CeO2/ZrO2 as green catalyst for one-pot synthesis of new pyrano[2,3-c]-pyrazoles

Article abstract of DOI:10.1007/s11164-017-2878-7

Ceria-doped zirconia (CeO₂/ZrO₂)-catalyzed synthesis of pyrano[2,3-c]-pyrazoles via four-component reaction of malononitrile, hydrazine hydrate, ethyl acetoacetate, and substituted aldehydes is described. The catalytic material CeO

Full text of DOI:10.1007/s11164-017-2878-7

Res Chem Intermed
DOI 10.1007/s11164-017-2878-7
CeO2/ZrO2 as green catalyst for one-pot synthesis
of new pyrano[2,3-c]-pyrazoles
Surya Narayana Maddila1 Suresh Maddila1
•
•
Werner E. van Zyl1 Sreekantha B. Jonnalagadda1
•
Received: 21 September 2016 / Accepted: 19 January 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract Ceria-doped zirconia (CeO2/ZrO2)-catalyzed synthesis of pyrano[2,3-c]-
pyrazoles via four-component reaction of malononitrile, hydrazine hydrate, ethyl
acetoacetate, and substituted aldehydes is described. The catalytic material CeO2/
ZrO2 was prepared and characterized by different techniques including powder
X-ray diffraction (P-XRD), scanning electron microscopy (SEM), transmission
electron microscopy (TEM), and Brunauer–Emmett–Teller (BET) analysis. Twelve
new pyrano[2,3-c]-pyrazole derivatives (5a–k) were synthesized in good to excel-
lent yield (89–98%) and their structures established and confirmed by different
1
spectroscopic methods, viz. H, 13C, and 15N nuclear magnetic resonance (NMR)
and high-resolution mass spectrometry (HRMS). The environmental benefits of the
process include excellent yield, short reaction time, simple work-up, elimination of
toxic solvents, and avoidance of chromatographic separation. The CeO2/ZrO2 cat-
alyst enables a facile synthesis procedure, is inexpensive, and has good reusability
(at least six times).
Keywords Multicomponent reaction Á Green synthesis Á Pyrazoles Á One-pot
reaction Á CeO2
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2878-7)
contains supplementary material, which is available to authorized users.
&
Sreekantha B. Jonnalagadda
jonnalagaddas@ukzn.ac.za
1
School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Chiltern
Hills, Durban 4000, South Africa
123

S. N. Maddila et al.
Introduction
Multicomponent reactions (MCRs) are assimilation reactions in which three or more
starting materials react with each other simultaneously to form a desired product [1].
This approach has been identified as a potent method for use in drug discovery due
to the generation of essential target compounds [1–3]. MCR approaches have
numerous significant benefits over classical, stepwise procedures, leading to
formation of several bonds in a single step without the need for intermediate
separations or purifications [4]. Thus, MCRs accomplish their goals in an efficient,
fast, and environmentally benign manner with substantial time and cost savings
[2, 3].
Development of heterogeneous catalysts for synthesis of heterocyclic compounds
has become a key issue for researchers [5]. Heterogeneous materials as catalysts for
green organic reactions offer both environmental and economic benefits. Many such
materials are easy to recover and recycle, making their use appealing [6–8]. Such
recyclable catalysts have numerous benefits such as being amenable to separation
from the reaction without difficult work-up as well as offering long life, stability,
recyclability, and high selectivity. This reduces waste production, whilst giving high
product yields in short reaction times through green procedures [9].
Zirconia (ZrO2) is an ecofriendly, widely available, and low-cost material [6]. It
stands out amongst other metal oxides due to its excellent stability and mechanical
properties, which can promote the activity of supported metal catalysts [9, 10]. It
has been commonly used due to its substantial chemical and thermal stability,
inertness, and high surface area [9–11]. Use of pure zirconia and its composites
(with other metals) as catalysts for various organic transformations has been
reported in literature [12, 13]. Cerium salts are generally used as dopants, offering
advantages including ease of handling, low cost, high stability, and nonhazardous
nature [14]. Cerium salts as dopant material are thus an appropriate choice for use in
green organic conversions, playing a major role in green catalysis.
