Alpha-Casein: an efficient, green, novel, and eco-friendly catalyst for one-pot multi-component synthesis of bis (pyrazol-5-ols), dihydro-pyrano[2,3-c]pyrazoles and spiropyranopyrazoles in an environmentally benign manner

Article abstract of DOI:10.1007/s13738-019-01641-2

For the first time, alpha-Casein was used as an efficient and eco-friendly catalyst for an effective and facile preparation of dihydropyranopyrazoles and spiropyranopyrazoles. The synthesis of bis (pyrazol-5-ols) derivatives was developed via one-pot, pseudo-five-component condensation, and the target dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles were prepared by one-pot four-component reaction. This new method of employing alpha-Casein, which is a green, recyclable, non-toxic and commercially available catalyst, offers advantages such as mild condition, short reaction times, easy work-up, no need for column chromatography, and high yields of the products which make it more economic than other environmentally synthetic protocols.

Full text of DOI:10.1007/s13738-019-01641-2

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01641-2
ORIGINAL PAPER
Alpha-Casein: an efficient, green, novel, and eco-friendly catalyst
for one-pot multi-component synthesis of bis (pyrazol-5-ols),
dihydro-pyrano[2,3-c]pyrazoles and spiropyranopyrazoles
in an environmentally benign manner
Jalili Milani1 · Malek Taher Maghsoodlou1 · Nourallah Hazeri1 · Mahmoud Nassiri2
Received: 6 September 2018 / Accepted: 15 February 2019
© Iranian Chemical Society 2019
Abstract
For the first time, alpha-Casein was used as an efficient and eco-friendly catalyst for an effective and facile preparation of
dihydropyranopyrazoles and spiropyranopyrazoles. The synthesis of bis (pyrazol-5-ols) derivatives was developed via one-
pot, pseudo-five-component condensation, and the target dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles were
prepared by one-pot four-component reaction. This new method of employing alpha-Casein, which is a green, recyclable,
non-toxic and commercially available catalyst, offers advantages such as mild condition, short reaction times, easy work-up,
no need for column chromatography, and high yields of the products which make it more economic than other environmen-
tally synthetic protocols.
Keywords Alpha-Casein · Novel catalyst · One-pot · Bis(pyrazole-5-ols) · Spiropyranopyrazoles · Dihydropyrano[2,3-c]
pyrazoles
Introduction
because of simultaneous formation of two or more bonds
and scope for green solvent, MCRs have many considerable
advantages, such as reduction in reaction time, simple pro-
tocols, inexpensive reactants, green principle, lower costs,
high atom-economy, energy saving, expensive purification
procedure; Thus, such environmentally benign protocols are
opportune and well desired [5–10].
The synthesis of complex molecules from simple and readily
available materials has become one of the important aspects
of synthesis of organic compounds. In this context, multi-
component reactions (MCRs) are considered, because three
or more simple and flexible starting materials are brought
together in a highly convergent approach to immediately
make molecular structure and complexity [1–4]. In modern
synthetic chemistry, multicomponent reactions have been
proved to be a powerful and useful tool. Due to the compact
reactions, easy procedures and high yields, they are in the
forefront in bioactive medicinal, combinatorial, synthesis
of organic, agro and heterocyclic molecules. Moreover,
Pyrazoles are considered as an important class of N-het-
erocycles owing to their wide occurrence, various applica-
tions, pharmacological and biological activity, agrochemi-
cal, chemical industries and ease of synthesis. They are
five-membered ring containing a pyrrole-like N-atom in
adjacent positions [8, 11]. Pyrazole ring can be found in
natural products including withasomnine, formycin, pyra-
zofurin, fluviol and drug molecules such as phenazone,
Celecoxib, Celebrex, Fomepizole, Ceftolozane, Metami-
zole, R1530, Viagra, Crizotinib, Lonazolac and Rimona-
bant (Fig. 1) [12–17]. It has been reported that substituted
pyrazoles display a wide range of biological properties
in medicinal chemistry, for example, as anti-microbial,
anti-bacterial, anti-inflammatory, anti-prostate, anti-dia-
betic, anti-pyretic, anti-depressant, anti-histaminic, anti-
biotic, anti-fungal, anti-viral, anti-neoplastic, analgesic,
* Malek Taher Maghsoodlou
mt_maghsoodlou@yahoo.com;
mt_maghsoodlou@chem.usb.ac.ir
1
Department of Chemistry, Faculty of Science, University
of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan,
Iran
2
Department of Marine Chemistry, Faculty of Marine Science,
Chabahar Maritime University, Chabahar, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Fig. 1 Some drugs containing pyrazole core
herbicidal, acaricidal and insecticidal [12, 13, 18–20].
