Cuprous oxide on charcoal-catalyzed ligand-free synthesis of 1,4-disubstituted 1,2,3-triazoles via click chemistry

Article abstract of DOI:10.3998/ark.5550190.0014.312

Cuprous oxide on charcoal (Cu₂O/C), the preparation of which is described for the first time, catalyzes the formation of 1,4-disubstituted 1,2,3-triazoles from organic azides and terminal alkynes in good to excellent yields (69-94%). These disu

Full text of DOI:10.3998/ark.5550190.0014.312

General Papers
ARKIVOC 2013 (iii) 139-164
Cuprous oxide on charcoal-catalyzed ligand-free synthesis of
1,4-disubstituted 1,2,3-triazoles via click chemistry
Heraclio López-Ruiz,a* José Emilio de la Cerda-Pedro,a Susana Rojas-Lima,a*
Imelda Pérez-Pérez,a Brianda Viridiana Rodríguez-Sánchez,a Rosa Santillan,b
and Oscar Coreñoc
a Área Académica de Química, Universidad Autónoma del Estado de Hidalgo, Carretera
Pachuca-Tulancingo Km 4.5, Ciudad Universitaria, 42184 Mineral de la Reforma,
Hidalgo, México
b
Departamento de Química, Centro de Investigación y de Estudios Avanzados del
Instituto Politécnico Nacional, Apto. Postal 14-740, 07000 México D.F., México
c Departamento de Ingeniería Civil, Universidad de Guanajuato, Juárez 77, Col. Centro,
36000 Guanajuato, México
E-mail: heraclio@uaeh.edu.mx
Abstract
Cuprous oxide on charcoal (Cu2O/C), the preparation of which is described for the first time,
catalyzes the formation of 1,4-disubstituted 1,2,3-triazoles from organic azides and terminal
alkynes in good to excellent yields (69-94%). These disubstituted triazoles can be equally
efficiently generated in a one-pot process from alkyl bromides, sodium azide, and terminal
acetylenes in 50% aqueous isopropanol containing a suspension of the catalyst. This obviates the
necessity to isolate potentially explosive organic azides.
Keywords: 1,3-Dipolar cycloaddition, click chemistry, Cu2O/C, triazoles
Introduction
Recent advances in the Huisgen 1,3-dipolar cycloaddition reaction have led to a renewed interest
in its applications to the synthesis of 1,2,3-triazoles.1 Small molecules containing the triazole
functionality have been shown to exhibit a range of biological functions, including antitumor,
antibacterial, antiparasitic and antiviral activity (Figure 1).2
Page 139
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Figure 1. Representative examples of biologically active 1,2,3-triazoles.
Historically, 1,2,3-triazoles have been prepared via the Huisgen 1,3-dipolar cycloaddition
reaction of azides and alkynes.1a,3 This reaction sometimes requires relatively high temperatures
and long reaction times. The main disadvantage of this methodology is that regioisomeric
mixtures of the 1,4- and 1,5-disubstituted 1,2,3-triazoles are often formed. Recently, Fokin and
coworkers developed new methodology for the preparation of 1,5-dialkyl 1,2,3-triazoles in high
yields from aryl azides and terminal alkynes in the presence of catalytic tetramethylammonium
hydroxide or Cp*RuCl(PPh3)2.4 In addition, Sharpless1c and Meldal1e have found that catalytic
copper(I) dramatically accelerates the reaction resulting in the highly regioselective formation of
1,4-disubstituted triazoles. This powerful, highly reliable, and selective reaction meets the set of
stringent criteria required in click chemistry as defined by Sharpless et al.1b Thus, the copper(I)-
catalysed process is the preferred methodology for effecting this reaction (See Scheme 1). The
sources of copper(I) include: a) copper(I) salts, normally in the presence of a base and/or a
ligand, b) in-situ reduction of copper(II) salts (e.g., copper sulfate with sodium ascorbate) and c)
disproportionation of copper(0) and copper(II), generally limited to special applications.5 For
instance, reactions performed in some of the commonly used solvents (e.g. water-alcohol solvent
mixtures) can be problematic, especially for insoluble reagents or very soluble products, thus
reducing the application scope. Another aspect to consider is the reaction time, which, in general,
is relatively long, requiring 12-24 h for completion. The addition of some copper complexes6 or
ligands5,7 was found to enhance the reaction rate. New and interesting advances in the title
reaction involve heterogeneous catalysis. Thus copper(I) on charcoal, in the presence of
triethylamine, was shown to be an efficient heterogeneous catalyst for the title reaction, the
reaction times being reduced to 10-120 min.8 Copper(I) on zeolite was also recently found to
catalyze the cycloaddition reaction from halides or tosylates, sodium azide, and alkynes.9
Page 140
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
N
N
R1
N
N
N
CuAAC
R
R1
R1
N
Huisgen
N
N
N
R1N3
+
RC CH
+
cycloaddition
R
R
N
R1
Me4NOH (aq)
N
N
or Cp*RuCl(PPh3)2
R
Scheme 1
Recently, increasing attention has been devoted to the use of copper nanoparticles (CuNPs),
as substitutes for bulk copper metal, in order to reduce both the catalyst loading and the reaction
time.10 Also the use of CuNPs has shown a general beneficial effect in the cycloaddition of
alkynes and azides. Furthermore, easy-to-prepare and versatile heterogeneous copper catalysts
that can efficiently promote the multicomponent 1,3-dipolar cycloaddition of organic azides and
alkynes in water are welcome. Herein we describe the virtues of Cu2O on charcoal (Cu2O/C) as a
simple, inexpensive, general, and efficient heterogeneous catalyst for use in click chemistry.
Results and Discussion
(a) Preparation of catalyst
The copper catalyst immobilized on charcoal (Aldrich, Graphite 99.999%, 325 mesh) was
readily prepared in a two-step procedure. 1) Preparation of graphite. A high energy mill Spex
8000D, D2 tool steel and hardened steel balls were used. 50 balls of 1.04 g each, and 1.0 g of
graphite (99.999%, 325 mesh) were introduced into the vial. Graphite was milled for 40 minutes
under a static air atmosphere. 2) Impregnation of charcoal with Cu2O particles was done using
CuSO4·5H2O as the copper source. CuSO4·5H2O (0.3062 g) was dissolved in 5.68 mL of
deionized water and 1.0 g of milled graphite was added to this solution. The volumetric flask (50
mL) containing this mixture was placed in an ultrasonic bath for 1 h. Finally, the resulting
suspension was filtered and dried in an oven for 4 h at 110oC, to obtain nanoparticle-size
Cu2O/C.11 The cuprous oxide on charcoal catalyst was characterized by its X-ray diffraction
pattern (XRD). The copper content in the catalyst (0.89 wt%), was determined by flame atomic
absorption spectrophotometry (in 2% nitric acid). Analysis by SEM images revealed the
presence of agglomerates of around up to 5 µm, Figure 2a. Each of these agglomerates is formed
of platelets with sizes of up to around 200 nm, as can be seen in the dark field transmission
electron microscopy image shown in Figure 3a. Each platelet is formed by nanocrystals with
Page 141
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
sizes below around 10 nm. The backscattered electron image confirmed the presence of Cu2O
sizes of up to around 1 µm (see Figure 4).
Figure 2. Secondary electron SEM images of graphite milled for 40 minutes.
Figure 3. (a) Dark field TEM image of milled graphite, and (b) the corresponding selected area
electron diffraction pattern.
Page 142
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Figure 4. Backscattered electrons SEM image of milled graphite, after treatment with a CuSO4
solution in an ultrasonic bath. Bright particles correspond to Cu2O.
Figure 5. X-ray diffraction patterns of a) unmilled graphite, b) graphite milled for 40 minutes,
and c) milled graphite, after treatment with a CuSO4 solution in an ultrasonic bath. The
formation of Cu2O can be observed.