Heterocyclics play a vital role in drug discovery, pharmaceutical, agrochemical,
and computational fields. Heterocyclic compounds are the main precursors in
various clinical applications and play a pivotal role in generation of diverse
biological activities [15, 16]. Pyranopyrazoles and their derivatives are important
heterocyclic compounds, exhibiting remarkable biological properties including
antibacterial, antifungal, antiviral, antitumor, anti-human immunodeficiency virus
(HIV), anticonvulsant, antiinflammatory, and antioxidant actions [17–23]. Many
pyranopyrazoles are also used as herbicidal and insecticidal agents [24]. Catalysts
for synthesis of substituted pyranopyrazole derivatives reported in literature include
[ChCl][ZnCl2]2 [25], Amberlyst A21 [26], per-6-ABCD [27], [(CH2)4SO3-
HMIM][HSO4] [28], [DBU][Ac] [29], silicotungstic acid [30], NaOH/microwave
[30], [Dsim]AlCl4 [31], L-Proline [32], TEABr [33], and FeNi3/SiO2/HPGMNP
[34], to mention a few. Many of these reports suffer from various limitations and
weaknesses, such as use of severe reaction conditions, hazardous organic solvents,
costly reagents and catalysts, nonreusability, long reaction time, or low product
yield, limiting their scope for use in practical applications. Hence, development of
123

CeO2/ZrO2 as green catalyst for one-pot synthesis of new…
green protocols for heterocyclic synthesis involving facile and environmentally
friendly methods (using green solvents in the reaction and/or work-up method)
would be useful and desirable.
In our pursuit to develop efficient, environmentally benign, green approaches for
synthesis of different heterocyclic compounds [35–37], we recently reported various
synthetic methods for several biologically interesting products [38–42]. We report
herein a new approach using CeO2/ZrO2 as highly efficient reusable catalyst for
synthesis of a series of new pyranopyrazole derivatives by reaction of aromatic
aldehydes, malononitrile, hydrazine hydrate, and ethyl acetoacetate at room
temperature with ethanol as solvent.
Experimental
Catalyst preparation
A range of supported catalysts with CeO2/ZrO2 weight percentages of 1, 5, and
10 wt% were synthesized using the wet impregnation procedure [4, 6]. Each
heterogeneous catalyst was prepared from a mixture of zirconia (ZrO2, 3 g, catalyst
support, Alfa Aesar) and an appropriate amount (wt%) of cerium nitrate [Ce(NO3)3-
6H2O (Alfa Aesar)] in distilled water (50 mL). The reaction mixture was stirred at
room temperature (R.T.) for 10 h. The resulting slurry was filtered under vacuum
and dried in an oven at 110–120 °C for 5 h, then calcined in presence of air at
450 °C for 5 h to form 1, 5, and 10 wt% CeO2/ZrO2 catalysts.
General procedure for synthesis of pyranopyrazole derivatives
In a typical reaction, equimolar ratios of aldehydes (1 mmol), malononitrile
(1 mmol), hydrazine hydrate (1 mmol), and ethyl acetoacetate (1 mmol) were
dissolved in ethanol (10 mL) at R.T. followed by addition of CeO2/ZrO2 (50 mg) as
catalyst. The reaction mixture was stirred continuously for 15 min at R.T.
(Scheme 1) using a magnetic stirrer. The progress of the reaction was monitored
by thin-layer chromatography (TLC). The reaction mixture was then filtered, and
the filtrate subsequently extracted with ethyl acetate and evaporated under reduced
pressure to obtain crude product, which was then purified with ethanol to afford pure
product 5a–k. The reaction products were identified and validated by various
spectral techniques (1H, 15N, and 13C-NMR and HRMS). Spectral instrumentation
details are incorporated in the Electronic Supplementary Material (SI-II), along with
details on some of the compounds.
6-Amino-4-(2,4,6-trimethoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5a) 1H NMR (400 MHz, DMSO-d6) d = 1.79 (s, 3H, CH3), 3.73 (s,
3H, OCH3), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 5.12 (s, 1H, CH), 6.259 (s, 2H,
ArH), 6.69 (s, 2H, NH2), 12.29 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): 9.66,
25.39, 51.50, 55.01, 55.42, 55.63, 91.07, 112.27, 154.35, 159.53, 160.57, 161.22;
HRMS of [C17H18N4O3 ? H]? (m/z): 343.1141; Calcd.: 343.1141.
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S. N. Maddila et al.
6-Amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitrile (5b) 1H NMR (400 MHz, DMSO-d6) d = 1.76 (s, 3H, CH3), 5.06 (s,
1H, CH), 6.91 (s, 2H, NH2), 7.05 (t, J = 8 Hz, 1H, ArH), 7.25–7.31 (m, 2H, ArH),
7.41 (dd, J = 7.8 Hz, 1.08 Hz, 1H, ArH) 12.11 (s, 1H, NH); 13C NMR (400 MHz,
DMSO-d6): 161.12, 154.95, 152.15, 146.19, 137.29, 135.09, 123.98, 120.97,
120.72, 111.06, 97.75, 60.22, 56.66, 55.48, 30.32, 9.42; HRMS of [C14H11ClN4-
O3 ? H]? (m/z): 287.1340; Calcd.: 287.1344.
