Concentrated solar radiation-assisted one-pot/multicomponent synthesis of pyranopyrazole derivatives under neat condition

Article abstract of DOI:10.1007/s11164-021-04530-7

Concentrated solar radiation (CSR)-assisted synthesis of pyranopyrazole derivatives under solvent and catalyst-free condition has been reported in the present protocol. One-pot multicomponent synthesis from aromatic/heteroaldehyde, ethyl acetoacetate, malononitrile, and hydrazine hydrate leads to the final desired compounds in a good yield. This operationally simple methodology has several advantages such as green and clean reaction profile, simple workup and purification procedures, extremely short reaction time, atom efficiency, and being economical. The current energy-efficient method saves almost 98% of energy as compared to the conventional method. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-021-04530-7

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-021-04530-7
Concentrated solar radiation‑assisted one‑pot/
multicomponent synthesis of pyranopyrazole derivatives
under neat condition
Yatin U. Gadkari1 · Navnath T. Hatvate2 · Vikas N. Telvekar1
Received: 11 May 2021 / Accepted: 28 June 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021
Abstract
Concentrated solar radiation (CSR)-assisted synthesis of pyranopyrazole derivatives
under solvent and catalyst-free condition has been reported in the present protocol.
One-pot multicomponent synthesis from aromatic/heteroaldehyde, ethyl acetoac-
etate, malononitrile, and hydrazine hydrate leads to the fnal desired compounds in
a good yield. This operationally simple methodology has several advantages such
as green and clean reaction profle, simple workup and purifcation procedures,
extremely short reaction time, atom efciency, and being economical. The current
energy-efcient method saves almost 98% of energy as compared to the conven-
tional method.
Graphical abstract
Keywords Multicomponent reaction · Solar radiation · Pyranopyrazole · Energy
efcient · Eco-scale · E-factor
Extended author information available on the last page of the article
Vol.:(0123456789)
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Y. U. Gadkari et al.
Introduction
Currently, green chemistry has emerged as a vibrant tool in the feld of medicinal,
combinatorial, and organic chemistry owing to the use of environmentally benign
reagent and safe green conditions. Considering the well-known hazards of organic
solvents and poor recovery of catalyst impelled scientist to develop a green industrial
viable process which not only follows green chemistry principles but also achieves a
high yield of product in shorter duration [1–8]. For this, various methodologies have
been developed so far that involve the use of microwave irradiation, ultrasonication,
mechanochemistry, UV irradiation, etc. [9, 10]. But the need for skilled labors and
special costly equipment is a serious concern for scale-up study and sustainability.
Thus the development of a clean green viable approach is still in demand.
Nitrogen-containing heterocycles have a wide presence in naturally occurring and
biologically active compounds. They act as important precursors for the synthesis of
currently used pharmaceutical active molecules [11]. In particular, pyranopyrazole
derivatives have gained much attention in recent years due to their medicinal and
agrochemical signifcance. Some biologically active pyranopyrazoles are given in
Fig. 1 [12]. They represent privileged scafold having an interesting pharmacologi-
cal profle such as analgesic, anti-infammatory, fungicidal, anti-tumor, bactericidal,
vasodilatory, insecticidal, molluscicidal, anticancer agents, and also act as a potent
inhibitor of human Chk1 kinase [13–18].
In recent years, multicomponent reactions (MCRs) have become a powerful tool
in combinatorial chemistry as they can synthesize complex and diverse compounds
rapidly from assembling three or more reactants in one pot with high efcacy and
atom economy. MCRs have many advantages such as simplifed workup, short reac-
tion times, energy-efcient, minimization of waste, easy purifcation, wide substrate
scope tolerance, versatility, and eco-friendliness [19, 20].
Recent studies revealed
a
favorable approach for the synthesis of
dihydropyrano[2,3-c]pyrazoles involving a multicomponent reaction between alde-
hydes, ethyl acetoacetate, hydrazine hydrate, and malononitrile. This transformation
was carried out using diferent methods such as ultrasonication, microwave irradia-
tion, or use of a diferent catalyst such as CTACl, piperazine, piperidine, N-methyl
morpholine, L-proline, heteropolyacids, alumina, sodium benzoate, amberlyst, per-
6-amino cyclodextrin, imidazole, and glycine [21–33].
Although various methodologies are reported in the literature, many of them are
having limitations and shortcoming which includes the use of toxic chemicals, higher
Fig. 1 Examples of biologically important pyranopyrazole derivatives
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Concentrated solar radiation‑assisted…
reaction temperature, longer duration, expensive reagents, less yield, etc., with due
consideration, thus designing a new protocol for the synthesis of dihydropyrano[2,3-
c]pyrazoles derivatives is still in demand.