Figure 5 shows the X-ray diffraction patterns of a) unmilled graphite, b) milled graphite and
c) milled graphite after treatment with a CuSO4 solution followed by ultrasonication. The
patterns shown in a) and b) correspond with the card JCPDS 23-64, for graphite. The peak
broadening in Figure 5b is due to crystallite size under 100 nm,12 in agreement with the
nanoparticles shown in Figure 5a. The most noticeable peak broadening was produced in the
direction perpendicular to (002) planes, as could be expected for weak bonding between basal
planes in graphite. Figure 5c shows that the Cu2O (JCPDS 1-1142) was formed after
Page 143
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
ultrasonication of an aqueous CuSO4 solution containing suspended graphite (after drying at
120oC overnight). Assuming catalysis by Cu(I), reduction by charcoal could account for the
observed activity as described by Lipshutz.8a
(b) Application of the Cu2O/C catalyst for the preparation of 1,5-disubstituted
1,2,3-triazoles
The selected area electron-diffraction pattern of the copper is in agreement with the presence of
Cu2O.13 It is worthy of note that Cu2O very recently has been found to catalyze the 1,3-dipolar
cycloaddition of azides and terminal alkynes.14 The reaction of benzyl azide (1a) with phenyl
acetylene (2a) was chosen as a model system (Table 1). Initially, we attempted to adopt a
previously reported reaction protocol [PS-EPG-terpyridine copper(I) complex/H2O/40oC]15 to
synthesize the targeted product 3a, but to our surprise, 3a was not formed. Modification of the
procedure reported by Chowdhury16 with increased catalyst loading and manipulation of various
parameters (Table 1) including different solvent systems did, however, provide 3a. It was found
that the solvent system plays a very important role in terms of reaction rate, isolated yields, and
regioselectivity with the 50% aqueous isopropanol mixture being especially efficacious (Table 1,
entry 6). In addition, examination of the effect of various bases showed that triethylamine was
the preferred one (Table 1). The TON and the turnover frequency (TOF) of the catalyst reached
1957.32 and 13.5 h -1, respectively; these are, as far as we know, one of the higher TON and TOF
obtained for heterogeneous catalysts.8a,17
With the optimized conditions (Table 1, entry 6) in hand, the scope of the reaction was
explored by reacting various azido compounds (1a-f) with terminal alkynes (2a-e). The results
are summarized in Table 2. All products were characterized by spectral and analytical data (see
Experimental Section). The molecular structures of triazoles 3c, 3l, 3p and 3v were confirmed
unambiguously by single-crystal X-ray analyses (see Figure 6).18 It is obvious that a wide variety
of aryl, benzyl, and alkyl azides possessing different functional groups reacted successfully.
Table 1. 1,3-Dipolar Huisgen cycloaddition reaction of benzyl azide and phenylacetylene under
various conditions
Entry
Conditions
Charcoal, (no Cu2O), r.t., 2 h
H2O, with 5% Catalyst, r.t., 2 h
Acetonitrile, 5% Catalyst, Et3N, r.t., 1 h
Acetonitrile, 5% Catalyst, Et3N, r.t., 24 h
Acetonitrile, 10% Catalyst, Et3N, r.t., 1 h
Yield (%)a
1
2
3
4
5
0
0
78b
79
81
Page 144
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Table 1. Continued
Entry Conditions
Yield (%)a
6
7
9
10
11
12
13
14
15
H2O:Isopropanol, 5% Catalyst, Et3N, r.t., 2 h
82
83
77
85
64
57
66
65
0c
H2O:Isopropanol, 10% Catalyst, Et3N, r.t., 2 h
H2O:Isopropanol, 15% Catalyst, Et3N, r.t., 2 h
H2O:Isopropanol, 20% Catalyst, Et3N, r.t., 2 h
H2O:Isopropanol, 5% Catalyst, K2CO3, r.t., 24 h
H2O:Isopropanol, 10% Catalyst, K2CO3, r.t., 24 h
H2O:Isopropanol, 15% Catalyst, K2CO3, r.t., 24 h
H2O:Isopropanol, 20% Catalyst, K2CO3, r.t., 24 h
H2O:Isopropanol, 5% Catalyst, 2,6-lutidine, r.t., 24 h
a Chromatographically isolated yield of pure product. b The catalyst was not recovered. c No
product formation was observed despite increasing the amount of 2,6-lutidine and catalyst.
Figure 6. X-Ray structures of 3c, 3l, 3p and 3v.
Page 145
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Table 2. Click reactions catalyzed by Cu2O/Ca
Yield
(%)b
Entry
Azide
Alkyne
Triazole
1
82
2
3
4
84
69
77
5
6
79
84
7
8
89
76
Page 146
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Table 2. Continued
Yield
Entry
9
Azide
Alkyne
Triazole
(%)b
94
10
79
11
12
13
83
83
71
14
15
77
79
Page 147
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Table 2. Continued
Yield
(%)b
Entry
Azide
Alkyne
Triazole
16
80
17
18
87
79
19
20
80
80
OH
N3
Cl
1h
N
N
N
O
N
N
N
21
90
O
Br
3u
Br
Page 148
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Table 2. Continued
Yield
(%)b
Entry
Azide
Alkyne
Triazole
N
22
78
2g
23
79
aReaction was performed using 1 mL of H2O and 1 mL of Isopropanol at room temperature with
5 mol% Cu2O/C and 1.1 mL of Et3N. bProduct was further purified by silica gel
chromatography.
(c) Catalyst durability
Numerous control experiments indicated not only that the Cu2O/C on charcoal is essential for
catalysis, but that it is also quite robust. For example, the recyclability of Cu2O/C was examined
for the click reaction of benzyl azide (1a) with phenylacetylene (2a). Thus after the first reaction,
which give 82% of 1-benzyl-4-phenyl-1H-1,2,3-triazole (3a), the catalyst was recovered by
simple filtration, washed with water, dried under vacuum, and reused three times under similar
reaction conditions to give 3a in 78% and 61% yields (Scheme 2).
Scheme 2
(d) One pot procedure
In an attempt to circumvent the risk of working with potentially explosive organic azides, we
investigated the possibility of carrying out the click reaction without having to isolate the azides.
Page 149
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
It is known that 1,4-disubstituted 1,2,3-triazoles can be prepared efficiently in a two step one-pot
procedure, in a CuI-zeolite-catalyzed synthesis of triazoles from halides or tosylates, sodium
azide, and alkynes at 90oC.9a Benzyl bromide and phenylacetylene were selected as model
compounds to find the appropriate conditions for the desired one-pot process. Various reaction
conditions were examined including the amount of Cu2O/C, the reaction temperature, and
different solvent systems. Once again 50% aqueous isopropanol clearly stood out as the solvent
system of choice providing a fast reaction rate at 80oC (reflux), high yield, and selectivity (see
Table 3). The scope of the reaction was explored by reacting sodium azide, benzyl bromide or
alkyl bromides (4a-d) with terminal alkynes (2a-d). The results are summarized in Table 3.
Table 3. One-pot Cu2O/C synthesis of 1,4-disubstituted triazoles from halides and related
compounds a
Entry
1
Halide
Alkyne
Triazole
3a
Yield (%)b
84
2
83
3b
3
4
80
71
3c
3d
5
5
79
77
3e
3g
O
Br
N
H
4d
6
7
71
75
3h
3i
a Run at 2 equiv of sodium azide, 1 mL of H2O and 1 mL of isopropanol at 80oC with 5 mol %
Cu2O/C and 4 equiv. of Et3N for 2 h.
b Product was further purified by silica gel chromatography.
Page 150
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
(e) Application to other systems
The synthesis of 7a-e was carried out following recently described methodology.19 This
procedure involves the condensation of salicylaldehyde derivatives with 2-aminophenols in the
presence of phenylboronic and catalytic potassium cyanide to give the 2-(2-
hydroxyphenyl)benzoxazole derivatives (7a-e). (Scheme 3)
R
R1
-H -CH3
-H -Cl
-H -NO2
R2
-H
Yield (%)
81
57
69
70
56
a
b
c
-H
-Cl
-CH3
-H
-Br
-Br
-H
-H
d
e
Scheme 3
The 2-(2-hydroxyphenyl)benzoxazole derivatives (7a-e) were subsequently alkylated with
propargyl bromide in the presence of potassium carbonate to afford the corresponding
benzoxazole derivatives 8a-e. These compounds, without purification, were reacted with benzyl
azide, under the conditions described above to give the 1,2,3-triazole derivatives 9a-e. (Scheme
4). The structure of the 1,2,3-triazole derivatives 9a-e was unequivocally established by the usual
spectroscopic means, as well as by X-ray crystal structure for compound 9d (Figure 7, vide
infra).20
Figure 7. X-Ray structure of 9d.
Page 151
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
R
R
R1
R2
R1
R2
O
O
N
HC C-CH2Br
K2CO3, acetone
5 mol% Cu2O/C
9a-e
N
iPrOH:H2O (1:1) reflux, 4 h.
