Aspirin: an efficient catalyst for synthesis of bis (pyrazol-5-ols), dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles in an environmentally benign manner

Article abstract of DOI:10.1007/s13738-017-1133-x

Abstract: This article aimed to present two facile and environmental friendly routes for the rapid assembly of?biologically active compounds including pyrazol core using aspirin as a novel and green catalyst. The synthesis of bis(pyrazol-5-ol) 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. These reactions can be performed in tandem from readily available starting materials. The main merits of the present methods are operational simplicity, no need for column chromatography, inexpensive materials, avoidance of harmless and corrosive acid catalysts, short reaction times, good yields of the products, and utilization of aspirin as a non-toxic, cheap, commercially available, and efficient catalyst.

Full text of DOI:10.1007/s13738-017-1133-x

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1133-x
ORIGINAL PAPER
Aspirin: an effcient catalyst for synthesis of bis (pyrazol‑5‑ols),
dihydropyrano[2,3‑c]pyrazoles and spiropyranopyrazoles in an
environmentally benign manner
Maryam Fatahpour1 · Fatemeh Noori Sadeh1 · Nourallah Hazeri1 ·
Malek Taher Maghsoodlou1 · Mojtaba Lashkari2
Received: 2 December 2016 / Accepted: 2 May 2017
© Iranian Chemical Society 2017
Abstract This article aimed to present two facile and
environmental friendly routes for the rapid assembly
of biologically active compounds including pyrazol core
using aspirin as a novel and green catalyst. The synthesis
of bis(pyrazol-5-ol) derivatives was developed via one-
pot, pseudo-fve-component condensation, and the target
dihydropyrano[2,3-c]pyrazoles and spiropyranopyrazoles
were prepared by one-pot, four-component reaction. These
reactions can be performed in tandem from readily availa-
ble starting materials. The main merits of the present meth-
ods are operational simplicity, no need for column chroma-
tography, inexpensive materials, avoidance of harmless and
corrosive acid catalysts, short reaction times, good yields
of the products, and utilization of aspirin as a non-toxic,
cheap, commercially available, and effcient catalyst.
* Nourallah Hazeri
nhazeri@chem.usb.ac.ir; n_hazeri@yahoo.com
1
Department of Chemistry, Faculty of Sciences, University
of Sistan and Baluchestan, Zahedan, P.O. Box 98135-674,
Iran
2
Faculty of Sciences, Velayat University, Iranshahr, Iran
1 3

J IRAN CHEM SOC
Graphical abstract
drugs (Fig. 1). 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols)
as anti-viral agents restrain the peste des petits ruminants
virus (PPRV) [19]. Recently, the α-glucosidase inhibi-
tory activity of dihydropyrano[2,3-c]pyrazoles has been
reported as a useful factor to reduce post-prandial hyper-
glycemia in diabetic individuals [20]. Also, these classes of
compounds have served as valuable synthetic intermediates
[21].
Not surprisingly, due to existence of these precious scaf-
folds in biologically functional molecules, considerable
efforts have been documented toward the synthesis of these
heterocyclic motifs using various methodologies. In the lit-
erature, synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-
5-ols) has occurred in the presence of catalysts namely
pyridine trifuoroacetate [22], ZnAl2O4 NPs [23], sodium
dodecyl sulfate [24], and N-methylimidazolium perchlorate
[25]. On the other hand, some approaches for synthesis of
dihydropyrano [2,3-c] pyrazoles involve the use of cata-
lysts such as [MNP-PIm-SO3H]Cl [26], Fe3-xTixO4@SO3H
MNPs [27], β-cyclodextrin [28], lemon juice [29], morpho-
line trifate [30], triphenylphosphine [31], γ-alumina [32],
imidazole [33], [ChCl][ZnCl2]2 [34], and cerium ammo-
nium nitrate (CAN) [35].
Keywords Aspirin · Novel catalyst · One-pot ·
Bis(pyrazol-5-ols) · Dihydropyrano[2,3-c]pyrazoles ·
Spiropyranopyrazoles
Introduction
In recent years, one of enduring challenges facing chem-
ists is protection of our environment as an endowment
of nature. Thus, shifting to the extension of methods that
decrease the consumption of hazardous materials has an
utmost priority. Solvent and type of catalyst along with
notable parameters such as atom and step economy of pro-
cess as well as nature of by-products are the main aspects
in designing green synthetic routes for the synthesis of
prominent heterocyclic architectures of medicinal connec-
tion. In this context, multicomponent reactions (MCRs)
have served as pivotal synthetic procedures toward prepa-
ration of assemble libraries of various drug-like chemical
entities [1–6].
Pyrazoles and pyranopyrazoles as N-fused heterocyclic
compounds have exhibited a situation of prominence with
a broad spectrum of biological and pharmacological activi-
ties such as anti-pyretic [7] analgesic [8], anti-microbial
[9], anti-fungal [10], anti-infammatory [11], anti-anxiety
[12], anti-proliferative, and anti-tumor [13, 14]. Some com-
pounds such as celecoxib a NSAIDs (anti-infammatory
and analgesic agent) [15], ENMD-2076 and R1530 (anti-
angiogenic) [16], PNU-32945 (HIV-1 non-nucleoside
reverse transcriptase inhibitor) [17], and sulfaphenazole
(anti-bacterial) [18] have been manufactured as commercial
Over the last decade, organocatalytic methods have been
extensively employed in medicinal chemistry for design-
ing multicomponent and cascade reactions due to the need
for convenience, generality, and robustness catalysts for
the synthesis of complex molecular motifs without the
presence of any metal atoms. Therefore, the development
of new and versatile catalysts is benefcial for chemists
[36]. Acetylsalicylic acid or aspirin is a simple chemical
1 3