6-Amino-4-(2-fluorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (5c) 1H NMR (400 MHz, DMSO-d6) d = 1.79 (s, 3H, CH3), 4.86 (s, 1H,
CH), 6.90 (s, 2H, NH2), 6.90–7.29 (m, 4H, ArH), 12.10 (s, 1H, NH); 13C NMR
(400 MHz, DMSO-d6): 9.35, 30.02, 55.53, 96.59, 115.37, 120.53, 124.69, 128.87,
129.76, 130.76, 135.72, 154.87, 158.69, 161.28; HRMS of [C14H11FN4O3 ? H]?
(m/z): 271.0623; Calcd.: 271.0626.
6-Amino-4-(4-hydroxy-3-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (5d) 1H NMR (400 MHz, DMSO-d6) d = 1.81 (s, 3H, CH3), 3.70
(s, 3H, OCH3), 4.49 (s, 1H, CH), 6.55 (dd, J = 8.12 Hz, 1.84 Hz, 1H, ArH), 6.71 (t,
J = 108.8 Hz, 2H, ArH), 6.76 (s, 2H, NH2), 8.82 (s, 1H, OH), 12.03 (s, 1H, NH);
13C NMR (400 MHz, DMSO-d6): 9.79, 35.79, 55.41, 57.42, 97.67, 111.19, 111.72,
119.46, 120.81, 135.63, 136.86, 147.53, 148.51, 154.68, 160.72; HRMS of
[C15H14N4O3 ? H]? (m/z): 299.0786; Calcd.: 299.0800.
6-Amino-4-(3-hydroxy-4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyra-
zole-5-carbonitrile (5e) 1H NMR (400 MHz, DMSO-d6) d = 1.80 (s, 3H, CH3),
3.72 (s, 3H, OCH3), 4.42 (s, 1H, CH), 6.52 (s, 1H, ArH), 6.58–6.60 (m, 1H ArH),
6.76 (s, 2H, NH2), 6.82 (d, J = 8.2 Hz, 1H, ArH), 8.88 (s, 1H, OH), 12.04 (s, 1H,
NH); 13C NMR (400 MHz, DMSO-d6): 9.70, 35.63, 57.70, 97.70, 111.80, 114.45,
118.05, 120.80, 135.54, 137.08, 146.45, 154.71, 160.60; HRMS of [C15H14N4-
O3 ? H]? (m/z): 299.0732; Calcd.: 299.0732.
6-Amino-4-(4-ethylphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (5f) 1H NMR (400 MHz, DMSO-d6) d = 1.16 (t, J = 7.6 Hz, 3H, CH3),
1.78 (s, 3H, CH3), 2.58 (dd, J = 15.24 Hz, 7.56 Hz, 2H, CH2), 4.54 (s, 1H, CH),
6.59 (dd, J = 7.52 Hz, 1.28 Hz, 1H, ArH), 6.80 (s, 2H, NH2), 6.89 (d, J = 6.8 Hz,
1H, ArH), 6.99 (t, J = 7.96 Hz, 1H, ArH), 11.99 (s, 1H, NH); 13C NMR (400 MHz,
DMSO-d6): 9.73, 15.39, 27.68, 35.81, 57.33, 97.72, 120.82, 127.05, 127.31, 127.73,
128.31, 128.38, 135.50, 141.72, 141.96, 154.72, 160.78; HRMS of [C16H16N4-
O ? H]? (m/z): 281.1040; Calcd.: 281.1039.
6-Amino-4-(4-fluorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (5g) 1H NMR (400 MHz, DMSO-d6) d = 1.78 (s, 3H, CH3), 4.62 (s, 1H,
CH), 6.86 (s, 2H, NH2), 7.13–7.19 (m, 4H, ArH), 12.10 (s, 1H, NH); 13C NMR
(400 MHz, DMSO-d6): 9.67, 35.41, 57.10, 97.46, 115.01, 115.22, 129.25, 129.33,
135.59, 160.79; HRMS of [C14H11FN4O ? H]? (m/z): 271.0835; Calcd.: 271.0839.