The use of a renewable source of energy i.e. solar radiations in catalyzing chemi-
cal reactions has received much attention from researchers as it is a safe, reliable,
green, widely available, and cost-free approach. The presence of a large number of
UV and IR radiations in sunlight is responsible for photochemical and thermal reac-
tions [34, 35]. Previously CSR has been used to carry out various organic transfor-
mations such as N-acylation and N-formylation reactions in an aqueous medium,
synthesis of DES and N-Phenyl phthalimide, Hantzsch synthesis of dihydropyri-
dines, oxidation of alcohol, and benzylic bromination. [36–40]. Earlier, we used
concentrated solar radiation in the synthesis of 3, 4-dihydropyrimidin-2(1H)-ones/
thiones and isoxazole-5(4H)-one [41]. Due to our current interest in the synthesis
of heterocyclic compounds [42–44], in this report, we are extending the use of con-
centrated solar radiation (CSR) in the synthesis of pyranopyrazole derivatives under
solvent and catalyst-free conditions.
Experimental
All the chemicals and solvents used were purchased from commercial sources
Sigma-Aldrich, Avra, SD Fine chemical, and Spectrochem companies and were
used without further purifcation. The purity determination of the starting materi-
als and reaction monitoring was accomplished by thin-layer chromatography (TLC)
on Merck silica gel G F254 plates. All target compounds were characterized by their
1H, 13C NMR and Mass spectra. 1H and 13C NMR spectra were obtained on a 400-
MR NMR Spectrometer from Agilent Technologies using tetramethylsilane (TMS)
as an internal standard and DMSO-d6 as a solvent. Mass spectra were recorded on a
direct insertion probe on Agilent Technologies 5975 series. Melting points of all the
compounds were recorded by the AnalabThermoCal melting point apparatus in the
open capillary tube. The intensity of solar radiation was measured with the help of
a Pyranometer (Dynalab Tech. Ltd., India), i.e., solar radiation fux density (W/m2).
The reaction was carried out from 12.30 to 1.00 pm which is a peak solar intensity
time. It also measures solar irradiation over a view of 180°.
Concentrated solar radiation (CSR) assembly
Synthesis of dihydropyrano[2,3-c]pyrazoles was carried out by CSR, and the
setup is shown in Fig. 2 [45]. Assembly had Fresnel lens with a dimension of
30 cm (X-axis): 30 cm (Y-axis). The lens was fxed on a stand using a clamp in
such a way that its focal point should fall on the central portion of RBF and also,
its refraction could cover the complete volume of RBF. The reaction fask was
fxed to another stand using another clamp and a mechanical stirrer was used for
stirring. Sunlight was focused through the Fresnel lens directly on the reaction
mixture in a reaction fask. This setup could be rotated in 180° as per the moving
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Y. U. Gadkari et al.
Fig. 2 Actual image of the CSR assembly for synthesis of dihydropyrano[2,3-c]pyrazoles
position of the sun to achieve maximum solar efciency. A thermometer gun was
used to measure the temperature of the reaction mixture and it was 90–100 °C.
The atmospheric temperature at the same time was found to be 30 °C.
General procedure for the synthesis of pyranopyrazole derivatives
A mixture of aldehyde (10 mmol), ethyl acetoacetate (10 mmol), malononitrile
(10 mmol), and hydrazine hydrate (10 mmol) was taken in a round-bottom fask
(Scheme 1). RBF was kept under the concentrated solar radiation (CSR) setup
with continuous stirring on a magnetic stirrer. After 3–4 min, the precipitate
was observed. The progress of the reaction was monitored by TLC. The precipi-
tated product was recrystallized from hot ethanol to aford pure pyranopyrazole
derivatives.
Results and discussion
As a preliminary test, hydrazine hydrate, ethyl acetoacetate, benzaldehyde, and
malononitrile were taken in the round-bottom fask and stirred in water under
CSR for 10 min, the reaction led to 82% of the desired product. The reaction was
Scheme 1 One-pot multicomponent synthesis of pyranopyrazole using concentrated solar radiation
(CSR)
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Concentrated solar radiation‑assisted…
optimized using diferent solvents as shown in Table 1. Very less yield was obtained
in acetonitrile and dimethylformamide, whereas solvents like ethanol, toluene,
and the tetrahydrofuran reaction proceed with a product yield of 52, 68, and 40%,
respectively. As all reactants are liquid and taking advantage of this, we stirred the
mixture of all reactants without any solvent under CSR and remarkably, the desired
product was formed immediately and the reaction was completed within 3 min with
98% yield. Further, the recrystallization from ethanol leads to a spectroscopically
pure product.
Optimized reaction conditions were applied on a wide variety of substrates, and
results are incorporated in Table 2. It is observed that various substituent on the ben-
zaldehyde had no signifcant efect on the outcome of the reaction (Table 2, entries
5–13). Polar (Table 2, entries 8, 10, 11) and halide (Table 2, entries 6, 12, 13) substi-
tution was tolerated by these reaction conditions. Bulkier aldehyde such as the naph-
thaldehyde (Table 2, entries 14) has no issue in reactivity. Heterocyclic aldehydes
(Table 2, entries 15, 16) gave the fnal product without compromising on yield.