In coordination chemistry, pyrazoles are used as ligands.
They are able to create a bond with metals in different
modes and strong bridges [20, 21]. Pyrazole-based dyes
are also pharmacological intermediates and the dyestuff
industry uses them [20]. The literature survey reveals vari-
ous ways reported for the synthesis of pyrazole deriva-
tives in the presence of catalysts, namely N-methylimi-
dazolium perchlorate [22], pyridine trifluoroacetate [23],
sodium dodecylsulfate [24], triethylbenzylammonium
chloride [25], nano-structured diphosphate [26], lemon
juice [27], morpholine triflate [28], nanoparticles [29],
and triphenylphosphine [30]. Some of these methods have
their own weak points such as using toxic reagents, strict
reaction condition, costly reagents and catalysts, tedious
steps, strong acidic or basic condition, long reaction time
and low product yields [7]. However, they have their own
advantages too, including operational simplicity, environ-
mental compatibility, non-toxicity, simplified recovery and
reusability, low-cost and easy isolation [31–34]. Develop-
ment of environmentally benign, efficient, and economic
ways for the synthesis of biologically interesting com-
pounds remains a serious challenge in synthetic chemistry
[35–39]. The new method of applying α-Casein, which
is a green, recyclable, non-toxic and commercially avail-
able catalyst, brings advantages such as mild condition,
short reaction times, easy work-up, no need for column
chromatography, water/ethanol as solvent and high yields
of the products which make it more economic than other
environmentally synthetic protocols. Herein, we wish to
report an efficient one-pot, pseudo-five-component strat-
egy for the rapid synthesis of pyrazole-5-ols 4 from reac-
tion between ethyl acetoacetate 1, hydrazine monohydrate
2, and several aromatic aldehydes 3 and also an efficient
one-pot, four-component strategy for effective synthesis
of dihydropyrano[2,3-c]pyrazole 6 and spiropyranopyra-
zoles 8, 10 and 12 by condensation of ethyl acetoacetate
1, hydrazine monohydrate 2, several aromatic aldehydes
3, malononitrile 5 and isatins 7, acenaphthenequinone 9
or ninhydrin 11 in the presence of alpha-Casein as an effi-
cient, green, novel, and eco-friendly catalyst (Fig. 2) in an
environmentally benign conditions (Scheme 1) [1, 8, 35].
Fig. 2 The structure of α-Casein
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Journal of the Iranian Chemical Society
Scheme 1 Alpha Casein-catalyzed one-pot synthesis of pyrazole-5-ols, dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles
without further purification. TLC was performed on Poly-
gram SILG/UV 254 silica gel plates.