6-Amino-4-(4-hydroxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitrile (5h) 1H NMR (400 MHz, DMSO-d6) d = 1.78 (s, 3H, CH3), 4.46 (s, 1H,
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CeO2/ZrO2 as green catalyst for one-pot synthesis of new…
CH), 6.68 (d, J = 8.4 Hz, 2H, ArH), 6.74 (s, 2H, NH2), 6.94 (d, J = 8.4 Hz, 2H,
ArH), 9.26 (s, 1H, OH), 12.02 (s, 1H, NH); 13C NMR (400 MHz, DMSO-d6): 9.70,
35.45, 57.81, 98.03, 115.07, 120.84, 128.38, 134.72, 135.49, 154.72, 155.97,
160.59; HRMS of [C14H12N4O2 ? H]? (m/z): 269.0835; Calcd.: 269.0839.
6-Amino-4-(4-(dimethylamino)phenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (5i) 1H NMR (400 MHz, DMSO-d6) d = 1.78 (s, 3H, CH3), 2.85
(s, 6H, N(CH3)2), 4.45 (s, 1H, CH), 6.65 (d, J = 8.56 Hz, 2H, ArH), 6.73 (s, 2H,
NH2), 6.96 (d, J = 8.56 Hz, 2H, ArH), 12.02 (s, 1H, NH); 13C NMR (400 MHz,
DMSO-d6): 9.74, 35.34, 57.98, 98.15, 112.28, 120.92, 127.98, 129.45, 132.01,
135.44, 149.19, 154.76, 160.52.
6-Amino-4-(2,3-dimethoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5j) 1H NMR (400 MHz, DMSO-d6) d = 1.76 (s, 3H, CH3), 3.64 (s,
3H, OCH3), 3.79 (s, 3H, OCH3), 4.82 (s, 1H, CH), 6.59 (dd, J = 7.52 Hz, 1.28 Hz,
1H, ArH), 6.80 (s, 2H, NH2), 6.89 (d, J = 6.8 Hz, 1H, ArH), 6.99 (t, J = 7.96 Hz,
1H, ArH), 11.99 (s, 1H, NH); 13C NMR (400 MHz, DMSO-d6): 9.42, 30.32, 55.48,
56.66, 60.22, 97.75, 111.06, 120.97, 123.98, 135.09, 137.29, 146.19, 152.15, 154.95,
161.12.
6-Amino-4-(3,4-dimethoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-car-
bonitrile (5k) 1H NMR (400 MHz, DMSO-d6) d = 1.82 (s, 3H, CH3), 3.69 (s, 3H,
OCH3), 3.72 (s, 3H, OCH3), 4.54 (s, 1H, CH), 6.69 (dd, J = 7.52 Hz, 1.96 Hz, 1H,
ArH), 6.75 (d, J = 1.96 Hz, 1H, ArH), 6.80 (s, 1H, NH2), 6.88 (d, J = 8.28 Hz, 1H,
ArH), 12.07 (s, 1H, NH). 13C NMR (400 MHz, DMSO-d6): 9.79, 35.79, 55.41,
57.42, 97.67, 111.19, 111.72, 119.46, 120.81, 135.86, 147.53, 148.51, 154.68,
160.72; HRMS of [C16H16N4O3 ? H]? (m/z): 313.0952; Calcd.: 313.0957.
6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5l) 1H
NMR (400 MHz, DMSO-d6) d = 1.77 (s, 3H, CH3), 4.58 (s, 1H, CH), 6.84 (s, 2H,
NH2), 7.15–7.23 (m, 5H, ArH), 12.09 (s, 1H, NH); 13C NMR (400 MHz, DMSO-d6):
9.69, 36.22, 57.22, 97.61, 126.69, 127.42, 127.65, 128.39, 135.57, 144.40, 154.73,
160.84; HRMS of [C14H14N4O ? H]? (m/z): 253.0953; Calcd.: 299.0953.
Results and discussion
BET surface area and elemental (ICP) analysis
The porosity of the synthesized catalyst was determined by N2 adsorption–
desorption analysis. The N2 physisorption isotherms were determined for the 5%
ceria supported on zirconia catalyst. The N2 adsorption–desorption isotherms
showed a characteristic hysteresis loop of a type IV adsorption isotherm, indicating
mesoporous nature of the catalyst (Fig. 1). The mesoporous structure was confirmed
by the pore size values in the mesoporous region for the samples (3 nm \ pore
size \ 50 nm) and the p/p0 isotherm range of 0.76–0.94. The prepared catalyst
showed specific surface area of 56 m2 g-1 with pore volume of 0.212 cc g-1
.
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S. N. Maddila et al.
CeO2/ZrO2 N adsorption& desorption
2
150
120
90
60
30
0.2
0.4
0.6
0.8
1.0
Relative Pressure (P/Po)
Fig. 1 BET surface area results for 5% CeO2/ZrO2 catalyst
Inductively coupled plasma (ICP) analysis results confirmed the presence of the
anticipated amount of CeO2 in the catalyst (4.96 mol%).
