Regioselective synthesis of functionalized 1,2,3-triazoles via oxidative [3+2]-cycloaddition using Zn(OAc)2 - tBuOOH or ZnO nanoparticle as catalyst system in aqueous medium

Article abstract of DOI:10.1016/j.catcom.2017.05.006

The regioselective synthesis of functionalized pyrazole?1,2,3-triazoles is reported via oxidative [3 + 2]-cycloaddition reactions of azides with β-nitrostyrenes and chalcone derivatives using Zn(OAc)₂ - ^tBuOOH or ZnO nanoparticles as

Full text of DOI:10.1016/j.catcom.2017.05.006

CatalysisCommunications99(2017)115–120
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Catalysis Communications
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Short communication
Regioselective synthesis of functionalized 1,2,3-triazoles via oxidative
t
[3+2]-cycloaddition using Zn(OAc)2 - BuOOH or ZnO nanoparticle as
catalyst system in aqueous medium
Banoth Paplala, Sakkani Nagarajua, Balasubramanian Sridharb, Dhurke Kashinatha,⁎
a
Department of Chemistry, National Institute of Technology, Warangal 506 004, India
X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
1,2,3-Triazole
Pyrazole
[3 + 2]-Cycloaddition
Zinc acetate
Hybrid molecules
The regioselective synthesis of functionalized pyrazole˗1,2,3-triazoles is reported via oxidative [3 + 2]-cy-
cloaddition reactions of azides with β-nitrostyrenes and chalcone derivatives using Zn(OAc)2 - BuOOH or ZnO
nanoparticles as catalyst system in aqueous medium. The catalyst dependent product selectivity was observed
with β-nitrostyrenes to give the triazoles with and without -NO2 group Zn(OAc)2 and ZnO nanoparticles. The
chalcones gave the triazoles selectively as sole products with good regioselectivity. The resulting products were
further converted into sulfonamides and oxazoles respectively.
t
1. Introduction
nitrostyrenes gave -NO2 eliminated product when Ce(OTf)3 and Bi2WO6
nanoparticles are used as catalysts [14,15,18]. In contrast to these,
1,2,3-Triazole and pyrazole are considered as privileged structures
in medicinal chemistry because of their broad biological applications
[1]. In many reports, the 1,2,3-triazole has been introduced as a part of
parent molecule or as a linker to enhance the biological activity [2] and
used as bioisostere for the five member carbocycles [3]. Similarly,
pyrazole derivatives also known to show biological activity such as
antifungal [4], COX-2 inhibitor [5], and Human Dihydroorotate De-
hydrogenase (DHODH) inhibitors [6] etc., Covalently bonded 1,2,3-
triazole-pyrazole are rare and very few reports are available in the lit-
