Doped Nano-Sized Copper(I) Oxide (Cu2O) on melamine-formaldehyde resin: A highly efficient heterogeneous nano catalyst for 'Click' synthesis of some novel 1h-1,2,3-triazole derivatives having antibacterial activity

Article abstract of DOI:10.1002/hlca.201200224

A facile and simple protocol for the 1,3-dipolar cycloaddition of organic azides with terminal alkynes catalyzed by doped nano-sized Cu₂O on melamine-formaldehyde resin (nano-Cu₂O-MFR) as a new and convenient heterogeneous catalyst is described. In this method, 'click' cycloaddition of various structurally diverse β-azido alcohols and alkynes in the presence of nano-Cu₂O-MFR in H₂O/THF 1: 2 furnished the corresponding 1,4-disubstituted 1H-1,2,3-triazole adducts 1a-1o in good to excellent yields at room temperature (Scheme and Table 3). The nano-Cu ₂O-MFR was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), inductively coupled plasma (ICP) analysis, and FT-IR. The nano-Cu₂O-MFR could be easily recovered and recycled from the reaction mixture and reused for many consecutive trials without significant decrease in activity (Table 4). The in vitro antibacterial activities of all synthesized compounds were tested on several Gram-positive and/or Gram-negative bacteria (Table 5). The results demonstrate the promising antibacterial activity for some of the synthesized compounds. Copyright

Full text of DOI:10.1002/hlca.201200224

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Helvetica Chimica Acta – Vol. 96 (2013)
Doped Nano-Sized Copper(I) Oxide (Cu2O) on MelamineꢀFormaldehyde
Resin: a Highly Efficient Heterogeneous Nano Catalyst for ꢀClickꢁ Synthesis
of Some Novel 1H-1,2,3-Triazole Derivatives Having Antibacterial Activity
by Mohammad Navid Soltani Rad*a), Somayeh Behrouz*a), Abdollah Movahedianb),
Mohammad Mahdi Doroodmandc)d), Younes Ghasemib), Sara Rasoul-Aminib),
Abdol-Rasoul Ahmadi Gandomania), and Ramin Rezaiee)
a) Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
(phone: þ 98-711-7261392; fax: þ 98-711-7354523; e-mail: soltani@sutech.ac.ir, behrouz@sutech.ac.ir)
b) Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shiraz University of Medical
Sciences, Shiraz, Iran
c) Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
d) Nanotechnology Research Institute, Shiraz University, Shiraz, Iran
e) Department of Chemistry, Islamic Azad University, Firouzabad Branch, Firouzabad 74715-117, Iran
A facile and simple protocol for the 1,3-dipolar cycloaddition of organic azides with terminal alkynes
catalyzed by doped nano-sized Cu2O on melamineꢀformaldehyde resin (nano-Cu2OꢀMFR) as a new
and convenient heterogeneous catalyst is described. In this method, ꢀclickꢁ cycloaddition of various
structurally diverse b-azido alcohols and alkynes in the presence of nano-Cu2OꢀMFR in H2O/THF 1:2
furnished the corresponding 1,4-disubstituted 1H-1,2,3-triazole adducts 1a – 1o in good to excellent yields
at room temperature (Scheme and Table 3). The nano-Cu2OꢀMFR was characterized by scanning
electron microscopy (SEM), X-ray diffraction (XRD), inductively coupled plasma (ICP) analysis, and
FT-IR. The nano-Cu2OꢀMFR could be easily recovered and recycled from the reaction mixture and
reused for many consecutive trials without significant decrease in activity (Table 4). The in vitro
antibacterial activities of all synthesized compounds were tested on several Gram-positive and/or Gram-
negative bacteria (Table 5). The results demonstrate the promising antibacterial activity for some of the
synthesized compounds.
Introduction. – The 1H-1,2,3-triazoles [1] are an important class of N-heterocyclic
compounds with a wide range of applications in organic and medicinal chemistry. Many
bioactive compounds with a broad spectrum of activities such as anti-inflammatory [2],
antiviral [3], anticancer [4], anti-allergic [5], anticonvulsant [6], antibiotic [7],
antibacterial [8], and antimicrobial activity [9], contain a 1H-1,2,3-triazole core in
their scaffolds. Additionally, 1H-1,2,3-triazoles have also found industrial applications
as dyes, corrosion inhibitors, photostabilizers, photographic materials, and agrochem-
icals [10].
The Huisgen 1,3-dipolar cycloaddition of azides and alkynes is one of the most
widely used method for the synthesis of 1H-1,2,3-triazoles [11]. However, this
noncatalyzed process exhibits several disadvantages, including the requirement for high
temperature, low yields of the desired product, and poor regioselectivity affording a
mixture of 1,4- and 1,5-disubstituted triazoles [12]. The synthetic utility of the Huisgen
1,3-dipolar cycloaddition between azides and alkynes was significantly improved since
ꢂ 2013 Verlag Helvetica Chimica Acta AG, Zꢃrich