Experimental
Using an Electro thermal 9100 apparatus and FT-IR-
JASCO-460 plus spectrometer, the melting points and IR
General procedure for the synthesis of 4, 4′‑(aryl‑
methylene)bis(1H‑pyrazol‑5‑ol) derivatives (4)
spectra of all compounds were specified. The H and 13C
1
NMR spectra of known compounds were recorded on a
Bruker DRX-300 MHz Avance instrument in DMSO at
300 and 75 MHz. All of the reagents were provided from
the chemical producer Merck (Darmastadt, Germany),
Fluka (Buchs, Switzerland) and Alpha Aesar and used
A combination of ethyl acetoacetate (2.0 mmol), hydrazine
hydrate (2.0 mmol), and alpha-Casein 20 mmol% (0.157
gr) as catalyst was stirred in EtOH/H2O (2:1) (4 mL). After
5 min, aromatic aldehyde (1.0 mmol) was added, and the
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Journal of the Iranian Chemical Society
Table 1 Optimization of reaction conditions for synthesis of bis(pyrazol-5-ols) (4a)
Entry
Catalyst (mol%)
Solvent (H2O/EtOH)
Temperature (°C)
Time (min)
Isolated
yield (%)
1
2
3
4
5
6
7
8
15
15
15
15
10
20
–
20
20
20
20
25
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:2
2:1
2:0
0:2
1:2
60
70
80
r.t
60
60
60
60
60
60
60
60
20
30
30
180
60
15
24 (h)
15
20
45
89
87
90
57
85
93
52
94
89
75
82
94
9
10
11
12
60
15
mixture was stirred at 60 °C for the time shown in Table 1.
The completion of the reaction was observed through thin
layer chromatography (TLC). After completion, the reac-
tion mixture was left to cool down to room temperature,
and then, water (5 mL) was added to the mixture of reac-
tion, and filtered to separate the product. Finally, the crude
product was washed twice (5 mL) with a mixture of water
and ethanol (2:1). Then, the solid product was recrystallized
from ethanol to obtain the pure product.
98
96
94
92
90
88
86
Run 1
Run 2
96
Run 3
95
Run 4
91
General procedure for the synthesis
of dihydropyrano[2,3‑c]pyrazole (6) and spiro‑
pyranopyrazoles derivatives (8, 10 and 12)
Product (%)
98
Fig. 3 Reusability of α-Casein as catalyst
A mixture of hydrazine hydrate (1.0 mmol) and ethyl ace-
toacetate (1.0 mmol) was stirred for 5 min in EtOH/H2O (1:1)
until 3-methyl-2-pyrazolin-5-one was precipitated. Then, the
α-Casein, malononitrile 5 (1.0 mmol) and aromatic aldehyde
3 (1.0 mmol), isatins 7 (1.0 mmol), acenaphthenequinone 9
(1.0 mmol) or ninhydrin 11 (1.0 mmol) were added, and the
mixture was heated at 60 °C. The progress of the reaction
was monitored by TLC. After completion of the reaction,
the reaction mixture was cooled down to room temperature,
followed by addition of 5 mL water, and subsequent filtra-
tion of the mixture for separation of the product. Afterwards,
the solid product was washed twice (each time 5 mL) with a
mixture of water and ethanol. Then, the resultant product was
recrystallized from ethanol to obtain the pure pyranopyrazole
derivative. To recover the catalyst, the filtrate was extracted
by diethyl ether. The aqueous layer containing α-Casein was
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Journal of the Iranian Chemical Society
separated, followed by evaporation of the solvent component
under reduced pressure, resulting in the recovery of α-Casein
and reusing it (Fig. 3). As Fig. 3 shows, the catalytic system
worked well, up to four catalytic runs and slightly reduced the
product yield, which might have been due to the little weight
loss of the catalyst during the recovery processes.
4.70 (s, 1H, CH), 6.59 (d, J = 8.8 Hz, 2H, H–Ar), 6.90
(d, J = 8.4, 2H, H–Ar), 9.07 (s, 1H, OH), 11.27 (brs, 2H,
2NH).