J IRAN CHEM SOC
Fig. 1 Some pyrazoles contain-
ing drugs
O
O
S
H2N
H
N
N
O
H
N
N
N
HN
N
N
F
F
F
NH
N
F
N
N
Celecoxib
N
Cl
ENMD-2076
R1530
N
N
H
O
S
O
HN
N
N
N
N
1H-Pyrazole
NC
PNU-32945
H2N
Sulfaphenazole
compound which was produced by Hoffmann. Pharma-
cological effects of aspirin include analgetic, anti-pyretic,
anti-tumor, anti-infammatory [37], anti-platelet [38], anti-
thrombotic [39], and anti-oxidan [40]. Aspirin as a non-
steroidal anti-infammatory drug (NSAIDs) has earned
remarkable position in the prevention of myocardial infarc-
tion, stroke, dementia, and schizophrenia [41].
spectra of known compounds were recorded on a Bruker
DRX-300 and 400 Avance instrument in DMSO at 300,
400, and 75 MHz. All chemicals were provided from the
chemical producer Merck (Darmastadt, Germany) and
Fluka (Buchs, Switzerland) and used without further purif-
cation. Aspirin was prepared by procedure reported by Pal-
leros [51].
In a continuation of our endeavors toward the develop-
ment of green catalytic fashion for important organic con-
versions, [42–46] herein, we wish to report an effcient one-
pot, pseudo-fve-component strategy for the rapid synthesis
of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) from reaction
between ethyl acetoacetate 1, hydrazine monohydrate 2,
and aldehydes 3 and also an effcient one-pot, four-compo-
nent strategy for effective synthesis of dihydropyrano[2,3-
c]pyrazole, and spiroindoline-pyranopyrazole derivatives
by condensation of hydrazine monohydrate 1, ethyl ace-
toacetate 2, malononitrile derivatives 5, and arylaldehydes
3 or isatins in the presence of aspirin as a catalyst in an
environmentally benign conditions (Scheme 1).
General procedure for the synthesis
of 4,4′‑(arylmethylene)bis(1H‑pyrazol‑5‑ol)derivatives
A mixture of ethyl acetoacetate (2.0 mmol), hydrazine
hydrate (2.0 mmol), and aspirin (15 mol%) as catalyst was
stirred in EtOH/H2O (3 mL). After 5 min, aromatic alde-
hyde (1.0 mmol) was added, and the mixture was stirred
at 60 °C for the appropriate time. The completion of the
reaction was monitored through thin layer chromatog-
raphy (TLC). Finally, the reaction mixture was cooled to
room temperature, and then ethanol (5 mL) was added to
the mixture of reaction, and fltered to separate the product.
Finally, the crude product was recrystallized from ethanol
to afford the pure product.
The combination of readily available substrates with a
non-toxic, cheap, commercially available, and effcient cat-
alyst features would offer an attractive gateway to assemble
a library of heterocyclic with pyrazole motifs.
General procedure for the synthesis
of dihydropyrano[2,3‑c]pyrazole
and spiroindoline‑pyranopyrazole derivatives
Experimental
General
A mixture of hydrazine hydrate (1.0 mmol) and ethyl
acetoacetate (1.0 mmol) was stirred for 5 min until
3-methyl-2-pyrazolin-5-one was precipitated. Aromatic
aldehydes (1.0 mmol) or isains (1.0 mmol), malononi-
trile derivatives (1.0 mmol), and aspirin (20 mol%) were
then added, and the mixture was heated to 80 °C under
Melting points and IR spectra of all compounds were deter-
mined using an Electro thermal 9100 apparatus and FT-
IR-JASCO-460 plus spectrometer. The H and 13C NMR
1
1 3