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689
Sharpless and co-workers [13] and Meldal and co-workers [14] have found that CuI salts
dramatically accelerate the reaction. The CuI-catalyzed Huisgen cycloaddition, has
enabled the practical and efficient preparation of 1,4-disubstituted 1H-1,2,3-triazoles,
with favorable selectivity, which normally cannot be prepared via traditional Huisgen
approaches. The required copper(I) catalysts are usually prepared by in situ reduction
of copper(II) salts with ascorbate [15], oxidation of copper(0) [16], or by compro-
portionation of copper(0) and copper(II) [15][17]. The catalysts might be copper(0)
nanosize clusters [18], or appropriate copper(I) salts (CuI or CuBr) with triphenyl-
phosphine [19], iminopyridine [20], or mono- [13][14] or polydentate [21] N-ligands.
To improve reuse and recovery, copper species have been immobilized onto various
supports such as activated carbon [22], amine-functionalized polymers [23], zeolites
[24], aluminium oxyhydroxide nanofiber [25], Wyoming montmorillonite [26], alumina
[27], silica-supported N-heterocyclic carbenes [28], and amine-functionalized silica
[29]. However, the immobilized catalysts on solid supports frequently suffer from
leakage of catalysts, high reaction temperatures, low yields of product, low activity, and
requiring additives.
Melamineꢀformaldehyde resin (MFR; melamine ¼ 1,3,5-triazine-2,4,6-triamine) is
the most useful thermosetting material [30]. MFR is extensively employed for
manufacturing composites and panels as well as textile coatings in industry (for
information about MFR, see [31]). The ability of MFR to host several cations has been
established [32]. The presence of spaces and/or cavities between triazine cores, and also
the presence of multi-coordinating N-atoms as well as the capability of forming H-
bonds in this cavity turn MFR into a suitable solid support for absorbing metal salts
(Fig. 1). Additionally, MFR contains many electron-deficient triazine cores that
potentially can generate pꢀp* interaction between rich p-electron reactants and also
triazine cores. Therefore, this property makes MFR a suitable binding site for reactants.
Considering the recently reported properties of MFR, we were encouraged to apply
MFR as a useful support in organic transformations [33].
Fig. 1. Schematic view for potential hosting of cation (left) and anion (right) by MFR
In line with our efforts toward the synthesis of new bioactive compounds having
1H-1,2,3-triazole cores [34], hereby we establish that doped nano-sized Cu2O on
melamineꢀformaldehyde resin (nano-Cu2OꢀMFR) is a highly efficient heterogeneous

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catalyst for Huisgen 1,3-dipolar cycloaddition between different terminal alkynes and
b-azido alcohols at room temperature resulting in 1H-1,2,3-triazole derivatives 1a – 1o
(Scheme).
Scheme. Reaction of b-Azido Alcohols and Alkynes in the Presence of Nano-Cu2OꢀMFR. For R1 and R2,
see Table 3.
To reveal the bioactivity of the synthesized 1H-1,2,3-triazoles 1a – 1o, they were
screened for their in vitro antibacterial activity against some pathogenic Gram-negative
(Salmonella typhi (PTCC-1609), Pseudomonas aeruginosa (PTCC-1074), and Escher-
ichia coli (PTCC-1338)), and Gram-positive bacteria (Staphylococcus epidermidis
(PTCC-1114) and Bacillus subtilis (PTCC-1023)).
Results and Discussion. – Scanning electron microscopy (SEM) and FT-IR
spectrometry were utilized to evaluate the morphology and study the formation of
nano-Cu2OꢀMFR, respectively. The SEM image of nano-Cu2OꢀMFR (Fig. 2) showed
that a narrow size distribution was obtained when adopting the proposed synthetic
procedure (see Exper. Part). The histogram based on the SEM image, and shown
in Fig. 3 clearly revealed the size distribution and the average size of the nano-
Cu2OꢀMFR.
Fig. 2. Scanning electron microscopy (SEM) image of nano-Cu2OꢀMFR
Metal oxides generally give IR absorption bands below 1000 cmꢀ1. In the FT-IR
spectrum (KBr disk) of the solid nano-Cu2OꢀMFR (Fig. 4), an asymmetric band
appeared at 470 cmꢀ1 which was assigned to the CuꢀO bond.
Spectroscopic techniques such as inductively coupled plasma (ICP) analysis and
patterned X-ray diffraction (XRD) were employed for the characterization of nano-

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691
Fig. 3. Histogram representing the average diameter of nano-Cu2OꢀMFR
Fig. 4. FT-IR Spectrum of nano-Cu2OꢀMFR
Cu2OꢀMFR. In the XRD pattern of nano-Cu2OꢀMFR (Fig. 5), the strong peaks
correspond to the copper nanostructure, the relevant data of which have been reported
in our previous study [35].
Fig. 5. XRD Pattern of nano-Cu2OꢀMFR

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To establish the optimized cycloaddition conditions, we chose the reaction of
phenylacetylene and 1-azido-3-phenoxypropan-2-ol as the model substrates to afford 1-
phenoxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-ol (1a). The effect of various
solvents on this cycloaddition was studied with nano-Cu2OꢀMFR (0.3 g, 0.072 mol-%
of Cu) at room temperature (Table 1). A solution in H2O/THF 1:2 (Table 1, Entry 6)
proved to be the most appropriate, and this solvent mixture was thus the solvent of
choice for all subsequent reactions. When H2O or THF were employed alone, moderate
yields of 1a were obtained (Entries 8 and 9). Other solvents in a 1:2 mixture with H2O,
such as DMSO (Entry 2), DMF (Entry 4), and t-BuOH (Entry 5) led to the desired
product in satisfactory yields; however, longer times were needed for the reactions to
be completed. Other solvents afforded lower yields of 1a.
Table 1. Effect of Various Solvents on the Conversion of Phenylacetylene into 1a in the Presence of Nano-
Cu2OꢀMFR at Room Temperature
Entry
Solventa)
Time [min]
Yield [%]b)
1
2
3
4
5
6
7
8
9
H2O/acetone
H2O/DMSO
H2O/CHCl3
H2O/DMF
H2O/t-BuOH
H2O/THF
H2O/MeCN
H2O
150
90
75
110
80
30
110
120
100
73
84
80
86
89
93
75
61
70
THF
a) For Entries 1 – 7, a 1 : 2 mixture of H2O/organic solvent was used. b) Yield of isolated product 1a.
To determine the optimized amount of nano-Cu2OꢀMFR, different amounts of
catalyst were employed in the model reaction (Table 2). With 0.3 g (0.072 mol-% of
Cu) of nano-Cu2OꢀMFR, the reaction progressed properly (Table 2, Entry 3). Lower
yields of 1a were obtained with 0.1 and 0.2 g of the catalyst (Entries 1 and 2), and an
extra amount of nano-CuꢀMFR had no distinguishable effect on the progress of the
reaction (Entries 4 and 5).
The appropriate stoichiometric ratio azide/alkyne for obtaining 1a under the
optimized conditions was found to be 1:1.2. This ratio must be precisely determined,
since an enhanced molar ratio of the alkyne can lead to the appearance of by-products
as the result of Cu(I)-catalyzed alkyneꢀalkyne coupling.
To establish the scope of this protocol, the optimized conditions were applied to
various structurally diverse azides and alkynes (Table 3). The results showed that nano-
Cu2OꢀMFR is an efficient catalyst for the Cu(I)-catalyzed Huisgen cycloaddition
between an azide and alkyne, producing the 1,4-disubstituted 1H-1,2,3-triazoles 1a – 1o
mainly in excellent yields and short reaction times at room temperature. Thus,
numerous functional groups in both the azide and alkyne were tolerated.