4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(3-nitrophenyl)
methyl)-3-methyl-1H-pyrazol-5-ol (4j)
Spectral data for the selected compounds
White powder; IR (KBr, cm−1): 3405, 3096, 2967, 1600,
1527; 1H NMR (400 MHz, DMSO-d6): 2.14 (s, 6H, 2CH3),
3.39 (1OH exchanged with water of DMSO-d6), 5.04 (s, 1H,
CH), 7.52–7.63 (m, 2H, H–Ar), 8.00–8.06 (m, 2H, H–Ar),
11.04 (brs, 3H, 2NH,1OH).
4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(4-nitrophenyl)
methyl)-3-methyl-1H-pyrazol-5-ol (4a)
White powder; IR (KBr, cm−1): 3428, 3145, 2968, 1606,
1
1505; H NMR (400 MHz, DMSO-d6): 2.10 (s, 6H,
3-Hydroxy-3-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)
indolin-2-one (4k)
2CH3), 3.35 (1OH exchanged with water of DMSO-d6),
5.00 (s, 1H, CH), 7.40 (d, J = 8.1 Hz, 2H, H–Ar), 8.14 (d,
J = 8.42 Hz, 2H, H–Ar), 11.09 (brs, 3H, 2NH,1OH).
White powder; IR (KBr, cm−1): 3376, 3146, 2876, 1690,
1
1471; H NMR (300 MHz, DMSO-d6): δ 2.15 (s, 3H,
4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(o-tolyl))
methyl-3-methyl-1H-pyrazol-5-ol (4d)
CH3), 3.39 (1OH exchanged with water of DMSO-d6),
6.36 (C–OH), 6.82 (d, J = 7.82 Hz, 1H, H–Ar), 6.93 (t,
J = 7.52 Hz, 1H, H–Ar), 7.20 (m, 2H, H–Ar), 10.24 (brs,
2H, 2NH). 13C NMR (75 MHz, DMSO-d6): δ 11.9 (CH3),
74.3 (C–OH), 101.1 (C=C–OH), 109.9, 122.0, 125.1, 129.3,
133.7 (C–Ar), 138.1 (CN), 142.2 (C–Ar), 159.1 (OH–C=C),
178.7 (C=O).
Pale orange powder, IR (KBr, cm−1): 3432, 3092, 2926,
1604.58, 1525.05; 1H NMR (400 MHz, DMSO-d6): 1.81
(s, 6H, 2CH3), 2.11 (s, 3H, CH3), 3.38 (2OH exchanged
with water of DMSO-d6), 4.92 (s, 1H, CH), 7.02–7.23 (m,
4H, H–Ar), 10.66 (brs, 2H, 2NH).
5-Bromo-3-hydroxy-3-(5-hydroxy-3-methyl-1H-pyra-
zol-4-yl)indolin-2-one (4l)
4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)
(4-hydroxy-3-methoxyphenyl)methyl)-3-methyl-1H-pyra-
zol-5-ol (4e)
White powder; IR (KBr, cm−1): 3443, 3327, 3071, 1704,
1617,1531; 1H NMR (300 MHz, DMSO-d6): δ 2.26 (s, 3H,
CH3), 6.35 (C–OH), 6.78 (d, J=8.12 Hz, 1H, H–Ar), 7.26
(s, 1H, H–Ar), 7.37 (d, J=7.52 Hz, 1H, H–Ar), 10.36 (brs,
3H, 2NH, 1OH). 13C NMR (75 MHz, DMSO-d6): δ 12.09
(CH3), 74.3 (C–OH), 101.0 (C=C–OH), 111.9, 113.5, 127.7,
131.8, 136.4 (C–Ar), 138.6 (H3C–C=N), 141.5 (C–Ar),
158.8 (C=C–OH), 178.2 (C=O).