J IRAN CHEM SOC
Aspirin
Ar '
O
O
O
OH
O
CN
H
Ar '
N
3
O
N
H
6a-o
NH2
O
HN
O
R2
R2
Ar
3
5
R1
2
NC
O
O
H
Ar
O
R1
N
N
N
Aspirin
Aspirin
7
EtO
O
N
H
N
H
N
H
H2N
Solvent-free, 80 °C
OH
HO
EtOH/H2O, 60 °C
N
8a-c
O
NH2
O
O
NH2.H2O
H
1
4a-n
O
R1
9
10
N
N
H
O
NH2
Scheme 1 Aspirin catalyzed one-pot synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) and dihydropyrano[2,3-c]pyrazoles and spiroindo-
line-pyranopyrazoles
solvent-free conditions. The progress of the reaction
was monitored by TLC. Then, the reaction mixture was
cooled to room temperature. The mixture was washed
with EtOH for separating the product. Finally, the crude
product was recrystallized from ethanol to afford the pure
pyranopyrazole derivatives.
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(4‑chlorophenyl)
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4e) Yield: (92%).
White powder, mp: 215–217 °C; IR (KBr) (νmax, cm−1):
1
3392, 3180, 2925, 1601, 1521, 1488; H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.08 (s, 6H, 2CH3), 3.39 (2OH
exchanged with water of DMSO-d6), 4.81 (s, 1H, CH),
7.12 (d, J = 8.4 Hz, 2H, H-Ar), 7.26 (d, J = 8.4 Hz, 2H,
H-Ar), 9.07 (s, 1H, OH), 11.28 (brs, 2H, 2NH).
Spectral data for the selected compounds
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(p‑tolyl))
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4h) Yield: (89%).
Pale orange powder, mp: 197–198 °C; IR (KBr) (νmax,
cm−1): 3301, 3104.77, 2924, 1607, 1512; 1H NMR
(400 MHz, DMSO-d6): δ (ppm) = 2.06 (s, 6H, 2CH3), 2.22
(s, 3H, CH3), 3.36 (2OH exchanged with water of DMSO-
d6), 4.76 (s, 1H, CH), 7.00 (s, 4H, H-Ar), 11.30 (brs, 2H,
2NH).
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(4‑nitrophenyl)
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4b) Yield: (93%).
White powder, mp: 269–271 °C; IR (KBr) (νmax, cm−1):
3428, 3145, 2928, 1597, 1518; 1H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.10 (s, 6H, 2CH3), 3.35 (2OH
exchanged with water of DMSO-d6), 4.99 (s, 1H, CH),
7.39 (d, J = 8.4 Hz, 2H, H-Ar), 8.13 (d, J = 8.8 Hz, 2H,
H-Ar), 11.36 (brs, 2H, 2NH).
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(o‑tolyl))
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4i) Yield: (77%).
Pale orange powder, mp: 281–283 °C; IR (KBr) (νmax,
cm−1): 3432, 3092, 2926, 1604.58, 1525.05; 1H NMR
(400 MHz, DMSO-d6): δ (ppm) = 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).
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(3‑nitrophenyl)
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4c) Yield: (89%).
White powder, mp: 254–257 °C; IR (KBr) (νmax, cm−1):
3405, 3095, 2979, 1600, 1528; 1H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.11 (s, 6H, 2CH3), 3.39 (2OH
exchanged with water of DMSO-d6), 4.99 (s, 1H, CH),
7.02–7.23 (m, 4H, H-Ar), 11.34 (brs, 2H, 2NH).
1 3