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Table 2. Effect of Different Amounts of Nano-Cu2OꢀMFR on the Conversion of Phenylacetylene into 1a
at Room Temperature
Entry
Nano-CuꢀMFR [mol-%]
Time [min]
Yield [%]a)
1
2
3
4
5
0.024
0.048
0.072
0.096
0.12
80
60
30
30
40
87
90
93
93
90
a) Yield of isolated product 1a.
Compounds 1a – 1o were fully characterized, and their structures were confirmed
1
by H- and 13C-NMR, and IR spectroscopy, and mass spectrometry, and elemental
analysis. Structural assignments of the triazolylmethyl alcohols 1a and 1b were made by
comparison of their 1H- and 13C-NMR spectra with those reported in [36]. In
1
particular, a s at d(H) 7.50 – 8.20 in the H-NMR spectra is a criterion for a proton at
C(5) of the 1H-1,2,3-triazole moiety, which perfectly agrees with the literature data.
The synthesis of b-azido alcohols used in this research was achieved via the
regioselective ring opening reaction of corresponding oxiranes with sodium azide in
quantitative yields [34b]. The prerequisite terminal alkynes for Entries 4, 5 and 11 – 15
of Table 3 were obtained by means of an SN2-type reaction of propargyl bromide (¼ 3-
bromoprop-1-yne) and corresponding nucleophiles. This strategy permitted the
incorporation of bioactive moieties in the structure of the alkynes and finally the
1H-1,2,3-triazole adducts. For instance, a therapeutic agent such as theophylline (¼ 3,7-
dihydro-1,3-dimethyl-1H-purine-2,6-dione) was incorporated in the structure of
compounds 1k and 1l (Table 3, Entries 11 and 12). This approach allows the synthesis
of many adducts with potential biological activities in various medicinal domains.
As expected, disubstituted alkynes such as diphenylacetylene were inactive in the
cycloaddition with b-azido alcohols (Table 3, Entry 16). This behavior is completely
consistent with the mechanism of the CuI-catalyzed azideꢀalkyne cycloaddition in
which the formation of a copper(I) acetylide species is inevitable.
The applicability of this protocol on a preparative scale, was testet with the 1,3-
dipolar cycloaddition of the model substrates phenylacetylene and 1-azido-3-phenoxy-
propan-2-ol on a 100-mmol scale, which gave 1a efficiently after 30 min in 88% yield
under optimized conditions. This compares well to the smaller-scale synthesis (Table 3,
Entry 1).
The reusability of nano-Cu2OꢀMFR was also investigated in the ꢀclickꢁ cyclo-
addition of the model substrates in several runs (Table 4). After each run, the solution
was vacuum-filtered through a sintered-glass funnel, and the solid was washed
successively with THF and dried in a vacuum oven at 1008 for 30 min. The catalyst was
then reused directly without further purification, and no fresh catalyst was added in
subsequent runs. Thus, according to the results (Table 4), the catalyst can be recovered,

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Table 3. Nano-Cu2OꢀMFR-Catalyzed ꢀClickꢁ Cycloaddition of b-Azido Alcohols with Alkynes in H2O/
THF 1 : 2 at Room Temperature
Entry
b-Azido alcohol (R1)
Alkyne (R2)
Product 1a)
Time [h]
Yieldb) [%]
1
2
PhO
Ph
Ph
1a
1b
0.5
0.5
93
92
3
4
5
6
7
8
9
10
11
CH2¼C(Me)COO
2,4-Cl2ꢀC6H3O
4-BnꢀC6H4O
PhO
4-BnꢀC6H4O
4-MeOꢀC6H4O
PhO
Ph
1c
1d
1e
1f
1g
1h
1i
1
1
1
0.75
0.5
0.5
0.33
0.33
0.33
83
80
81
85
91
93
88
86
90
4-ClꢀC6H4ꢀOꢀCH2
4-ClꢀC6H4ꢀOꢀCH2
Me2C(OH)
Me2C(OH)
Me2C(OH)
HOCH2
4-ClꢀC6H4O
BrCH2
1j
1k
4-MeOꢀC6H4O
12
13
14
15
16
Me
1l
0.5
0.5
0.5
1
88
93
92
83
–
4-MeOꢀC6H4O
Naphthalen-2-yloxy
1m
1n
1o
PhꢀCꢁCꢀPh
n.r.c)
10
a) All products were characterized by 1H- and 13C-NMR, IR, CHN and MS analysis. b) Yield of isolated
product. c) No reaction.

