Green synthesis of pyranopyrazoles via biocatalytic one-pot Knoevenagel condensation–Michael-type addition–heterocyclization cascade in non-aqueous media

Article abstract of DOI:10.1007/s11164-020-04122-x

Abstract: An efficient, green and facile route for the one-pot four-component synthesis of pyranopyrazole derivatives through the condensation of the aromatic aldehydes, ethyl acetoacetate, malononitrile and hydrazine hydrate using baker’s yeast as biocat

Full text of DOI:10.1007/s11164-020-04122-x

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04122-x
Green synthesis of pyranopyrazoles via biocatalytic
one‑pot Knoevenagel condensation–Michael‑type
addition–heterocyclization cascade in non‑aqueous media
Prabhakar Shrivas1 · Rajat Pandey1 · Sangesh Zodape1 · Atul Wankhade1 ·
Umesh Pratap1
Received: 8 December 2019 / Accepted: 3 March 2020
© Springer Nature B.V. 2020
Abstract
An efcient, green and facile route for the one-pot four-component synthesis of
pyranopyrazole derivatives through the condensation of the aromatic aldehydes,
ethyl acetoacetate, malononitrile and hydrazine hydrate using baker’s yeast as bio-
catalyst is presented. The important aspects of the present methodology are the use
of an environmentally friendly catalyst, high yield of products and mild reaction
conditions, i.e. at neutral pH and ambient temperature.
Graphic abstract
Keywords Baker’s yeast · Pyranopyrazoles · Heterocyclization · Biocatalysis ·
Multicomponent reaction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04122-x) contains supplementary material, which is available to authorized users.
* Umesh Pratap
umeshpratap2014@gmail.com
1
Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, South
Ambazari Road, Nagpur, Maharashtra 440010, India
Vol.:(0123456789)
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P. Shrivas et al.
Introduction
The pyranopyrazole derivatives are fused heterocyclic compounds, having vari-
ous biological properties such as antifungal, antibacterial, antimicrobial, analge-
sic, antipyretic, anti-infammatory, vasodilator, antioxidant and anticancer [1–8].
They are also very useful as agrochemical and molluscicidal agents, and some
derivatives are also used as precursors of cosmetics and pigments [9–12].
The frst pyranopyrazole was reported in 1973 by the reaction between
3-methyl-1-phenyl-pyrazole-5-one and tetracynomethylene [13]. The 2-amino-
4-substituted pyrano-[2,3-c]pyrazol-3-carbonitriles derivatives were obtained
in 1974 by the addition of malononitrile on 4-arylidene-2-pyrazolin-5-one [14].
Afterwards, many other synthetic methods to synthesize these compounds were
documented [15]. Those schemes include a one-pot four-component cyclocon-
densation reaction of aromatic aldehydes, ethyl acetoacetate, malononitrile and
hydrazine hydrate [16–18] which is more convenient than multistep reactions.
Later on, multicomponent reactions (MCR) came into the limelight over usual
multistep synthesis because of atom economy, energy and cost efciency and
less reaction time. Therefore, they became a more facile route for organic syn-
thesis, and nowadays, heterocyclic compounds are synthesized by MCR methods
[19–21].
In the recent past, the pyranopyrazoles are synthesized using diferent catalysts
including d, l-proline [22], bleaching earth clay (pH 12.5) [23], cetyltrimethyl-
ammonium chloride (CTACl) [24], aspirin [25], sulphonic acid-functionalized
ionic liquid [26], glycine [27], [bmim]OH [28], meglumine [29], boric acid [30],
Ph3CCl [31], choline chloride/thiourea [32], l-proline [33], piperidine [34],
maltose [35] and choline chloride–urea deep eutectic solvent-modifed magnetic
nanoparticles [36]. Since most of these catalysts are having one or other kinds
of drawbacks such as the requirement of high energy, generation of waste and
tedious work set-up and some catalysts are costly and hazardous too, the devel-
opment of greener method for the synthesis of pyranopyrazoles is still desired.
The organic transformation which is directed towards “Greenery” arouses always
attention from many years [37].
