by a Schiff base–type ligand promoted the Cu-catalyzed,
three-component synthesis of 1,2,3-triazoles in water at
room temperature [28]. Several silica-supported chelating
absorbents containing multidentate nitrogenated ligands
were developed by Santoyo-Gonzalez et al., and their Cu
(I) complexes could be utilized for the click synthesis of the
triazole products [29]. Our group have also utilized copper-
doped silica cuprous sulfate (CDSCS) as a highly efficient
and new heterogeneous nano catalyst for Huisgen cycload-
dition, CDSCS catalyzes 1,3-dipolar Huisgen cycloaddition
of different functionalized β-azido alcohols and alkynes at
room temperature [30].
Procedure for immobilization of [Cu(cdsalMeen)]
on silica
To a solution of [Cu(cdsalMeen)] (0.4 g, 1 mmol) in anhy-
drous dichloromethane (50 mL), it was added a fresh and
active silica gel (0.6 g, 10 mmol) in 0.063–0.200 mm or
70–230 mesh size. The suspension solution was stirred for
48 h at room temperature. Afterward, the suspension solu-
tion was flash filtered (sintered glass) and the solid residue
(catalyst) was washed with anhydrous dichloromethane
(2 × 50 mL). The catalyst was then dried in a vacuum oven
at 60 °C for 4 h and stored in a refrigerator. Inductively cou-
pled plasma (ICP) analysis indicated that in each gram of
catalyst, there is 0.032 g of active Cu catalyst (0.05 mol-%).
In recent years, a great deal of drug research activity has
focused upon the development of selective adrenergic ago-
nists and antagonists, which widely were used to control
the hypertension [31–33]. These drugs belong to the group
of β-blocking agents known as aryloxy propranolamines.
The general features of all of these compounds can be
1 3

J IRAN CHEM SOC
Fig. 1 General structure of
famous classes of β-adrenergic
blocking agents (I), clinically
approved drugs: propranolol
(II), alprenolol (III), metoprolol
(IV), and carazolol (V) and their
1,2,3-triazolyl analogs (VI)
OH
G
O
N
(I)
Me
O
N
H
Me
Me
Me
OH
(II)
O
N
H
OH
(III)
Me
O
N
H
Me
MeO
Me
OH
O
N
H
Me
N
OH
(IV)
H
(V)
N
OH
N
N
R2
R1
(VI)
1
General procedure for catalytic test
(EtOAc/n-hexane, 3:1) 0.66; H NMR (400 MHz, DMSO-
d6) δ ppm: 3.15 (s, 1H, OH, exchangeable with D2O), 3.28
(s, 1H, OH, exchangeable with D2O), 3.34 (dd, J = 6,
11.6 Hz, 2H, N-CH2), 3.46 (dd, J = 3.2, 11.6 Hz, 2H,
OCH2), 3.83 (m, 1H, CHOH), 5.02 (s, 1H, CH2OH), 6.96
(m, 10H, aryl), 8.12 (s, 1H, C (5)-H, triazole). 13C NMR
(100 MHz, DMSO-d6) δ ppm: 52.8, 68.5, 70.4, 71.0, 114.3,
115.8, 128.2, 128.5, 129.1, 129.3, 129.4, 129.6, 136.9,
137.8, 157.6; IR (KBr) ν cm−1: 3610, 3550, 3080, 3045,
2930, 1620, 1550, 1423; MS [m/z (%)]: 352.14; Anal.
Calcd for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90; found:
C, 64.75; H, 5.73; N, 15.92.
To a round bottom flask (50 mL) was added a mixture of
alkyne (0.012 mol), catalyst (0.3 g), the appropriate β-azido
alcohol (0.01 mol), and ascorbic acid (0.18 g, 1 mmol)
in a mixture of THF/H2O (2:1 V/V, 20 mL). The reac-
tion mixture was stirred at room temperature until TLC
monitoring indicated no further progress in the conver-
sion. The catalyst was filtered off, washed with THF/H2O
(5 × 10 mL), and the filtrate was evaporated under vacuum
to remove the solvent. The remaining foam was dissolved
in CHCl3 (100 mL) and subsequently washed with water
(2 × 100 mL). The organic layer was dried (Na2SO4) and
evaporated. The crude product was purified by column
chromatography on silica gel and eluted with proper sol-
vents. Characterization data of all synthesized compounds
are described below.
9H‑Fluoren‑9‑one O‑(2‑hydroxy‑3‑(4‑(hydroxymethyl)‑
1H‑1,2,3‑triazol‑1‑yl)propyl) oxime (1b) Column chro-
matography on silica gel (EtOAc/n-hexane, 2:1) afforded
the product as a brown foam; yield: (92%); Rf (EtOAc/n-
hexane, 2:1) 0.55; 1H NMR (400 MHz, DMSO-d6) δ
ppm: 3.26 (s, 1H, OH, exchangeable with D2O), 3.66 (dd,
J = 5.6, 11.2 Hz, 2H, N-CH2), 3.74 (dd, J = 4, 11.6 Hz,
2H, OCH2), 3.88 (s, 1H, OH, exchangeable with D2O), 4.11
Benzophenone
O‑(2‑hydroxy‑3‑(4‑(hydroxymethyl)
‑1H‑1,2,3‑triazol‑1‑yl)propyl) oxime (1a) Column
chromatography on silica gel (EtOAc/n-hexane, 3:1)
afforded the product as a yellow foam; yield: (94%); Rf
1 3

J IRAN CHEM SOC
1
(m, 1H, CHOH), 4.81 (s, 2H, CH2OH), 7.19 (m, 8H, aryl),
8.25 (s, 1H, C(5)–H, triazole). NMR (100 MHz, DMSO-d6)
δ ppm: 53.1, 68.2, 69.2, 71.0, 119.2, 127.3, 128.0, 128.2,
128.4, 129.1, 129.3, 129.6, 133.1, 136.2, 140.9, 142.4,
143.3, 157.6.; IR (KBr) ν cm−1: 3610, 3550, 3080, 3045,
2930, 1620, 1550, 1423; MS [m/z (%)]: 350.14; Anal.