J IRAN CHEM SOC
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(4‑hydroxyphe-
nyl)methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4j) Yield: (82%).
White powder, mp: 255–257 °C; IR (KBr) (νmax, cm−1):
1H, H-Ar), 8.34-8.35 (m, 2H, H-Ar), 11.10 (brs, 4H, 2NH,
2OH). 13C NMR (75 MHz, DMSO-d6): δ (ppm) = 10.7
(CH3), 31.1 (CH), 103.8, 123.3, 135.5, 139.1, 140.1, 147.0,
149.5, 161.4 (C-Ar).
1
3415, 3268, 3107, 2928, 1600, 1514; H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.05 (s, 6H, 2CH3), 3.37 (2OH
exchanged with water of DMSO-d6), 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)(4‑hydroxy‑3‑meth-
oxyphenyl)methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4n) Yield:
(87%). White powder, mp: 254–257 °C; IR (KBr) (νmax,
1
cm−1): 3373, 3193, 2959, 1609, 1485; H NMR (300 MHz,
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(thiophen‑2‑yl))
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4l) Yield: (78%).
White powder, mp: 239–241 °C; IR (KBr) (νmax, cm−1):
3582, 3112, 2926, 1606, 1483; 1H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.09 (s, 6H, 2CH3), 3.38 (2OH
exchanged with water of DMSO-d6), 4.97 (s, 1H, CH),
6.84-6.86 (m, 1H, H-Ar), 6.59–6.60 (m, 1H, H-Ar), 7.27
(d, J = 5.2 Hz, 2H, H-Ar), 11.36 (brs, 2H, 2NH).
DMSO-d6): δ (ppm) = 2.07 (s, 6H, 2CH3), 3.65 (s, 3H,
OCH3), 4.75 (s, 1H, CH), 6.55 (dd, J = 8.1 Hz, J = 1.2 Hz,
1H, H-Ar), 6.63 (d, J = 8.1 Hz, 1H, H-Ar), 6.76 (d,
J = 1.5 Hz, 1H, H-Ar), 11.30 (brs, 5H, 2NH, 3OH). 13C
NMR (75 MHz, DMSO-d6): δ (ppm) = 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).
6‑amino‑1,4‑dihydro‑3‑methyl‑4‑(2‑chlorophenyl)
pyrano[2,3‑c]pyrazole‑5‑carbonitrile (6f) Yield: (86%).
White powder, mp: 231–233 °C; IR (KBr) (νmax, cm−1):
3391, 3357, 3314, 3169, 2190,1609, 1489, 1408, 1350,
1052, 763; H NMR (400 MHz, DMSO-d6): 1.77 (s, 3H,
CH3), 5.08 (s, 1H, CH), 6.99 (s, 2H, NH2), 7.18–7.43 (m,
4H, Ar), 12.16 (s, 1H, NH).
4‑((5‑Hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)(pyridin‑3‑yl)
methyl)‑3‑methyl‑1H‑pyrazol‑5‑ol (4m) Yield: (82%).
White powder, mp: 295–298 °C; IR (KBr) (νmax, cm−1):
3193, 3055, 2926, 1596, 1530; 1H NMR (300 MHz,
DMSO-d6): δ (ppm) = 2.12 (s, 6H, 2CH3), 4.92 (s, 1H,
CH), 7.26 (dd, J = 7.8 Hz, 1H, H-Ar), 7.54 (d, J = 7.8 Hz,
1
Table 1 Optimization of reaction conditions for synthesis of bis(pyrazol-5-ols)
NO2
O
H
O
O
H2N
Aspirin
2
2
N
N
NH2. H2O
OEt
N
H
N
H
OH
HO
NO2
Entry
Temperature (°C)
Solvent
Catalyst (mol%)
Time (min)
Isolated yield (%)
1
60
60
60
60
60
60
60
r.t
EtOH
5
10
15
20
15
15
15
15
15
15
–
35
81
80
91
90
90
93
87
45
76
90
35
2
EtOH
30
3
EtOH
25
4
EtOH
25
5
EtOH:H2O (1:1)
EtOH:H2O (2:1)
H2O
30
6
20
7
30
8
EtOH:H2O (2:1)
EtOH:H2O (2:1)
EtOH:H2O (2:1)
EtOH:H2O (2:1)
24 (h)
240
20
9
50
70
60
10
11
24 (h)
1 3

J IRAN CHEM SOC
Table 2 Optimization of reaction condition for synthesis of dihydropyrano[2,3-c]pyrazoles
O
H
O
O
CN
H2N
Aspirin
+
+
+
N
OEt
NH2. H2O
NC
CN
N
H
O
NH2
Entry
Temperature (°C)
Catalyst (mol%)
Time (min)
Isolated yield
(%)
1
2
3
4
5
6
7
8
9
70
70
5
10
15
20
15
15
15
15
–
40
35
76
81
86
85
45
91
90
90
30
70
30
70
25
60
180
25
80
90
25
100
80
20
24 (h)
Table 3 Synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols)
Ar
O
O
O
NH2. H2O
Aspirin
N
N
H2N
2
+
2
+
Ar
H
EtOH/H2O, 60 °C
N
H
OEt
N
H
OH
HO
1
3
2
4a-n
Entry
Ar
Product
Time (min)
Yield (%)
Mp (°C)
Found
Reported
[Refs]
1
C6H5
4a
4b
4c
4d
4e
4f
25
20
40
50
30
40
55
40
50
50
55
45
45
50
91
93
89
83
92
85
79
89
77
82
76
78
82
87
207–208
269–271
254–257
240–241
215–217
259–261
265–267
197–198
281–283
255–257
209–211
239–241
295–298
254–257
206–207 [23]
271–273 [47]
253–255 [47]
237–240 [22]
214–216 [23]
265–268 [23]
267–270 [22]
194–196 [47]
278–280 [23]
267–270 [22]
209–211 [23]
200–202 [47]
This work
2
4-NO2 C6H4
3-NO2 C6H4
2-NO2 C6H4
4-Cl C6H4
3
4
5
6
2-Cl C6H4
7
2,4-diCl C6H3
4-Me C6H4
2-Me C6H4
4-OH C6H4
3-OH C6H4
Thiophene-2-
Pyridine-3-
4g
4h
4i
8
9
10
11
12
13
14
4j
4k
4l
4m
4n
4-OH-3-OMeC6H3
This work
1 3