White powder; IR (KBr, cm−1): 3373, 3192, 2959, 1610,
1
1485; H NMR (300 MHz, DMSO-d6): δ 2.08 (s, 6H,
2CH3), 3.35 (3OH exchanged with water of DMSO-d6),
3.66 (s, 3H, OCH3), 4.77 (s, 1H, CH), 6.57 (dd, J=8.1 Hz,
J = 1.2 Hz, 1H, H–Ar), 6.65 (d, J = 8.1 Hz, 1H, H–Ar),
6.78 (d, J = 1.5 Hz, 1H, H–Ar), 10.17 (brs, 2H, 2NH). 13
C
NMR (75 MHz, DMSO-d6): δ 10.9 (CH3), 32.8 (CH), 56.0
(OCH3), 105.0, 112.7, 115.3, 120.4, 134.8, 140.0, 144.9,
147.4, 161.4 (C–Ar).
2-Hydroxy-2-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-1H-in-
dene-1,3(2H)-dione (4m)
White powder; IR (KBr, cm−1): 3516, 3370, 3019, 1768,
1748,1710; 1H NMR (300 MHz, DMSO-d6): δ 2.38 (s, 3H,
CH3), 3.47 (1OH exchanged with water of DMSO-d6), 6.41
(C–OH), 7.98 (s, 4H, H–Ar), 10.84 (brs, 1H, 1NH). 13C
NMR (75 MHz, DMSO-d6): δ 16.8 (CH3), 80.8 (C–OH),
102.7 (CH), 128.7 (C–Ar), 141.5 (H3C–C=N), 145.3 and
145.7 (C–Ar), 163.0 (C=C–OH), 204.1 (C=O).
4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(4-hydroxyphenyl)
methyl)-3-methyl-1H-pyrazol-5-ol (4h)
White powder; IR (KBr, cm−1): 3415, 3268, 3107, 2928,
1600, 1514; 1H NMR (400 MHz, DMSO-d6): 2.05 (s, 6H,
2CH3), 3.37 (2OH exchanged with water of DMSO-d6),
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Journal of the Iranian Chemical Society
6-Amino-1,4-dihydro-3-methyl-4-(4-nitrophenyl)
pyrano[2,3-c]pyrazole-5-carbonitrile (6b)
NMR (400 MHz, DMSO-d6): δ 1.80 (s, 3H, CH3), 5.60 (s,
1H, CH), 7.04 (s, 2H, NH2), 7.33 (t, J=8.12 Hz, 1H), 7.40
(dd, J = 7.82 Hz, J = 1.5 Hz, 1H), 7.55 (dd, J = 8.82 Hz,
J = 1.5 Hz, 1H), 12.13 (s, 1H, NH). 13C NMR (75 MHz,
DMSO-d6): δ 9.80 (CH3), 32.98 (CH), 53.29 (C–NH2),
95.27 (O–C–CN),120.67, 128.93, 130.06, 131.33, 134.93,
135.43, 135.63, 136.39, 156.0 (C–Aro), 162.56 (CN); MS
m/z (%):321.1 (100), 304.3 (51), 282.3 (41), 221.1 (40),
219.1 (56), 185.1 (32) (M+, 1).
White powder; IR (KBr, cm−1): 3476, 3229, 3113, 2975,
2195, 1623, 1648, 1598, 1519, 1402, 1350, 748; 1H NMR
(400 MHz, DMSO-d6): δ 1.83 (s, 3H, CH3), 4.85 (s, 1H,
CH), 7.08 (s, 2H, NH2), 7.49 (d, J=7.52 Hz, 2H), 8.22 (d,
J=7.52 Hz, 2H), 12.27 (s, 1H, NH).