Calcd for C19H18N4O3: C, 65.13; H, 5.18; N, 15.99; found:
C, 65.11; H, 5.20; N, 15.98.
mp = 141-143 °C; Rf (EtOAc/n-hexane, 4:1) = 0.51; H
NMR (250 MHz, DMSO-d6) δ ppm: 3.64 (s, 3H, OCH3),
3.81 (m, 2H, NCH2CH), 4.17 (s, 1H, OH, exchangeable
with D2O), 4.33 (dd, J = 7.8, 13.8 Hz, 1H, ArOCHAHB),
4.50 (dd, J = 3.4, 13.8 Hz, 1H, ArOCHAHB), 4.83 (s, 2H,
NCH2C=C), 5.50 (m, 1H, CHOH), 6.81 (m, 4H, aryl), 7.80
(m, 4H, aryl), 8.03 (s, 1H, C(5)–H, triazole); 13C NMR
(62.5 MHz, DMSO-d6) δ ppm: 32.8, 52.7, 55.2, 67.8, 70.0,
114.5, 115.4, 123.1, 124.1, 131.5, 134.4, 142.0, 152.3,
153.4, 167.3; IR (KBr) ν cm−1: 3326, 3145, 2990, 2971,
1764, 1709, 1506, 1427; MS [m/z (%)]: 408; Anal. Calcd
for C21H20N4O5: C, 61.76; H, 4.94; N, 13.72; found: C,
61.70; H, 5.03; N, 13.76.
(Z)‑Acetophenone O‑(2‑hydroxy‑3‑(4‑(hydroxymethyl)‑
1H‑1,2,3‑triazol‑1‑yl)propyl) oxime (1c) Column chro-
matography on silica gel (EtOAc/n-hexane, 2:1) afforded
the product as a creamy foam; yield: (89%); Rf (EtOAc/n-
1
hexane, 2:1) 0.55; H NMR (400 MHz, DMSO-d6) δ ppm:
2.15 (s, 3H, CH3), 3.06 (s, 1H, OH, exchangeable with
D2O), 3.51 (dd, J = 5.6, 11.2 Hz, 2H, N-CH2), 3.59 (dd,
J = 4, 11.6 Hz, 2H, OCH2), 3.78 (s, 1H, OH, exchangeable
with D2O), 3.92 (m, 1H, CHOH), 4.98 (s, 2H, CH2OH),
7.55 (m, 5H, aryl), 7.92 (s, 1H, C(5)–H, triazole). 13C
NMR (100 MHz, DMSO-d6) δ ppm: 18.9, 53.5, 63.7, 69.5,
71.4, 127.9, 128.2, 129.1, 132.5, 136.3, 142.4, 158.2.; IR
(KBr) ν cm−1: 3610, 3550, 3080, 3045, 2930, 1620, 1550,
1423; MS [m/z (%)]: 290.32; Anal. Calcd for C14H18N4O3:
C, 57.92; H, 6.25; N, 19.30; found: C, 57.90; H, 6.24; N,
19.32.
7‑((1‑(2‑Hydroxy‑3‑(4‑methoxyphenoxy)‑propyl)‑1
H‑1,2,3‑triazol‑4‑yl)methyl)‑1,3‑dimethyl‑1H‑purine
‑2,6(3H,7H)‑dione (1f) Column chromatography on sil-
ica gel (EtOAc) afforded the product as a white solid; yield:
1
(83%); mp = 183–186 °C; Rf (EtOAc) = 0.21; H NMR
(250 MHz, DMSO-d6) δ ppm: 3.16 (s, 3H, N(3)-CH3),
3.35 (s, 3H, N(1)-CH3), 3.65 (s, 3H, OCH3), 3.80 (m, 2H,
NCH2CH), 4.15 (s, 1H, OH, exchangeable with D2O), 4.35
(dd, J = 7.5, 13.8 Hz, 1H, ArOCHAHB), 4.51 (dd, J = 3.3,
13.8 Hz, 1H, ArOCHAHB), 5.49 (m, 1H, CHOH), 5.54 (s,
2H, NCH2C=C), 6.75 (m, 4H, aryl), 8.07 (s, 1H, C(5)–
H, triazole), 8.13 (s, 1H, C(8)-H, theophylline); 13C NMR
(62.5 MHz, DMSO-d6) δ ppm: 27.4, 29.3, 41.0, 52.7, 55.2,
67.7, 70.0, 105.7, 114.4, 115.3, 124.8, 142.0, 142.3, 148.2,
150.9, 152.2, 153.4, 154.3; IR (KBr) ν cm−1:3222, 3127,
2931, 1725, 1710, 1657, 1549, 1439; MS [m/z (%)]: 441
(10.3); Anal. Calcd for C20H23N7O5: C, 54.42; H, 5.25; N,
22.21; found: C, 54.31; H, 5.39; N, 22.27.