TEM analysis
TEM analysis provided more structural information on the catalyst. Figure 2 shows
a distinctive TEM image of CeO2 supported on ZrO2, showing black ceria particles
with irregular cube-like shape and particle dimension ranging between 20 and
28 nm, and zirconia as white globular-shape particles. No drastic change in the
morphology of the catalyst was noticed after use.
Fig. 2 TEM micrograph of 5% CeO2/ZrO2 catalyst
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CeO2/ZrO2 as green catalyst for one-pot synthesis of new…
SEM analysis
Figure 3a exhibits a representative SEM surface morphology micrograph of the
sample of CeO2 on ZrO2. A few large cubic sheet asymmetrical silhouettes are
observed in the SEM image of CeO2/ZrO2, revealing the aggregated state of the
zirconia particles with ceria. The SEM-EDX analysis confirmed uniform distribu-
tion of ceria on the zirconia surface (Fig. 3b). The SEM-EDX results agreed well
with the data from ICP elemental analysis. Furthermore, the morphology of the
catalyst on SEM images highlighted the crystallinity and homogeneity of the
sample.
Powder X-ray diffraction (XRD) analysis
The powder XRD patterns of calcined ceria-doped zirconia are shown in Fig. 4. The
diffraction peaks at 2h values of 28.7°, 33.2°, 47.5°, 56.3°, 59.3°, 69.8°, 76.6°, and
Fig. 3 a SEM micrograph and b SEM-EDX micrograph of 5% CeO2/ZrO2 catalyst
123

S. N. Maddila et al.
1000
800
600
400
200
CeO2
ZrO2
20
40
60
80
2 Theta (degrees)
Fig. 4 Powder X-ray diffractogram of 5% CeO2/ZrO2 catalyst
79.4° were assigned to ceria. All these diffraction peaks agree with International
Centre for Diffraction Data data [Joint Committee on Powder Diffraction Standards
(JCPDS) file no. 43-1002]. The 5% CeO2/ZrO2 sample exhibited diffraction peaks
at 2h values of 24.7°, 28.8°, 31.8°, 34.6°, 41.4°, 50.9°, and 60.5°, corresponding to
ZrO2 (JCPDS file no. 01-089-9066). The peaks identified in the diffractogram
confirm the polycrystalline nature of the material. The average crystallite size of the
sample was about 6.9 nm, as obtained from the highest-intensity diffraction peaks
of CeO2/ZrO2 using the Scherrer equation.
Optimization procedure
A model reaction with benzaldehyde (1 mmol), malononitrile (1 mmol), hydrazine
hydrate (1.2 mmol), and ethyl acetoacetate (1 mmol) as reactants was investigated
in detail under varied conditions, i.e., absence and presence of different catalysts
and using various solvents and temperature conditions. First, the reaction was
studied without catalyst or solvent at both R.T. and reflux conditions, showing no
reaction even after 10 h (Table 1, entries 1 and 2). When the reaction was carried
out with various basic catalysts such as triethylamine (TEA), Na2CO3, pyridine, and
Na2S and with ethanol as solvent, yield of product was low, even after 6 h (Table 1,
entries 3–6). Then, the reaction was examined in ethanol condition at R.T. and in
the presence of different acidic catalysts such as AcOH, trifluoroacetic acid (TFA),
and p-toluenesulfonic acid (PTSA), but even after 6 h afforded very low product
yield (Table 1, entries 7–9). Next, the reaction was tried in presence of ionic liquids,
L-proline or (Bmim)BF4, with moderate product yield at R.T. conditions (Table 1,
entries 10 and 11). Further, when pure oxide catalysts, such as Al2O3, SiO2, and
ZrO2, were employed using the same solvent at R.T., the reaction revealed moderate
to good yield after 1.5–3.0 h reaction time (Table 1, entries 12–14). Noting the
encouraging result with ZrO2, to enhance the reaction efficiency it was used as
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CeO2/ZrO2 as green catalyst for one-pot synthesis of new…
Table 1 Optimization of
Entry Catalyst
Temperature Time (h) Yield (%)b
conditions for model reactiona
1
–
R.T.
Reflux
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
R.T.
10
–
2
–
10
–
3
TEA
8.0
6.0
7.0
7.5
6.5
7.0
7.5
4.5
5.0
3.0
2.5
1.5
0.75
0.50
0.25
0.35
0.25
19
27
23
20
09
12
14
39
48
51
59
70
84
89
98
90
97
4
Na2CO3
Pyridine
Na2S
5
6
7
AcOH
8
TFA
9
PTSA
10
11
12
13
14
15
16
17
18
19
L-Proline
(Bmim)BF4
Al2O3
SiO2
ZrO2
5% Fe2O3/ZrO2
5% V2O5/ZrO2
5% CeO2/ZrO2
1% CeO2/ZrO2
a
All products characterized by
1H, 13C, and 15N NMR and
HRMS spectral analysis
b
Isolated yield
10% CeO2/ZrO2 R.T.
