ZnO nanoparticles-mediated regioselective synthesis of methyl-iV-alkylated 1,2,3-triazole-4-carboxylates

Article abstract of DOI:10.1007/s11164-011-0446-0

The 1,2,3-triazoles are versatile synthetic intermediates of many biologically active compounds, and their N-1 substituted analogues are potential pharmaceutically important derivatives. In this study, an efficient regioselective N-alkylation reaction of

Full text of DOI:10.1007/s11164-011-0446-0

Res Chem Intermed (2012) 38:1101–1109
DOI 10.1007/s11164-011-0446-0
ZnO nanoparticles-mediated regioselective synthesis
of methyl-N-alkylated 1,2,3-triazole-4-carboxylates
•
K. Prabakaran Fazlur-Rahman Nawaz Khan
Jong Sung Jin
•
Received: 3 August 2011 / Accepted: 21 November 2011 / Published online: 7 December 2011
Ó Springer Science+Business Media B.V. 2011
Abstract The 1,2,3-triazoles are versatile synthetic intermediates of many
biologically active compounds, and their N-1 substituted analogues are potential
pharmaceutically important derivatives. In this study, an efficient regioselective N-
alkylation reaction of methyl-1H-1,2 3-triazole-4-carboxylate 3 with alkyl halides 4
catalyzed by ZnO nanoparticles in the presence of potassium hydroxide as base and
DMSO as solvent is reported which leads to methyl N1-alkylated 1,2,3-triazole-4-
carboxylates 5 in good yields.
Keywords ZnO nanoparticles Á N-alkylation of 1,2,3-triazole Á Regioselectivity
Introduction
In recent years there has been unprecedented growth in nanoscience and
nanotechnology research and applications [1]. There is increasing optimism that
nanotechnology, as applied to medicine, will lead to significant advances in the
diagnosis and treatment of diseases [2]. Expected applications in medicine include
drug delivery [3], in-vitro and in-vivo diagnostics, nutraceuticals, and production of
materials with improved biocompatibity [4]. Copper nanoparticles have excellent
catalytic activity in the 1,3-dipolar cycloaddition reaction between aryl and
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-011-0446-0) contains supplementary material, which is available to authorized users.
K. Prabakaran Á F.-R. Nawaz Khan (&)
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632 014,
Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F.-R. Nawaz Khan Á J. S. Jin
Division of High Technology Materials Research, KBSI, Busan 618-230, South Korea
123

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K. Prabakaran et al.
sugar-based terminal alkynes and azides [5]. The 1,2,3-triazole ring system has been
the subject of much research, mainly because of its usefulness in synthetic organic
chemistry and because of its pharmacological properties.
The N-substituted 1,2,3-triazoles are versatile intermediates of many biologically
active compounds which are valuable for new drugs development. The anti-
bacterial, anti-fungal, anti-viral, anti-inflammatory, and analgesic properties of
1,2,3-triazole have been extensively studied [6–10]. Some new 1,2,3-triazole
isomers have been reported as inhibiting tumor proliferation, invasion, and
metastasis [11]. The N-sulfonyl aziridines are well-known alkylating agents and
are used for synthesis of several types of heterocyclic compound [12].
Nitrogen-containing heterocycles have much potential in the various fields of
chemistry [13]. Nowadays, attention focuses on novel organic compounds, for
example the triazoles, and on addition of the salts of such compounds to inorganic or
organic acids. Russell et al. identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-
triazolo [3,4-a] phthalazines as potent partial agonists of the a3 receptor subtype with
fivefold selectivity in binding affinity over the a1 receptor. Triazole-based compounds
are known to be involved in many biochemical processes [14–17], and a wide range of
1,2,3-triazole-derived compounds are important to medicinal, agricultural, and
organic chemists. The N-substituted aziridines are versatile intermediates of many
biologically active compounds [18]. New 1,2,3-triazole derivatives have recently
been synthesized via ring-opening of N-sulfonylaziridines [19].
Most triazoles are synthesized by click chemistry between azides and terminal
alkynes, catalyzed by a variety of copper reagents; they can be used to synthesize
3,5-disubstituted-1,2,3-triazoles [20, 21]. In this study of regioselective synthesis of
N-substituted-1,2,3-triazoles, much effort has been directed to developing an efficient
catalytic system for regioselective synthesis of methyl N1-alkyl-1H-1,2,3-triazole-4-
carboxylates 5 (Scheme 1), and copper catalysts have been replaced with special
nanoparticlestoenhance regioselectivity. Itwasenvisagedthat useofZnOnanoparticles
(ZONPs) as catalyst, KOH, and DMSO at elevated temperature would result in greater
efficiency in the synthesis of methyl N1-alkyl-1H-1,2,3-triazole-4-carboxylates 5.
Results and discussion
In continuation of our interest in synthesis of 1,2,3-triazole derivatives [22–24],
in this paper a regioselective synthesis of methyl N1-alkyl-1H-1,2,3-triazole-4-
4
I
R
R
N
O
O
+
H
N
Heated in
ZnO/KOH
Sealed tube
N
N
N
Si N3
N
100 °C/ 90h
DMSO/120 °C
CO2CH3
CO2CH3
1
2
3
5
a = -CH3, b = -C2H5
Scheme 1 Synthesis of methyl-N1-alkylated-1H-1,2,3-triazole-4-carboxylates 5
123