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Table 4. The Reusability of Nano-CuꢀMFR in Successive Runs for the Synthesis of 1a
Run
Time [min]
Yield [%]a)
1
2
3
4
5
30
40
48
56
60
93
90
90
88
85
a) Yield of isolated product 1a.
recycled, and reused for many consecutive trials without significant loss of its activity.
The amount of leached copper from nano-Cu2OꢀMFR was negligible (0.0015% after
five runs), as indicated by the CuI contents in both fresh catalyst and recycled catalyst
(after five runs) determined by ICP analysis.
Compounds 1a – 1o were evaluated for their in vitro antibacterial activity against
several Gram-negative (Salmonella typhi, Pseudomonas aeruginosa, and Escherichia
coli) and Gram-positive (Staphylococcus epidermidis, and Bacillus subtilis) bacteria
(Table 5). The antibacterial activity of 1a – 1o was compared with that of gentamycin
and ampicillin as reference drugs for Gram-negative and Gram-positive bacteria,
respectively.
The minimum inhibitory concentration (MIC) values of the examined compounds
were measured by a serial dilution assay by using the disc-plate method (Table 5).
Among the synthesized compounds, 1d and 1e were the most potent compounds against
Gram-positive bacteria. In the case of S. epidermidis, compound 1a also demonstrated
promising activity; however its antibacterial activity was weaker (MIC > 37.5 mg/ml)
than that of 1d and 1e. Other tested compounds were inactive or showed varying
antibacterial activity against the two examined Gram-positive bacteria. In general,
compounds 1m and 1n were the most active compounds against all examined Gram-
negative bacteria. Compound 1n demonstrated a comparable activity (MIC > 18.75 mg/
ml) against P. aeruginosa in comparison with gentamycin as the reference drug (MIC >
12.5 mg/ml), whereas 1b, 1g, and 1m showed lower activity in comparison with 1n.
Additionally, compounds 1m, 1n, 1g, and 1j exhibited a promising antibacterial activity
against S. typhi. On the other hand, compounds 1d and 1l – 1n had the best activity
against E. coli (MIC > 37.5 mg/ml).
Concerning the structureꢀactivity relationship (SAR), as the MIC results indicate,
the antibacterial activity of the synthesized compounds seems to depend on the
substituent at the 1,2,3-triazol-1-yl cores. As expected, the maximum antibacterial
activity against Gram-positive bacteria was observed when a 4-chlorophenoxy was
methyl-linked at C(4) of the 1,2,3-triazol-1-yl core (compounds 1d and 1e). The activity
of 1d and 1e can be explained by the intrinsic antibacterial activity of chlorophenols
[37]. Compounds 1m and 1n having a phthalimide moiety linked to the methyl group at

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Table 5. In vitro Antibacterial Study of Compounds 1a – 1oa)
MIC [mg/ml]
Compound
S. epidermidis
B. subtilis
P. aeruginosa
S. typhi
E. coli
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
> 37.5
> 50
> 100
> 25
> 25
> 75
100
100
100
> 50
100
> 75
> 75
> 75
> 75
> 18.75
–
> 75
> 50
> 75
> 25
> 25
> 75
> 50
100
> 75
100
> 50
100
> 50
> 50
> 50
> 12.5
–
100
> 37.5
> 50
> 50
> 50
> 50
> 37.5
> 75
> 75
> 75
> 50
> 50
> 25
> 18.75
100
> 50
> 75
> 50
100
> 75
> 50
> 75
> 37.5
> 75
> 50
> 50
> 50
> 50
> 50
> 75
> 37.5
> 37.5
> 37.5
> 75
–
> 50
> 50
> 37.5
> 75
> 50
> 37.5
> 50
> 75
> 25
> 25
100
Ampicillinb)
Gentamycinc)
–
–
> 12.5
> 12.5
> 12.5
a) Examined bacteria: Staphylococcus epidermidis (PTCC 1114), Bacillus subtilis (PTCC 1023),
Pseudomonas aeruginosa (PTCC 1047), Salmonella typhi (PTCC 1609), and Escherichia coli (PTCC
1338). b) Reference drug for Gram-positive bacteria. c) Reference drug for Gram-negative bacteria.
C(4) of the 1,2,3-triazol-1-yl core demonstrated good activity against all examined
Gram-negative bacteria. However, 1o showed a different antibacterial activity against
the five examined bacteria although it contains a phthalimide core. The presence of the
theophylline moiety in 1k and 1l did not enhance the activity against the micro-
organisms. The quantitative structuralꢀactivity relationships (QSAR) of 1a – 1o are
under investigation, and results will be reported in due course.
In summary, the preparation, characterization, and application of nano-
Cu2OꢀMFR as a highly efficient heterogeneous catalyst in the 1,3-dipolar cycloaddition
of various b-azido alcohols and alkynes were examined. The cycloadditions proceeded
under very mild conditions and efficiently in H2O/THF 1:2 at room temperature. This
protocol allowed the facile and regioselective synthesis of 1,4-disubstituted 1H-1,2,3-
triazoles in good to excellent yields. The nano-Cu2OꢀMFR was shown to be a
chemically and thermally stable, cheap, and environmentally compatible heteroge-
neous nanocatalyst that could be reused for many consecutive experiments without any
significant loss of its activity. Antibacterial screening of all synthesized compounds was
conducted, revealing promising antibacterial activity against some Gram-positive and
Gram-negative bacteria.
We thank the Shiraz University of Technology and Shiraz University of Medical Sciences Councils
for partial support of this work.

