ZnO nanoparticles as reusable heterogeneous catalyst for efficient one pot three component synthesis of imidazo-fused polyheterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.02.045

An efficient, simple, environmentally benign synthetic protocol is developed for synthesis of biologically and medicinally relevant pyrazole coupled imidazo[1,2-a]pyridine derivatives via three component reaction of alkyl-4-formyl-1-phenyl-1H-pyrazole-3-c

Full text of DOI:10.1016/j.tetlet.2016.02.045

Accepted Manuscript
ZnO nanoparticles as reusable heterogeneous catalyst for efficient one pot three
component synthesis of imidazo-fused polyheterocycles
Suman Swami, Nisha Devi, Arunava Agarwala, Virender Singh, Rahul
Shrivastava
PII:
S0040-4039(16)30154-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.045
TETL 47320
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 November 2015
10 February 2016
12 February 2016
Please cite this article as: Swami, S., Devi, N., Agarwala, A., Singh, V., Shrivastava, R., ZnO nanoparticles as
reusable heterogeneous catalyst for efficient one pot three component synthesis of imidazo-fused polyheterocycles,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.045
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ZnO nanoparticles as reusable
heterogeneous catalyst for efficient one pot
three component synthesis of imidazo-fused
polyheterocycles
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Suman Swami,a Nisha Devi, b Arunava Agarwala,a Virender Singh,b Rahul Shrivastava*a
R1
R2
R1
R2
N
N
COOEt
N
4a-4e
N
COOEt
H
CHO
ZnO Nps (10 mol%)
R5
R3
N
R6
R4
N
Ethanol, 4h
N
7a- 7q
R6
R3
CN
6a-6c
Yield: 88 - 92%
N
5a-5g
NH2
R4
R5

1
Tetrahedron Letters
ZnO nanoparticles as reusable heterogeneous catalyst for efficient one pot three
component synthesis of imidazo-fused polyheterocycles
Suman Swami,a Nisha Devi, b Arunava Agarwala,a Virender Singh,b Rahul Shrivastava*a
a Department of Chemistry, Manipal University Jaipur, VPO-Dehmi Kalan, Teshil Sanganer, Off Jaipur Ajmer Expressway, Jaipur-303007, Rajasthan, India
b Department of Chemistry, National Institute of Technology, Jalandhar, Jalandhar-144011,Punjab, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient, simple, environmentally benign synthetic protocol is developed for synthesis of
biologically and medicinally relevant pyrazole coupled imidazo[1,2-a]pyridine derivatives via
three component reaction of alkyl-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate, 2-
aminopyridine and isocyanide in presence of nano-crystalline ZnO in ethanol through one pot
chemical operation. The present synthetic protocol provides several advantages like operational
simplicity, short reaction time, reusable catalyst and easy work-up procedure.
Available online
Keywords:
Multicomponent reaction
Nanoparticles
2009 Elsevier Ltd. All rights reserved.
Imidazo[1,2-a]pyridine
Pyrazole
Imidazole fused polyheterocycles containing ring junction
nitrogen have attracted considerable interest in medicinal
chemistry in view of their uses as anti-inflammatory,8 anti-
cancer,9 anti-bacterial,10 and anti-tuberculosis11 agents. The
importance of imidazo[1,2-a]pyridine is evident from the fact
that it is prevalent in several marketed drugs such as Olprinone
(cardio tonic agent),12 Zolpidem (hypnotic),13 Levamisole
(anticancer),14 Alpidem (a nonsedative anxiolytic),15 Zolimidine
(anti-inflammatory)16 (Figure 1). They are also used in molecular
recognition and bio-imaging probes due to their structural
characteristics.17 On the other hand, pyrazole is also considered
as privileged heterocyclic system because of their wide range of
biological and pharmaceutical activities such as anti-
microbial,18a-b anti-inflammatory,18c anti-tubercular,18d anti-
parasitic,18e anti-tumor18f and anti-fungal18g activities. In addition,
aryl pyrazole and its derivatives have been reported recently to
Multicomponent reactions are well established synthetic tool
for designing chemical reactions those are capable of providing
complex target molecules with structural diversity.1
Multicomponent reactions combined with eco-compatibility offer
elegance of atom and step economy, multiple bonds forming
efficiency, environmentally benign, milder reaction conditions
and lesser reaction time in a single chemical operation.2 The
isocyanides based multicomponent reactions have emerged as a