Benzyl azide
OH
O
7a-e
8a-e
NO2
Cl
Cl
O
O
O
N
N
O
N
CH3
O
O
N
N
N
N
N
N
N
N
N
9c (82% isolated yield)
9b (75% isolated yield)
9a (87% isolated yield)
Br
Br
O
N
O
N
CH3
O
O
N
N
N
N
N
N
9d (80% isolated yield)
9e (89% isolated yield)
Scheme 4
The mechanism of these reactions proceeds similarly to previous reports.8a-b,21,22
Conclusions
We describe in this paper a facile preparation of a new supported catalyst (Cu2O/C) for Copper-
Catalyzed Alkyne-Azide Cycloaddition. This material was found to efficiently catalyze the
formation of several 1,4-disubstituted 1,2,3-triazoles from organic azides and various terminal
alkynes. In addition, a multicomponent, one-pot protocol for the synthesis of 1,4-disubstituted
1,2,3-triazoles from alkyl azides was devised. Considering the good triazole yields, the
operational ease with which these reactions can be carried out, and the inexpensive chemicals
involved, we believe this protocol will be of great benefit to medicinal and synthetic organic
chemistry.
Experimental Section
General. TLC was performed on Merck-DC-F254 plates, detection was made by shining UV
light. Flash column chromatography was performed using Merck silica gel (230-240 mesh).
Page 152
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
Melting points were measured in open capillary tubes on a Büchi Melting Point B-540 apparatus
1
13
and have not been corrected. H and C NMR spectra were recorded on a JEOL Eclipse+400
(400 MHz, 100 MHz)) and a Varian VNMRS 400 (400 and 100 MHz) spectrometers. Chemical
shifts (δ) are indicated in ppm downfield from internal TMS used as reference; the coupling
constants (J) are given in Hz. IR spectra were measured on a Perkin Elmer GX FT-IR. Elemental
analyses were performed on a Perkin-Elmer Series II CHNS/O Analyzer 2400.
General procedure for the preparation of 1,2,3-triazoles
In a 10 mL round-bottomed flask fitted with a magnetic stirring bar was placed 1.0 equiv. of
azide 1 and 1.0 equiv. of terminal alkyne 2 in 2 mL of [H2O:iPrOH (1:1)], further was added
Cu2O/C (5% w/w) and 1.1 mL of Et3N (for 100 mg of alkyl azide). The reaction mixture was
warmed to 80 °C and monitored by TLC until total conversion of the starting material. The crude
reaction mixture was filtered through a filter paper, washed and extracted with EtOAc or CH2Cl2
(3 × 20 mL). The combined organic extracts were washed with 15 mL of saturated aq. NH4Cl,
dried over anhydrous sodium sulfate, and evaporated under reduced pressure in vacuum. The
crude reaction mixture was purified by column chromatography or crystallization to afford 3a-w.
General procedure for the one-pot direct synthesis of 1,2,3-triazoles
In a 10 mL round-bottomed flask fitted with a magnetic stirring bar was placed 1.0 equiv. of
alkyl halide 4, 2 equiv. of sodium azide in 2 mL of [H2O:iPrOH (1:1)], 1.0 equiv. of terminal
alkyne 2, Cu2O/C (5% w/w) and 1.1 mL of Et3N (for 0.734 mmol of alkyl halide). The reaction
mixture was warmed to 80 °C and monitored by TLC until total conversion of the starting
material. The crude reaction mixture was filtered through a filter paper, washed and extracted
with EtOAc or CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with 15 mL of
saturated aq. NH4Cl, dried over anhydrous sodium sulfate, and evaporated under reduced
pressure in vacuum. The crude reaction mixture was purified by column chromatography or
crystallization to afford 3a-e and 3g-i.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (3a).7a,8a,8d,9a,15,23,24 The general procedure was followed
using 0.1 g (0.734 mmol) of benzyl azide (1a), 0.81 mL (0.734 mmol) of phenylacetylene, 5 mg
of Cu2O/C and 1.1 mL of Et3N to give 0.139 g (82%) of 3a as a white solid. Purification was
performed by crystallization using (ethyl acetate/diethyl ether). Mp 131-133 °C (lit.23a mp: 130-
132°C; lit.8c mp: 129-129.5°C).
(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl benzoate (3b). The general procedure was followed
using 0.10 g (0.734 mmol) of benzyl azide (1a), 0.10 mL (0.734 mmol) of propargyl benzoate, 5
mg of Cu2O/C and 1.1 mL of Et3N to give 0.180 g (84%) of 3b as a white solid. The solid
residue was purified by crystallization using (ethyl acetate/diethyl ether). Mp 106-109 °C; IR
1
(film) vmax/cm-1: 3070, 1722, 1603, 1453, 1275, 1111, 1052, 956, 713; H NMR (400 MHz,
CDCl3) δ/ppm: 7.94 (m, 2H), 7.54 (s, 1H), 7.45 (m, 1H), 7.35-7.19 (m, 7H,), 5.44 (s, 2H), 5.36
(s, 2H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 166.4, 143.3, 134.3, 133.2, 129.8, 129.6, 129.1,
Page 153
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
128.8, 128.3, 128.1, 123.8, 58.0, 54.2 Anal. Calcd for C17H15N3O2 C, 69.61; H, 5.15; N, 14.33.
Found: C, 69.98; H, 4.86; N, 13.96%.
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanol (3c).8c,18a,25 The general procedure was followed
using 0.10 g (0.734 mmol) of benzyl azide (1a), 0.16 mL (1.1 mmol) of propargyl alcohol, 5 mg
of Cu2O/C and 1.1 mL of Et3N to give 0.096 g (69%) of 3c as a white solid. The solid residue
was purified by crystallization using (hexane/diethyl ether). Mp 77-79°C (lit.8c mp: 78-78.5 °C.
Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (3d).8d,10,23a,24a The general procedure was
followed using 0.10 g (0.825 mmol) of ethyl azidoacetate (1b), 0.09 mL (0.825 mmol) of
phenylacetylene, 5 mg of Cu2O/C and 1.1 mL of Et3N to give 0.150 g (77%) of 3d as a white
solid. The solid residue was purified by crystallization using (hexane/diethyl ether). Mp 94-96 °C
(lit.23a mp: 93-95 °C; lit.10 mp: 94-95 °C).
1,4-Bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]benzene (3e). The general procedure was
followed using 0.10 g (0.531 mmol) of 1,4-bis(azidomethyl)benzene (1c), 0.116 mL (1.06 mmol)
of phenylacetylene, 5 mg of Cu2O/C and 1.1 mL of Et3N to give 0.280 g (79%) of 3e as a yellow
solid. The solid residue was purified by flash chromatography using (ethyl acetate / hexane). Mp
1
253-255 °C; IR (film) vmax/cm-1: 3098, 2924, 1470, 1363, 772, 482; H NMR (400 MHz, CDCl3)
δ/ppm: 8,61 (s, 2H), 7.80 (m, 4H), 7.41-7.29 (m, 10H), 5.61 (s, 4H). 13C NMR (CDCl3, 100
MHz) δ/ppm: 147.1, 136.4, 131.0, 129.3, 128.8, 128.3, 125.6, 122.1, 53.1. Anal. Calcd for
C24H20N6 C, 73.45; H, 5.14; N, 21.41. Found: C, 73.25; H, 4.98; N, 21.32%.
1,4-diphenyl-1H-1,2,3-triazole (3f).10a, 23a, 23b, 23d, 24a The general procedure was followed using
0.515 g (4.3 mmol) of phenyl azide (1d), 0.47 mL (4.3 mmol) of phenylacetylene, 5 mg of
Cu2O/C and 5.6 mL of Et3N to give 0.767 g (84%) of 3f as a yellow solid. The solid residue was
purified by crystallization using (dichloromethane/diethyl ether). Mp 183-185 °C (lit.23a mp: 183-
184°C).
(R)-2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-N-(1-phenylethyl)acetamide (3g). The general procedure
was followed using 0.480 g (2.35 mmol) of (R)-2-azido-N-(1-phenylethyl)acetamide (1e), 0.258
mL (2.35 mmol) of phenylacetylene, 25 mg of Cu2O/C and 5.3 mL of Et3N to give 0.640 g
(89%) of 3g as a white solid. The solid residue was purified by crystallization using
(hexane/diethyl ether). Mp 244-245 °C; IR (film) vmax/cm-1: 3275, 3095, 1658, 1561, 750, 688 ;
1H NMR (DMSO-d6, 400 MHz) δ/ppm: 8.86 (d, 1H, J 6.4 Hz), 8.47 (s, 1H), 7.81 (m, 2H), 7.41-
7.20 (m, 8H), 5.15 (s, 2H), 4.90 (m, 1H), 1.36 (d, 3H, J 6.8 Hz). 13C NMR (DMSO-d6, 100 MHz)
δ/ppm: 164.8, 146.4, 144.4, 131.1, 129.3, 128.8, 128.3, 127.3, 126.4, 125.5, 123.4, 52.1, 48.8,
22.8. Anal. Calcd for C18H18N4O C, 70.57; H, 5.92; N, 18.29. Found: C, 70.31; H, 5.69; N,
18.65%.