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697
Experimental Part
1. General. All chemicals were obtained from commercial sources. Solvents were purified and stored
over 3-ꢄ molecular sieves. TLC: SILG/UV 254 silica-gel plates. Column chromatography (CC): silica gel
60 (SiO2; 0.063 – 0.200 mm, 70 – 230 mesh; ASTM). M.p.: Bꢂchi-510 apparatus; open capillaries;
.
uncorrected. IR Spectra: Shimadzu-FT-IR-8300 spectrophotometer; n in cmꢀ1 1H- and 13C-NMR
Spectra: Bruker-Avance-DPX-250 spectrometer; at 250 and 62.5 MHz, resp.; d in ppm rel. to Me4Si as
internal standard, J in Hz. GC/MS: Shimadzu-GC/MS-QP-1000-EX apparatus; in m/z (rel.%).
Elemental analyses (CHNS): Perkin-Elmer-240-B micro-analyzer.
2. Nano-Cu2OꢀMelamine-Formaldehyde Resin (nano-Cu2OꢀMFR). A suspension of pure MFR
(0.5 g) in 0.01m aq. NaOH (20 ml) was refluxed for 12 h. Then, the mixture was cooled, the extra soln.
decanted, and the remaining suspension containing MFR centrifuged at 5000 rpm. The separated MFR
powder was dried in a vacuum oven at 2508 for 4 h. To dry MFR (0.3 g), solid CuI (0.045 g, 0.24 mmol)
was added, and the mixture was mechanically homogenized in a ball mill and exposed to microwave
irradiation at 800 W for 5 min. Afterward, the sample was sonicated in a sonicator at 400 W (freq.
50 MHz), and nano-Cu2OꢀMFR was dried in a vacuum oven at 2508 for 2 h. Scanning electron
microcopy (SEM-XL-30-FEG instrument (Philips; 20 KV) inductively coupled plasma (ICP) analysis
and patterned X-ray diffraction (XRD, D8 Advance, Bruker AXS) were employed for the character-
ization of nano-Cu2OꢀMFR.
3. 1,3-Dipolar Cycloaddition of b-Azido Alcohols with Terminal Alkynes: General Procedure. A
mixture of alkyne (6 mmol), nano-Cu2OꢀMFR (0.3 g, 0.072 mol-% of Cu), and the appropriate b-azido
alcohol (5 mmol) in H2O/THF 1:2 (12 ml) was stirred at r.t. until TLC monitoring indicated no further
progress in the conversion (Table 3). The catalyst was filtered off and the filtrate concentrated. The
remaining foam was dissolved in CHCl3 (50 ml), the soln. washed with H2O (2 ꢂ 50 ml), dried (Na2SO4),
and concentrated, and the crude product purified by CC (SiO2).
1-Phenoxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-2-ol (¼a-(Phenoxymethyl)-4-phenyl-1H-1,2,3-
triazole-1-ethanol; 1a): CC (AcOEt/hexane 2 :1) yielded 1.37 g (93%). Colorless solid. M.p. 125 – 1268.
IR (KBr): 3420 (br.), 3071s, 2927m, 1661s, 1595m, 1490s. 1H-NMR (CDCl3): 3.84 (s, OH, exchangeable
with D2O); 4.03 – 4.09 (m, NCH2CH); 4.51 (dd, J ¼ 3.6, 12.8, ArOCH2); 4.66 – 4.78 (m, CHOH); 6.92 –
7.04 (m, 3 arom. H); 7.60 – 7.64 (m, 5 arom. H); 7.69 – 7.73 (m, 2 arom. H); 7.87 (s, HꢀC(5) of triaz.).
13C-NMR (CDCl3): 53.56; 68.63; 68.94; 114.55; 121.47; 121.62; 125.54; 128.15; 128.82; 129.66; 130.09;
147.23; 158.27. MS: 295.13 (7.1, Mþ). Anal. calc. for C17H17N3O2 (295.34): C 69.14, H 5.80, N 14.23; found:
C 69.05, H 5.91, N 14.15.
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)cyclohexanol (1b): CC (AcOEt/hexane 2 :1) yielded 1.11 g (92%).
White solid. M.p. 181 – 1828. IR (KBr): 3300 (br.), 3045s, 2974m, 1590s, 1586m, 1455s. 1H-NMR (CDCl3):
1.25 – 1.46 (m, CH2, CH); 1.87 – 2.21 (m, 2 CH2, CH); 3.66 (s, OH, exchangeable with D2O); 4.11 (br. s,
NCHCHOH); 7.30 – 7.33 (m, 3 arom. H); 7.62 – 7.72 (m, 2 arom. H, HꢀC(5) of triaz.). 13C-NMR (CDCl3):
24.03; 24.78; 31.49; 33.75; 67.56; 72.53; 125.47; 128.09; 128.75; 131.28; 133.62; 147.39. MS: 243.14 (6.4,
Mþ). Anal. calc. for C14H17N3O (243.30): C 69.11, H 7.04, N 17.27; found: C 69.18, H 7.00, N 17.35.
2-Hydroxy-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propyl 2-Methylprop-2-enoate (1c): CC (AcOEt/hex-
ane 2 :1) yielded 1.19 g (83%). White solid. M.p. 105 – 1068. IR (KBr): 3346 (br.), 3050s, 2982m, 1596s,
1585m, 1458s. 1H-NMR ((D6)DMSO): 2.46 (s, Me); 3.31 – 3.39 (m, NCH2CH); 3.86 (s, OH, exchangeable
with D2O); 4.02 (br. s, ¼CH2); 4.18 (dd, J ¼ 8.0, 13.5, OCH2); 4.48 – 4.54 (m, CHOH); 7.28 – 7.43 (m, 3
arom. H); 7.80 – 7.83 (m, 2 arom. H); 8.45 (s, HꢀC(5) of triaz.). 13C-NMR ((D6)DMSO): 18.25; 53.51;
63.73; 70.88; 122.70; 125.52; 128.14; 129.31; 131.39; 133.52; 136.71; 146.41; 167.36. MS: 287.13 (4.7, Mþ).
Anal. calc. for C15H17N3O3 (287.31): C 62.71, H 5.96, N 14.63; found: C 62.60, H 6.05, N 14.69.
1-{4-[(4-Chlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}-3-(2,4-dichlorophenoxy)propan-2-ol (¼4-
[(4-Chlorophenoxy)methyl]-a-[(2,4-dichlorophenoxy)methyl]-1H-1,2,3-triazole-1-ethanol; 1d): CC
(AcOEt/hexane 2 :1) yielded 1.71 g (80%). Pale yellow solid. M.p. 129 – 1308. IR (KBr): 3264 (br.),
3028s, 2921m, 1647s, 1590m, 1491s. 1H-NMR ((D6)DMSO): 3.97 – 4.08 (m, NCH2CH); 4.28 (s, OH,
exchangeable with D2O); 4.45 (dd, J ¼ 7.5, 13.8, 1 H, ArOCH2); 4.61 (dd, J ¼ 3.2, 13.8, 1 H, ArOCH2);
5.13 (s, OCH2C¼C); 5.66 – 5.68 (m, CHOH); 7.02 – 7.34 (m, 6 arom. H); 7.51 (s, 1 arom. H); 8.19 (s,
HꢀC(5) of triaz.). 13C-NMR ((D6)DMSO): 52.52; 61.32; 67.58; 70.64; 115.17; 116.36; 122.54; 124.52;