J IRAN CHEM SOC
Table 4 Synthesis of
dihydropyrano[2,3-c]
pyrazoles and spiroindoline-
pyranopyrazoles
Entry
1
Substrate
R
Product
Time (min) Yield (%) Mp (°C)
Found
Reported
[Refs]
CN
6a
25
91
253–255
247–248 [30]
CHO
2
3
CN
6b
6c
15
93
221–223
226–228 [26]
CHO
O2N
CO2Et
35
88
179–181
180–182 [53]
CHO
NO2
4
5
CN
CN
6d
6e
30
15
87
93
198–200
233–235
204–205 [26]
238–240 [26]
CHO
NO2
CHO
Cl
6
7
8
9
CN
6f
25
40
20
30
86
84
92
89
231–233
235–238
238–240
183–185
226–227 [26]
235–237 [42]
239–241 [26]
182–184 [53]
CHO
Cl
CN
6g
6h
6i
CHO
Cl
Br
Br
Cl
CN
CHO
CO2Et
CHO
1 3

J IRAN CHEM SOC
Table 4 continued
Entry
10
Substrate
R
Product
Time (min) Yield (%) Mp (°C)
Found
Reported
[Refs]
CN
6j
30
87
224–226
220–222 [48]
CHO
Br
11
12
13
14
CN
CN
CN
CN
6k
6l
15
30
35
40
86
87
82
83
231–233
205–208
225–226
237–239
233–234 [26]
208–209 [30]
219–221 [49]
235–237 [32]
CHO
F
CHO
CHO
CHO
Me
6m
6n
HO
HO
OMe
15
16
CN
CN
6o
8a
40
30
81
89
216–218
285–287
208–210 [50]
279–280 [52]
S
CHO
O
O
N
H
17
18
CN
8b
8c
25
30
91
85
283–285
250–254
282–283 [52]
>250 [53]
O
Br
O
N
H
CO2Et
O
Br
O
N
H
1 3

J IRAN CHEM SOC
Table 4 continued
Entry
19
Substrate
R
Product
Time (min) Yield (%) Mp (°C)
Found
Reported
[Refs]
CN
10
150
87
278–282
>300 [54]
O
O
6‑Amino‑1,4‑dihydro‑3‑methyl‑4‑(4‑bromophenyl)
pyrano[2,3‑c]pyrazole‑5‑carbonitrile (6h) Yield: (92%).
White powder, mp: 254–257 °C; IR (KBr) (νmax, cm−1):
3470, 3227, 3120, 2195, 1651, 1595, 1560, 1401, 1353,
were gained when the reaction was performed at 80 °C
in the presence of aspirin (15 mol%) under solvent-free
conditions.
After optimizing the reaction conditions, we evaluated
the range and feasibility of reactions using a various aryl
aldehydes. As shown in Tables 3 and 4, it was shown that
the two reactions tolerated both electron-withdrawing and
electron-donating groups on the aldehyde aromatic rings
including ortho-, meta-, and para-substituted with the
corresponding products in satisfed yields. In synthesis of
4,4′-(arylmethylene)bis(1H-pyrazol-5-ols), substitution of
NO2 group in the 4th 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.
Then, we investigated the utilization of acenaphth-
ylene-1,2-dione or isatins as a substrate to react with the
hydrazine hydrate, ethyl acetoacetate, and malononitrile
under the optimized conditions. As expected, the reaction
developed well to afford spiro[indoline-3,4′-pyrano[2,3-c]
pyrazole] derivatives (8a–c) and spiro[acenaphthylene-1,4′-
pyrano[2,3-c]pyrazole (10) in good yields.
A suggested mechanism, illustrating the role of aspirin
in the tandem synthesis of 4,4′-(arylmethylene)bis(1H-
pyrazol-5-ol), dihydropyrano[2,3-c]pyrazole deriva-
tive, and spiroindoline-pyranopyrazole was suggested in
Scheme 4. At frst, pyrazolone A would be formed from
the reaction between ethyl acetoacetate 1 and hydra-
zine hydrate 2. For the synthesis of 4,4′-(arylmethylene)
bis(1H-pyrazol-5-ol), the activated carbonyl group of
the aldehydes 3 by aspirin via Knoevenagel condensa-
tion with pyrazolone to create the intermediated B where
through Michael addition to another pyrazolone to give
desirable products (4a–n).
1
1107, 883, 810, 744, 543; H NMR (400 MHz, DMSO-
d6): 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).
Results and discussion
At frst, we centralized our attention to the synthesis of
4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) and the reac-
tion 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 experi-
ments. The effect of catalyst loading was envisaged,
and the results were summarized in Table 1. At a cata-
lyst loading of 15 mol%, the highest yield of product was
obtained in EtOH (Table 1, entry 3). Further increases to
the catalyst loading did not considerably infuence the
reaction progress. Next, the effects of solvents, water,
ethanol, and aqueous ethanol were evaluated and it was
found that the rate 2:1 EtOH/Water is better than other
rates. Finally, to optimize the reaction temperature, the
model reaction was carried out using 15 mol% of the
catalyst at different temperatures. It was found that 60 °C
is an effcient temperature in terms of reaction time and
yield obtained (Table 1, entry 6). As shown in (Table 1,
entry 11), a test reaction was accomplished in the absence
of catalyst at the optimum condition and offered only
30% yield of the expected product.
For the synthesis of dihydropyrano[2,3-c]pyrazoles is
proposed the arylidene malononitrile C to generate in situ
via Knoevenagel condensation active aldehyes 3 and malo-
nonitrile 4. Michael addition of A and C gives the acyclic
adduct products D, which undergoes intramolecular cycli-
zation and tautomerization to afford the corresponding
products (6a–o) (Scheme 2).
In
another
study
for
the
synthesis
of
dihydropyrano[2,3-c], pyrazoles, we selected reaction
of ethyl acetoacetate (1.0 mmol), hydrazine hydrate
(1.0 mmol), malononitrile (1.0 mmol), and benzalde-
hyde (1.0 mmol) as model under solvent-free conditions
and the effect of amount of catalyst and temperature was
envisaged. As shown in (Table 2, entry 6), optimization of
the reaction conditions demonstrated that the best results
In order to appraise the privileged features of our pro-
cedure, we compared our results for the synthesis of
1 3