[1,1-[1,4-phenylenebis(methylene)]bis(1H-1,2,3-triazol-4,1-diyl)]dimethanol (3h). The general
procedure was followed using 0.10 g (0.531 mmol) of 1,4-bis(azidomethyl)benzene (1c), 0.065
mL (1.06 mmol) of propargyl alcohol, 5 mg of Cu2O/C and 1.1 mL of Et3N to give 0.767 g
(84%) of 3h as a yellow solid. The solid residue was purified by crystallization using (ethyl
acetate/diethyl ether). Mp 71-74 °C; IR (film) vmax/cm-1: 3163, 2928, 1652, 1467, 1258, 1041,
1
860, 766; H NMR (DMSO-d6, 400 MHz) δ/ppm: 7.98 (s, 2H), 7.37 (s, 4H), 5.54 (s, 4H), 5.15
Page 154
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
(m, 2H), 4.44 (m, 4H). 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 148.8, 135.9, 129.2, 123.3, 55.4,
53.6. Anal. Calcd for C14H16N6O2 C, 55.99; H, 5.36; N, 27.98. Found: C, 55.71; H, 4.99; N,
27.72%.
4,4-[Oxybis(methylene)]bis(1-benzyl-1H-1,2,3-triazole) (3i).7a The general procedure was
followed using 0.10 g (0.367 mmol) of benzyl azide (1a), 0.047 mL (1.06 mmol) of propargyl
ether, 5 mg of Cu2O/C and 1.1 mL of Et3N to give 0.248 g (94%) of 3i as a yellow solid. The
solid residue was purified by crystallization using (dichloromethane/diethyl ether). Mp 124-126
1
°C; IR (film) vmax/cm-1: 3141, 2937, 2869, 1606 ,1457, 1223, 1129, 1055, 728 ; H NMR
13
(DMSO-d6, 400 MHz) δ/ppm: 8.13 (s, 2H), 7.34-7.24 (m, 10H), 5.54 (s, 4H), 4.50 (s, 4H),. C
NMR (DMSO-d6, 100 MHz) δ/ppm: 144.3, 136.5, 129.1, 128.5, 128.3, 124.6, 63.1, 53.1. Anal.
Calcd for C20H20N6O C, 66.65; H, 5.59; N, 23.32. Found: C, 66.40; H, 5.40; N, 22.99%.
(R)-2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-N-(1-phenylethyl)acetamide (3j). The general
procedure was followed using 0.20 g (0.979 mmol) of (R)-2-azido-N-(1-phenylethyl)acetamide
(1e), 0.058 mL (1.06 mmol) of propargyl alcohol, 10 mg of Cu2O/C and 2.2 mL of Et3N to give
0.189 g (79%) of 3j as a yellow solid. The solid residue was purified by crystallization using
(ethyl acetate/diethyl ether). Mp 92-94 °C; IR (film) vmax/cm-1: 2934, 1670, 1562, 1252, 1041,
702 ; 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 8.78 (m, 1H), 7.85 (s, 1H), 7.30-7.20 (m, 5H), 5.07
13
(s, 2H), 4.88 (m, 1H), 4.45 (d, 2H, J 5.6 Hz), 1.33 (d, 3H, J 7.2 Hz). C NMR (DMSO-d6, 100
MHz) δ/ppm: 164.9, 148.0, 144.4, 128.8, 127.3, 126.4, 124.6, 55.4, 51.9, 48.7, 22.8. Anal. Calcd
for C13H16N4O2 C, 59.99; H, 6.20; N, 21.52. Found C, 60.22; H, 6.64; N, 21.71%.
2,2-[4,4-[Oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl)]]bis-N-[(R)-1-phenylethyl]acet-
amide (3k). The general procedure was followed using 0.210 g (1.02 mmol) of (R)-2-azido-N-
(1-phenylethyl)acetamide (1e), 0.048 mL (1.06 mmol) of propargyl ether, 10 mg of Cu2O/C and
2.3 mL of Et3N to give 0.603 g (83%) of 3k as a yellow solid. The solid residue was purified by
flash chromatography using ethyl acetate/hexane. Mp 182-184 °C; IR (film) vmax/cm-1: 3300,
2976, 2681, 2499, 1669, 1565, 1059, 701 ; 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 8.96 (m, 2H),
8.01 (s, 2H), 7.29-7.18 (m, 10H), 5.13 (s, 4H), 4.87 (m, 2H), 4.51 (s, 4H), 1.34 (d, 6H, J 6.8 Hz).
13C NMR (DMSO-d6, 100 MHz) δ/ppm: 164.9, 144.5, 143.7, 128.5, 127.5, 126.4, 126.1, 62.9,
51.9, 48.8, 22.9.
1-Benzyl-4-(phenoxymethyl)-1H-1,2,3-triazole (3l).1c,8d,15,23b,25 The general procedure was
followed using 0.10 g (0.734 mmol) of benzyl azide (1a), 0.097 g (0.734 mmol) of (prop-2-yn-1-
yloxy)benzene (2e), 5 mg of Cu2O/C and 1.1 mL of Et3N to give 0.161 g (83%) of 3l as a white
solid. The solid residue was purified by crystallization using (ethyl acetate/diethyl ether). Mp
1
126-128 °C; IR (film) vmax/cm-1: 3134, 1599, 1495, 1224, 1007, 756; H NMR (CDCl3, 400
MHz) δ/ppm: 7.51 (s, 1H), 7.35-7.23 (m, 7H,), 6.95-6.93 (m, 3H), 5.47 (s, 2H), 5.15 (s, 2H). 13C
NMR (CDCl3, 100 MHz) δ/ppm: 158.1, 144.6, 134.3, 129.5, 129.2, 128.8, 128.1, 122.6, 121.3,
114.7, 61.9, 59.3. Anal. Calcd for C16H15N3O C, 72.43; H, 5.70; N, 15.84. Found: C, 72.48; H,
5.62; N, 15.98%.
1,4-Bis[[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]methyl]benzene (3m). The general procedure
was followed using 0.15 g (0.797 mmol) of 1,4-bis(azidomethyl)benzene (1c), 0.240 g (1.59
Page 155
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
mmol) of (prop-2-yn-1-yloxy)benzene (2e), 7.5 mg of Cu2O/C and 1.65 mL of Et3N to give
0.255 g (71%) of 3m as a white solid. The solid residue was purified by crystallization using
(ethyl acetate/diethyl ether). Mp 192-194 °C; IR (film) vmax/cm-1: 3145, 1595, 1433, 1212, 1006,
1
758 ; H NMR (CDCl3, 400 MHz) δ/ppm: 7.53 (s, 2H), 7.27-7.23 (m, 8H), 6.94-6.92 (m, 6H),
5.50 (s, 4H), 5.17 (s, 4H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 158.1, 144.8, 135.2, 129.6,
128.8, 122.7, 121.3, 114.7, 61.9, 53.7. Anal. Calcd for C26H24N6O2 C, 69.01; H, 5.35; N, 18.57.
Found: C, 69.07; H, 5.16; N, 18.44%.
(R)-2-[4-(Phenoxymethyl)-1H-1,2,3-triazol-1-yl]-N-(1-phenylethyl)acetamide (3n). The general
procedure was followed using 0.200 g (0.797 mmol) of (R)-2-azido-N-(1-phenylethyl)acetamide
(1e), 0.130 g (0.980 mmol) of (prop-2-yn-1-yloxy)benzene (2e), 10 mg of Cu2O/C and 2.2 mL of
Et3N to give 0.253 g (77%) of 3n as a white solid. The solid residue was purified by
crystallization using (ethyl acetate/diethyl ether). Mp 132-135 °C; IR (film) vmax/cm-1: 3287,
1
3063, 1669, 1599, 1551, 1494, 1240, 1032, 754; H NMR (CDCl3, 400 MHz) δ/ppm: 7.76 (s,
1H), 7.29-7.18 (m, 7H), 6.97-6.93 (m, 3H), 5.14 (s, 2H), 5.03 (m, 1H), 4.94 (m, 2H), 1.40 (d, 3H,
13
J 7.2 Hz). C NMR (CDCl3, 100 MHz) δ/ppm: 164.1, 158.0, 144.6, 142.3, 129.6, 128.7, 127.5,
126.1, 124.6, 121.4, 114.7, 61.8, 52.8, 49.6, 21.7. Anal. Calcd for C19H20N4O2 C, 67.84; H, 5.99;
N, 16.66. Found: C, 67.67; H 5.35; N, 16.78%.