2 ‑ ( ( 1 ‑ ( 2 ‑ H y d r o x y ‑ 3 ‑ ( n a p h t h a l e n ‑ 2 ‑ y l o x y )
propyl)‑1H‑1,2,3‑triazol‑4‑yl)methyl)isoindoline‑1,3‑di‑
one (1d) Column chromatography on silica gel
(EtOAc/n-hexane, 4:1) afforded the product as a pale yel-
low solid; yield: (93%); mp = 208–210 °C; Rf (EtOAc/n-
hexane, 4:1) 0.56; 1H NMR (250 MHz, DMSO-d6) δ
ppm:4.03 (m, 2H, NCH2CH), 4.28 (s, 1H, OH, exchange-
able with D2O), 4.42 (dd, J = 7.5, 13.8 Hz, 1H, ArO-
CHAHB), 4.57 (dd, J = 3.6, 13.8 Hz, 1H, ArOCHAHB),
4.84 (s, 2H, NCH2C=C), 5.61 (m, 1H, CHOH), 7.12 (m,
4H, aryl), 7.74 (m, 7H, aryl), 8.08 (s, 1H, C(5)–H, tria-
zole); 13C NMR (62.5 MHz, DMSO-d6) δ ppm:32.8, 52.6,
67.7, 69.5, 106.7, 118.5, 123.1, 123.6, 124.2, 126.3, 126.6,
127.4, 128.5, 129.2, 131.5, 134.1, 134.4, 142.0, 156.1,
167.3; IR (KBr) ν cm−1: 3366, 3152, 3087, 3048, 2931,
1775, 1723, 1628, 1558, 1423; MS [m/z (%)]: 428; Anal.
Calcd for C24H20N4O4: C, 67.28; H, 4.71; N, 13.08; found:
C, 67.36; H, 4.63; N, 13.19.
7‑((1‑(2‑Hydroxybutyl)‑1H‑1,2,3‑triazol‑4‑yl)
methyl)‑1,3‑dimethyl‑1H‑purine‑2,6(3H,7H)‑dione
(1g) Column chromatography on silica gel (EtOAc)
afforded the product as a white solid; (81%); mp = 144–
1
146 °C; Rf (EtOAc) 0.17; H NMR (250 MHz, DMSO-d6)
δ ppm: 0.82 (t, J = 7.2 Hz, 3H, CH2CH3), 1.13 (m, 2H,
CH2CH3), 3.16 (s, 3H, N(3)-CH3), 3.35 (s, 3H, N(1)-
CH3), 3.68 (s, 1H, OH, exchangeable with D2O), 4.12
(dd, J = 7.6,13.7 Hz, 1H, NCHAHB), 4.28 (dd, J = 3.2,
13.7 Hz, 1H, NCHAHB), 4.94 (m, 1H, CHOH), 5.52 (s, 2H,
NCH2C=C), 8.00 (s, 1H, C(5)–H, triazole), 8.11 (s, 1H,
C(8)-H, theophylline); 13C NMR (62.5 MHz, DMSO-d6) δ
ppm: 9.6, 27.0, 27.4, 29.3, 41.0, 55.0, 70.2, 105.7, 124.5,
141.9, 142.3, 148.2, 150.9, 154.3; IR (KBr) ν cm−1: 3252,
3107, 2961, 1719, 1708, 1665, 1542, 1431; MS [m/z (%)]:
333; Anal. Calcd for C14H19N7O3: C, 50.44; H, 5.75; N,
29.41; found: C, 50.49; H, 5.87; N, 29.54.
2‑((1‑(2‑Hydroxy‑3‑(4‑methoxyphenoxy)‑propyl)‑
1H‑1,2,3‑Triazol‑4‑yl)methyl)isoindoline‑1,3‑dione
(1e) Column chromatography on silica gel (EtOAc/n-
hexane, 4:1) afforded the product as a yellow solid; (92%);
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J IRAN CHEM SOC
1‑((1‑(3‑Butoxy‑2‑hydroxypropyl)‑1H‑1,2,3‑triazol‑4‑yl)
methyl)indoline‑2,3‑dione (1h) Column chromatog-
raphy on silica gel (EtOAc/n-hexane, 2:1) afforded the
product as a scarlet foam; (91%); Rf (EtOAc/n-hexane,
MS MS [m/z (%)]: 428; Anal. Calcd for C18H16Cl3N3O3:
C, 50.43; H, 3.76; Cl, 24.81; N, 9.80; found: C, 50.57; H,
3.81; Cl, 24.87; N, 9.71.
1
4:1) 0.45, H NMR (250 MHz, CDCl3) δ ppm: 0.53 (t,
J = 7.2 Hz, 3H, CH3), 0.95 (m, 2H, CH2CH3), 1.13 (m,
2H, OCH2CH2), 3.08 (m, 4H, CH2OCH2), 3.49 (m, 1H,
CHOH), 3.84 (s, 1H, OH, exchangeable with D2O), 4.02
(dd, J = 7.3, 14.0 Hz, 1H, NCHAHB), 4.20 (dd, J = 3.4,
14.0 Hz, 1H, NCHAHB), 4.65 (s, 2H, NCH2C=C), 6.72
(m, 2H, aryl), 7.18 (m, 2H, aryl), 7.58 (s, 1H, C(5)–H,
triazole); 13C NMR (62.5 MHz, CDCl3) δ ppm: 13.8, 18.8,
31.5, 35.3, 53.2, 69.0, 71.3, 71.6, 111.4, 117.4, 123.9,
124.6, 125.1, 138.5, 141.3, 150.2, 157.9, 183.1; IR (liq-
uid film) ν cm−1: 3419, 3035, 2950, 1739, 1614, 1585,
1471; MS [m/z (%)]: 358; Anal. Calcd for C18H22N4O4:
C, 60.32; H, 6.19; N, 15.63; found: C, 60.47; H, 6.13; N,
15.68.