erature as anti-invasive, HIF (hypoxia inducible factor) inhibitors and
cytotoxic/apoptosis inducing agents as shown in Fig. 1 [7].
Chen and Elangovan groups independently reported the synthesis of
nitro substituted 1,2,3-triazoles via oxidative [3 + 2]-cycloaddition of
β-nitrostyrenes and azides in presence of Cu(OTf)2 and CuO nano-
particles [19]. Thus, keeping in view of the importance of functiona-
lized 1,2,3-triazoles and our interest in green methods, here in we re-
port an eco-friendly method for the preparation of the 1,2,3-triazoles
t
using Zn(OAc)2 - BuOOH or ZnO nanoparticles as catalyst system in
water.
2. Experimental
The construction of 1,5-disubstituted 1,2,3-triazoles via Cu(I), Ru
(II)-catalyzed [3 + 2]-cycloaddition reactions (popularly known as Cu/
Ru AAC) between azides and terminal alkynes (conventional starting
material) is well established under homogeneous and heterogeneous
conditions [8–9]. Along with these, the use of ketones, chalcones and β-
nitrostyrenes (non-conventional starting materials) has got lot of at-
tention in recent times. Some of these include the use of DBU, piper-
idine and proline as organocatalysts (enamine catalysis) [10–12], CuI/
K2CO3 [13], morpholine/pTSA [14], Ce(OTf)3 [15,16] (homogeneous
conditions) and CuO nanoparticles [17], Bi2WO6 nanoparticles [18]
(heterogeneous conditions). However, chalcones show solvent depen-
dent reactivity with organic azides in presence of Ce(OTf)3 to give
enaminones (in toluene) and triazoles (in DMF) [16]. Similarly, β-
a) Preparation, Characterization of ZnO nanoparticles by powder XRD.
ZnO nanoparticles were prepared by using reported method and
characterized by powder XRD data as shown in Fig. 2. After con-
firmation of the ZnO nanoparticles to test the catalyst activity, we
selected [3 + 2]-cycloaddition of organic azides and β-nitrostyrenes
as model reaction. The recovered catalyst was reused up to six cycles
for the same reaction without loss in the catalytic activity which is
supported by the yields of the products and powder XRD data of
cycle-6 (Fig. 2).
b) Procedure for the triazole synthesis: To a mixture of β-nitrostyrene/
chalcone (1 eqv) in water (4 mL) were added azide (1.5 eqv), Zn
⁎
Corresponding author.
E-mail address: kashinath@nitw.ac.in (D. Kashinath).
http://dx.doi.org/10.1016/j.catcom.2017.05.006
Received 21 February 2017; Received in revised form 4 May 2017; Accepted 5 May 2017
Availableonline05May2017
1566-7367/©2017ElsevierB.V.Allrightsreserved.