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Helvetica Chimica Acta – Vol. 96 (2013)
124.75; 125.61; 128.00; 128.68; 129.14; 142.14; 152.79; 156.82. MS: 427.03 (2.6, Mþ). Anal. calc. for
C18H16Cl3N3O3 (427.70): 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-Benzylphenoxy)-3-{4-[(4-chlorophenoxy)methyl]-1H-1,2,3-triazol-1-yl}propan-2-ol (¼4-[(4-
Chlorophenoxy)methyl]-a-{[4-(phenylmethyl)phenoxy]methyl}-1H-1,2,3-triazole-1-ethanol; 1e): CC
(AcOEt/hexane 2 :1) yielded 1.82 g (81%). White solid. M.p. 110 – 1118. IR (KBr): 3262 (br.), 3029s,
2912m, 1604s, 1575m, 1492s. 1H-NMR ((D6)DMSO): 3.59 (s, PhCH2), 3.85 – 3.88 (m, NCH2CH); 4.10 (s,
OH, exchangeable with D2O); 4.39 (dd, J ¼ 7.6, 13.8, 1 H, ArOCH2); 4.56 (dd, J ¼ 3.3, 13.8, 1 H,
ArOCH2); 5.13 (s, OCH2C¼C); 5.57 – 5.59 (m, CHOH); 6.83 (d, J ¼ 8.3, 2 arom. H); 7.04 – 7.56 (m, 11
arom. H); 8.18 (s, HꢀC(5) of triaz.). 13C-NMR ((D6)DMSO): 40.44; 52.63; 61.31; 67.77; 69.47; 114.46;
116.42; 124.50; 125.61; 125.79; 128.31; 128.51; 129.18; 129.64; 133.53; 141.63; 142.02; 156.60; 156.86. MS:
449.15 (3.2, Mþ). Anal. calc. for C25H24ClN3O3 (449.93): C 66.74, H 5.38, Cl 7.88, N 9.34; found: C 66.86, H
5.34, Cl 7.81, N 9.45.
1-[4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]-3-phenoxypropan-2-ol (¼4-(1-Hydroxy-1-meth-
ylethyl)-a-(phenoxymethyl)-1H-1,2,3-triazole-1-ethanol; 1f): CC (AcOEt/hexane 2 :1) yielded 1.17 g
1
(85%). White solid. M.p. 92 – 938. IR (KBr): 3316 (br.), 3100s, 2970m, 1597m, 1588m, 1468s. H-NMR
((D6)DMSO): 1.39 (s, 2 Me), 3.84 – 3.86 (m, NCH2CH); 4.15 (s, CHOH, exchangeable with D2O); 4.29
(dd, J ¼ 7.3, 13.8, 1 H, ArOCH2); 4.44 (dd, J ¼ 3.8, 13.8, 1 H, ArOCH2); 5.03 (s, (Me)2COH, exchangeable
with D2O); 5.48 – 5.50 (m, CHOH); 6.85 – 6.88 (m, 3 arom. H); 7.18 – 7.24 (m, 2 arom. H); 7.78 (s, HꢀC(5)
of triaz.). 13C-NMR ((D6)DMSO): 30.69; 52.42; 67.01; 67.86; 69.40; 114.46; 120.73; 121.44; 129.45;
155.50; 158.28. MS: 277.14 (1.3, Mþ). Anal. calc. for C14H19N3O3 (277.32): C 60.63, H 6.91, N 15.15; found:
C 60.75, H 6.83, N 15.10.
1-(4-Benzylphenoxy)-3-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-y])propan-2-ol (¼4-(1-Hy-
droxy-1-methylethyl)-a-{[4-(phenoxymethyl)phenoxy]methyl}-1H-1,2,3-triazole-1-ethanol; 1g): CC
(AcOEt/hexane 2 :1) yielded 1.67 g (91%). White solid. M.p. 86 – 878. IR (KBr): 3329 (br.), 3065s,
2971m, 1643s, 1584m, 1511m, 1453s. 1H-NMR ((D6)DMSO): 1.22 (s, 2 Me); 3.18 (s, PhCH2); 3.63 – 3.65
(m, NCH2CH); 3.95 (s, CHOH, exchangeable with D2O); 4.09 (dd, J ¼ 7.5, 13.7, 1 H, ArOCH2); 4.25 (dd,