Baker’s yeast is easily available, is inexpensive biocatalyst and can be used
without any special kind of expertise in microbiology [38, 39]. This is the reason
why baker’s yeast got a lot of attention among synthetic organic chemists. Later
on, it is considered as a microbial reagent for organic synthesis [40, 41]. The
synthesis of alcohols by the reduction of a variety of ketone using baker’s yeast
is a very well-established technology for organic transformation [42]. It has been
also used for the production of bioethanol by immobilising it over sodium algi-
nate gel, commercially [43]. Besides redox reactions, it is also found to catalyse
useful cyclocondensation, leading to value-added heterocycles [44–46]. Enanti-
oselective synthesis of various organic molecules using baker’s yeast is a well-
established method in synthetic organic chemistry [47–49].
Most of the baker’s yeast-catalysed organic reactions have been operated
mainly in an aqueous medium to protect its catalytic activity. An aqueous medium
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Green synthesis of pyranopyrazoles via biocatalytic one-pot…
is not practicable for many organic reactions due to the solubility issue of the
substrates; therefore, biocatalysis using an organic solvent is gaining much more
attention. So, the main advantages of using biocatalyst in an organic medium are
higher solubility of organic compounds and easy recovery of the product [50, 51].
Keeping the above facts in mind, we have designed a one-pot four-component
synthesis of pyranopyrazole derivatives using aromatic aldehydes, ethyl acetoace-
tate, malononitrile, hydrazine hydrate and easily available, cheaper biocatalyst, i.e.
baker’s yeast. According to the best of our knowledge, this is the frst endeavour to
use baker’s yeast as a biocatalyst for this multicomponent reaction.
Experimental section
General information
All required chemicals were purchased from commercial suppliers and used as such
without any further purifcation. The dry baker’s yeast was purchased from A. B.
Mauri India Pvt. Ltd, India. The 1H NMR and 13C NMR spectra of compounds were
determined by using a Bruker Avance II spectrometer at 400 MHz and 100 MHz,
respectively, using DMSO-d6 as a solvent. Thin-layer chromatography (TLC) was
carried out on silica gel-precoated aluminium-backed plates and visualized under
UV light.
General procedure for the synthesis of pyranopyrazoles derivatives (5a)
A mixture of various aromatic aldehydes (5 mmol), malononitrile (5 mmol),
hydrazine hydrate (5 mmol) and ethyl acetoacetate (5 mmol) was taken with etha-
nol (20 mL) as a solvent in a round-bottom fask (50 mL), and then, baker’s yeast
(2 g) was added to the reaction mixture. The resulting reaction mass was stirred at
room temperature on a magnetic stirrer, and the procession of the reaction is moni-
tored using thin-layer chromatography (TLC) in a solvent system having n-hexane/
ethyl acetate (3:1). After 34 h of constant stirring at room temperature, the reaction
mass was fltered under reduced pressure using silica bed to remove the catalyst and
washed it with ethanol (50 mL). The crude products were purifed by recrystalliza-
tion in ethanol and by column chromatography using n-hexane and ethyl acetate.
Spectral data of some representative compounds
6‑Amino‑3‑methyl‑4‑phenyl‑1,4‑dihydropyrano[2,3‑c]pyrazole‑5‑carbonitrile
1
(5a) M.P. 210–212 °C. H NMR—(400 MHz, DMSO d6)—δ ppm 12.00 (1H, s),
7.30 (2H, t, J = 7.56), 7.22 (3H, m, J = 7.28 and 11.24), 6.71 (2H, s), 4.50 (1H, s),
1.79 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.35, 155.26, 144.93,
136.04, 128.91, 127.94, 127.20, 121.24, 98.13, 57.71, 36.73, 10.20. MS (EI): m/z
Calcd. for C14H12N4O = 252.10. Found = 253.15 [M+ + 1].
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P. Shrivas et al.