– No reaction
support for different metal oxides. As such, Fe2O3/ZrO2, V/ZrO2, and CeO2/ZrO2
composites were prepared and screened for activity. The mixed oxide catalytic
reactions afforded very good to excellent yield (84–98%) within 45 min in ethanol
at R.T. (Table 1, entries 15–17). In particular, CeO2/ZrO2 as catalyst recorded
excellent yield (98%) of pyranopyrazoles in 15 min. Furthermore, use of 1% CeO2/
ZrO2 catalyst yielded 90% product in 35 min in ethanol solvent (Table 1, entry 18).
A further increase of the metal loading (10%) led to slightly decreased yield (97%)
(Table 1, entry 19). Given these impressive results, CeO2/ZrO2 was chosen as the
ideal catalyst for further study.
Next, to evaluate the influence of the quantity of catalyst on the synthesis of
pyrano [2,3-c]pyrazoles, the reaction of hydrazine hydrate, malononitrile, ethyl
acetoacetate, and benzaldehyde was studied using different amounts (10, 30, 50, 70,
90 mg) of CeO2/ZrO2. The 50 mg amount of catalyst proved optimal to complete
the reaction in terms of yield and reaction time. Increased amount of catalyst did not
improve either the yield or reaction time (Table 2). However, decrease in the
quantity of catalyst to \50 mg affected the product yield, reducing it to 88%
(Table 2). Thus, 50 mg of CeO2/ZrO2 at R.T. with ethanol as solvent was identified
as the optimum reaction condition.
When the efficiency using different polar and nonpolar solvents was investigated,
ethanol as solvent was found to be crucial for the reaction (Table 3). Under
otherwise comparable conditions, the CeO2/ZrO2-catalyzed reaction in presence of
relatively nonpolar solvents such as n-hexane, 1,4-dioxane, and toluene gave trivial
123

S. N. Maddila et al.
Yield (%)
Table 2 Optimization of amount of 5% CeO2/ZrO2 as catalyst in model reactiona
Entry
Catalyst (mg)
Time (min)
1
2
3
4
5
a
10
30
50
70
90
45
35
15
20
15
88
92
98
97
94
Reaction conditions: ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), malononitrile
(1.1 mmol), benzaldehyde (1 mmol), catalyst, and ethanol (10 mL) as solvent, stirred at room
temperature
Table 3 Optimization of solvent for synthesis of pyrano[2,3-c]pyrazole derivatives using 5% CeO2/ZrO2
catalyst
Entry
Solvent
Yield (%)
1
2
3
4
5
6
7
8
a
n-Hexane
Toluene
9
13
10
34
37
78
69
71
1,4-Dioxane
CH3CN
DMF
Ethanol
Methanol
Isopropanol
Reaction conditions: ethyl acetoacetate (1 mmol), hydrazine hydrate (1 mmol), malononitrile
(1.1 mmol), benzaldehyde (1 mmol), catalyst (50 mg), and solvent (10 mL), stirred at room temperature
yields even after protracted reaction time (Table 3, entries 1–3). Even with polar
aprotic solvents such as CH3CN and dimethylformamide (DMF), the reaction yield
was low (Table 3, entries 4 and 5). Although good results were also obtained when
polar solvents CH3OH, C2H5OH, and isopropanol were used (Table 3, entries 6–8),
based on criteria such as reaction time, green nature, cost-effectiveness, and
excellent yield, ethanol proved to be superior and the best solvent for the reaction.
CeO2/ZrO2 could catalyze synthesis of pyrano[2,3-c]pyrazole derivatives by
facile one-pot reaction with excellent yields. Under the optimal reaction conditions,
the flexibility and applicability of the protocol were confirmed by using a variety of
other aromatic aldehydes instead of benzaldehyde. Convincingly, irrespective of use
of aldehydes possessing different electron-withdrawing or electron-releasing
substituents in ortho, meta, and/or para positions on the aryl ring, all the reactions
gave impressive results, providing respective pyrano[2,3-c]pyrazole derivatives in
very good to excellent yield (Table 4). All reaction products were characterized and
1
their structures confirmed by H, 15N, and 13C NMR and HRMS spectral data
(Electronic Supplementary Material).