1,3,5-Tris[(4-phenyl-1H-1,2,3-triazol-yl)methyl]benzene (3o).7a,24 The general procedure was
followed using 0.10 g (1.23 mmol) of 1,2,3-tris(azidomethyl)benzene (1f), 0.134 mL (1.23
mmol) of phenylacetylene (2a), 5 mg of Cu2O/C and 1.1 mL of Et3N to give 0.120 g (79%) of 3n
as a white solid. The solid residue was purified by flash chromatography using (ethyl
1
acetate/hexane). Mp 221-223 °C; IR (film) vmax/cm-1: 3076, 2938, 1430, 1353, 762 ; H NMR
(DMSO-d6, 400 MHz) δ/ppm: 8.56 (s, 3H), 7.76 (d, 6H, J 7.3 Hz), 7.37 (t, 6H, J 7.3 Hz), 7.29
(m, 9H), 5.61 (s , 6H). 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 147.2, 137.8, 131.2, 129.4,
128.5, 127.8, 125.7, 122.0, 53.1.
1-Benzyl-4-[(4-bromophenoxy)methyl]-1H-1,2,3-triazole (3p). The general procedure was
followed using 0.20 g (1.46 mmol) of benzyl azide (1a), 0.308 g (1.46 mmol) of 1-bromo-4-(pro-
2-yn-1-yloxy)benzene (2f), 10 mg of Cu2O/C and 2.2 mL of Et3N to give 0.402 g (80%) of 3p as
a white solid. The solid residue was purified by crystallization using (acetone/diethyl ether). Mp
132-134 °C; IR (film) vmax/cm-1: 3139, 1623, 1585, 1489, 1227, 995, 619 ; 1H NMR (CDCl3, 400
MHz) δ/ppm: 7.44 (s, 1H), 7.30-7.23 (m, 5H,), 7.19-7.15 (m, 2H), 6.76 (d, 2H, J 8.8 Hz), 5.12 (s,
2H), 5.03 (s, 2H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 157.2, 144.1, 134.3, 132.3, 129.1, 128.8,
128.1, 127.7, 122.7, 116.5, 113.4, 62.1, 54.2 Anal. Calcd for C16H14BrN3O C, 55.83; H, 4.10; N,
12.21. Found: C, 55.84; H, 4.03; N, 11.88% HRMS (ESI) Calcd for C16H14BrN3O [(M+H)+]
344.0399; Found 344.0393.
1,4-Bis[[4-[(4-bromophenoxy)methyl]-1H-1,2,3-triazol-4-yl]methyl]benzene (3q). The general
procedure was followed using 0.20 g (1.06 mmol) of 1,4-bis(azidomethyl)benzene (1c), 0.45 g
(2.12 mmol) of 1-bromo-4-(pro-2-yn-1-yloxy)benzene (2f), 10 mg of Cu2O/C and 2.2 mL of
Et3N to give 0.564 g (87%) of 3q as a yellow solid. The solid residue was purified by
crystallization using (ethyl acetate/hexane). Mp 177-179°C; IR (film) vmax/cm-1: 3074, 1590,
Page 156
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
1489, 1238, 1040, 814, 619 ; 1H NMR (DMSO-d6, 400 MHz) δ/ppm: 8.23 (s, 2H), 7.40 (d, 4H, J
8.8 Hz), 7.27 (s, 4H), 6.95 (d, 4H, J 9.2 Hz), 5.55 (s, 4H), 5.07 (s, 4H). 13C NMR (DMSO-d6, 100
MHz) δ/ppm: 157.7, 143.1, 136.4, 132.6, 128.8, 125.2, 117.5, 112.7, 61.7, 52.8 Anal. Calcd for
C26H22Br2N6O2 C, 51.17; H, 3.63; N, 13.77. Found: C, 51.02; H, 3.60; N, 13.50%. HRMS (ESI)
Calcd for C26H22Br2N6O2 [(M+H)+] 609.0250; Found 609.0244.
1,3-Bis[(4-benzyl-1H-1,2,3-triazol-yl)methyl]benzene (3r). The general procedure was
followed using 0.50 g (2.65 mmol) of 1,3-bis(azidomethyl)benzene (1g), 0.58 mL (5.31 mmol)
of phenylacetylene (2a), 25 mg of Cu2O/C and 5.5 mL of Et3N to give 0.821 g (79%) of 3r as a
white solid. The solid residue was purified by crystallization using ethyl acetate. Mp 162-164°C;
1
IR (film) vmax/cm-1: 3130, 2919, 1609, 1432, 1221, 1074, 764 ; H NMR (CDCl3, 400 MHz)
δ/ppm: 7.77 (dd, 4H, J 1.2 Hz, J 8.0 Hz), 7.68 (s, 2H,), 7.40-7.37(m, 4H), 7.32-7.24 (m,6H), 5.54
(s, 4H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 148.3, 135.9, 130.2, 130.0, 128.8, 128.3, 128.2,
127.3, 125.7, 119.6, 53.8 Anal. Calcd for C24H20N6 C, 73.45; H, 5.14; N, 21.41 Found: C, 73.02;
H, 5.16; N, 21.59%. HRMS (ESI) Calcd for C24H20N6, [(M+H)+] 393.1828 ; Found 393.1826.
1,3-Bis[[(4-phenoxymethyl)-1H-1,2,3-triazol-1-yl]methyl]benzene (3s). The general procedure
was followed using 0.39 g (2.07 mmol) of 1,3-bis(azidomethyl)benzene (1g), 0.540 g (4.14
mmol) of (prop-2-yn-1-yloxy)benzene (2e), 19 mg of Cu2O/C and 4.3 mL of Et3N to give 0.739
g (80%) of 3s as a white solid. The solid residue was purified by crystallization using ethyl
1
acetate. Mp 115-117°C; IR (film) vmax/cm-1: 3140, 2924, 1601, 1498, 1247, 1030, 756; H NMR
(CDCl3, 400 MHz) δ/ppm: 7.54 (s, 2H), 7.34 (t, 1H, J 7.6 Hz), 7.27-7.15 (m, 6H,), 7.13 (m, 1H)
6.95-6.92 (m, 6H), 5.47 (s, 4H), 5.15 (s, 4H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 158.1, 144.8,
135.6, 130.0, 129.5, 128.3, 127.5, 122.8, 121.3, 114.7, 61.9, 53.7 Anal. Calcd for C26H24N6O2 C,
69.01; H, 5.35; N, 18.57. Found: C, 68.70; H, 5.32; N, 18.43%. HRMS (ESI) Calcd for
C26H24N6O2 [(M+H)+] 453.2040; Found 453.2034.
5-Chloro-2-(4-phenyl-1H-1,2,3-triazol-1-yl)phenol (3t). The general procedure was followed
using 0.375 g (2.22 mmol) of 2-azido-5-chlorophenol (1h), 0.244 mL (2.22 mmol) of
phenylacetylene (2a), 19 mg of Cu2O/C and 4.12 mL of Et3N to give 0.480 g (80%) of 3t as a
white solid. The solid residue was purified by flash chromatography using (ethyl acetate/hexane).
1
Mp 276-278 °C; IR (film) vmax/cm-1: 3452, 2919, 2850, 1601, 1438, 1235, 1060, 757; H NMR
(DMSO-d6, 400 MHz) δ/ppm: 8.93 (s, 1H), 7.95(d, 2H, J 6.8), 7.67 (d, 1H, J 8 Hz), 7.48 (m,
2H), 6.37 (m, 1H), 7.20 (d, 1H, J 2 Hz), 7.09 (dd, 1H, J 2.4 Hz, J 8.4 Hz). 13C NMR (DMSO-d6,
100 MHz) δ/ppm: 151.7, 146.7, 134.5, 130.8, 129.4, 128.5, 127.3, 125.7, 124.2, 123.5, 119.7,
117.1. Anal. Calcd for C14H10ClN3O C, 61.89; H, 3.71; N, 15.47. Found: C, 61.50; H, 3.66; N,
14.89%. HRMS (ESI) Calcd for C14H10ClN3O [(M+H)+] 272.0591; Found 272.0584.