highly efficient and diversity oriented synthetic methodology for
synthesis of complex drug like molecule having wide range of
medicinal and biological activities.3 Moreover, the development
of new synthetic protocols involving use of low cost, readily
available and reusable catalysts which minimize the consumption
of auxiliary substances, energy, time required in achieving
separation can result the synthetic method environmentally and
economically viable. Catalysis by nanoparticles seems to be an
attractive approach in organic transformations due to their larger
reactive surface to volume ratio with higher potential for
selectivity.4 Moreover, possibility of reusing the catalyst, milder
reaction conditions and easier isolation of product are additional
advantages of nanoparticle catalyzed multicomponent reactions.5
The metal oxide nanoparticles are well known to exhibit both
Lewis base-Lewis acid and redox properties on their surfaces.6
Among the others, zinc oxide nanoparticles are well established
for having Lewis acidic sites at their surfaces7a which have been
extensively employed as inexpensive heterogeneous catalyst to
promote acid catalyzed organic transformations.7b-i
N
CH3
N
N
MeO
Et
H3C
O
N
O
N
O
O
N
NH
HO
N
CH3
Divaplon
Zolpidem
N
Soraprazan
N
Cl
N
O
Cl
N
CN
O
N
S
O
N
N
H
O
N
Zolmidine
Alpedim
Olprinone
Figure 1. Representative example of imidazo[1,2-a]pyridine containing
pharmaceutically important molecules.
 Corresponding author. Tel.: +91-141-3999100 (ext. 273); e-mail:
chem.rahul@gmail.com
exhibit high affinity towards A2b adenosine receptor antagonist,
non-nucleoside HIV-1 reverse transcriptase inhibitory activity

2
Tetrahedron
and many other applications.19 Due to the prevalence of
R1
R2
R1
R2
imidazo[1,2-a]pyridine and pyrazole in the numerous
medicinally valuable chemical agents,20,21 we are attracted by the
possibility of coupling both entities via covalent linkage to
N
N
COOEt
N
4a-4e
N
COOEt
H
CHO
ZnO Nps (10 mol%)
Ethanol
R5
R3
N
provide
valuable
pyrazole
coupled
imidazo
fused
R6
R4
N
polyheterocyclic systems for useful bio-pharmaceutical
applications because of their structural characteristics involving
four nitrogens in condensed heterocyclic system integrated with
secondary amine and ester functionality for non-covalent
interactions. To achieve target molecules, our studies involved
isocyanide based Groebke-Blackburn-Bienayme3c-e three
component reactions in which aldehyde, 2-aminopyridine and
isocyanide are condensed in presence of acid catalyst. Different
methodology have been reported for this type of condensation
reactions such as Sc(OTf)3,22a ZnCl2,22b MgCl2,22c ZrCl4,22d
SnCl2.2H2O,22e HClO4,3d AcOH,3e p-TSA,22f montmorillonite K-
10,22g cellulose sulfuric acid,3c catalyst free and solvent free
reaction conditions.23 Most of these methods have many
limitations in terms of lower product yields, toxicity, longer
reaction time, higher energetic reaction conditions or use of
hazardous and volatile organic solvents like acetonitrile, toluene,
chloroform etc. Moreover, most of those catalysts are not
reusable. Thus, in view of existing synthetic methods for
imidazo[1,2-a]pyridine derivatives and related compounds,
development of environmentally benign, efficient and high-
yielding synthetic protocol is highly desirable with high
convergence of products. In this paper, we report a straight
forward one pot three component method for the synthesis of
pyrazole coupled imidazo[1,2-a]pyridine derivatives in excellent
yield. To the best of our knowledge, this is the first report for the
synthesis of pyrazole coupled imidazo[1,2-a]pyridine scaffolds
using nanocrystalline ZnO as a heterogeneous catalyst in ethanol.
Our primary objective is to develop a green synthetic protocol
using recyclable and reusable heterogeneous catalyst with benign
reaction condition.
N
R3
CN
6a-6c
7a- 7q
R6
N
5a-5g
NH2
R4
R5
Scheme 2. Synthesis of pyrazole coupled imidazo[1,2-a]pyridines
derivatives.
ZnO nanoparticles were prepared by reported literature.25 The
powder XRD analysis and SEM micrographs of synthesized ZnO
indicated the high crystalline nature and nanometer range of
materials respectively (see supporting information). TEM
measurements further confirmed the nanostructure of ZnO with a
mean diameter of 24 nm in semi-spherical nanoparticles as
shown in Figure S2.