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑(4‑nitrophenyl)pyrano[2,3‑c]pyrazole‑5‑carboni‑
trile (5b) M.P. 249–250 °C. 1H NMR—(400 MHz, DMSO d6)—δ ppm 12.19 (1H,
s), 8.21 (2H, m, J = 8.8 Hz), 7.47 (2H, m, J = 8 Hz), 7.10 (2H, s), 4.82 (1H, s),
1.79 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.06, 154.58, 152.01,
146.30, 135.86, 129.52, 128.77, 124.07, 120.45, 96.48, 55.80, 35.79, 9.66. MS: m/z
Calcd. for C14H11N5O3 = 297.09. Found = 298.14 [M+ + 1].
6‑Amino‑4‑(4‑chlorophenyl)‑1,4‑dihydro‑3‑methylpyrano[2,3‑c]pyrazole‑5‑carboni‑
trile (5c) M.P. 228–230 °C. 1H NMR—(400 MHz, DMSO d6)—δ ppm 12.12 (1H,
s), 7.38 (2H, m, J = 11.2 Hz), 7.21 (2H, m, J = 11.2 Hz), 6.90 (2H, s), 4.63 (1H, s),
1.79 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 160.84, 154.61, 143.38,
135.68, 132.49, 131.19, 129.96, 128.39, 120.62, 97.12, 56.68, 18.45, 9.66. MS: m/z
Calcd. for C14H11ClN4O = 286.06. Found = 287.10 [M+ + 1].
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑p‑tolylpyrano[2,3‑c]pyrazole‑5‑carbonitrile
(5d) M.P. 207–208 °C . 1H NMR—(400 MHz, DMSO d6)—δ ppm 12.19 (1H, s),
8.21 (2H, m, J = 8.8 Hz), 7.47 (2H, m, J = 8.8 Hz), 7.03 (2H, s), 4.82 (1H, s), 3.32
(3H, s), 1.79 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.06, 154.58,
152.02, 146.30, 135.84, 128.51, 128.77, 123.83, 120.45, 96.48, 55.80, 35.80, 9.66.
MS: m/z Calcd. for C15H14N4O = 266.12. Found = 267.14 [M+ + 1].
6‑Amino‑1,4‑dihydro‑4‑(4‑methoxyphenyl)‑3‑methylpyrano[2,3‑c]pyrazole‑5‑car‑
bonitrile (5e) M.P. 209–210 °C. 1H NMR—(400 MHz, DMSO d6)—δ ppm 12.08
(1H, s), 7.10 (2H, m, J = 8 Hz), 6.89 (2H, m, J = 4 Hz), 6.82 (2H, s), 4.55 (1H,
s), 3.74 (3H, s), 1.80 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.16,
158.45, 155.24, 136.96, 136.02, 128.96, 121.28, 114.25, 98.37, 58.15, 55.48, 35.93,
10.21. MS: m/z Calcd. for C15H14N4O2 = 282.12. Found = 283.16 [M+ + 1].
6‑Amino‑4‑(4‑(dimethylamino)phenyl)‑1,4‑dihydro‑3‑methylpyrano[2,3‑c]pyra‑
1
zole‑5‑carbonitrile (5f) M.P. 234–235 °C. H NMR—(400 MHz, DMSO d6)—δ
ppm 11.13 (1H,s), 7.21-6.96 (4H, m, J = 12 Hz), 6.69 (2H, s), 4.64 (1H, s), 2.52
(6H, s), 1.97 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 160.59, 148.91,
129.44, 128.05, 124.75, 124.08, 121.28, 115.99, 105.45, 55.61, 29.16, 10.36. MS:
m/z Calcd. for C16H17N5O = 295.14. Found = 296.15 [M+ + 1].
6‑Amino‑4‑(2‑chlorophenyl)‑1,4‑dihydro‑3‑methylpyrano[2,3‑c]pyrazole‑5‑carboni‑
trile (5g) M.P. 244–245 °C. 1H NMR—(400 MHz, DMSO d6)—δ ppm 12.13 (1H,
s), 7.44 (1H, m, J = 12 Hz), 7.33 (1H, m, J = 4 Hz), 7.29 (1H, s), 7.20 (1H, m, J =
4 Hz), 6.95 (2H, s) 5.08 (1H, s), 1.78 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ
ppm 161.78, 155.45, 141.41, 135.85, 132.45, 131.19, 129.96, 128.24, 120.85, 97.34,
56.26, 9.99. MS: m/z Calcd. for C14H11ClN4O = 286.06. Found = 287.10 [M+ + 1].