1,3-Bis[[4-[(4-bromophenoxy)methyl]-1H-1,2,3-triazol-1-yl]methyl]benzene (3u). The general
procedure was followed using 0.20 g (1.06 mmol) of 1,3-bis(azidomethyl)benzene (1g), 0.45 mL
(1.14 mmol) of 1-bromo-4-(prop-2-yn-1-yloxy)benzene (2f), 10 mg of Cu2O/C and 2.2 mL of
Et3N to give 0.580 g (90%) of 3u as a brown solid. The solid residue was purified by
crystallization using dichloromethane. Mp 166-168 °C; IR (film) vmax/cm-1: 3153, 1592, 1489,
1
1253, 1044, 825; H NMR (DMSO-d6, 400 MHz) δ/ppm: 8.25 (s, 2H), 7.42 (d, 4H, J 9.2 Hz),
Page 157
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
7.35 (t, 1H, J 7.6 Hz ), 7.30 (m, 1H), 7.22 (dd, 2H, J 1.6 Hz, J 7.6 Hz), 6.97 (d, 4H, J 9.2 Hz),
13
5.57 (s, 4H), 5.09 (s, 4H). C NMR (DMSO-d6, 100 MHz) δ/ppm: 157.7, 143.1, 137.0, 132.5,
129.8, 128.2, 128.0, 125.3, 117.5, 112.7, 61.7, 53.0. Anal. Calcd for C26H22Br2N6O2 C, 51.17; H,
3.63; N, 13.77. Found: C, 51.13; H, 3.46; N, 13.01%. HRMS (ESI) Calcd for C26H22 Br2N6O2
[(M+H)+] 609.0250; Found 609.0239.
2-(1-Benzyl-1H-1,2,3-triazol-1-yl)pyridine (3v). The general procedure was followed using
0.10 g (0.734 mmol) of benzyl azide (1a), 0.073 mL (0.734 mmol) of 2-ethynylpyridine (2g), 5
mg of Cu2O/C and 1.1 mL of Et3N to give 0.130 g (78%) of 3v as a white solid. The solid
residue was purified by crystallization using (ethyl acetate/hexane). Mp 118-120 °C; IR (film)
1
vmax/cm-1: 3106, 1595, 1421, 1224, 1045, 786, 727 ; H NMR (CDCl3, 400 MHz) δ/ppm: 8.50
(m, 1H), 8.14 (dd, 1H, J 1.2 Hz, J 8.4 Hz), 8.02 (s,1H), 7.37 (td, 1H, J 2.4 Hz, J 8.4 Hz), 7.35-
7.29 (m, 5H), 7.18-7.16 (m, 1H), 5.55 (s, 2H). 13C NMR (CDCl3, 100 MHz) δ/ppm: 150.2, 149.3,
148.7, 136.9, 134.3, 129.1, 128.8, 128.3, 122.8, 121.9, 120.2, 54.3. Anal. Calcd for C14H12N4 C,
71.17; H, 5.12; N, 23.71. Found: C, 70.93; H, 5.13; N, 23.78%. HRMS (ESI) Calcd for C14H12N4
[(M+H)+] 237.1141; Found 237.1136.
1,3,5-Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyloxy]benzene (3w). The general procedure
was followed using 0.20 g (1.46 mmol) of benzyl azide (1a), 0.117 g (0.489 mmol) of 1,3,5-
tris(prop-2-ynyloxy)benzene (2h), 10 mg of Cu2O/C and 2.2 mL of Et3N to give 0.130 g (78%)
of 3w as a white solid. The solid residue was purified by crystallization using (ethyl
acetate/hexane). Mp 144-146°C; IR (film) vmax/cm-1: 3141, 1610, 1457, 1153, 1051, 804, 720 ;
1H NMR (DMSO-d6, 400 MHz) δ/ppm: 8.24 (s, 3H), 7.33-7.26 (m, 15H), 6.27 (s,3H), 7.57 (s,
6H), 5.03 (s, 6H). 13C NMR (DMSO-d6, 100 MHz) δ/ppm: 160.2, 143.3, 136.4, 129.2, 128.6,
128.4, 125.2, 94.9, 61.5, 53.3. Anal. Calcd for C36H33N9O3 C, 67.59; H, 5.20; N, 19.71. Found:
C, 67.36; H, 5.07 N, 19.62%. HRMS (ESI) Calcd for C36H33N9O3 [(M+H)+], 640.2785; Found
640.2778.
2-[2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl]-5-methylbenzoxazole (9a). The general
procedure was followed using 0.1 g (0.73 mmol) of benzyl azide (1a), 0.20 g (0.76 mmol) of 5-
methyl-2-(2-prop-2-yn-1-yloxy)phenyl)benzoxazole (8a), 10 mg of Cu2O/C and 2.2 mL of Et3N
to give 0.26 g (87%) of 9a as a white solid. The solid residue was purified by flash
chromatography using (ethyl acetate/hexane). Mp. 179-180oC. IR (film) vmax/cm-1: 3412, 2346,
1
1585, 1603, 133.2, 2918; H NMR (400 MHz, CDCl3) δ/ppm: 8.04 (dd, J 2.0 Hz, J 7.6 Hz, 1H,
2H), 7.74 (s, 1H), 7.40 (ddd, J 2.0 Hz, J 7.6 Hz, J 8.4 Hz, 1H), 7.32 (m, 1H), 7.30 (m, 3H), 7.21
(m, 2H), 7.40 (d, J 8.4 Hz, 1H), 7.10 (d, J 8.0 Hz, 1H), 7.03 (m, 2H), 5.46 (s, 2H), 5.32 (s, 2H),
2.41 (s, 3H).13C NMR (100 MHz, CDCl3) δ/ppm: 161.6, 156.9, 148.6, 145.2, 142.2, 134.6,
134.0, 132.7, 131.2, 129.2, 128.8, 128.1, 126.1, 122.8, 121.5, 119.8, 116.9, 114.0, 109.7, 63.9,
54.3, 21.5. Anal. Calcd for C24H20N4O2 C, 72.71; H, 5.08; N, 14.13. Found: C, 72.43; H, 5.09; N,
14.16%.
2-[2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxyl]phenyl]-6-chlorobenzoxazole (9b). The general
procedure was followed using 0.10 g (0.73 mmol) of benzyl azide (1a), 0.20 g (0.73 mmol) of 6-
Page 158
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
chloro-2-(2-prop-2-yn-1-yloxy)phenyl)benzoxazole (8b), 10 mg of Cu2O/C and 2.2 mL of Et3N
to give 0.22 g (75%) of 9b as a white solid. The solid residue was purified by crystallization
using (ethyl acetate/hexane). Mp. 171-172oC. IR (film) vmax/cm-1: 763, 3453, 2346, 1452, 1598,
133.2, 2920; 1H NMR (400 MHz, CDCl3) δ/ppm: 8.07 (dd, J 1.7 Hz, J 7.8 Hz, 1H), 7.74 (s, 1H),
7.47 (ddd, J 1.7 Hz, J 7.3 Hz, 1H), 7.47 (d, J 8.4 Hz, 1H), 7.39 (d, J 1.8 Hz, 1H), 7.36 (m, 3H),
7.27 (m, 3H), 7.17 (dd, J 0.7 Hz, J 8.4 Hz, 1H), 7.09 (td, J 1.0 Hz, J 7.7 Hz, 1H), 5.53 (s, 2H),
5.37 (s, 2H). 13C NMR (100 MHz, CDCl3) δ/ppm: 162.2, 157.0, 150.5, 144.9, 140.7, 134.4,
133.2, 131.3, 130.5, 129.2, 128.9, 128.2, 125.0, 122.7, 121.5, 120.4, 116.2, 113.9, 110.9, 63.8,
54.3. Anal. Calcd for C23H17ClN4O2 C, 66.27; H, 4.11; N, 13.44. Found: C, 66.25; H, 4.02; N,
13.47%.