The optimization of reaction conditions was established using
three model reactant ethyl-4-formyl-1-phenyl-1H-pyrazole-3-
carboxylate (4a), 2-amino pyridine (5a) and ethylisocyanoacetate
(6b). The efficiency of ZnO nanoparticles as catalyst over other
catalysts and feasibility of present synthetic methodology using
different solvents are also examined (Table 1). It was observed
that, no product was formed in absence of catalyst at room
temperature or refluxing temperature even after 24 h (Table 1,
entry 1). However, when the model reaction was performed in
presence of p-TSA (15 mol%) at 78˚C, the corresponding product
was obtained in 55% yield (Table 1, entry 2). To improve the
yield, various catalysts such as CH3COOH, TFA, Sc(OTf)3,
Bi(OTf)3, Cu(OTf)2 were screened, but the desired product was
obtained in moderate yield (Table 1. entries 3-8). To improve the
yield, reaction was performed in presence of ZnO nanoparticles
as catalyst (Table 1, entry 10). The result clearly indicated that
higher yield was achieved in presence of ZnO nanoparticles with
shorter reaction time in ethanol. The effect of catalyst loading on
reaction was investigated by varying the loading amount (such as
5%, 10%, 15%, 20%) and maximum yield was obtained in
presence of 10 mol% of ZnO nanoparticles (Table 1, entries 10-
13). However, it was observed that reducing the amount the
catalyst from 10 mol % to 5 mol %, reduced the yield while
increasing the amount of catalyst have no significant effect on the
yield of the product. The effect of solvent on reaction was also
evaluated by employing various solvents (Table 1, entries 14-18).
It was interesting to observe that maximum yield was obtained in
ethanol.
In our effort to prepare medicinally useful pyrazole coupled
imidazo[1,2-a]pyridine heterocyclic system, first we prepared
ethyl-4-formyl-1-substituted phenyl-1H-pyrazole-3-carboxylate
derivatives (4a-4e) via two step synthetic protocol.24 In the first
step, ethylpyruvate (1) reacted with substituted phenyl hydrazine
(2a-2e) in presence of trifluoroacetic acid in water for 5-15
minutes to give 3a-3e in more than 95% yield. Reaction of 3a-3e
with DMF-POCl3 afforded the desired product (4a-4e) in 92-97%
yields (Scheme 1).
R1
R1
O
Table 1. Optimization of reaction conditionsa,b
COOC2H5
DMF-POCl3,
0 oC - rt, 2.5-3 h
R2
TFA, H2O,
rt, 5-15 min
1
S.no.
1.
Catalyst (mol%)
Catalyst free
Solventc
Ethanol
Time
(h)
Yieldd
R2
N
N
NH
NHNH2
R2
N
C2H5OOC
CHO
C2H5OOC
R1
>24
No
3a-3e
4a-4e
2a-2e
reaction
a: R1= Br; R2= H; b: R1= Cl, R2= H, c: R1= Cl, R2= Cl; d: R1= H; R2= CH3; e: R1= H, R2= H
2.
3.
p-TSA (15 mol%)
Ethanol
Ethanol
9
9
55%
58%
CH3COOH (15
mol%)
Scheme1. Synthesis of ethyl-4-formyl-1-substituted phenyl-1H-pyrazole-3-
carboxylate derivatives.
4.
5.
TFA (15 mol%)
Ethanol
Ethanol
8
8
65%
55%
Boric acid (15
mol%)
Targeted pyrazole containing imidazo[1,2-a]pyridines
derivatives (7a-7q) were synthesized via three component
condensation reaction between alkyl-4-formyl-1-substituted
phenyl-1H-pyrazole-3-carboxylate (4a-4e), 2-aminopyridines
(5a-5g) and an isocyanide (6a-6c) in presence of reusable nano-
crystalline ZnO as catalyst in ethanol (Scheme 2).
6.
7.
8.
9.
Sc(OTf)3(15 mol%)
Bi(OTf)3(15 mol%)
Cu(OTf)2 (15 mol%)
ZnO (15 mol%)
Ethanol
Ethanol
Ethanol
Ethanol
7
6
6
6
70%
70%
75%
85%

3
10.