6-Amino-1,4-dihydro-3-methyl-4-(4-chlorophenyl)
pyrano[2,3-c]pyrazole-5-carbonitrile (6d)
Results and discussion
White powder; IR (KBr, cm−1): 3476, 3227, 3094, 2191,
1
1641, 1592, 1488, 1394, 1082, 797, 744, 499; H NMR
At first, we focused our attention on the synthesis of
4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols) and the reaction
between ethyl acetoacetate (2.0 mmol), hydrazine hydrate
(2.0 mmol), and 4-nitrobenzaldehyde (1.0 mmol) was chosen
as a model reaction for preliminary experiments. First, to
optimize the reaction temperature, the model reaction was
performed using 10, 15 and 20 and 25 mol% of the cata-
lyst at different temperatures. It was revealed that 60 °C is
an efficient temperature in terms of reaction time and yield
obtained (Table 1, entry 8). When the mixture was stirred
at room temperature for 180 min, the product was gained
57% (Table 1, entry 4). Next, the reaction was investigated
with different amounts of catalyst and the results were sum-
marized in (Table 1, entries 1–12). The best result was
obtained, 94% yield within 15 min, with 20 mol% of cata-
lyst at 60 °C (Table 1, entry 8). Higher amounts of catalyst
did not result in significant change in the reaction yields
(Table 1, entry 12). If the amount of catalyst was reduced
from 20 to 10 mol%, the reaction time increased but the yield
decreased (Table 1, entry 5). As it can be seen in Table (1,
entry 7), in the absence of catalyst at 60 °C the reaction time
improved and offered 52% yield of the expected product.
Finally, the effect of solvents, water, ethanol, 1:1 EtOH/H2O,
2:1 EtOH/H2O and 1:2 EtOH/H2O was evaluated and it was
found that the rate 2:1 EtOH/H2O is better than other rates
(Table 1, entry 8) [1, 37]. In another study for the synthesis
of dihydropyrano[2,3-c]pyrazoles, we chose reaction of ethyl
acetoacetate (1.0 mmol), hydrazine hydrate (1 mmol), malo-
nonitrile (1.0 mmol), and 4-nitrobenzaldehyde (1.0 mmol)
as a model reaction. The reaction was investigated with dif-
ferent amounts 10, 15 and 20 mol% of the catalyst at 60,
70 and 80 °C, and also room temperature in water, ethanol
and the mixture of them. The summary of results is shown
in Table 2. As shown in Table (2, entry 1), the optimization
of the reaction conditions demonstrated that the best result
was gained 95% when the reaction was performed within
15 min, at 60 °C in the presence of α-Casein (15 mol%) in
the rate of 1:1 EtOH/H2O. The yield of the product did not
(400 MHz, DMSO-d6): δ 1.82 (s, 3H, CH3), 4.66 (s, 1H,
CH), 6.96 (s, 2H, NH2), 7.22 (d, J=8.42 Hz, 2H), 7.39 (d,
J=8.42 Hz, 2H), 12.17 (s, 1H, NH).
6-Amino-1,4-dihydro-3-methyl-4-(4-bromophenyl)
pyrano[2,3-c]pyrazole-5-carbonitrile (6e)
White powder; IR (KBr, cm−1): 3470, 3227, 3120, 2195,
1651, 1595, 1560, 1401, 1353, 1107, 883, 810, 744, 543;
1H NMR (400 MHz, DMSO-d6): δ 1.80 (s, 3H, CH3), 4.63
(s, 1H, CH), 6.96 (s, 2H, NH2), 7.15 (d, J=8 Hz, 2H), 7.52
(d, J=8 Hz, 2H), 12.16 (s, 1H, NH).
6-Amino-1,4-dihydro-3-methyl-4-(4-fluorophenyl)
pyrano[2,3-c]pyrazole-5-carbonitrile (6f)
White powder; IR (KBr, cm−1): 3479, 3232, 3117, 2195,
1648, 1595, 1508, 1492, 1398, 1230, 1218, 1156, 807, 560;
1H NMR (400 MHz, DMSO-d6): δ 1.81 (s, 3H, CH3), 4.66
(s, 1H, CH), 6.95 (s, 2H, NH2), 7.09–7.26 (m, 4H),12.18 (s,
1H, NH).