1 ‑ ( 4 ‑ B e n z y l p h e n o x y ) ‑ 3 ‑ ( 4 ‑ ( 2 ‑ h y d r o x y ‑
propan‑2‑yl)‑1H‑1,2,3‑triazol‑1‑yl)propan‑2‑ol
(1k) Column chromatography on silica gel (EtOAc/n-
hexane, 2:1) afforded the product as a white solid; (91%);
mp = 86–89 °C; Rf (EtOAc/n-hexane, 4:1) 0.36; 1H
NMR(250 MHz, DMSO-d6) δ ppm: 1.22 (s, 6H, 2CH3),
3.18 (s, 2H, PhCH2), 3.63 (m, 2H, NCH2CH), 3.95 (s,
1H, CHOH, exchangeable with D2O), 4.09 (dd, J = 7.5,
13.7 Hz, 1H, ArOCHAHB), 4.25 (dd, J = 2.7, 13.4 Hz,
1H, ArOCHAHB), 4.88 (s, 1H, (CH3)2COH, exchangeable
with D2O), 5.29 (m, 1H, CHOH), 6.60 (d, J = 8.2 Hz, 2H,
aryl), 6.86 (m, 7H, aryl), 7.61 (s, 1H, C(5)–H, triazole); 13
C
NMR (62.5 MHz, DMSO-d6) δ ppm: 30.7, 40.4, 52.4, 67.0,
67.9, 69.5, 114.5, 121.6, 125.8, 128.3, 128.5, 129.7, 133.5,
141.6, 155.7, 156.6; IR (KBr) ν cm−1: 3329, 3065, 2971,
1643, 1584, 1511, 1453; MS [m/z (%)]: 367; Anal. Calcd
for C21H25N3O3: C, 68.64; H, 6.86; N, 11.44; found: C,
68.50; H, 6.81; N, 11.53.
1‑((1‑(3‑(Allyloxy)‑2‑hydroxypropyl)‑1H‑1,2,3‑tria‑
zol‑4‑yl)methyl)indoline‑2,3‑dione (1i) Column chro-
matography on silica gel (EtOAc/n-hexane, 2:1) afforded
the product as a scarlet foam; (93%); Rf (EtOAc/n-hexane,
1
4:1) 0.39; H NMR (250 MHz, CDCl3): δ ppm: 3.18 (m,
2H, OCH2CHOH), 3.58 (m, 1H, CHOH), 3.73 (m, 2H,
CH2CH = C), 3.96 (s, 1H, OH, exchangeable with D2O),
4.13 (dd, J = 7.2, 14.0 Hz, 1H, NCHAHB), 4.29 (dd,
J = 3.6, 14.0 Hz, 1H, NCHAHB), 4.75 (s, 2H, NCH2C=C),
4.89 (m, 2H, =CH2), 5.53 (m, 1H, CH), 6.86 (m, 2H, aryl),
7.28 (m, 2H, aryl), 7.67 (s, 1H, C(5)–H, triazole); 13C NMR
(62.5 MHz, CDCl3) δ ppm: 35.3, 53.2, 69.0, 71.0, 72.3,
111.4, 117.4, 117.5, 123.9, 124.6, 125.2, 134.1, 138.6,
141.3, 150.2, 158.0, 183.1; IR (liquid film) ν cm−1: 3400,
3083, 2984, 1734, 1625, 1591, 1468; MS [m/z (%)]: 342;
Anal. Calcd for C17H18N4O4: C, 59.64; H, 5.30; N, 16.37;
found: C, 59.60; H, 5.21; N, 16.46.
1‑(4‑(2‑Hydroxypropan‑2‑yl)‑1H‑1,2,3‑tria‑
zol‑1‑yl)‑3‑phenoxypropan‑2‑ol (1l). Column chro-
matography on silica gel (EtOAc/n-hexane, 2:1) afforded
the product as a white solid; (90%); mp 92–95 °C; Rf
1
(EtOAc/n-hexane, 4:1) 0.35; H NMR (250 MHz, DMSO-
d6) δ ppm: 1.39 (s, 6H, 2CH3), 3.84 (m, 2H, NCH2CH),
4.15 (s, 1H, CHOH, exchangeable with D2O), 4.29 (dd,
J = 7.3, 13.8 Hz, 1H, ArOCHAHB), 4.44 (dd, J = 3.8,
13.8 Hz, 1H, ArOCHAHB), 5.03 (s, 1H, (CH3)2COH,
exchangeable with D2O), 5.48 (m, 1H, CHOH), 6.85 (m,
3H, aryl), 7.18 (m, 2H, aryl), 7.78 (s, 1H, C(5)–H, tria-
zole); 13C NMR (62.5 MHz, DMSO-d6): δ ppm: 30.7, 52.4,
67.0, 67.9, 69.4, 114.5, 120.7, 121.4, 129.4, 155.5, 158.3;
IR (KBr) ν cm−1: 3316, 3100, 2970, 1597, 1588, 1468; MS
[m/z (%)]: 277; Anal. Calcd for C14H19N3O3: C, 60.63; H,
6.91; N, 15.15; found: C, 60.75; H, 6.83; N, 15.10.