ZnO nanoparticles mediated regioselective synthesis
1103
carboxylates by ZONPs-catalyzed N-alkylation of methyl-1H-1,2,3-triazolecarb-
oxylate is reported. Our investigation began with an attempted synthesis of methyl-
1H-1,2,3-triazole carboxylate intermediate 3 from trimethylsilylazide 1 and methyl
propionate 2; direct heating in a pressure tube without solvent at 90–95 °C afforded
methyl-1H-1,2,3-triazole carboxylate 3 [14, 25]. Among 1,2,3-triazole derivatives
N1-substituted analogs are important potential pharmaceuticals. In order to
synthesize particular regioisomers, much effort has been directed to developing
an efficient catalytic system for this regioselective synthesis of methyl N1-alkyl-1H-
1,2,3-triazole-4-carboxylates 5 (Fig. 1). A method of alkylation involving ZONPs
(Fig. 2) (5 mol%) and KOH in DMSO solution heated at 110 °C is reported.
Reaction conditions were optimized for N-alkylation of methyl-1H-1,2,3-triazole
carboxylate 3 with methyl iodide 4a (Scheme 2). The screening of a variety of
nanoparticles in the presence of potassium hydroxide as base was explored as shown
in Table 2, entries 1–5. The reaction works very well with synthesized ZONPs
(Table 2, entry 4), with good yield. However commercial ZONPs resulted in
moderate yields (Table 2, entry 5), and other nanoparticles, for example Co(0),
Fe(0) and Ni–Fe were found to be less effective (Table 2, entries 1–3).
The effect of the amount of ZONPs was investigated for alkylation of 3 with 4a
(Scheme 2; Table 3, entries 1–7). The results indicated that increasing the amount
of nanoparticles above 5 mol% did not significantly increase the yield of 5a
(Table 3, entries 7 and 8). Low catalyst loading often prolonged reaction time and
reduced yield (Table 3, entries 2–5), because of lower conversion. Without catalyst
there was no conversion (Table 3, entry 1) and 5 mol% nanoparticle loading was
found to be the optimum amount for good conversion (Table 3, entry 6). The
alkylation was compared by carrying out the reaction with alkyl iodide, bromide,
and chloride; in this study, however, only the alkyl iodide are active and produced
the regioselective product in the presence of ZONPs.
In continuation, the isomers of methyl-N-alkylated-1H-1,2,3-triazole-4-carbox-
ylate were prepared using cesiumcarbonate as base in NMP solvent (Scheme 3).
All three isomers of each derivative were separated by preparative HPLC and each
isomer was characterized by use of 2D NMR HMBC techniques (see Supporting
Documents). The yield and ratio of isomers obtained are shown in Table 4.
On the basis of the 2D NMR HMBC results, it was confirmed that major products
5a and 5b were formed by ZONPs catalyzed N-alkylation of methyl-1H-1,2,3-
triazole-4-carboxylate. The correlated 2D NMR HSQC spectra of the methyl and
ethyl analogues are depicted (see Supporting Documents). Moreover the yields from
Fig. 1 Single-crystal structure
of 5a
123

1104
K. Prabakaran et al.
Fig. 2 TEM images
of synthesized ZONPs
Scheme 2 Synthesis of methyl-
1-methyl-1H-1,2,3-triazole-4-
carboxylate 5a
CH3
N
4a
H3C I
H
N
ZnO/KOH
N
N
N
N
DMSO/120 °C
CO2CH3
CO2CH3
3
5a
R
N
R
N
4
I
Cs2CO3
R
H
N
N
N
N
N
N
N
N
N
CO2CH3
N
R
NMP/ 0 °C - RT
CO2CH3
6
CO2CH3
5
CO2CH3
3
7
a Methyl
b Ethyl
R=
R=
Scheme 3 Synthesis of the three N-alkylated regioisomers of methyl-1H-1,2,3-triazole-4-carboxylate 3
both methods are compared in Table 4. The results showed that the ZONPs-
catalyzed reaction enabled efficient regioselective alkylation. The N-alkylated
1
triazole isomers were characterized by different spectral techniques including H
and 13C 2D NMR (HMBC techniques), IR analysis, CHNS, and LC–MS. The
correlated 2D NMR HMBC diagrams of the methyl and ethyl analogues are shown
in the Supporting Documents. The N-methyl analogue in the ZnO catalyzed reaction
product was further confirmed by single-crystal structure analysis which further
confirmed the regioselectivity (Fig. 1).
In summary, the reaction with ZONPs (Fig. 2) as catalyst gave regioselective
isomers 5a and 5b, as established by 2D NMR HMBC studies. The regioselective
isomers obtained were found to be synthetically and medicinally active compounds.
123