According to the literature [46, 47], the formation of pyranopyrazole is
a three-step process, the frst step is believed to be the formation of 5-methyl-
2,4-dihydro-pyrazol-3-one 17, and the second one is the condensation of an alde-
hyde with malononitrile 18, while in the third step, both Intermediates 17 and
18 are condensed to form the fnal product 5. To know, which step requires solar
radiation, we carried several control experiments (Scheme 2), and we found that
every step which is in Scheme 2 required CSR because they did not give any sig-
nifcant conversion at room temperature or conventional heating at 90–100 °C.
Solar radiation contains UV–Visible radiation and infra-red radiation as well. The
photocatalytic property of UV radiations and very rapid vibrational movements
of bonds (IR irradiation) leads to rapid collision of reactants which ultimately
Table 1 Optimization for synthesis of 5.a
Entry
Solvents
Yield of 5(%)b
1
2
3
4
5
6
7
Water
Acetonitrile
DMF
Ethanol
Toluene
THF
82
30
24
52
68
40
98
None
aReaction conditions: 10 mmol of 1, 10 mmol of 2, 10 mmol of 3, 10 mmol of 4 were stirred under CSR
in mentioned solvents. bIsolated yield
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Y. U. Gadkari et al.
Table 2 Substrate scope for pyranopyrazole derivatives [a,b]
aReaction conditions: 10 mmol of 1, 10 mmol of 2, 10 mmol of 3, 10 mmol of 4 were stirred using CSR
under solvent-free conditions. bIsolated yield
Scheme 2 Control experiments on intermediates
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Concentrated solar radiation‑assisted…
boosts chemical transformation in a very short time. The synergistic efect of UV
and IR radiation could be the probable reason for the enhancement of the chemi-
cal reaction rate. [42–44]
By considering the interest of the pharmaceutical industries, we carried out
the scale-up study of the above compound and as expected reaction underwent
smoothly without sacrifcing the outcome. Thus, the above reactions were scaled
up at 50 mmol under CSR and were completed in ca. 5 min. Further recrystal-
lization of the crude product with ethanol gave a spectroscopically pure product
(Scheme 3).
Eco‑scale and E‑Factor calculation
To access the environmentally benign nature of this process, we determined E-fac-
tor and Eco-scale value and reported herewith. For the calculation of the E-factor,
we adopted two methods based on ethanol used for recrystallization and compared
it with the literature [48]. For current work, E-factors without ethanol recycling is
2.89, and with ethanol recycling, it found to be 1.60 respectively (Scheme 4). For
the synthesis of pharmaceuticals and fne chemicals, we should know that this value
is at least an order of magnitude lower than Sheldon E-Factor [49, 50]. However;
this waste (ethanol) is biodegradable. Similarly, for the literature work, a high E-fac-
tor (23.08) was calculated. An Eco-scale value [51] for current and literature work
was found to be 98 and 75.5, respectively. Thus it clearly shows the greener nature
of the current method than the literature one. (See ESI).
Scheme 3 On top: scale up of reaction and at the bottom: NMR spectra of fltered product
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Y. U. Gadkari et al.
Scheme 4 Eco-scale and E-Factor calculations
Efciency of energy consumption
The energy required for the synthesis of pyranopyrazoles is the total energy con-
sumed (kJ) per unit of the pyranopyrazoles obtained (g). The time required for
the synthesis of pyranopyrazoles was 6 h for the conventional method [52] while
3 min for the CSR technique. As per earlier records [36–40], energy required to
synthesize pyranopyrazole per gram is calculated and found to be 35.17 (kJ)/g
while using CSR, only 0.68 (kJ)/g was required (Table 3). Thus, the current CSR
protocol is highly energy efcient which saves almost 98% of energy than a con-
ventional method and reduces reaction time as well (98%).
To understand the signifcance of the current approach, the results obtained
using the CSR technique is compared with various catalysts already reported in
the literature [24, 52–59] for the synthesis of pyranopyrazoles. As can be seen
from Table 3, CSR-assisted synthesis of pyranopyrazoles derivatives under sol-
vent and the catalyst-free condition is more efcient than any other catalyst in
terms of shorter reaction time, higher yield, better energy efciency, greener, and
environmentally friendlier conditions suitable for industrial applications.
Conclusion
A highly efcient, sustainable and environmentally benign approach for the syn-
thesis of pyranopyrazole derivatives via concentrated solar radiation was success-
fully developed. Extremely fast conversion using renewable energy source under
solvent and catalyst-free condition make this protocol attractive to a green chem-
ist. Multigram scale up to 50 mmol denotes its pharmaceutical signifcance. Fur-
ther key features include simple experimental setup, broad substrate tolerance,
high yield, economical, easy workup procedures, etc.
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Concentrated solar radiation‑assisted…
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Y. U. Gadkari et al.
Supplementary Information The online version contains supplementary material available at https://doi.
org/10.1007/s11164-021-04530-7.
Acknowledgements YUG acknowledges COEPI, TEQIP–III for fnancial support.
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Authors and Afliations
Yatin U. Gadkari1 · Navnath T. Hatvate2 · Vikas N. Telvekar1
* Vikas N. Telvekar
vn.telvekar@ictmumbai.edu
1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Mumbai 400 019, India
2
Institute of Chemical Technology, Marathwada Campus, Jalna 431213, India
1 3