J IRAN CHEM SOC
Cat
R1
O
H
O
Cat
R1
NC
H O
3
O
H
Cat
+
O
Ar
NC
H
Ar
3
4
Ar
Ar
C
H
HN N
HN N
HN N
O
N
N
O
NH2
N
H
A
O
N
H
OH
HO
H
Ar
HN N
Ar
B
O H N C
Cat
4a-n
O
R1
D
O
O
Ar
O
+
NH2.H2O
H
R1
OEt
H2N
HN
R2
1
2
N
HN N
O
N
NH
R1
H
NH2
O
N
H
R2
R2
R1
NC
N
Ar
N C
O
NH2
H
O
R1
R1
N
H
O
N
8a-d
Cat O H
7
N
H
N
O
6a-m
NH2
H
Scheme 2 The suggested mechanism for the synthesis 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols), dihydropyrano[2,3-c]pyrazoles, and spiroin-
doline-pyranopyrazoles
Table 5 Comparison of the
results afforded from the
synthesis of 4b and 6a in the
presence of aspirin with those
obtained via other catalysts
Product
Catalyst
Reaction conditions
Time
Yield (%)
References
Pyridine trifuoroacetate
ZnAl2O4 Nps
H2O, 70 °C
12 h
85 [22]
92 [23]
88 [24]
85 [47]
90 [25]
H2O, 60 °C
14 min
1 h
NO2
Sodium Dodecyl Sulfate
–
H2O, refux
H2O, refux
6 h
N-Methylimidazolium per-
50 °C, solvent-free
20 min
chlorate
N
N
Aspirin
H2O/EtOH, 60 °C
20 min
93 (This work)
N
H
N
H
OH
HO
NiFe2O4@SiO2–H3PW12O40 EtOH, refux
5 min
84 [49]
(NFS–PWA)
Fe3-xTixO4@SO3H MNPs
β-Cyclodextrin
Lemon juice
105 °C, solvent-free
90 min
15 min
50 min
9 h
90 [27]
H2O/EtOH, 80 °C
H2O/EtOH, 90 °C
EtOH, refux/H2O
H2O, refux
90 [28]
CN
96 [29]
N
Morpholine trifate
Triphenylphosphine
γ-Alumina
92 [30]
N
H
O
NH2
1 h
84 [31]
H2O, 100 °C
50 min
25 min
25 min
80 [32]
Imidazole
H2O, 80 °C
89 [33]
Aspirin
80 °C, solvent-free
91 (This work)
1 3