B. Paplal et al.
CatalysisCommunications99(2017)115–120
Fig. 1. Biological active compounds with pyrazole-triazole hybrids.
catalysts, Cu(OAc)2 and Zn(OAc)2 gave 75% and 95% (total yield of 2
and 2′ respectively. However, the reaction time was too high (12 h).
Further to reduce reaction time, optimization studies were conducted
using best catalyst i.e. Zn(OAc)2 in presence of different oxidants such
as molecular oxygen, I2, H2O2, DMSO and tBuOOH as shown in Table 1.
Among all, the catalyst-oxidant combinations, a set of Zn(OAc)2
ZnO
ZnO-CYCLE-6
t
(20 mol%) and BuOOH (1 equiv) was found to be good giving the re-
geoisomers 1-benzyl-4-nitro-5-phenyl-1H-1,2,3-triazole (2a; 95%) and
1-benzyl-5-phenyl-1H-1,2,3-triazole (2a′;5%) with over all quantitative
yield in 3 h. Though the reactivity of H2O2 and TBHP (entries 15 and
18; Table 1) are comparable, TBHP is better because of its reactivity
(solubility in water and dissociation at lower temperatures). To define
the independent roles of Zn(OAc)2 and TBHP, separate experiments
were conducted and found that Zn(OAc)2 alone require more time for
the completion of reaction and more than 1 equivalents of TBHP does
not influence the rate of the reaction considerably (see ESI).
(a.u.)
Intensity
Then, different β-nitrostyrenes and pyrazole based β-nitrostyrenes
(with electron donating, withdrawing groups) were synthesized and
treated with arylazides to give the functionalized pyrazole-triazole
hybrids 2b-2o (Scheme 1). It is noteworthy to mention that the present
reaction conditions are giving the intended products (with -NO2) in
excellent yield (up to 95%). All the products synthesized were char-
acterized using spectroscopic methods (see Electronic Supporting In-
formation for 1H, 13C NMR and mass spectral data). Further the re-
gioselectivity of the isomeric structures and presence of –NO2
functional group was established by single X-ray crystallography as
shown in Scheme 1 (for compound 2b). Later on, the same reaction was
attempted with ZnO nanoparticles (10 mol%) in water. To our surprise,
the formation of -NO2 elimination product (2a′) was observed as a
major rigeoisomer with excellent yield (95%) along with 2ab (5%) in
shorter reaction times (3 h) (Scheme 1).
Then, different β-nitrostyrenes and pyrazole based β-nitrostyrenes
(with electron donating, withdrawing groups) were synthesized and
treated with arylazides to give the functionalized pyrazole-triazolehy-
brids 2b-2o (Scheme 1). All the products synthesized were character-
ized using spectroscopic methods (see Electronic Supporting Informa-
tion for 1H, 13C NMR and mass spectral data). Further the
regioselectivity of the isomeric structures and presence of –NO2 func-
tional group was established by single X-ray crystallography as shown
in Scheme 1 (for compound 2b). Later on, the same reaction was at-
tempted with ZnO nanoparticles (10 mol%) in water. To our surprise,
the formation of elimination product (2a′) was observed as a major
rigeoisomer with excellent yield (95%) along with 2ab (5%) in shorter
reaction times (3 h) (Scheme 1).
20
40
2 (degree)
60
80
100
120
Fig. 2. Powder XRD data of ZnO nanoparticles overlapping with recovered catalyst after
6th cycle from the reaction in water.
t
(OAc)2 (20 mol%) and BuOOH (1 eqv)/ZnO nanoparticle (10 mol
%) at room temperature and the mixture was heated at 80–90 °C for
3–5 h (monitoring by TLC). After that the reaction mixture was
cooled to room temperature and extracted with EtOAc (3 × 10 mL).
The organic layers were washed with brine, dried using sodium
sulphate to give the crude product. Purification of the crude product
using petroleum ether-EtOAc gave the desired product (please see
the Electronic Supporting Information for spectral data).
3. Results and discussion
Nitro group is an important functionality on any scaffold which can
be easily converted in to amine which intern can be used for the for-
mation of CeN bond, amide, sulfonamide, carbamate etc. Considering
the importance of NO2, we plan to develop a simple method for the
preparation of 1,2,3-triazoles. Towards this, the reaction of β-ni-
trostyrene (1) and BnN3 in presence of NaOAc (20 mol%) in water
(4 mL) at 100 °C in 12 h gave the isomeric products 2a and 2a′ in 50%
and 20% yields respectively (Scheme 1). After confirmation of the
products, different metal acetates [Ca, Co, Ni, Pb, Cu and Zn (entries
2–9; Table 1)] were screened for the reaction. Among screened
After successfully demonstrating the synthesis of nitro-triazole and
pyrazole-triazole hybrids starting from β-nitrostyrenes, the focus was
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B. Paplal et al.
CatalysisCommunications99(2017)115–120
Scheme 1. Reaction of 1 with BnN3 in presence of (i) NaOAc; (ii) Zn(OAc)2 - tBuOOH and (iii) ZnO nanoparticles and water and ORTEP diagram: A view of 2b (CCDC 1475846) showing
the atom- labeling scheme.
117