J ¼ 2.7, 13.4, 1 H, ArOCH2); 4.88 (s, Me2COH, exchangeable with D2O); 5.29 – 5.31 (m, CHOH); 6.60 (d,
J ¼ 8.2, 2 arom. H); 6.86 – 7.04 (m, 7 arom. H); 7.61 (s, HꢀC(5) of triaz.). 13C-NMR ((D6)DMSO): 30.71;
40.40; 52.44; 67.01; 67.87; 69.52; 114.46; 121.56; 125.79; 128.31; 128.51; 129.65; 133.52; 141.62; 155.66;
156.62. MS: 367.19 (5.1, Mþ). Anal. calc. for C21H25N3O3 (367.44): C 68.64, H 6.86, N 11.44; found: C
68.50, H 6.81, N 11.53.
1-[4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]-3-(4-methoxyphenoxy)propan-2-ol (¼4-(1-Hy-
droxy-1-methylethyl)-a-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole-1-ethanol; 1h): CC (AcOEt/hex-
ane 2 :1) yielded 1.42 g (93%). White solid. M.p. 70 – 718. IR (KBr): 3310 (br.), 3080s, 2976m, 1590m,
1584m, 1475s. 1H-NMR (CDCl3): 1.44 (s, 2 Me); 3.64 (s, MeO); 3.79 – 3.83 (m, NCH2CH); 4.27 – 4.34 (m,
ArOCH2, CHOH); 4.47 – 4.53 (m, CHOH, (Me)2COH); 6.66 – 6.74 (m, 4 arom. H); 7.54 (s, HꢀC(5) of
triaz.). 13C-NMR (CDCl3): 30.89; 53.29; 55.64; 68.09; 68.65; 69.81; 114.66; 115.52; 121.59; 152.34; 154.14;
155.08. MS: 307.15 (5.8, Mþ). Anal. calc. for C15H21N3O4 (307.34): C 58.62, H 6.89, N 13.67; found: C
58.73, H 6.85, N 13.79.
1-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-3-phenoxypropan-2-ol (¼4-(Hydroxymethyl)-a-(phe-
noxymethyl)-1H-1,2,3-triazole-1-ethanol; 1i): CC (AcOEt/hexane 2 :1) yielded 1.09 g (88%). Bright
1
yellow oil. IR (film): 3325 (br.); 3063s, 2981m, 1595s, 1580m, 1464s. H-NMR (CDCl3): 3.94 – 3.95 (m,
NCH2CH); 4.34 – 4.37 (m, ArOCH2); 4.54 – 4.59 (m, CH2OH, CHOH); 4.91 (s, CHOH, exchangeable
with D2O); 5.35 (s, CH2OH, exchangeable with D2O); 6.83 – 6.95 (m, 3 arom. H); 7.19 – 7.25 (m, 2 arom.
H); 7.75 (s, HꢀC(5) of triaz.). 13C-NMR (CDCl3): 53.26; 53.28; 56.12; 68.75; 114.46; 121.51; 123.69;
129.63; 148.57; 158.05. MS: 249.11 (11.5, Mþ). Anal. calc. for C12H15N3O3 (249.27): C 57.82, H 6.07, N
16.86; found: C 57.95, H 6.14, N 16.78.
1-[4-(Bromomethyl)-1H-1,2,3-triazol-1-yl]-3-(4-chlorophenoxy)propan-2-ol (¼(4-Bromomethyl)-a-
[(4-chlorophenoxy)methyl]-1H-1,2,3-triazole-1-ethanol; 1j): CC (AcOEt/hexane 2 :1) yielded 1.49 g
1
(86%). Bright yellow oil. IR (film): 3400 (br.), 3025s, 2983m, 1592s, 1587m, 1452s. H-NMR (CDCl3):
3.87 – 3.91 (m, NCH2CH); 4.39 – 4.43 (m, ArOCH2); 4.52 – 4.55 (m, CHOH); 4.72 (s, CH2Br); 4.95 (s,
CHOH, exchangeable with D2O); 6.84 (d, J ¼ 8.4, 2 arom. H);7.09 (d, J ¼ 8.4, 2 arom. H); 7.75 (s, HꢀC(5)
of triaz.). 13C-NMR (CDCl3): 53.12; 53.58; 56.52; 68.83; 115.76; 122.40; 125.94; 129.47; 149.71; 160.28.