2-[2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl]-5-chloro-6-nitrobenzoxazole (9c). The
general procedure was followed using 0.08 g (0.61 mmol) of benzyl azide (1a), 0.20 g (0.61
mmol) of 5-chloro-6-nitro-2-(2-prop-2-ynyloxy)phenyl)benzoxazole (8c), 10 mg of Cu2O/C and
2.2 mL of Et3N to give 0.23 g (82%) of 9c as a yellow solid. The solid residue was purified by
crystallization using (ethyl acetate/hexane). Mp. 188-189oC.1H NMR (400 MHz, CDCl3) δ/ppm:
8.07 (dd, J 2.0 Hz, J 8.0 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 7.5 (ddd, J 1.6 Hz, J
7.2 Hz, J 8.8 Hz, 1H), 7.34-7.31 (m, 3H), 7.23 (dd, J 2.8 Hz, J 7.6 Hz, 2H), 7.18 (d, J 7.6 Hz,
13
1H), 7.07 (td, J 1.0 Hz, J 7.6 Hz, J 8.4 Hz, 1H), 5.50 (s, 1H), 5.33 (s, 1H). C NMR (100 MHz,
CDCl3) δ/ppm: 166.5, 157.6, 147.7, 145.8, 144.4, 134.5, 134.3, 131.7, 129.3, 129.1, 128.2,
123.4, 122.6, 122.0, 121.6, 114.9, 113.9, 108.4, 63.6, 54.4. Anal. Calcd for C23H16ClN5O4; C,
59.81; H, 3.49; N, 15.16. Found: C, 59.58; H, 3.29; N, 14.88%.
2-[2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-5-bromophenyl]-5-methylbenzoxazole (9d).
The general procedure was followed using 0.079 g (0.58 mmol) of benzyl azide (1a), 0.20 g
(0.58 mmol) of 2-(5-bromo-2-(prop-2-ynyloxy)phenyl)-5-methylbenzoxazole (8d), 10 mg of
Cu2O/C and 2.2 mL of Et3N to give 0.22 g (80%) of 9d as a white solid The solid residue was
purified by flash chromatography using (ethyl acetate/hexane). Mp. 193-195oC. IR (film)
1
vmax/cm-1: 757, 3440, 2345, 1594, 1592, 1033, 2919.3. H NMR (400 MHz, CDCl3) δ/ppm: 8.16
(s, 1H), 7.71 (s, 1H), 7.46 (d, J 8 Hz, 1H), 7.34-7.30 (m, 4H), 7.14-7.21 (m, 3H), 7.05 (d, J 8 Hz,
13
1H), 7.01 (d, J 8 Hz, 1H), 5.46 (s, 2H), 5.29 (s, 2H), 2.41 (s, 3H). C NMR (100 MHz, CDCl3)
δ/ppm: 160.0, 155.8, 148.5, 144.5, 141.9, 135.1, 134.4, 134.3, 133.5, 129.2, 128.8, 128.1, 126.5,
122.8, 119.9, 118.6, 115.8, 113.7, 109.7, 64.0, 54.31, 21.5. Anal. Calcd for C24H19BrN4O2; C,
60.64; H, 4.04; N, 11.79. Found: C, 60.66; H, 3.64; N, 11.56%.
2-[2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyloxy]-5-bromophenyl]benzoxazole (9e). The
general procedure was followed using 0.09 g (0.66 mmol) of benzyl azide (1a), 0.200 g (0.61
mmol) of 2-(5-bromo-2-(prop-2-yn-1-yloxy)phenyl)benzoxazole (8e), 10 mg of Cu2O/C and 2.2
mL of Et3N to give 0.25 g (89%) of 9e as a white solid. The solid residue was purified by
crystallization using (ethyl acetate/hexane). Mp. 179-180oC. IR (film) vmax/cm-1: IR (film)
1
vmax/cm-1: 739, 3440, 2341, 1541, 1613, 1033, 2926; H NMR (400 MHz, CDCl3) δ/ppm: 8.18
(d, J 2.0 Hz, 1H), 7.70 (s, 1H), 7.56 (ddd, J 0.6 Hz, J 3.0 Hz, J 7.5 Hz, 1H), 7.48 (dd, J 2.5 Hz, J
13
8.8 Hz, 1H), 7.27 (m, 6H), 7.20 (m, 2H), 7.03 (d, J 8.9 Hz, 1H), 5.46 (s, 2H), 5.30 (s, 2H). C
Page 159
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
NMR (100 MHz, CDCl3) δ/ppm: 160.0, 156.0, 150.3, 144.5, 141.7, 135.3, 134.4, 133.6, 129.2,
128.9, 128.2, 125.4, 124.5, 122.9, 120.1, 118.5, 116.0, 113.8, 110.4, 64.0, 54.3. Anal. Calcd for
C23H17BrN4O2; C, 59.88; H, 3.71; N, 12.15. Found: C, 59.86; H, 3.78; N, 11.98%.
Acknowledgements
We are indebted to Dr. Joseph M. Muchowski for friendly, helpful discussions and to
CONACyT for financial support (grant CB-2009-01-135172), PROMEP (Síntesis Química y
Supramolecular-project-2012) and Dr. José Antonio Rodríguez-Ávila for determination of
copper content in the catalyst.
References
1. (a) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984.
(b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004-2021.
http://dx.doi.org/10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.3.CO;2-X
(c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596-2599.
http://dx.doi.org/10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4
(d) Kelly, A. R.; Wei, J.; Kesavan, S.; Marié, J.–C.; Windmon, N.; Young, D. W.;
Marcaurelle, L. A. Org. Lett. 2009, 11, 2257-2260.
http://dx.doi.org/10.1021/ol900562u; PMid:19473044 PMCid:2702139.
(e) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057- 3064.
http://dx.doi.org/10.1021/jo011148j
2. (a) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radiӕ, Z.; Carlier, P. R.; Taylor, P.; Finn, M.
G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 1053-1057.
(b) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A.
Med. Res. Rev. 2008, 28, 278-308.
http://dx.doi.org/10.1002/med.20107; PMid:17763363.
(c) Lee, T.; Cho, M.; Ko, S.-Y.; Youn, H.-J.; Baek, D. J.; Cho, W.-J.; Kang, C.-Y.; Kim, S. J.
Med. Chem. 2007, 50, 585-589.
http://dx.doi.org/10.1021/jm061243q; PMid:17266209.
(d) Maurya, S. K.; Gollapalli, D. R.; Kirubakaran, S.; Zhang, M.; Johnson, C. R.; Benjamin,
N. N.; Hedstrom, L.; Cuny, G. D. J. Med. Chem. 2009, 52, 4623-4630.
http://dx.doi.org/10.1021/jm900410u; PMid:19624136 PMCid:2810100.
(e) Kold, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128-1137.
Page 160
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
(f) Puig-Basagoiti, F.; Qing, M.; Dong, H.; Zhang, B.; Zou, G.; Yuan, Z.; Shi, P.-Y. Antiviral
Res. 2009, 83, 71-79.
http://dx.doi.org/10.1016/j.antiviral.2009.03.005; PMid:19501258 PMCid:3214651.
(g) Guezguez, R.; Bougrin, K.; Akri, K. E.; Benhida, R. Tetrahedron Lett. 2006, 47, 4807-
4811.
http://dx.doi.org/10.1016/j.tetlet.2006.05.050
3. (a) Huisgen, R.; Knorr, R.; Moebius, L.; Szeimies, G. Chem. Ber. 1965, 98, 4014-4021.
http://dx.doi.org/10.1002/cber.19650981228
(b) Huisgen, R. Pure Appl. Chem. 1989, 61, 613-628.
http://dx.doi.org/10.1351/pac198961040613
4. (a) Kwok, A. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin, V. V. Org. Lett. 2010,
12, 4217-4219.
(b) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, L. D.; Sharples, K. B.; Fokin, V.
V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998- 15999.
http://dx.doi.org/10.1021/ja054114s; PMid:16287266.
5. For recent reviews, see: (a) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org.
Chem. 2006, 54-68.
(b) Moses, H. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249-1262.
http://dx.doi.org/10.1039/b613014n; PMid:17619685.
(c) Melda, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952-3015.
http://dx.doi.org/10.1021/cr0783479; PMid:18698735.
6. (a) Diez-González, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem, Eur. J. 2006, 12, 7558-
7564.
http://dx.doi.org/10.1002/chem.200600961; PMid:16969776.
(b) Broggi, J.; Díez-González, S.; Petersen, J. L.; Berteina-Raboin, S.; Nolan, S. P.; Agrofolio, L.
A. Synthesis 2008, 141-148.
7. (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2853-2855.
PMid:15330631.
(b) Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A. Jr. Tetrahedron 2006, 62, 6405-6411.
http://dx.doi.org/10.1016/j.tet.2006.04.025
8. (a) Lipshutz, B. H.; Taft, B. R. A. Angew. Chem., Int. Ed. 2006, 45, 8235-8238.
(b) Lipshutz, B. Frieman, B. A.; Tomaso, A. E. Jr. Angew. Chem., Int. Ed. 2006, 45, 1259-
1264.
http://dx.doi.org/10.1002/anie.200503149; PMid:16425315.