ZnO Nps (10
mol%)
Ethanol
4
92%
Under optimized reaction conditions, we turned to explore the
generality of reaction by extending the methodology to different
isocyanides and aminopyridines substituted with electron
donating as well as electron withdrawing functional groups as
depicted in Table 3. It was interesting to observe that 2-amino
pyridine with electron donating and electron withdrawing
functional groups (5a-5g) reacted successfully to furnish the
products (7a-7q). In addition, a model reaction was also
performed by taking reactants (4a, 5a and 6b) in 100 fold excess
concentrations which resulted the product (7a) in almost similar
yield.26 This result indicated that the reported protocol can be
utilized for large scale synthesis. All the products were
11.
12.
13.
14.
15.
16.
17.
18.
ZnO Nps (5 mol%)
ZnO Nps (15 mol%)
ZnO Nps (20 mol%)
ZnO Nps (10 mol%)
ZnO Nps (10 mol%)
ZnONps (10 mol%)
ZnO Nps (10 mol%)
ZnO Nps (10 mol%)
Ethanol
4
85%
92%
92%
90%
80%
80%
78%
84%
Ethanol
4
Ethanol
4
1-propanol
4
1,4-Dioxane
Tetrahydrofuran
Dichloromethanee
Dimethylformamide
4.5
4.5
4
1
characterized by FT-IR, H, 13C NMR and mass spectroscopic
4
aBold row indicates the optimized reaction condition. bEthyl 4-
analysis.
formyl-1-phenyl-1H-pyrazole-3-carboxylate (1 mmol), 2-amino
pyridine (1 mmol) and ethylisocyanoacetate (1 mmol) were
Table 3. Synthesis of pyrazole coupled imidazo[1,2-a]
pyridine derivative
stirred at 78˚C till completion of reaction as indicated by TLC.
d
cSolvents (4.0 mL).
Isolated yield after purification by
e
R1
R2
recrystallization from EtOAc – n-hexane. reaction was carried
N
N
out at 40˚C.
COOEt
H
N
R3
In addition, it was observed that 78˚C was optimum temperature
for maximum catalytic efficiency of ZnO nanoparticles (Table 2).
Further, catalyst was easily recovered by filtration after
completion of reaction, washed with ethanol and dried in vacuum
followed by drying in hot air oven. Recovered ZnO nanoparticles
could be used for at least eight times without any appreciable loss
of its catalytic activity to provide structurally diverse pyrazole
coupled imidazo[1,2-a]pyridine in excellent yield. It was found
that after use of eight reaction cycles (Figure 3), the catalytic
activity of ZnO nanoparticle decreased probably due to the
aggregation of ZnO nanoparticles during the course of reaction.
However, the post treatment of catalyst by calcination at 450˚C
for 4 h restored its catalytic activity and then reused for five more
reaction cycles.
N
N
R4
R6
R5
Entry Product R1
R2
R3
R4
R5
R6
Yield
(%)
90
1
7a
7b
7c
7d
7e
7f
Br
Br
Br
Br
Br
Br
Br
Cl
H
H
CH2COOMe
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOEt
CH2COOMe
H
H
H
2
H
H
H
H
H
H
H
Br
H
H
H
Br
H
H
92
92
92
90
3
H
4
CH3
H
H
5
CH3
H
6
H
CH3 91
Table 2. Effect of Temperaturea
7
7g
7h
7i
H
H
Cl
H
92
90
90
88
90
92
92
90
91
90
91
S. no.
Catalyst
Temp (˚C) Time (h)
Yieldb (%)
8
H
H
1.
ZnO NPs (10mol%)
ZnO NPs (10mol%)
ZnO NPs (10mol%)
ZnO NPs (10mol%)
ZnO NPs (10mol%)
r.t.
7-12
55
75
85
90
92
9
CH3 CH2COOEt
CH3 CH2COOMe
H
H
H
2.
45˚C
60˚C
70˚C
78 ˚C
6
6
5
4
10
11
12
13
14
15
16
17
7j
H
H
CH3
H
H
3.
7k
7l
Cl Cl
CH2COOEt
CH2COOMe
CH2COOMe
H
H
4.
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
Cl
Br
H
5.
7m
7n
7o
7p
7q
H
H
aReaction conditions: Ethyl-4-formyl-1-phenyl-1H-pyrazole-
3-carboxylate (1 mmol), 2-amino pyridine (1 mmol) and
CH2COOMe Br
H
CH2COOEt
tert-butyl
tert-butyl
H
H
H
H
Cl
H
ethylisocyanoacetate (1 mmol); Catalyst: ZnO NPs (10 mol%);
b
Solvent: ethanol.