1‑(4‑((4‑Chlorophenoxy)methyl)‑1H‑1,2,3‑tria‑
zol‑1‑yl)‑3‑(2,4‑dichlorophenoxy)propan‑2‑ol (1j) Col-
umn chromatography on silica gel (EtOAc/n-hexane,
2:1) afforded the product as a pale-yellow solid; (88%);
mp = 129–132 °C; Rf (EtOAc/n-hexane, 4:1) 0.62;
1H NMR (250 MHz, DMSO-d6) δ ppm: 3.97 (m, 2H,
NCH2CH), 4.28 (s, 1H, OH, exchangeable with D2O), 4.45
(dd, J = 7.5, 13.8 Hz, 1H, ArOCHAHB), 4.61 (dd, J = 3.2,
13.8 Hz, 1H, ArOCHAHB), 5.13 (s, 2H, OCH2C=C), 5.66
(m, 1H, CHOH), 7.02 (m, 6H, aryl), 7.51 (s, 1H, aryl), 8.19
(s1H, C(5)–H, triazole); 13C NMR (62.5 MHz, DMSO-d6)
δ ppm: 52.5, 61.3, 67.6, 70.6, 115.2, 116.4, 122.5, 124.5,
124.7, 125.6, 128.0, 128.7, 129.1, 142.1, 152.8, 156.8; IR
(KBr) ν cm−1: 3264, 3028, 2921, 1647, 1590, 1491, 1036;
1‑(4‑Benzylphenoxy)‑3‑(4‑((4‑chlorophenoxy)
methyl)‑1H‑1,2,3‑triazol‑1‑yl)propan‑2‑ol (1m) Col-
umn chromatography on silica gel (EtOAc/n-hexane,
2:1) afforded the product as a white solid; (92%);
1
mp = 201–205 °C; Rf (EtOAc/n-hexane, 4:1) 0.31; H
NMR(250 MHz, DMSO-d6) δ ppm: 3.85 (s, 2H, ArCH2Ph),
3.88 (m, 2H, NCH2CH), 4.10 (s, 1H, CHOH, exchangeable
with D2O), 4.89 (dd, J = 7.6, 13.8 Hz, 1H, ArOCHAHB),
4.25 (dd, J = 3.3, 13.4 Hz, 1H, ArOCHAHB), 5.13 (s,2H,
OCH2C=C), 5.57 (m, 1H, CHOH), 6.83 (d, J = 8.2 Hz,
1 3

J IRAN CHEM SOC
Scheme 1 Routes to prepare
the [Cu(cdsalMeen)]
O
NH2
NH
NH
+
S-NH4
S
SH
S
SMe
CS2 , NH4OH
8h, 0oC
Me2 (SO4)
HCl
ice cooling
NaOH
S
(2)
(3)
(<20oC)
(4)
(5)
Me
S
MeS
H
N
H2N
C
NH
NH NH2
NH2
H
SH
H2O
Me
24h
N
S
S
Me
(6)
C
(HcdMeen)
MeS
SMe
SMe
(7)
CHO
OH
Me
N
Me
N
O
Cu(OAC)2.H2O
MeOH/CHCl3
Cu
NH
N
S
MeS
HO
S
Cu(cdsalMeen)
MeS
(8)
(9)
2H, aryl), 7.04 (m, 10H, aryl), 8.1 (s, 1H, C(5)–H, tria-
zole); 13C NMR (62.5 MHz, DMSO-d6) δ ppm: 52.6,
61.3, 67.77, 69.4, 114.4, 116.4, 124.5, 125.6, 128.1, 129.1,
20 °C. The brown product 5 was then separated, dried and
recrystallized from (1:1,V:V) methanol–water. The brown
powder was dissolved in 35 mL of methanol, and 0.1 mol of
1,2-diaminopropane was added. After 24 h, the red solution
gradually turned pale yellow. The yellow crystalline prod-
uct 6 was separated, washed with water, dried and recrystal-
lized from dioxane. Then, water (120 mL) was added to the
filtrate. The yellow crystals 7 were separated, washed with
water and dried. The crude product was recrystallized from
3:2 (V:V) water/methanol. The yellow plates are Methyl-
2-(1-methyl-2′-aminoethane) amino-1-cyclopentenedithio-
carboxylate (HcdMeen). Ligand 7 (in methanol) was added
to a methanolic solution containing the stoichiometric
amount of salicylaldehyde. The resultant yellow powder 8
was recrystallized from methanol/chloroform 2:1 (V:V). For
synthesis of [Cu(cdsalMeen]) 9 complex, solution of copper
acetate in 10 mL of methanol was added to a solution of the
appropriate ligand 8 (yellow color) (0.1 mmol) in 10 mL of
chloroform/methanol 2:1 (V:V). The solution was stirred for
15 min and then allowed to stand at room temperature for
24 h. After filtering, the crude was recrystallized from ace-
tonitrile/methanol 1:1 (V:V), the Cu(II) complex has brown
color.
After synthesis and supporting the catalyst on silica gel,
we applied this catalyst in synthesis of some 1,2,3-triazole
derivatives. The first step of this synthetic approach was
started by optimizing the reaction conditions. At first, we
carried out the cycloaddition reaction of benzophenone
O-(3-azido-2-hydroxypropyl) oxime and prop-2-yn-1-ol as
a model reaction to acquire the corresponding 1,2,3-tria-
zole (1a) (Table 1). The 1,3-dipolar cycloaddition of model
reaction was carried out in the presence of ascorbic acid
(1 mmol) and [Cu(cdsalMeen)]–SiO2 (0.05 mol%) in H2O
129.6, 133.5, 141.6, 142.0, 156.6, 156.8; IR (KBr) ν cm−1
:
3358, 3059, 2971, 1640, 1510, 1450; MS [m/z (%)]: 449;
Anal. Calcd for C25H24ClN3O3: C, 66.74, H, 5.38; Cl, 7.88;
N, 9.34; O, 10.67; found: C, 66.72, H; 5.36, Cl; 7.87, N,
9.35; O, 10.69.