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CeO2/ZrO2 as green catalyst for one-pot synthesis of new…
Table 4 Synthesis of pyrano[2,3-c]pyrazoles using 5% CeO2/ZrO2 catalyst
Entry
R
Product
Yield (%)
M.p. (°C)
Lit. m.p. (°C)
1
2,4,6-(OMe)3
2-Cl
5a
5e
5f
92
90
91
90
93
95
89
92
89
94
92
98
227–228
145–147
258–260
236–237
209–211
241–243
171–172
210–212
162–165
215–216
192–193
167–168
–
2
145–146 [27]
3
2-F
–
4
3-OMe, 4-OH
3-OH, 4-OMe
4-Et
5d
5e
5f
–
5
–
6
–
7
4-F
5g
5h
5i
–
8
4-OH
210–211 [27]
9
NN-(Me)2
2,3-(OMe)2
3,4-(OMe)2
H
–
10
11
12
5j
–
5k
5l
–
167–169 [27]
– New compounds/no literature available
100
80
60
40
20
0
1
2
3
4
5
6
Catalytic Runs
Fig. 5 Recyclability of CeO2/ZrO2 catalyst
Reusability of catalyst
Reusability of the synthesized heterogeneous catalyst is an important requirement
from the environmental and economic points of view. In heterogeneous catalysis,
poisoning of the catalyst and leaching of metal are the main limitations, impacting
on the activity of catalyst in further use. To examine the stability of the catalyst,
recycling experiments were performed. After each run, the catalyst was separated by
filtration. The recovered catalyst was subjected to washing with dichloromethane,
dried, and then reused for up to six cycles. No significant loss was observed in the
123

S. N. Maddila et al.
first five cycles. The catalytic activity of the CeO2/ZrO2 decreased by 4% when the
recovered catalyst was reused in the sixth cycle (Fig. 5).
Conclusions
We present a simple, robust, efficient, and green multicomponent one-pot method
for synthesis of pyrano[2,3-c]pyrazole derivatives in good to excellent yield using
CeO2/ZrO2 as catalyst at R.T. The catalyst proved effective and recyclable for the
MCR protocol. The advantages of the approach are excellent yield, cost-
effectiveness, easy work-up, environmentally friendly reaction conditions, short
reaction time, green solvent, and reusable catalyst. This procedure is promising for
diversity-oriented synthesis of potentially bioactive heterocycles.
Acknowledgements The authors are grateful to the National Research Foundation (NRF) of South
Africa and University of KwaZulu-Natal, Durban for financial support and research facilities.
References
1. P.P. Ghosh, G. Pal, S. Paula, A.R. Das, Green Chem. 14, 2691 (2012)
2. R.C. Cioc, E. Ruijter, R.V.A. Orru, Green Chem. 16, 2958 (2014)
3. S. Brauch, S.S. van Berkel, B. Westermann, Chem. Soc. Rev. 12, 4948 (2013)
4. S. Maddila, S. Rana, R. Pagadala, S. Kankala, S.N. Maddila, S.B. Jonnalagadda, Catal. Commun. 61,
26 (2015)
5. P.T. Anastas, M.M. Kirchhoff, Acc. Chem. Res. 35, 686 (2002)
6. S. Shabalala, S. Maddila, W.E. Van Zyl, S.B. Jonnalagadda, Catal. Commun. 79, 21 (2016)
7. S.N. Maddila, S. Maddila, W.E. Van Zyl, S.B. Jonnalagadda, Chem. Open 5, 38 (2016)
8. S.N. Maddila, S. Maddila, W.E. Van Zyl, S.B. Jonnalagadda, Res. Chem. Intermed. 42, 2553 (2016)
9. S.N. Maddila, S. Maddila, W.E. van Zyl, S.B. Jonnalagadda, RSC Adv. 5, 37360 (2015)
10. Q. Zhao, J. Yao, L. Shi, X. Wang, RSC Adv. 6, 84553 (2016)
11. C.E. Hori, H. Permana, K.Y.S. Ng, A. Brenner, K. More, K.M. Rahmoeller, D. Belton, Appl. Catal.
B: Environ. 16, 105 (1998)