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑(3‑nitrophenyl)pyrano[2,3‑c]pyrazole‑5‑carboni‑
trile (5h) M.P. 214–215 °C. 1H NMR—(400 MHz, DMSO d6)—δ ppm 12.19 (1H,
s), 8.13 (1H, m, J = 10.4 Hz), 8.02 (1H, m, J = 1.2 Hz), 7.63 (2H, s), 7.03 (1H,
1 3

Green synthesis of pyranopyrazoles via biocatalytic one-pot…
s), 4.87 (1H, s), 1.80 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.07,
154.61, 147.80, 146.74, 135.88, 134.34, 130.19, 121.94, 121.77, 120.49, 96.59,
56.04, 35.55, 9.68. MS: m/z Calcd. for C14H11N5O3 = 297.09. Found = 298.13 [M+
+ 1].
6‑Amino‑4‑(2‑chloroquinolin‑3‑yl)‑1,4‑dihydro‑3‑methylpyrano[2,3‑c]pyra‑
1
zole‑5‑carbonitrile (5i) M.P. 216–217 °C. H NMR—(400 MHz, DMSO d6)—δ
ppm 12.19 (1H, s), 8.40 (1H,s), 8.07 (1H, m, J = 8 Hz), 7.98 (1H, m, J = 4 Hz),
7.84 (1H, m, J = 12 Hz), 7.68 (1H, m, J = 12 Hz), 7.08 (2H, s), 5.21(1H, s), 1.79
(3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.99, 155.57, 149.61,
146.67, 140.00, 136.05, 131.31, 128.43, 127.99, 120.88, 10.16. MS: m/z Calcd. for
C17H12ClN5O = 337.07. Found = 338.70 [M+ + 1].
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑(4‑trifluoromethyl)pyrano[2,3‑c]pyrazole‑5‑car‑
1
bonitrile (5j) M.P. 249–250 °C. H NMR—(400 MHz, DMSO d6)—δ ppm 12.18
(1H, s), 7.72 (2H, d, J = 4 Hz), 7.43 (2H, d, J = 8 Hz), 7.00 (2H, s), 4.77 (1H, s),
1.81 (3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.55, 155.21, 149.63,
136.22, 128.83, 128.02, 127.77, 125.97, 123.70, 121.04, 97.37, 56.86, 36.44, 10.21.
MS: m/z Calcd. for C15H11F3N4O = 320.09. Found = 321.14 [M+ + 1].
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑(4‑fluoro)pyrano[2,3‑c]pyrazole‑5‑carbonitrile
1
(5k) M.P. 216–218 °C. H NMR—(400 MHz, DMSO d6)—δ ppm 12.12 (1H, s),
7.98 (1H. m, J = 4 Hz), 7.39 (1H, t, J = 8 Hz), 7.23 (1H, t, J = 8 Hz), 7.17 (1H, t,
J = 8 Hz), 6.90 (2H, s), 4.65 (1H, s), 1.80 (3H, s). 13C NMR—(100 MHz, DMSO
d6)—δ ppm 161.31, 160.87, 155.20, 136.10, 131.20, 129.85, 116.64, 116.47,
115.75, 99115.56, 97.98, 57.61, 35.93, 10.19. MS: m/z Calcd. for C14H11FN4O =
270.09. Found = 271.14 [M+ + 1].
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑(2,3,4‑trimethoxy)pyrano[2,3‑c]pyrazole‑5‑car‑
1
bonitrile (5l) M.P. 196–198 °C. H NMR—(400 MHz, DMSO d6)—δ ppm 11.99
(1H, s), 6.79-6.73 (4H, m), 4.75 (1H, s), 3.78 (3H, s), 3.75 (3H, s), 3.68 (3H, s), 1.80
(3H, s). 13C NMR—(100 MHz, DMSO d6)—δ ppm 161.53, 155.45,152.56, 151.58,
141.93, 135.53, 130.16, 123.84, 121.50, 108.52, 98.49, 61.31, 60.69, 57.39, 56.19,
30.97, 9.92. MS: m/z Calcd. for C17H18N4O4 = 342.13. Found = 343.15 [M+ + 1].