Isolated yield after purification by
H
recrystallization from EtOAc – n-hexane.
H
H
aYields refer to isolated products after purification by
recrystallization from EtOAc – n-hexane.
On the basis of results of studies, a plausible mechanism for the
formation of pyrazole coupled imidazo[1,2-a]pyridine derivatives
is depicted in Scheme 3. It is proposed that initially hydroxyl
group present on surface of ZnO nanoparticles formed hydrogen
bond with aldehyde oxygen, which activates carbonyl group to
generate the carbonium ion, facilitating nucleophilic attack by
aminopyridine resulting in imine formation. The resulting imine
is further activated by ZnO nanoparticles to form electrophilic
imine carbon (I) which is subsequently attacked by isocyanide
followed by [4+1] cycloaddition to give cyclic adduct III.
Finally, cyclic adduct (III) undergoes 1,3-H shift to furnish the
desired product (7a-q).27
Figure 3. Recyclability and reusability of ZnO nanoparticles.

4
Tetrahedron
R1
R1
4.
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N
N
R1
N
N
N
COOEt
COOEt
N
COOEt
4a-e
O
-H2O
R3
H
O
N
R3
O
H
O
H
O
N
R3
NH2
NH2
N
5a-g
ZnO Nps
N
I
5.
R1
R1
N
R1
N
N
N
N
N
COOEt
COOEt
C
COOEt
1,3-H Shift
R2
[4+1]
R2
N
H
N
H
R2
N
N
6.
7.
(a) Bell, A. T. Science, 2003, 299, 1688. (b) Ibrahim, S. Catal.
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H
O
C
N
N
N
N
R2
N
N
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7a-q
III
II
Scheme 3. Plausible mechanism for synthesis of imidazo[1,2-a]
pyridine derivatives.
In conclusion, we have successfully developed an efficient
and environmentally benign isocyanide based synthetic protocol
for synthesis of biologically and medicinally relevant pyrazole
coupled imidazo[1,2-a]pyridine derivatives involving three
component reaction of alkyl-4-formyl-1-substitutedphenyl-1H-
8.
9.
pyrazole-3-carboxylate,
2-aminopyridine
and
ethylisocyanoacetate/methylisocyanoacetate/tert-butyl isocyanide
catalyzed by nanocrystalline ZnO in ethanol through one pot
chemical operation. The present synthetic protocol offers several
advantages such as environmentally benign, operational
simplicity, wide functional group tolerance, short reaction time,
reusable catalyst and easy work-up procedure. This methodology
might prove as a better alternative to the existing literature
methods.
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Acknowledgments
R.S. and A. A. acknowledge Manipal University Jaipur for
seed money grant. N. S. and V. S. gratefully acknowledges the
financial support in the form of research grant from DST (CS-
361/2011), and Council of Scientific and Industrial Research
(02(0202)/14/EMR-II), New Delhi (India). S. S. acknowledges
MUJ for teaching assistantship. Material Research Center,
MNIT, Jaipur is gratefully acknowledged for recording SEM,
TEM, XRD, FT-IR and NMR spectra reported in this paper.
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5
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refluxing. After the completion of reaction, as monitored by
TLC, 150 mL of water was added to the reaction mixture and
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layers were combined and washed with 10% NaHCO3 and brine
500 mL each. Organic layer was dried over anhydrous Na2SO4 and
evaporated under vacuum to give desired product. The product
was further purified with the help of recrystallization using EtOAc
and n-hexane to afford the desired product in high purity with
90% yield.
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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26. A mixture of 4a (38.8 g, 120 mmol), 5a (9.5 g, 100 mmol) and
ZnO Nps (1.0 g, 10 mol%) was refluxed in ethanol (350 mL) for
10 min. Then, ethylisocyanoacetate (12 mL, 110 mmol) was added
to the reaction mixture and the reaction mixture was stirred under
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6
Tetrahedron
Graphical Abstract
R1
R2
R1
R2
N
N
COOEt
N
4a-4e
N
COOEt
H
CHO
ZnO Nps (10 mol%)
R5
R3
N
R6
R4
N
Ethanol, 4h
N
7a- 7q
R3
CN
Yield: 88 - 92%
N
5a-5g
NH2
6a-6c
R4
R6
R5