6-Amino-1,4-dihydro-3-methyl-4-(4-hydroxy-3-methoxy-
phenyl)pyrano[2,3-c]pyrazole-5-carbonitrile (6i)
White powder; IR (KBr, cm−1): 3491, 3412,3274, 3221,
2195, 1657, 1617, 1604, 1512,1399, 1265, 1028; 1H NMR
(400 MHz, DMSO-d6): δ 1.85 (s, 3H, CH3), 3.74 (s, 3H,
OCH3), 4.53 (s, 1H, CH), 6.58 (dd, J=8.1 Hz, J=1.8 Hz,
1H, H–Ar), 6.73–6.76 (2d,2H), 6.83 (s, 2H, NH2), 12.10 (s,
1H, NH).
6-Amino-1,4-dihydro-3-methyl-4-(2,6-dichlorophenyl)
pyrano[2,3-c]pyrazole-5-carbonitrile (6j)
White powder; IR (KBr, cm−1): 3405, 3368, 3309,3153,
1
2183, 1653, 1614, 1599, 1406, 1293, 1072, 826, 789; H
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Journal of the Iranian Chemical Society
Table 2 Optimization of reaction condition for synthesis of dihydropyrano[2,3-c]pyrazoles (6b)
Entry
Catalyst (mol%)
Solvent (H2O/EtOH)
Temperature (°C)
Time (min)
Isolated
yield (%)
1
2
3
4
5
6
7
8
15
15
15
15
10
20
–
15
15
15
15
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:2
2:1
2:0
0:2
60
70
80
r.t
60
60
60
60
60
60
60
15
20
20
20 (h)
25
20
24 (h)
20
35
2 (h)
60
95
94
84
62
82
94
31
93
88
42
68
9
10
11
change significantly with the increased amount of catalyst
from 15 to 20 mol% (Table 2, entry 6), but with decreased
amount of catalyst from 15 to 10 mol% the yield of the prod-
uct decreased (Table 2, entry 5). In the absence of catalyst,
a low yield of the product was achieved after 24 h (Table 2,
entry 7) [1, 29, 37, 38].
The probable reaction mechanism for the synthe-
sis of 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols),
dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles
was suggested in Scheme 2. At first, 3-methyl-1H-pyrazol-
5(4H)-one 13 was formed from the reaction between ethyl
acetoacetate 1 and hydrazine hydrate 2. For the synthesis
of 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ol) 4, 3-methyl-
1H-pyrazol-5(4H)-one by α-Casein via Knoevenagel con-
densation with the activated carbonyl group of the aromatic
aldehydes 3 to create the intermediated 14 where through
Michael addition to another 3-methyl-1H-pyrazol-5(4H)-
one to give desirable products 4a–j. For the synthesis of
dihydropyrano[2,3-c]pyrazoles 6 is proposed the arylidene
malononitrile 15 to generate in situ via Knoevenagel conden-
sation by adding malononitrile 5 and active aromatic alde-
hyde 3. Michael addition of compounds 13 and 15 gives the
acyclic adduct products 16, which undergoes intramolecular
cyclization and tautomerization to afford the correspond-
ing products 6a-j. On the other hand, for the synthesis of
spiropyranopyrazoles, ninhydrine 11, malononitrile 5 and
3-methyl-1H-pyrazol-5(4H)-one 13, undergo Michael
addition with Knoevenagel adduct, followed by intramo-
lecular cyclization 17 and 18 and provides the target spiro
Interestingly, a variety of aromatic aldehydes includ-
ing electron-donating and electron-withdrawing groups
on the rings (ortho-, meta-, and para-substituted) partici-
pated well in this reaction and gave the 4,4ʹ-(arylmethylene)
bis(1H-pyrazol-5-ols) 4a–j, 4k–m and dihydropyrano[2,3-
c]pyrazoles 6a–j derivatives in good to excellent yield. In
the synthesis of compounds 4 and 6, substitution of NO2
group in the fourth position of aromatic aldehyde led to a
relatively faster rate and higher yield than the substitution of
other groups in various positions of aromatic ring (Tables 3,
4). Then, under this optimized reaction conditions, we used
isatins 7, acenaphthenequinone 9 or ninhydrin 11 as a sub-
strate to react with malononitrile 5 and 3-methyl-1H-pyra-
zol-5(4H)-one. As expected, the reaction developed well
to afford spiro[indoline-3,4ʹ-pyrano[2,3-c]pyrazol] 8a-b,
spiro[acenaphthylene-1,4ʹ-pyrano[2,3-c]pyrazol] 10a and
spiro[ninhydrin-3,4ʹ-pyrano[2,3-c] pyrazole] 12a in good
to excellent yields [5, 6, 37] (Table 4).