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MS: 344.99 (7.3, Mþ). Anal. calc. for C12H13BrClN3O2 (346.61): C 41.58, H 3.78, Br 23.05, Cl 10.23, N
12.12; found: C 41.64, H 3.70, Br 23.17, Cl 10.18, N 12.25.
3,7-Dihydro-7-{{1-[2-hydroxy-3-(4-methoxyphenoxy)propyl]-1H-1,2,3-triazol-4-yl}methyl}-1,3-di-
methyl-1H-purine-2,6-dione (1k): CC (AcOEt) yielded 1.98 g (90%). White solid. M.p. 183 – 1848. IR
(KBr): 3222 (br.), 3127s, 2931m, 1725s, 1710s, 1657s, 1549m, 1439s. 1H-NMR ((D6)DMSO): 3.16 (s,
MeꢀN(3)); 3.35 (s, MeꢀN(1)); 3.65 (s, MeO); 3.80 – 3.83 (m, NCH2CH); 4.15 (s, OH, exchangeable with
D2O); 4.35 (dd, J ¼ 7.5, 13.8, 1 H, ArOCH2); 4.51 (dd, J ¼ 3.3, 13.8, 1 H, ArOCH2); 5.49 – 5.51 (m,
CHOH); 5.54 (s, NCH2C¼C); 6.75 – 6.83 (m, 4 arom. H); 8.07 (s, HꢀC(5) of triaz.); 8.13 (s, HꢀC(8) of
theophyl.). 13C-NMR ((D6)DMSO): 27.42; 29.28; 41.04; 52.68; 55.21; 67.75; 69.96; 105.72; 114.40; 115.31;
124.77; 141.99; 142.27; 148.17; 150.85; 152.22; 153.43; 154.29. MS: 441.18 (10.3, Mþ). Anal. calc. for
C20H23N7O5 (441.44): C 54.42, H 5.25, N 22.21; found: C 54.31, H 5.39, N 22.27.
3,7-Dihydro-7-{[1-(2-hydroxybutyl)-1H-1,2,3-triazol-4-yl]methyl}-1,3-dimethyl-1H-purine-2,6-dione
(1l): CC (AcOEt) yielded 1.46 g (88%). White solid. M.p. 144 – 1458. IR (KBr): 3252 (br.), 3107s, 2961m,
1719s, 1708s, 1665s, 1542m, 1431s. 1H-NMR ((D6)DMSO): 0.82 (t, J ¼ 7.2, MeCH2); 1.13 – 1.38 (m,
MeCH2); 3.16 (s, MeꢀN(3)); 3.35 (s, MeꢀN(1)); 3.68 (s, OH, exchangeable with D2O); 4.12 (dd, J ¼ 7.6,
13.7, 1 H, CH2N); 4.28 (dd, J ¼ 3.2, 13.7, 1 H, CH2N); 4.94 – 4.97 (m, CHOH); 5.52 (s, NCH2C¼C); 8.00 (s,
HꢀC(5) of triaz.); 8.11 (s, HꢀC(8) of theophyl.). 13C-NMR ((D6)DMSO): 9.57; 27.04; 27.42; 29.29; 41.04;
55.04; 70.21; 105.69; 124.47; 141.85; 142.28; 148.16; 150.86; 154.29. MS: 333.15 (11.7, Mþ). Anal. calc. for
C14H19N7O3 (333.35): 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}-1H-isoindole-1,3(2H)-
dione (1m): CC (AcOEt/hexane 4 :1) yielded: 1.89 g (93%). White solid. M.p. 141 – 1428. IR (KBr): 3326
1
(br.), 3145s, 2990m, 2971m, 1764s, 1709s, 1506m, 1427s. H-NMR ((D6)DMSO): 3.64 (s, MeO); 3.81 –
3.83 (m, NCH2CH); 4.17 (s, OH, exchangeable with D2O); 4.33 (dd, J ¼ 7.8, 13.8, 1 H, ArOCH2); 4.50
(dd, J ¼ 3.4, 13.8, 1 H, ArOCH2); 4.83 (s, NCH2C¼C); 5.50 – 5.52 (m, CHOH); 6.81 – 6.85 (m, 4 arom. H);
7.80 – 7.82 (m, 4 arom. H); 8.03 (s, HꢀC(5) of triaz.). 13C-NMR ((D6)DMSO): 32.84; 52.67; 55.22; 67.79;
70.04; 114.46; 115.38; 123.09; 124.13; 131.48; 134.41; 141.92; 152.25; 153.44; 167.26. MS: 408.14 (3.9, Mþ).
Anal. calc. for C21H20N4O5 (408.41): C 61.76, H 4.94, N 13.72; found: C 61.70, H 5.03, N 13.76.
2-{{1-[2-Hydroxy-3-(naphthalen-2-yloxy)propyl]-1H-1,2,3-triazol-4-yl}methyl}-1H-isoindol-1,3(2H)-
dione (1n): CC (AcOEt/hexane 4 :1) yielded 1.97 g (92%). Pale yellow solid. M.p. 208 – 2098. IR (KBr):
1
3366 (br.), 3152m, 3087s, 2931m, 1775s, 1723s, 1628s, 1558m, 1423s. H-NMR ((D6)DMSO): 4.03 – 4.05
(m, NCH2CH); 4.28 (s, OH, exchangeable with D2O); 4.42 (dd, J ¼ 7.5, 13.8, 1 H, ArOCH2); 4.57 (dd, J ¼
3.6, 13.8, 1 H, ArOCH2); 4.84 (s, NCH2C¼C); 5.61 – 5.64 (m, CHOH); 7.12 – 7.42 (m, 4 arom. H); 7.74 –
7.86 (m, 7 arom. H); 8.08 (s, HꢀC(5) of triaz.). 13C-NMR ((D6)DMSO): 32.87; 52.68; 67.71; 69.52; 106.72;
118.57; 123.09; 123.59; 124.19; 126.33; 126.64; 127.43; 128.48; 129.24; 131.49; 134.13; 134.42; 141.97;
156.14; 167.27. MS: 428.15 (7.5, Mþ). Anal. calc. for C24H20N4O4 (428.44): C 67.28, H 4.71, N 13.08; found:
C 67.36, H 4.63, N 13.19.
2-{[1-(2-Hydroxycyclohexyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-isoindol-1,3(2H)-dione (1o): CC
(AcOEt/hexane 2 :1) yielded 1.35 g (83%). White solid. M.p. 170 – 1718. IR (KBr): 3290 (br.), 3100s,
1
2985m, 1593s, 1580m, 1465s. H-NMR (CDCl3): 0.94 – 0.99 (m, 2 CH2); 1.65 – 1.82 (m, 2 CH2); 3.30 (s,
OH, exchangeable with D2O); 3.94 – 3.97 (m, CHOH); 4.12 – 4.22 (m, NCH); 4.96 (s, NCH2C¼C); 7.26 (s,
HꢀC(5) of triaz.); 7.68 – 7.71 (m, 2 arom. H); 7.81 – 7.84 (m, 2 arom. H). 13C-NMR (CDCl3): 14.11; 23.93;
24.65; 29.34; 31.61; 33.67; 72.43; 123.45; 131.98; 134.09; 134.73; 147.28; 167.66. MS: 326.14 (9.7, Mþ). Anal.
calc. for C17H18N4O3 (326.35): C 62.57, H 5.56, N 17.17; found: C 62.45, H 5.63, N 17.10.
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Received April 29, 2012