Results and discussion
Initially, we prepared an active catalyst due to procedure
reported in a literature [36]. As is shown in Scheme 1, the
ammonium salt of the thioacid 3 was prepared by stirring
a mixture of cyclopentanone 2 (0.3 mol), carbon disulfide
(0.39 mol) and 28% aqueous ammonia (100 mL) at 0 °C
for eight hours. The yellow crude product was collected,
washed with ether. The ammonium salt 3 is not stable at
room temperature and loses ammonia on standing. The acid
4 was prepared by dissolving the crude product in water and
slowly neutralizing with HCl (2N) under ice-cooling. The
yellow prismatic crystals were collected, washed with water
and dried. The crude acid was dissolved in air-free cold eth-
anol until saturation, an equal volume of water was added to
the filtered solution and kept in an ice bath for half an hour
and the shining yellow crystals 4 were collected, washed
with water–ethanol (1:1,V:V) and dried over CaCl2. Yel-
low crystals (0.03 mol) of 4 were dissolved in a solution of
sodium hydroxide (0.03 mol) in 50 mL of water. Dimethyl-
sulfate (0.03 mol) was added in portions under cooling and
vigorous stirring, with the temperature being kept below
1 3

J IRAN CHEM SOC
Table 1 Influence of various temperatures on conversion of O-(3-azido-2-hydroxypropyl) oxime into 1a using [Cu(cdsalMeen)]–SiO2 in H2O
N
OH
N
N
OH
OH
O
O
N3
+
N
N
[Cu(cdsalMeen)]
H2O /
1a
OH
∆
Ascorbic acid
Entry
Temperature (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
25
50
4
46
61
70
73
79
79
80
80
80
2
80
1. 5
1.25
1
90
100
110b
155b
200b
220b
1
1
1
1
a
Isolated yield
b
The reaction is conducted in a pressure bottle
at room temperature, which was afforded 1a in 46% yield
after stirring for 4 h (Table 1, entry 1).
increasing the temperature up to 220 °C (in a pressure bot-
tle) did not affect the reaction yield, considerably.
In order to optimize the reaction conditions, the influ-
ence of various 2:1 (V/V) organic solvents/H2O was exam-
ined in the presence of [Cu(cdsalMeen)]–SiO2 at room
temperature (Table 2).
To study the influence of temperature, the model reac-
tion was carried out at different temperatures (Table 1,
entries 2–9). Due to Table 1, an increase in the temperature
resulted in the promotion of cycloaddition reaction. The
best result obtained when the cycloaddition reaction was
conducted at 100 °C for 1 h (Table 1, entry 5). However,
From Table 2, it is well demonstrated the solvent has
a significant role in progress of reaction. Among the
Table 2 Influence of various miscible organic solvents on conversion of O-(3-azido-2-hydroxypropyl) oxime into 1a using [Cu(cdsalMeen)]–
SiO2 at room temperaturea
N
OH
N
N
OH
OH
O
O
N3
+
N
N
[Cu(cdsalMeen)]
1a
OH
solvent / r.t
Ascorbic acid
Entry
Solventa
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
H2O/DMSO
H2O/DMF
H2O/t-BuOH
H2O/MeCN
H2O/THF
H2O/DMSO
H2O/acetone
H2O
0.75
0.75
1.5
1.25
0.5
1
89
83
70
73
94
79
55
46
63
2
4
THF
4
a
For entries 1–7, a mixture of 1:2 (V/V) solvents was used
Isolated yield
b
1 3

J IRAN CHEM SOC
Table 3 Influence of time on conversion of O-(3-azido-2-hydroxypropyl) oxime into 1a using [Cu(cdsalMeen)]–SiO2
N
OH
N
N
OH
OH
O
O
N3
+
N
N
[Cu(cdsalMeen)]
1a
OH
THF:H2O (2:1) /r.t
Ascorbic acid
Entry
Time (h)
Yielda (%)
Conversionb (%)
1
2
3
4
5
6
7
0.1
0.2
0. 3
0.4
0.5
0.7
0.8
55
72
82
90
94
94
94
61
79
90
96
100
100
100
a
Isolated yield
GC yield
b
examined solvents, a solution of THF/H2O (2:1, V/V)
(Table 2, entry 5) afforded the best result.
applied. It is important to use nearly an equimolar ratio of
azide/alkyne. The use of large quantities of alkyne can lead
to the appearance of by-products because of alkyne–alkyne
homo-coupling reaction in the presence of Cu(I) salts.
Additionally, the influence of time on the progress of
reaction for model substrates was investigated (Table 3).
As the results in Table 3 indicate, the reaction proceeds
smoothly and the best result was obtained when the reac-
tion was terminated after 0.5 h (Table 3, entries 5). Pro-
longing the reaction time had no distinguishable effect on
the progress of the reaction.
Moreover, using the ratio of organic solvents/water
(2:1, V/V), such as DMSO (Table 2, entry 1) and/or DMF
(Table 2, entry 2) also yielded the product in reasonable
time. Employing the other mixtures afforded a moderate
yield of product over longer periods of time (>0.5 h). Addi-
tionally, when water and THF were used alone, the yields
of 46 and 63% for 1a were obtained after 4 h, respectively
(Table 2, entries 8 and 9). The low yield obtained for 1a
using water is attributed to lack of organic solubility in H2O.
The optimized stoichiometric ratio of azide/alkyne found
to be 1:1.2 for 1a when 0.3 g (0.05 mol%) of catalyst was
To investigation the catalytic potency of homogeneous
and heterogeneous [Cu(cdsalMeen)] catalyst and other
Table 4 Comparison of various copper catalysts with [Cu(cdsalMeen)]–SiO2 on conversion of O-(3-azido-2-hydroxypropyl) oxime into 1a
N
OH
N
N
OH
OH
O
O
N3
+
N
N
copper catalyst
1a
OH
THF:H2O (2:1) /r.t
Ascorbic acid
Entryref
Catalyst
Time (h)
Yielda (%)
1
–
2
0
94
94
84
73
87
2
Heterob
Homoc
CuI
0.5
0.5
8
3
436
537
614
Cu(OAc)2
Cu/C
7
1
a
Isolated yield
Heterogeneous
Homogeneous
b
c
1 3

J IRAN CHEM SOC
reported copper catalysts in the 1,3-dipolar cycloaddi-
tion, the comparative results are summarized in (Table 4).