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Journal of the Iranian Chemical Society
Table 3 Synthesis of 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols) in the presence of Casein as a catalyst
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Journal of the Iranian Chemical Society
Table 3 (continued)
compounds 12a. α-Casein can catalyze the probable reac-
tions activated by hydrogen bonds [36, 39, 40] (Scheme 2).
To show the capability and efficiency of this
work with respect to the reported catalysts for the
preparation of 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols)
and dihydropyrano[2,3-c]pyrazoles, Table 5 compares
our results obtained from the synthesis of compounds 4a
and 6b from the reaction of ethyl acetoacetate, hydrazine
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Journal of the Iranian Chemical Society
Table 4 Synthesis of dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles
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Journal of the Iranian Chemical Society
Table 4 (continued)
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Journal of the Iranian Chemical Society
Scheme 2 The suggested mechanism for the synthesis 4,4ʹ-(arylmethylene)bis(1H-pyrazol-5-ols), dihydropyrano[2,3-c]pyrazoles, and spiro-
pyranopyrazoles
monohydrate, aromatic aldehyde and malononitrile in the
presence of α-Casein with different catalyst and conditions.
As it is evident from Table 5, our method was more efficient.
Conclusion
In summary, this paper describes a convenient and
highly efficient and green process for the synthesis of
functionalized pyrazole-5-ols 4 from reaction between
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Journal of the Iranian Chemical Society
Table 5 Comparison of efficiency of α-Casein with some reported catalysts for the synthesis of 4a and 6b
Product
Catalyst
Reaction conditions
Time
9 h
Yield (%)
92
References
[28]
Morpholine triflate
EtOH, reflux/H2O
γ-Alumina
Lemon juice
Ultra sound irradiation
Ag/TiO2
Imidazole
Triphenylphosphine
{Fe3O4@SiO2@(CH2)3-thiourea dioxide SO3H/HCl}
[MNP-PIm-SO3H]Cl
SnO2 QDs
H2O,100 °C
H2O/EtOH, 90 °C
H2O, 50 °C
Solvent-free
H2O, 80 °C
50 min
50 min
30 min
20 min
25 min
1 h
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80
96
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98
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88
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[24]
α-Casein
Sodium dodecyl sulfate
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–
N-Methylimidazolium per-chlorate
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{Fe3O4@SiO2@(CH2)3-thiourea dioxide SO3H/HCl}
α-Casein
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50 °C, solvent-free
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H2O/EtOH, 60 °C
12 h
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ethyl acetoacetate 1, hydrazine monohydrate 2, and
several aromatic aldehydes 3 and also synthesis of
dihydropyrano[2,3-c]pyrazole 6 and spiropyranopyra-
zoles 8, 10 and 12 by condensation of ethyl acetoacetate
1, hydrazine monohydrate 2, several aromatic aldehydes
3, malononitrile 5 and isatins 7, acenaphthenequinone 9
or ninhydrin 11, using α-Casein as a catalyst at 60 °C.
The advantages of the present work can be described as:
efficiency, simplicity, high generality, short reaction time,
high yield and ease of handling of the catalyst. In addition,
the catalyst is green, recyclable, non-toxic and removed
from the reaction mixture, which make it a useful and
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