J IRAN CHEM SOC
13. M.G. LaPorte, Z. Wang, R. Colombo, A. Garzan, V.A. Peshkov,
M. Liang, P.A. Johnston, M.E. Schurdak, M. Sen, D.P. Camarco,
Y. Hua, Bioorg. Med. Chem. Lett. 26, 3581–3588 (2016)
14. J.L. Wang, D. Liu, Z.J. Zheng, S. Shan, X. Han, S.M. Sriniva-
sula, C.M. Croce, E.S., Z. Huang. Proc. Natl. Acad. Sci. 97,
7124–7129 (2009)
15. B.P. Bandgar, H.V. Chavan, L.K. Adsul, V.N. Thakare, S.N.
Shringare, R. Shaikh, R.N. Gacche, Bioorg. Med. Chem. Lett.
23, 912–916 (2013)
bis(pyrazol-5-ols) and dihydropyrano[2,3-c]pyrazoles with
other results reported in the literature, as shown in Table 5.
Compounds including pyrazol core have extensively been
used in the synthesis of drugs and pharmaceuticals. Thus,
the elimination of residual metal species plays a pivotal
role when a metal-containing catalyst was applied [12]. So,
this method, compared to the existing ones, uses aspirin
as an effcient, non-toxic, inexpensive, and commercially
available organocatalyst along with merits including high
yields and short reaction time.
16. K.M. Kasiotis, E.N. Tzanetou, S.A. Haroutounian, Front. Chem.
2, 1–7 (2014)
17. M.J. Genin, C. Biles, B.J. Keiser, S.M. Poppe, S.M. Swaney,
W.G. Tarpley, Y. Yagi, D.L. Romero, J. Med. Chem. 43, 1034–
1040 (2000)
18. F. Abrigach, R. Touzani, Med. Chem. (Los Angeles) 6, 292–298
(2016)
19. K. Sujatha, G. Shanthi, N.P. Selvam, S. Manoharan, P.T. Peru-
mal, M. Rajendran, Bioorg. Med. Chem. Lett. 19, 4501–4503
(2009)
The reusability of aspirin was examined in the synthesis
of 4b as an example. It was observed that the yield of prod-
uct reduced in the 3rd and 4th runs.
20. H. Kashtoh, M.T. Muhammad, J.J. Khan, S. Rasheed, A. Khan,
S. Perveen, K. Javaid, K.M. Khan, M.I. Choudhary, Bioorg.
Chem. 65, 61–72 (2016)
Conclusions
21. A.V. Stachulski, N.G. Berry, A.C.L. Low, S.L. Moores, E. Row,
D.C. Warhurst, I.S. Adagu, J.F. Rossignol, J. Med. Chem. 49,
1450–1454 (2006)
22. E. Soleimani, S. Ghorbani, M. Taran, A. Sarvary, C. R. Chim. 15,
955–961 (2012)
In compendium, we expanded an effcient strategy for
one-pot synthesis of biologically 4,4′-(arylmethylene)
bis(1H-pyrazol-5-ol), dihydropyrano[2,3-c]pyrazole, and
spiropyranopyrazole derivatives in the presence of aspirin
as a commercially available, and eco-compatibility catalyst
under environmental benign conditions. Good to excellent
yields, simplicity of operation, comfortable purifcation,
and high atom-economy are the noteworthy advantages of
the present method.
23. J. Safaei-Ghomi, B. Khojastehbakht-Koopaei, H. Shahbazi-
Alavi, RSC Adv. 4, 46106–46113 (2014)
24. W. Wang, S.X. Wang, X.Y. Qin, J.T. Li, Synth. Commun. 35,
1263–1269 (2005)
25. N.G. Khaligh, S.B.A. Hamid, S.J. Titinchi, Chin. Chem. Lett. 27,
104–108 (2016)
26. M.A. Zolfgol, R. Ayazi-Nasrabadi, S. Baghery, V. Khakyzadeh,
S. Azizian, J. Mol. Catal. A-Chem. 418–419, 54–67 (2016)
27. D. Azarifar, Y. Abbasi, Synth. Commun. 46, 745–758 (2016)
28. Y.A. Tayade, S.A. Padvi, Y.B. Wagh, D.S. Dalal, Tetrahedron
Lett. 56, 2441–2447 (2015)
Acknowledgements We gratefully appreciate the fnancial support
from the Research Council of University of Sistan and Baluchestan.
29. R.H. Vekariya, K.D. Patel, H.D. Patel, Res. Chem. Intermed. 42,
7559–7579 (2016)
30. C.F. Zhou, J.J. Li, W.K. Su, Chin. Chem. Lett. 27, 1686–1690
(2016)
References
31. A.K. Imene, F. Amina, L. Oumeima, B. Raouf, B. Boudjemaa,
D. Abdelmadjid, Lett. Org. Chem. 13, 85–91 (2016)
32. H. Mecadon, M.R. Rohman, M. Rajbangshi, B. Myrboh, Tetra-
hedron Lett. 52, 2523–2525 (2011)
33. A. Siddekha, A. Nizam, M.A. Pasha, Spectrochim. Acta A. 81,
431–440 (2011)
1. S. Karamthulla, S. Pal, M.N. Khan, L.H. Choudhury, RSC Adv.
4, 37889–37899 (2014)
2. P.T. Anastas, T.C. Williamson (eds.), Green Chemistry: Frontiers
in Benign Chemical Syntheses and Processes (Oxford University
Press, Oxford, 1998)
34. A.R. Hajipour, M. Karimzadeh, H. Tavallaei, J. Iran. Chem. Soc.
3. G.M. Ziarani, S. Faramarzi, N. Lashgari, A. Badiei, J. Iran.
12, 987–991 (2015)
Chem. Soc. 11, 701–709 (2014)
35. K. Ablajan, W. Liju, Y. Kelimu, F. Jun, Mol. Divers. 17, 693–700
(2013)
4. P.T. Anastas, M.M. Kirchhoff, Acc. Chem. Res. 35, 686–694
(2002)
36. D.W.C. MacMillan, Nature 455, 304–308 (2008)
37. C.M. Ulrich, J. Bigler, J.D. Potter, Nat. Rev. Cancer 6, 130–140
(2006)
38. C. Cena, M.L. Lolli, L. Lazzarato, E. Guaita, G. Morini, G.
Coruzzi, S.P. McElroy, I.L. Megson, R. Fruttero, A. Gasco, J.
Med. Chem. 46, 747–754 (2003)
39. A. Undas, K.E. Brummel-Ziedins, K.G. Mann, Blood 109,
2285–2592 (2007)
40. X. Shi, M. Ding, Z. Dong, F. Chen, J. Ye, S. Wan, S.S. Leonard,
V. Castronova, V. Vallyathan, Mol. Cell. Biochem. 199, 93–102
(1999)
5. E. Ruijter, R. Scheffelaar, R.V.A. Orru, Angew. Chem. Int. Ed.
50, 6234–6246 (2011)
6. J.L. Tucker, Org. Process Res. Dev. 10, 315–319 (2006)
7. O.A. Attanasi, D. Spinelli, Soc. Chim. Italiana, Roma. 4, 105–
137 (2000)
8. M.M.F. Ismail, Y.A. Ammar, H.S.A. EI-Zahaby, S.I. Eisa, S.E.
Barakat, Arch. Pharm. Chem. Life Sci. 340, 476–479 (2007)
9. S.P. Prajapati, D.P. Patel, P.S. Patel, J. Chem. Pharm. Res. 4,
2652–2655 (2012)
10. Y. Liu, G. He, C. Kai, Y. Li, H. Zhu, J. Heterocycl. Chem. 19,
1370–1375 (2012)
41. T. Roberts, F. Shokraneh, S. Nur, Cochrane Libr (2016).
doi:10.1002/14651858.CD012116
11. G. Mariappan, B.P. Saha, L. Sutharson, A. Singh, S. Garg, L.
Pandey, D. Kumar, Saudi Pharm. J. 19, 115–122 (2011)
12. C.E. Rosiere, M.I. Grossman, Science 131, 651 (1951)
1 3