When the reaction was carried out in the absence of cata-
lyst, no products were formed even if the reaction time
was prolonged (Table 4, entry 1). According to the results
in Table 4, higher yield of 1a and shorter reaction time
were obtained using homogeneous and heterogeneous
[Cu(cdsalMeen)] (Table 4, entry 2, 3) in comparison with
other examined copper catalysts. Using the other catalysts
afforded the satisfactory results of 1a, however, the reac-
tions were required longer reaction times. As can be seen in
Table 4, entry 2, 3, both of homogeneous and heterogene-
ous [Cu(cdsalMeen)] catalysts are effective, but we applied
immobilized [Cu(cdsalMeen)] on silica as a heterogeneous
Table 5 ‘Click’ cycloaddition of β-azido alcohols with alkynes
Entry
ß-Azido alcohol
Alkyne
Product
Time (h)
0.5
Yield (%) a
94
1
2
3
0.5
0.5
92
89
4
5
6
7
8
0.5
0.5
1
93
92
83
81
93
N
OH
O
N
N
O
N
Me
O
N
N
N
MeO
1f
Me
N
OH
N
N
O
N
Me
O
N
N
1
N
1g
Me
0.5
9
0.5
0.5
0.5
0.5
0.5
91
87
83
81
88
10
11
12
13
a
Isolated yield
1 3

J IRAN CHEM SOC
Table 6 Reusability of [Cu(cdsalMeen)]–SiO2 in successive trails for synthesis of 1a
N
OH
N
N
OH
OH
O
O
N3
+
N
N
copper catalyst
1a
OH
THF:H2O (2:1) /r.t
Ascorbic acid
Run
Time (h)
Yielda (%)
1
2
3
4
5
0.5
94
94
86
84
80
0.5
1. 0
1.25
1.5
a
Isolated yield
catalyst, because of its thermal and chemical stability, envi-
ronmentally compatibility and low catalyst loading that can
be easily prepared and reused for many consecutive runs
without a significant decrease in its catalytic reactivity.
To illustrate the scope of this method, we extended the
optimized reaction condition to other azides and alkynes
cycloadditions (Table 5). As the results in Table 5 indi-
cate, [Cu(cdsalMeen)]–SiO2 proved to be useful catalyst
for Huisgen cycloaddition between the structurally diverse
β-azido alcohols and alkynes. Using [Cu(cdsalMeen)]–
SiO2, compounds 1a–m were regioselectively synthesized
as 1,4-disubstituted 1,2,3-triazoles in excellent yields and
short reaction times. The chemistry works well with vari-
ous β-azido alcohols involving aryloxy, alkoxy and alkyl
residues, and also tolerates a wide spectrum of electron-
donating and electron-withdrawing functional groups in
both alkyne and azide molecules (Table 5). Most of β-azido
alcohols used in these experiments were pre-synthesized by
the regioselective ring opening reaction of corresponded
epoxides with sodium azide, whereas the majority of termi-
nal alkynes were prepared via SN2-type reaction of propar-
gyl bromide and corresponded nucleophiles.
without significant desorption of Cu species from silica
matrix. As it is well indicated, the amount of leached Cu from
[Cu(cdsalMeen)]–SiO2 is extremely negligible (0.006% after
five consecutive runs). As the results in Table 6 indicate, the
catalyst can be reused for many consecutive runs without
considerable decrease in its catalytic reactivity.
Conclusions
In conclusion, we have reported a robust and recyclable het-
erogeneous catalysts that contributes to expanding the reli-
ability and scope of the Huisgen 1,3-dipolar cycloaddition.
The process showed the considerable synthetic advantages
in terms of product diversity, mild reaction condition, sim-
plicity of the reaction procedure and good to excellent yields.
Furthermore, copper (II) catalyst can be recovered and recy-
cled by simple filtration of the reaction mixture and reused
for at least five consecutive trials without decrease in activity.
Supporting information
All synthesized compounds 1a–m were fully character-
1
ized, and their structures were confirmed by H and 13C
More experimental details including characterization data,
1H NMR and 13C NMR for all new and known compounds
are available online.
NMR, elemental analysis, mass spectrometry and IR spec-
troscopy methods.
The reusability of the immobilized [Cu(cdsalMeen)] on
silica gel was studied during the synthesis of 1a (Table 6). In
this context, prior to use and also final testing of the catalyst
for determination of its activity in many subsequent runs, the
catalyst was recycled from the reaction mixture through a sin-
tered glass funnel (vacuum-filtering). The catalyst was then
washed successively with THF/H2O (2:1, V/V, 5 × 10 mL)
and dried in a vacuum oven at 100 °C for 30 min. The cata-
lyst was tested for five consecutive runs and through each run,
no fresh catalyst was added. Furthermore, the ICP analysis
has confirmed the reusability of the [Cu(cdsalMeen)]–SiO2
References
1. H. Dehne, in Methoden der Organischen Chemie (Houben-Weyl),
vol. E 8d, ed. by E. Schumann (Thieme, Stuttgart, 1994), pp.