Results and discussion
We have initiated our study by considering the reaction of benzaldehyde, malononi-
trile, ethyl acetoacetate and hydrazine hydrate in ethanol as our model reaction using
baker’s yeast as a catalyst (Scheme 1).
The selection of solvent is the frst and foremost step for a multicomponent
reaction, especially for biocatalytic reactions. So, at frst, we observed the efect
of solvent in our model reaction. We carried out our reaction in some protic and
aprotic solvents in the presence of baker’s yeast. To our delight, the frst glimpse
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P. Shrivas et al.
Scheme 1 Non-aqueous biocatalytic synthesis of compound (5a) via one-pot Knoevenagel condensa-
tion–Michael-type addition–heterocyclization cascade
of success was obtained by carrying out model reaction in ethanol as a solvent at
ambient temperature and pH under stirring and delivering a target product 5a with
84% yield after 34 h (Table 1, entry 1). We have continuously monitored the model
reaction, and it was found that within a few hours, there was formation of the inter-
mediates (Intermediate I and II) and the complete conversion of the intermediates to
product 5a needs 34 h of constant stirring.
Table 1 Optimization of
Entry Solvent
Catalyst
amount
(g)
Time (h) Yieldb (%)
reaction conditions for the non-
aqueous biocatalytic synthesis
of compound (5a) via one-pot
Knoevenagel condensation–
Michael-type addition–
1
Ethanol
2
2
2
2
2
2
2
2
2
2
2
–
2
–
0.5
1
1.5
2.5
3
34
34
34
34
50
50
50
50
50
34
34
50
50
50
50
50
50
50
50
84
82
56
50
Trace
Trace
–
–
Trace
75
70
No reaction
No reaction
–
–
2
3
4
Methanol
Acetonitrile
DCM
heterocyclization cascade
5
DMF
6
DMSO
7
THF
8
Toluene
9
Water
10
11
12
13
14
15
16
17
18
19
Ethanol/water (3:1)
Methanol/water (3:1)
Solvent-free
Solvent-free
Ethanolc
Ethanol
Ethanol
Ethanol
Ethanol
Trace
30
73
65
Ethanol
aReaction conditions: benzaldehyde (5 mmol), malononitrile
(5 mmol), hydrazine hydrate (5 mmol) and ethyl acetoacetate
(5 mmol) in a solvent (20 mL) with baker’s yeast at room tempera-
ture
bIsolated yield
cWithout baker’s yeast
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Green synthesis of pyranopyrazoles via biocatalytic one-pot…
Invigorated by the above interesting result, other solvents such as methanol
(MeOH), acetonitrile (ACN), dichloromethane (DCM), dimethylformamide
(DMF), dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) were also used
as media for the model reaction, in which only methanol, acetonitrile and DCM
gave desired product in 82, 56 and 50% yield, respectively (Table 1, entries 2–4).
Unfortunately, other solvents did not work well for model reaction (Table 1,
entries 5–8).
The model reaction proceeds well in the protic solvents as compared to aprotic
solvents in which there was no reaction or trace amount of product 5a is formed
even after 50 h of the reaction. Therefore, we turned our attention to use an abundant
protic solvent which is widely accepted for biocatalysis, i.e. water, but unfortunately,
there was the formation of trace amount of product (Table 1, entry 9). That might be
due to insolubility of organic substrates; hence, we tried the combination of water/
ethanol and water/methanol for the model reaction. This attempt leads to the target
product by 75 and 70% yields, respectively (Table 1, entries 10–11). It indicates that
adding water to reaction reduces the yield of 5a from 84 to 75% and 82 to 70%. We
have also carried out the model reaction in a solvent-free condition using baker’s
yeast as well as in the absence of baker’s yeast at room temperature, but in both the
cases the expected products did not observe even after 50 h (Table 1, entries 12, 13).