12. N. Ei-ichi, M. Jean-Luc, A. Luigi, E. Arkadij, C. Daniele, Tetrahedron Lett. 39, 2503 (1998)
13. S. Pradhan, B.G. Mishra, RSC Adv. 5, 86179 (2015)
14. A. Trovarelli, Catal Rev. 38, 439 (1996)
15. R. Dua, S. Shrivastava, S.K. Sonwane, S.K. Srivastava, Adv. Biol. Res. 5, 120 (2011)
16. S. Maddila, R. Pagadala, S.B. Jonnalagadda, Lett. Org. Chem. 10, 693 (2013)
17. H.N. Hafez, A.G. Alshammari, A.R. El-Gazzar, Acta Pharm. 65, 399 (2015)
18. A.H. Shamroukh, M.E. Zaki, E.M. Morsy, F.M. Abdel-Motti, F.M. Abdel-Megeid, Arch Pharm.
(Weinheim) 340, 236 (2007)
19. W. Fu-Qiang, Y. Hui, H. Bin, J. Yong-Kang, M. Shi-Yao, Z. Chao, L. Hong-Min, L. Feng-Wu,
Tetrahedron 72, 5769 (2016)
20. M. Khoobi, F. Ghanoni, H. Nadri, A. Moradi, M.P. Hamedani, F.H. Moghadam, S. Emami, M.
Vosooghi, R. Zadmard, A. Foroumadi, A. Shafiee, Eur. J. Med. Chem. 7, 296 (2015)
21. A.H. Mandour, E.R. El-Sawy, M.S. Ebaid, S.M. Hassan, Acta Pharm. 62, 15 (2012)
22. R. Shrestha, K. Sharma, Y.R. Lee, Y.J. Wee, Mol. Divers. (2016). doi:10.1007/s11030-016-9670-2
23. A. Kumar, P. Lohan, D.K. Aneja, G.K. Gupta, D. Kaushik, O. Prakash, Eur. J. Med. Chem. 50, 81
(2012)
24. H. Junek, H. Aigner, Chem. Ber. 106, 914 (1973)
25. R.H. Abdol, K. Morteza, T. Hamed, J. Iran. Chem. Soc. 12, 987 (2015)
26. B. Manisha, P. Pranjal, G.B. Bora, A. Hassan, ACS Sustain. Chem. Eng. 1, 440 (2013)
27. K. Kuppusamy, P. Kasi, Tetrahedron Lett. 51, 3312 (2010)
123

CeO2/ZrO2 as green catalyst for one-pot synthesis of new…
28. E. Javad, M. Ali, P. Vahid, B. Ehsan, H. Amir, J. Chem. Sci. 5, 1013 (2012)
29. R.S. Hamid, S. Marziyeh, M. Ebrahim, Res. Chem. Intermed. 40, 2721 (2014)
30. V.C. Hemant, B.B. Santosh, U.H. Rahul, P.B. Babasaheb, Bull. Korean Chem. Soc. 32, 3963 (2011)
31. R.M.Z. Ahmad, A.Z. Mohammad, N.M.T. Ehsan, K. Vahid, Z. Abdolkarim, New J. Chem. 37, 4089
(2013)
32. M.M. Hormi, R. Rumum, K. Iadeishisha, M.L. Badaker, K. Icydora, R. Mantu, M. Bekington,
Tetrahedron Lett. 52, 3228 (2011)
33. G.S. Kumar, C. Kurumurthy, B. Veeraswamy, R.P. Sambasiva, P. Shanthan, B. Rao, Org. Prep. Proc.
Int. 45, 429 (2013)
34. A.N. Mohammad, M.S. Seyed, Monatsh. Chem. 144, 1551 (2013)
35. S. Maddila, S.B. Jonnalagadda, J. Chile Chem. Soc. 57, 1099 (2012)
36. S. Maddila, S. Rana, R. Pagadala, S.B. Jonnalagadda, Res. Chem. Intermed. 41, 8269 (2015)
37. S. Maddila, S.N. Maddila, S.B. Jonnalagadda, P. Lavanya, J. Heterocycl. Chem. 53, 658 (2016)
38. S. Maddila, K. Naicker, S. Gorle, S. Rana, K. Yalagala, S.N. Maddila, M. Singh, P. Singh, S.B.
Jonnalagadda, Anti Cancer Agent Med. Chem. 16, 1031 (2016)
39. S. Maddila, K. Naicker, M. Momin, S. Rana, S. Gorle, S.N. Maddila, Y. Kotaiah, M. Singh, S.B.
Jonnalagadda, Med. Chem. Res. 25, 283 (2016)
40. S. Maddila, M. Momin, S. Gorle, L. Palakondu, S.B. Jonnalagadda, J. Chile Chem. Soc. 60, 2774
(2015)
41. S. Maddila, S. Gorle, N. Seshadri, P. Lavanya, S.B. Jonnalagadda, Arab. J. Chem. 9, 681 (2016)
42. S. Maddila, S. Gorle, M. Singh, P. Lavanya, S.B. Jonnalagadda, Lett. Drug Des. Discov. 10, 977
(2013)
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