305–405
2. W.-Q. Fan, A.R. Katritzky, in Comprehensive Heterocyclic Chem-
istry II, vol. 4, ed. by A.R. Katritzky, C.W. Rees, E.F.V. Scriven
(Elsevier, Oxford, 1996), pp. 1–126
3. L. Zhou, A. Amer, M. Korn, R. Burda, J. Balzarini, E. De Clercq,
E.R. Kern, P.F. Torrence, Antivir. Chem. Chemother. 16, 375
(2005). doi:10.1177/095632020501600604
1 3

J IRAN CHEM SOC
19. A.F. Trindade, P.M.P. Gois, C.A.M. Afonso, Chem. Rev. 109,
418 (2009). doi:10.1021/cr800200t
20. J.M. Fraile, J.I. García, J.A. Mayoral, Chem. Rev. 109, 360
(2009). doi:10.1021/cr800363y
21. A.P. Wight, M.E. Davis, Chem. Rev. 102, 3589 (2002).
doi:10.1021/cr020068s
22. L. Yin, J. Liebscher, Chem. Rev. 107, 133 (2007). doi:10.1021/
cr0505674
4. F. Pagliai, T. Pirali, E. Del Grosso, R. Di Brisco, G.C. Tron,
G. Sorba, A.A. Genazzani, J. Med. Chem. 49, 467 (2006).
doi:10.1021/jm051118z
5. R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E. De Clercq,
C.-F. Perno, A. Karlsson, J. Balzarini, M.J. Camarasa, J. Med.
Chem. 37, 4185 (1994). doi:10.1021/jm00050a015
6. A. Romero, C.H. Liang, Y.H. Chiu, S. Yao, J. Duffield, S.J.
Sucheck, K. Marby, D. Rabuka, P.Y. Leung,Y.K. Shue,Y. Ichikawa,
C.K. Hwang, Tetrahedron Lett. 46, 1483 (2005). doi:10.1016/j.
tetlet.2005.01.023
23. A. Corma, H. Garcia, Adv. Synth. Catal. 348, 1391 (2006).
doi:10.1002/adsc.200606192
24. S. Minakata, M. Komatsu, Chem. Rev. 109, 711 (2009).
doi:10.1021/cr8003955
25. C.A. McNamara, M.J. Dixon, M. Bradley, Chem. Rev. 102, 3275
(2002). doi:10.1021/cr0103571
26. T. Miao, L. Wang, Synthesis 33, 63 (2008). doi:10.105
5/s-2008-1032037
27. P.H. Li, L. Wang, Y.C. Zhang, Tetrahedron 64, 10825 (2008).
doi:10.1016/j.tet.2008.09.021
7. M.J. Genin, D.A. Allwine, D.J. Anderson, M.R. Barbachyn, D.E.
Emmert, S.A. Garmon, D.R. Graber, K.C. Grega, J.B. Hester, D.K.
Hutchinson, J. Morris, R.J. Reischer, C.W. Ford, G.E. Zurenko,
J.C. Hamel, R.D. Schaadt, D. Stapert, B.H.Yagi, J. Med. Chem. 43,
953 (2000). doi:10.1021/jm990373e
8. B.S. Holla, M. Mahalinga, M.S. Karthikeyan, B. Poojari, P.M.
Akberali, N.S. Kumari, Eur. J. Med. Chem. 40, 1173 (2005).
doi:10.1016/j.ejmech.2005.02.013
28. T. Shamim, S. Paul, Catal. Lett. 136, 260 (2010). doi:10.1007/
s10562-010-0330-3
29. A. Megia-Fernandez, M. Ortega-Munoz, F. Hernandez-Mateo,
F. Santoyo-Gonzalez, Adv. Synth. Catal. 354, 1797 (2012).
doi:10.1002/adsc.201100813
9. X. Li, Chem. Asian J. 6, 2606 (2011). doi:10.1002/asia.201190040
10. R. Huisgen, Angew. Chem. Int. Ed. 75, 565 (1963). doi:10.1002/
anie.196305651
11. J.F. Lutz, Angew. Chem. Int. Ed. 46, 1018 (2007). doi:10.1002/
anie.200604050
30. M.N. Soltani Rad, S. Behrouz, M.M. Doroodmand, A.
Movahediyan, Tetrahedron 68, 7812 (2012). doi:10.1016/j.
tet.2012.07.032
31. C. Kaiser, J. Timothy, G. Eleanor, B. Wyne, D. Collela, F. Don-
ald, J.R. Wardell, J. Med. Chem. 20, 687 (1977). doi:10.1021/
jm00215a014
12. C.W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 67, 3057
(2002). doi:10.1021/jo011148j
13. V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless,
Angew. Chem. Int. Ed. 41, 2596 (2002). doi:10.1002/1521-
3773(20020715)41:14<2596:aid-anie2596>3.0.co;2-4
14. L. Zhang, X.G. Chen, P. Xue, H.H.Y. Sun, I.D. Williams, K.B.
Sharpless, V.V. Fokin, G.C. Jia, J. Am. Chem. Soc. 127, 15998
(2005). doi:10.1021/ja054114s
32. J. Walle, T.E. Gaffney, J. Pharmacol. Exp. Ther. 182, 83 (1972).
doi:10.1002/rcm.4130
33. P. Lechat, Hot Top. Cardiol. 10, 7 (2008). doi:10.4147/htc-081000
34. A. Kleeman, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical
Substances, 3rd edn. (Thieme, Stuttgart, 1999)
35. G. Biagi, G. Dell’Omodarme, M. Ferretti, I. Giorgi, O. Livi, V.
Scartoni, Farmaco 45, 1181 (1990)
15. H. Sharghi, M.H. Beyzavi, A. Safavi, M.M. Doroodmand, R.
Khalifeh, Adv. Synth. Catal. 351, 2391 (2009). doi:10.1002/
adsc.200900353
16. F. Cozzi, Adv. Synth. Catal. 348, 1367 (2006). doi:10.1002/
adsc.200606096
36. M. Asadi, K. Mohammadi, S. Esmaielzadeh, B. Etemadi, F.
Hoong-Kun, Inorg. Chim. Acta 362, 4913 (2009). doi:10.1016/j.
ica.2009.07.025
17. K. Binnemans, Chem. Rev. 109, 4283 (2009). doi:10.1021/cr8003983
18. C. Baleizão, H. Garcia, Chem. Rev. 106, 3987 (2006).
doi:10.1021/cr050973n
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