After the screening of the solvents, ethanol comes out as a winner among all other
solvents. Therefore, ethanol was chosen as the best solvent for further studies.
The control experiment demonstrated that the reaction did not produce the
desired product in the absence of baker’s yeast even after 50 h of stirring (Table 1,
entry 14). Since the efciency of the multicomponent reactions is also afected by
the catalyst dose and the reaction time apart from the solvent, for getting the best
possible results, we have done the condensation of benzaldehyde, malononitrile,
ethyl acetoacetate and hydrazine hydrate using a variable amount of baker’s yeast
from 0.5 to 3 g. The reaction initially failed to work when we use 0.5 and 1 g of the
catalyst and did not get any yield of the product. When we increase the amount of
catalyst to 1.5 g, the product formation commences at 30%. It was found that when
we increase the amount of the catalyst, we got a better yield of the product. Hence,
the amount was further enhanced to 2.5 and 3 g which led to 73 and 65% yield
(Table 1, entries 15–19). As indicated in Table 1, entry 1, maximum yield obtained
was 84% for the product 5a, when the reaction was carried out with 2 g of the cata-
lyst. It means that further increase of catalyst loading decreases the yield, which
might be due to an increase in reaction mass, resulting in slowing down the mixing
of reactants that ultimately afects the formation of the product. Therefore, here it
has been concluded that this multicomponent cyclocondensation occurs well using
2 g of baker’s yeast as a catalyst and ethanol as a medium.
Having established an efcient condition for the model reaction, we turned our
attention to investigate the scope of the aldehydes for this methodology (Scheme 2).
A wide range of various substituted aromatic aldehydes were successfully
treated with hydrazine hydrate, malononitrile and ethyl acetoacetate, and results
are summarized in Table 2. The attached functional group on the aromatic ring
of the aldehyde exerts a slight infuence on the product yield. The aldehydes with
electron-withdrawing and electron-donating groups could be tolerated under
1 3

P. Shrivas et al.
Scheme 2 Non-aqueous biocatalytic synthesis of pyranopyrazoles via one-pot Knoevenagel condensa-
tion–Michael-type addition–heterocyclization cascade (5a–5o)
Table 2 Physical data of
Entry
Compounds
R–
Yieldb (%)
6-amino-4-aryl-1,4-dihydro-3-
methylpyrano[2,3-c]pyrazole
carbonitrile
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
–H
4-NO2
4-Cl
84
80
88
78
82
76
76
80
78
68
66
74
76
78
74
4-Me
4-OMe
4-N(Me)2
2-Cl
3-NO2
4-(2-Chloroquinolin)
4-CF3
4-F
2,3,4-(OMe)3
2-OH
9
10
11
12
13
14
15
4-OH
4-Et
aReaction condition: aromatic aldehyde (5 mmol), malononi-
trile (5 mmol), hydrazine hydrate (5 mmol) and ethyl acetoacetate
(5 mmol) in ethanol (20 mL) with baker’s yeast (2 g) at room tem-
perature stirring for 34 h
bIsolated yield
cCompounds are characterized by 1H and 13C-NMR spectral analysis
[52–55]
these conditions. The substrate scope is also checked with heterocyclic aldehyde,
i.e. 2-chloro-3-formyl quinoline, which surprisingly gave a good yield of the tar-
get product (5i).
In order to get some mechanistic details of this transformation, a series of con-
trol experiments were carried out. When we separately reacted benzaldehyde and
malononitrile in ethanol and ethyl acetoacetate with hydrazine, we got 2-ben-
zylidenemalononitrile and 3-methyl-1H-pyrazol-5(4H)-one, respectively, after
3 h and 1 h of constant stirring with baker’s yeast, respectively. It indicates that
the frst two intermediates are formed and then condensed to form pyranopyra-
zoles in the presence of baker’s yeast.