(c) Sharghi, H.; Khalifeh, R.; Doroodmand, M. M. Adv. Synth. Catal. 2009, 351, 207-212.
(d) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Adv. Synth. Catal. 2010, 352, 3208-3214.
http://dx.doi.org/10.1002/adsc.201000637
(e) Lee, C.-T.; Hung, S.; Lipshutz, B. H. Adv. Synth. Catal. 2009, 351, 3139-3142.
http://dx.doi.org/10.1002/adsc.200900604
(f) Fuch, M.; Goessler, W.; Pilger, C.; Kappe, C. O. Adv. Synth. Catal. 2010, 352, 323-228.
Page 161
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
(g) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Org. Biomol. Chem. 2011, 9, 6385-6395.
http://dx.doi.org/10.1039/c1ob05735a; PMid:21789331.
9. (a) Bénéteau, V.; Olmos, A.; Boningari, T.; Sommer, J.; Pale, P. Tetrahedron Lett. 2010, 51,
3673-3677.
(b) Alix, A.; Chassaing, S.; Pale, P.; Sommer, J. Tetrahedron 2008, 64, 8922-8929.
http://dx.doi.org/10.1016/j.tet.2008.06.086
10. (a) Alonso, F., Moglie, Y.; Radivoy, G.; Yus, M. Tetrahedron Lett. 2009, 50, 2358-2362.
http://dx.doi.org/10.1016/j.tetlet.2009.02.220
(b) Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Eur. J. Org. Chem. 2010, 1875-1884.
http://dx.doi.org/10.1016/j.tetlet.2005.02.127
(c) Durán-Pachón, L; van Maarseveen, J. H.; Rothenberg, G. Adv. Synth. Catal. 2005, 347,
811-815.
(d) Orgueira, H. A.; Fokas, D.; Isome, Y.; Chan, P. C.-M.; Baldino, C. M. Tetrahedron Lett.
2005, 46, 2911-2914.
http://dx.doi.org/10.1016/j.tetlet.2005.02.127
(e) García-Muñoz, A.; González, J, Trujillo-Reyes, J.; Morales-Luckie, R. A.; Sánchez-
Mendieta, V.; González, C.; Fuentes, A.; Cuevas-Yañez, E. Lett. Org. Chem. 2012, 9, 160-
164.
(f) Kantam, M. L.; Jaya, V. S.; Sreedhar, B.; Mohan Rao, M. M.; Choudary, B. M. J. Mol.
Catal. A: Chemical 2006, 256, 273-277.
http://dx.doi.org/10.1016/j.molcata.2006.04.054
11. (a) Song, S.; Rao, R.; Yang, H.; Zhang, A. J. Phys. Chem. C, 2010, 114, 13998-14003.
(b) Orel, Z. C.; Anzlovar, A.; Drazic, G.; Zigon, M. Crystal Growth & Design, 2007, 7, 453-
458.
http://dx.doi.org/10.1021/cg060615t
(c) Liu, H.; Miao, W.; Yang, S.; Zhang, Z.; Chen, J. Crystal Growth & Design, 2009, 9,
1733-1740.
http://dx.doi.org/10.1021/cg800703n
12. Klug, H. P.; Alexander, L. E. X-Ray Diffraction Procedures for Polycrystalline and
Amorphous Materials, John Wiley and Sons, 1974, pp. 643.
13. De Jongh, P. E.; Vanmaekelbergh, D.; Kelly, J. Chem. Commun. 1999, 1069-1070.
http://dx.doi.org/10.1039/a901232j
14. Shao, C.; Zhu, R.; Luo, S.; Zhang, Q.; Wang, X.; Hu, Y. Tetrahedron Lett. 2011, 52, 3782-
3785.
http://dx.doi.org/10.1016/j.tetlet.2011.05.061
15. Suzuka, T.; Ooshiro, K.; Kina, K. Heterocycles 2010, 81, 601-610.
http://dx.doi.org/10.3987/COM-09-11872
16. Chowdhury, C.; Sasmal, A. K.; Dutta, P. K. Tetrahedron Lett. 2009, 50, 2678-2681.
http://dx.doi.org/10.1016/j.tetlet.2009.03.120
Page 162
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
17. (a)Yamaguchi, K.; Oishi, T.; Katayama, T.; Mizuno, N. Chem. Eur. J. 2009, 15, 10464-
10472.
(b) Jin, T.; Yan, M.; Menggenbateer; Minato, T. Bao, M.; Yamamoto, Y. Adv. Synth. Catal.
2011, 353, 3095-3100.
http://dx.doi.org/10.1002/adsc.201100760
(c) Megia-Fernández, A.; Ortega-Muñoz, M.; López-Jaramillo, J.; Hernández-Mateo, F.;
Santoyo-Gonzaleza, F. Adv. Synth. Catal. 2010, 352, 3306-3320.
(d) Duran-Panchón, L.; van Maarseven, J. H.; Rothenberg, G. Adv. Synth. Catal. 2005, 347,
811-815.
(e) Park, I. S.; Kwon, M. S.; Kim, Y.; Lee, J. S.; Park, J. Org. Lett. 2008, 10, 497-500.
http://dx.doi.org/10.1021/ol702790w; PMid:18181635.
(f) Rejander Reddy, K.; Rajgopal, K.; Kantam, M. L. Catal. Lett. 2007, 114, 36-40.
(g) Chassaing, S.; Kummarraja, M.; Sido, A. S. S.; Pale, P.; Sommer, J. Org. Lett, 2007, 9,
883-886.
http://dx.doi.org/10.1021/ol0631152; PMid:17286410.
(h) Chassaing, S.; Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale, P.; Sommer, J. Chem. Eur. J.
2008, 14, 6713-6721.
http://dx.doi.org/10.1002/chem.200800479; PMid:18576412.
(i) Namitharan, K.; Kumarraja, M.; Pitchumani, K. Chem. Eur. J. 2009, 15, 2755-2758.
(j) Katayama, K.; Kamata, K.; Yamaguchi, K.; Mizumo, N. ChemSusChem 2009, 2, 59-62.
http://dx.doi.org/10.1002/cssc.200800202; PMid:19132695.
18. Crystallographic data (excluding structure factors) for the structures in this paper has been
deposited with the Cambridge Crystallographic Data Centre as a Supplementary Publication
Numbers, CCDC 887985 No. for 3c, CCDC 887987 No. for 3l, CCDC 887986 No. for 3p
and CCDC 887989 No. for 3v Copy of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk].
19. López-Ruiz, H.; Briseño-Ortega, H.; Rojas-Lima, S.; Santillan, R.; Farfán, N. Tetrahedron
Lett. 2011, 52, 4308-4312.
http://dx.doi.org/10.1016/j.tetlet.2011.06.039
20. Crystallographic data (excluding structure factors) for the structures in this paper has been
deposited with the Cambridge Crystallographic Data Centre as a Supplementary Publication
Numbers, CCDC 887990 No. for 9d.
21. Wang, Y.; Liu, J.; Xia, C. Adv. Synth. Catal. 2011, 353, 1534-1542.
http://dx.doi.org/10.1002/adsc.201000868
22. Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302-1315.
http://dx.doi.org/10.1039/b904091a; PMid:20309487 PMCid:3073167.
23. (a) Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y. J. Org. Chem. 2010, 75, 7002-
7005.
Page 163
©ARKAT-USA, Inc

General Papers
ARKIVOC 2013 (iii) 139-164
(b) Jlalia, I.; Elamari, H.; Meganem, F.; Herscovici, J.; Girard, C. Tetrahedron Lett. 2008, 49,
6756-6758.
http://dx.doi.org/10.1016/j.tetlet.2008.09.031
(c) Li, P.; Wang, L.; Zhang, Y. Tetrahedron 2008, 64, 10825-10830.
http://dx.doi.org/10.1016/j.tet.2008.09.021
(d) Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2008, 47, 8881-8884.
24. (a) Feldman, A.; Colasson, B. Fokin, V. V. Org. Lett. 2004, 6, 3897-3899.
http://dx.doi.org/10.1021/ol048859z; PMid:15496058.
(b) López-Ruiz, H.; Cortés-Hernández, M.; Rojas-Lima, S.; Höpfl, H. J. Mex. Chem. Soc.
2011, 55, 168-175.
25. Orgueira, H. A.; Fokas, D.; Isome, Y.; Chan, P.; Baldino, C. Tetrahedron Lett. 2005, 46,
2911-2914.
http://dx.doi.org/10.1016/j.tetlet.2005.02.127
Page 164
©ARKAT-USA, Inc