ZnO nanoparticles mediated regioselective synthesis
1105
The mechanism proposed for the ZONPs-catalyzed reaction is depicted in
Scheme 4. Because of the highly resonant structure of compound 3, N-alkylation
occurs at the nitrogen atom in position 1. Use of ZONPs enhances regioselective
alkylation because of the interaction between the carbonyl group and the ZONPs
[26]. The carbonyl group is activated by coordination with the ZONP and this is
followed by regioselective alkylation by the alkyl halide, in the presence of KOH as
base, in good yield.
Reusability of nanoparticles
The reusability of ZONPs was investigated using reaction of 3 and 4a as model
reaction. The efficiency of the catalyst was tested for successive runs of the reaction
using recycled catalyst. After the first reaction, the catalyst was recovered by
washing with methanol, centrifuged, removed, and reused for four consecutive runs
without any apparent loss of activity for the same reaction. It was noticed that the
use of recycled catalyst in subsequent experiments resulted in similar yields
(Tables 1, 2, 3, 4, 5). After 5 runs, a slight reduction in yield was noticed, as shown
in Table 5, entry 5.
R
N
N
O
N
H
5
O
N
CH3
N
N
N
O
HO
N
ZnO
N
nanoparticles
O
3
O
CH3
CH3
R
I
N
4
N
O
N
N
N
O
O
CH3
N
O
CH3
–OH
H+
KI
Scheme 4 Mechanistic pathway for regioselective alkylation of methyl-1H-1,2,3-triazole-4-
carboxylate 5
123

1106
K. Prabakaran et al.
Experimental
The materials were purchased from Sigma–Aldrich and Merck (India) and were
used without additional purification. All solvents used were of dry solvent
(anhydrous) or HPLC grade. All reactions were monitored by thin-layer chroma-
tography (TLC) on silica gel F254 plates. The silica gel (230–400 meshes) for
column chromatography was purchased from Spectrochem, India. Melting points
were taken in open capillary tubes and were corrected with reference to benzoic
1
acid. IR spectra were recorded on a Nucon Infrared spectrophotometer. H NMR,
13C NMR and two dimensional NMR spectra were recorded on a Bruker 400 MHz
1
spectrometer in CDCl3 or DMSO (with TMS for H and DMSO for 13C NMR as
internal references).
Synthesis of methyl 1,2,3-triazole-4-carboxylate 3
In a sealed tube, a mixture of methylpropiolate 1 (2 g) and trimethylsilylazide 2
(7.4 g) was heated at 100 °C until completion of the reaction, monitored by TLC.
The reaction mixture was then cooled and methanol was added dropwise with
cooling. The solid formed was left to stand for 30 min then isolated by filtration and
washed with ether then hexane. The product was then isolated as a colorless solid by
column chromatography using 10% pet. ether/EtOAc (2.75 g, 79%). The product
was analyzed by LC–MS using an Atlantis dC18 (75 9 4.6 mm, 5 lm) column,
positive mode, gradient solvent system A—0.1% HCOOH; B—ACN, flow 0.8 mL/
min. The product was also characterized by 1H and 13C NMR spectroscopic
analysis.
Table 1 N-alkylation of methyl-1H-1,2,3-triazole-4-carboxylate 3 and alkyl iodides 4
Entry
1
Alkyl iodides 4
Product 5
Yielda (%)
Melting point (°C)
94
154–155
H3C
I
CH3
N
4a
N
N
CO2CH3
5a
2
92
49–50
CH2CH3
N
I
H3C
4b
N
N
CO2CH3
5b
Reaction conditions: methyl-1H-1,2,3-triazole-4-carboxylate 3 (1.0 equiv), alkyl iodide 4 (1.1 equiv),
ZONPs (5 mol%), KOH, and DMSO, heated in a sealed tube at 120 °C
a
Isolated yields
123