B. Paplal et al.
CatalysisCommunications99(2017)115–120
Table 1
Optimization of the reaction conditions (catalyst, solvent and additive) using.
S. No.
Catalyst system
(20 mol%)
Reaction time
(h)
Reaction
temp
Isolated yields (%)a
(2a)
(2a′) [18]
1
2
3
4
5
6
7
8
NaOAc
NH4OAc
Ca(OAc)2
Co(OAc)2
Ni(OAc)2
Pb(OAc)2
Cu(OAc)2
Cu(OAc)2
12
12
12
12
12
12
12
14
12
12
12
12
12
12
5
100
100
100
100
100
100
90
110
90
90
90
90
90
90
90
90
90
50
50
25
20
40
20
65
27
90
60
Trace
50
75
Nf
80
Trace
80
20
20
25
20
30
20
10
36[19]
5
9
Zn(OAc)2
Zn(OAc)2
10
11
12
13
14
15
16
17
20b
Trace
5
Zinc metal
Zn(OAc)2/dioxane
Zn(OAc)2/O2
Zn(OAc)2/I2
Zn(OAc)2/H2O2
Zn(OAc)2/DMSO
Zn(OAc)2/Cu
(OAc)2
5
Nf
5
Trace
5
12
12
18
19
19
20
Zn(OAc)2/TBHP
Cu(OAc)2/TBHP
Zn(OAc)2/tBuOH
ZnO
3
8
12
3
90
90
90
90
95
90
20
Nf
5
5
5
95/5c
(nanoparticle)
Nf: Not found.
a
All the reactions were performed at 1 mmol scale using water as reaction medium.
DMF as solvent [19].
1,4-isomer.
b
c
shifted towards the synthesis of new hybrid molecules with acetyl
functional group. Towards this, the chalcone 3a was treated with BnN3
in the presence of Zn(OAc)2(20 mol%) and TBHP (1 eqv) in water at
90 °C for 5 h to give 1-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)etha-
none 4a as single isomer with 90% yield. Whereas the same reaction
with ZnO nanoparticle (10 mol%) in water at 80 °C, 5 h gave 4a in 98%
yield (Scheme 2). It is interesting to note that the formation enaminone
is not observed in both the conditions. After confirmation of the product
and rigeoselectivity (by single X-ray crystallography; Scheme 2 for 4p),
different simple and pyrazole based chalcones were reacted with azides
(1.5 eq) under optimized conditions to give substituted triazoles and
pyrazole-triazolehybrids 4b-4v in moderate to good yields (Scheme 2).
From the reaction conditions (Schemes 1 and 2), we assume that the
nitrostyrene is activated by the chelating Zn(OAc)2 which is reacting
with azide to give I via [3 + 2]-cycloaddition reaction which intern is
undergoing oxidation in presence of TBHP to give desired product II. It
is noteworthy to mention that the catalyst system used in the present
study i.e. Zn(OAc)2 and TBHP is very mild. Because of this the forma-
tion of 1,2,3-triazole with retention of NO2 group is more selective.
Whereas the ZnO nanoparticles gave the -NO2 eliminated product. Si-
milarly chalcone is getting activated by Zn(OAc)2 to facilitate the attack
of azide followed by the oxidation to give desired product IV (Scheme
3) which is supported by recent report for the oxidative-[2 + 3]-cy-
cloaddition reaction using TEMPO [20]. In both the cases, water play
important role to bring the reactive functional groups together by in-
ducing the hydrophobic interactions between the organic molecules
and enhancing the kinetics of the reaction. This is supported from the
entry 10 of Table 1 where the yield of the desired product is only 60%
in DMF as solvent [21]
Keeping in view of the importance of triazole-sulfonamides, pyr-
azole-triazole-oxazole hybrids and with the aim of creating more
complexity further, the nitro compound 2b was treated with iron
powder to give the amine (5; 90%) which was reacted with TsCl to give
expected sulfonamide (6) in 70%yield (Scheme 4). Similarly, activation
of acetyl group was achieved by the reaction of compound 4l with
bromine to give phenecyl bromide (7) followed by benzylamine to give
pyrazole-triazole-oxazole hybrid (8) in 85% yield (Scheme 4). Further
extension of this methodology is under progress in our laboratory.
4. Conclusions
In conclusion, we have developed a simple and green protocol for
functionalized 1,2,3-triazolesunder green conditions using inexpensive
reagents (Zn(OAc)2 - tBuOOH and ZnO nanoparticles) in water. In both
the conditions, the regioselectivity was observed without side products.
The compounds synthesized here are extended for functionalized sul-
fonamides and pyrazole-triazole-oxazole hybrids.
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CatalysisCommunications99(2017)115–120
Scheme 2. Different acetyl triazoles and pyrazole-triazole hybrids (4b-4v) prepared under optimized conditions; Yields given in parenthesis are from conditions 2. and ORTEP diagram: A
view of 4p (CCDC 1475845) showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are represented by circles of arbitrary radii.
119

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CatalysisCommunications99(2017)115–120
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