J IRAN CHEM SOC
42. M. Fatahpour, F. Noori Sadeh, N. Hazeri, M.T. Maghsoodlou, M.
Lashkari, Res. Appl. Chem. 6, 1569–1572 (2016)
49. Y. Zou, H. Wub, Y. Hua, H. Liu, X. Zhao, H. Ji, D. Shi, Ultrason.
Sonochem. 18, 708–712 (2011)
43. M. Kangani, N. Hazeri, M.T. Mghsoodlou, K. Khandan-Barani,
M. Kheyrollahi, F. Nezhadshahrokhabadi, J. Iran. Chem. Soc.
12, 47–50 (2015)
50. B. Maleki, H. Eshghi, M. Barghamadi, N. Nasiri, A. Khojasteh-
nezhad, S. Sedigh Ashraf, O. Pourshiani, Res. Chem. Intermed.
42, 3071–3093 (2016)
44. M. Fatahpour, N. Hazeri, M.T. Maghsoodlou, M. Lashkari,
Iran. J. Sci. Technol. Trans. A Sci. (2016). doi:10.1007/
s40995-016-0064-1
45. F. Mohamadpour, M.T. Maghsoodlou, R. Heydari, M. Lashkari,
J. Iran. Chem. Soc. 13, 1549–1560 (2016)
51. D.R. Palleros, Experimental Organic Chemistry (Wiley, Hobo-
ken, 2000), p. 494
52. Y. Zou, Y. Hu, H. Liu, D. Shi, ACS comb. Sci. 14, 38–43 (2011)
53. S. Paul, K. Pradhan, S. Ghosh, S.K. De, A.R. Das, Tetrahedron
70, 6088–6099 (2014)
46. M.T. Maghsoodlou, M. Karima, M. Lashkari, B. Adrom, J.
Aboonajmi, J. Iran. Chem. Soc. 14, 329–335 (2017)
47. J. Xu-dong, D. Hai-feng, L. Ying-jie, C. Jun-gang, L. Da-peng,
W. Mao-cheng, Chem. Res. Chin. Univ. 28, 999–1002 (2012)
48. M. Babaie, H. Sheibani, Arab. J. Chem. 11, 159–162 (2011)
54. M.N. Elinson, A.I. Ilovaisky, V.M. Merkulova, P.A. Belyakov, F.
Barba, B. Batanero, Tetrahedron 68, 5833–5837 (2012)
1 3