ZnO nanoparticles mediated regioselective synthesis
1107
Table 2 Selection of nanoparticles for synthesis of methyl-1-methyl-alkylated-1H-1,2,3-triazole-4-car-
boxylates 5a
Entry
Nanoparticles
Amount of catalyst (mol%)
Time (min)
Yielda (%)
1
2
3
4
5
Co(0)
5
5
5
5
5
30
30
30
5
Nil
Nil
Nil
94
SnO2
Fe(0)
ZnO (synthesized)
ZnO (commercial)
10
70
Reaction conditions: methyl-1H-1,2,3-triazole-4-carboxylate 3 (1.0 equiv), alkyl iodide 4 (1.1 equiv),
nanoparticles (5 mol%), KOH, and DMSO, heated in a sealed tube at 120 °C
a
Isolated yields
Table 3 Effect of nanoparticles loading in the reaction of methyl-1H-1,2,3-triazole-4-carboxylate and 4a
Entry
Amount of catalyst (mol%)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
None
120
30
30
20
10
5
Nil
50
58
71
85
94
94
94
1
2
3
4
5
6
7
5
5
Reaction conditions: methyl-1H-1,2,3-triazole-4-carboxylate 3 (1.0 equiv), alkyl iodide 4 (1.1 equiv),
nanoparticles, KOH, DMSO solvent (5 mL), heated in a sealed tube at 120 °C
a
Isolated yield
Table 4 Alkylation of methyl-1H-1,2,3-triazole-4-carboxylate 5
Entry
Compound
Yielda (%)
Melting points (°C)
Using Cs2CO3 (I)
Using ZONPs (II)
1
2
3
4
5
6
5a
6a
7a
5b
6b
7b
40
20
21
45
22
20
94
–
154–155
128–128.5
48.5–49.0
49–50
–
92
–
Liquid
–
Liquid
Reaction conditions: (I) Cs2CO3 (0.6 equiv), alkyl iodide (1.1 equiv), NMP solvent (5 vol) stirred from
0 °C to ambient temperature, 12 h; (II) ZnO (5 mol%), alkyl iodide (1.3 equiv), DMSO solvent (5 vol),
KOH, heated in a sealed tube at 120 °C for 5 min
a
Isolated yields
123

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K. Prabakaran et al.
Table 5 Efficiency of catalyst tested using alkylation of methyl-1H-1,2,3-triazole-4-carboxylate, 3 and
methyl iodide 4a
Entry
Number of runs
Yielda (%)
1
2
3
4
5
Cycle I
94
93
92
92
85
Cycle II
Cycle III
Cycle IV
Cycle V
Reaction conditions: methyl-1H-1,2,3-triazole-4-carboxylate, 3 (1.0 equiv), methyl iodide, 4a (1.1 equiv)
nanoparticles, DMSO solvent (5 mL) heated in a sealed tube at 120 °C
a
Isolated yield
Synthesis of isomeric N-alkylated products of triazoles 5
To achieve N-methylation, Cs2CO3 (1.3 g) and methyl iodide 4 (mL) were added to
triazole 3 (2 g) in dry NMP solvent (15 mL) maintained at 0 °C under a nitrogen
atmosphere, and the mixture was then stirred at 0 °C for 1 h. The mixture was
then left to warm to room temperature and stirred until completion of the reaction,
monitored by TLC (Table 1). LC–MS analysis of the reaction mixture revealed
three peaks—the three isomers were well separated with significant retention times
and high purity. The three fractions were identified by mass spectroscopy. The
solvent was evaporated under vacuum and the residue was isolated into individual
isomers by column chromatography. Some of the mixture was also analyzed by
HPLC analysis and the individual isomers were also isolated by preparative HPLC.
1
Characterization of the individual isomers 5a–b was confirmed by LC–MS, H and
13C NMR, and two-dimensional techniques.
Synthesis of ZONPs
ZONPs were prepared from zinc nitrate (Zn(NO3)2Á6H2O) in accordance with
a method described by Wu et al. (2006). Samples were used for N-alkylation
of methyl-1H-1,2,3-triazole-4-carboxylate with alkyl iodides and compared with
commercial ZONPs. Synthesized ZONPs were found to be superior to commercial
ZONPs. These results indicate that the efficiency of the catalytic activity is
dependent on the particle size of ZnO.
Conclusion
A simple, convenient, and effective method for facile N-alkylation of triazole 3
by use of ZONPs has been established. The method has very attractive features,
for example reduced reaction times, higher yields, and economic viability of the
catalyst, compared with conventional methods. The operational simplicity of the
123

ZnO nanoparticles mediated regioselective synthesis
1109
procedure is also attractive. The catalyst can be recovered and reused for three
cycles with almost identical activity.
Acknowledgments We gratefully acknowledge financial support from the Department of Science and
Technology, Government of India (grant no. SR/FTP/CS-99/2006). The authors are grateful to the VIT
University management for their generous support and facilities.
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