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Green synthesis of pyranopyrazoles via biocatalytic one-pot…
Fig. 1 Plausible mechanism for the synthesis of pyranopyrazole derivatives using baker’s yeast
On the basis of the obtained results and the literature, a plausible mechanism for
the synthesis of pyranopyrazole 5a can considerately be proposed using benzalde-
hyde, hydrazine hydrate, malononitrile and ethyl acetoacetate (Fig. 1).
Baker’s yeast contains imidazole residue [56], which can act as a catalyst for this
cyclocondensation. Imidazole abstracts the proton from malononitrile and also acti-
vates the aldehyde, which leads to the attack of malononitrile on aldehydes to give
2-benzylidenemalononitrile (I) [40].
Simultaneously, cyclocondensation takes place between ethyl acetoacetate and
hydrazine hydrate to give fve-membered ring, 3-methyl-1H-pyrazol-5(4H)-one
II, which is further converted to its corresponding enol form III in the presence of
imidazole residue. After that, Michael-type addition of intermediate III to the inter-
mediate I gave intermediate IV, which goes for intramolecular cyclization by the
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P. Shrivas et al.
Table 3 Comparison of the catalytic activity of baker’s yeast with reported catalysts for the synthesis of
pyranopyrazole derivatives
S. no. Catalysts
Reaction condition
Product yields (%) References
1.
2.
3.
Isonicotinic acid (10 mol%)
Bleaching earth clay (pH = 12.5)
Solvent-free, 85 °C
PEG-400, 40 °C
H2O, 90 °C
65–92
73–88
72–90
[1]
[23]
[24]
Cetyltrimethylammonium chloride
(CTACl)
4.
Aspirin
Solvent-free, 80 °C
76–93
[25]
5.
6.
7.
Ionic liquid [bmim]OH
boric acid [B(OH)3]
TrCl (10%)
Solvent-free, 50–60 °C 87–92
[28]
[30]
[31]
Solvent-free, 70 °C
Solvent-free, 60 °C
70–85
45–90
8.
9.
10.
11.
12.
13.
Choline chloride/thiourea
l-Proline (10 mol%)
Maltose (20%)
Nano-SiO2
LDH/SBA/HPA
EtOH, refux at 80 °C 73–98
[32]
[33]
[35]
[57]
[58]
This work
Ethanol, refux
Solvent-free, 100 °C
H2O, 80 °C
82–96
49–79
85–94
80–95
66–88
H2O, refux
Baker’s yeast
EtOH, R.T.
nucleophilic attack of oxygen to nitrile group leading to intermediate V. At the end,
the tautomerization of intermediate V gave dihydropyrano[2,3-c]pyrazole 5a.
In order to evaluate the advantages of our protocol for the synthesis of pyrano-
pyrazole derivatives, a comparison of reaction condition and yield with some of the
reported catalysts in the literature was done. For the synthesis of pyranopyrazole
derivatives, the majority of the reported protocols involves the condensations of aro-
matic aldehyde, ethyl acetoacetate, malononitrile and hydrazine hydrate. The results
obtained after comparing baker’s yeast with other catalysts are given in Table 3,
which clearly demonstrates the superiority of the present catalysts with other cata-
lysts. It is comparatively afording a truly green process with higher product yields.
Conclusion
Here, we have successfully demonstrated a green route for the one-pot four-compo-
nent synthesis of pyranopyrazole under a non-aqueous medium using a biocatalyst,
i.e. baker’s yeast, which shows a very good functional group tolerance. The products
obtained are with good to moderate yields at room temperature and neutral pH con-
dition without any special workup set-up. The promising points of the given proto-
col are that the catalyst is completely biodegradable and very cheaper as compared
to other chemical catalysts with ease of isolation of product and cleaner reaction
profle.
Acknowledgements We are very thankful to the Science and Engineering Research Board, New Delhi,
for providing essential fnancial support (SERB/EMEQ-279/2013). We are also grateful to SAIF, NEHU,
Shillong and CDRI, Lucknow, for providing spectral characterizations of our compounds.
1 3

Green synthesis of pyranopyrazoles via biocatalytic one-pot…
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