“On-water” one-pot four-component synthesis of novel 1H-furo[2,3-c]pyrazole-4-amine derivatives

Article abstract of DOI:10.1007/s11164-019-03837-w

A catalyst-free, simple and green protocol has been accomplished for the synthesis of novel 1H-furo[2,3-c]pyrazole-4-amines in a one-pot four-component domino reaction involving hydrazines, ethyl acetoacetate, aromatic amines and phenylglyoxal monohydrate in water. The protocol presented herein describes in situ generated pyrazolone as intermediate reactants with phenylglyoxal monohydrate in a Knoevenagel condensation followed by a Michael addition of amine, intramolecular cyclization, dehydration and the resulting to the title compound. It was observed that in this protocol bis(pyrazole-5-ols) are formed with amines bearing strong electron withdrawing groups under similar reaction conditions instead of the expected products. The reaction merits the use of water as solvent, no additive catalyst, easy workup, easy purification of products by non-chromatography and provides high yield of products with good purity.

Full text of DOI:10.1007/s11164-019-03837-w

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03837-w
“On‑water” one‑pot four‑component synthesis of novel
1H‑furo[2,3‑c]pyrazole‑4‑amine derivatives
Fatemeh Noruzian1 · Abolfazl Olyaei2 · Rahimeh Hajinasiri1
Received: 23 February 2019 / Accepted: 16 April 2019
© Springer Nature B.V. 2019
Abstract
A catalyst-free, simple and green protocol has been accomplished for the synthe-
sis of novel 1H-furo[2,3-c]pyrazole-4-amines in a one-pot four-component domino
reaction involving hydrazines, ethyl acetoacetate, aromatic amines and phenylg-
lyoxal monohydrate in water. The protocol presented herein describes in situ gen-
erated pyrazolone as intermediate reactants with phenylglyoxal monohydrate in a
Knoevenagel condensation followed by a Michael addition of amine, intramolecu-
lar cyclization, dehydration and the resulting to the title compound. It was observed
that in this protocol bis(pyrazole-5-ols) are formed with amines bearing strong elec-
tron withdrawing groups under similar reaction conditions instead of the expected
products. The reaction merits the use of water as solvent, no additive catalyst, easy
workup, easy purifcation of products by non-chromatography and provides high
yield of products with good purity.
Keywords 1H-Furo[2,3-c]pyrazole · Hydrazine hydrate · Phenylglyoxal
monohydrate · Ethyl acetoacetate · Heteroaryl amine
Introduction
The chemistry of pyrazoles and derivatives, one of the most valuable nitrogen con-
taining heterocyclic compounds, has attracted much attention in recent years. They
have been considered very important for pharmaceutical, chemical and agricultural
industries [1–3]. Pyrazoles have been reported to possess antimicrobial, anticancer,
antileukemic, antidepressant, antiinfammatory, antihelmintic, anticonvulsant, anti-
tubercular, analgesic, antiproliferative agents, angiogenic, antioxidant, antipyretic,
antioxidant or herbicidal properties [4–8]. In addition, fused pyrazoles possess a
* Abolfazl Olyaei
Olyaei_a@pnu.ac.ir
1
Chemistry Department, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
2
Department of Chemistry, Payame Noor University (PNU), PO BOX 19395-4697, Tehran, Iran
Vol.:(0123456789)
1 3

F. Noruzian et al.
wide range of biological properties such as fungicidal [9], herbicidal [10], veridical
[11] and insecticidal activity [12, 13] and have been used for the treatment of rheu-
matoid arthritis [14, 15].
Furans and their derivatives with substituent(s) at C-2 and/or C-3 have attracted
strong interest due to their widespread in a large number of natural products and for
their useful biological and pharmacological properties [16–18]. Among these com-
pounds, pyrazole-fused ring derivatives such as furopyrazoles have demonstrated
antitumour and antimicrobial activities [19]. Therefore, the preparation of furopyra-
zole derivatives is very important and challenging from a synthetic point of view. In
recent years, despite a number of synthetic routs accessible for ring-fused pyrazoles
such as dihydrofuro[2,3-c]pyrazole derivatives in the literature [20–25], synthesis
of furo[2,3-c]pyrazole derivatives has received little attention and only few proce-
dures have been reported. Among them, the majority has focused on the prepara-
tion of CF3-substituted furopyrazoles A based on Rh catalyzed [3+2] cycloaddition
of CF3-substituted diazocarbonyl compound with aromatic alkynes [26], reaction of
4-bromo pyrazolone with malononitrile, cyanoacetamide and/or ethyl cyanoacetate
to give furo[2,3-c]pyrazoles B using chitosan as a green basic catalyst by microwave
irradiation technique [27] and synthesis of benzo-bis-furopyrazole C an important
structural unit of cyanine dyes from p-chloranil and 3-methyl-1-phenyl-5-pyrazolone
[28] (Fig. 1).
With regard to the exploration of green chemistry, solvent selection is an impera-
tive part of most chemical processes. Organic reactions in water as a solvent with-
out use of any detrimental organic solvents are of immense interest. When water is
used as a reaction medium, it leads to some specifc interactions such as polarity,
hydrogen bonding, hydrophobic efect and trans-phase interactions due to its exclu-
sive structure and incredible physical and chemical assets [29, 30]. However, a clear-
cut understanding on the role of water in accelerating organic reactions is yet to be
made. Towards this direction various terminologies such as “on water,” in water,“in
the presence of water” have been coined [31–34]. However, the insolubility of most
organic reactants in water makes the reaction mixtures heterogeneous, which proves
to be a major difculty while using water as a solvent. But the efect of water on het-
erogeneous reactions is precisely opposite. Actually, depending on the nature of the
reaction, water was observed to accelerate most reactions appreciably on its inter-
face. The observed rate enhancement in water was explained by the hydrophobic
efect [35–38]. In recent years, various reactions have been carried out in water, and
mostly when the organic reactants are insoluble in the aqueous phase [39–44].
Fig. 1 Fused furopyrazoles (a–c)
1 3

“On-water”one-pot four-component synthesis of novel…
To the best of our knowledge, synthesis of 1H-furo[2,3-c]pyrazole-4-amines in
aqueous medium is not yet reported. In continuation of our ongoing program for the
development of sustainable processes the heterocyclic compounds [45–51], herein
we wish to report our results for the uncatalyzed domino synthesis of novel highly
substituted 1H-furo[2,3-c]pyrazole derivatives by a one-pot four-component con-
densation reaction between hydrazines, ethyl acetoacetate, aromatic amines and phe-
nylglyoxal monohydrate in water.
Results and discussion
For our initial study, the reaction of ethyl acetoacetate (1, 1.0 mmol), hydrazine
hydrate (2a, 1.0 mmol), 2-aminopyridine (3a, 1.0 mmol) and phenylglyoxal mono-
hydrate (4, 1.0 mmol) was chosen as a model reaction (Table 1). This combination
in the absence of any catalyst and solvent-free condition at 90 °C provided four-
component product 5a after 60 min in 54% yield (Table 1, entry 1). Next, the same
reaction mixture stirred at refux temperature in water for 40 min gave the desired
product 5a in 88% yield (Table 1, entry 2). Interestingly, the model reaction in water
and in the presence of a catalytic amount of guanidine hydrochloride or formic acid
was examined. The results indicated that using of the catalyst did not improve the
yield of the product. In order to study the solvent efect, the model reaction was
carried out in the presence of various polar protic and polar aprotic solvents. It was
found that polar protic solvents (EtOH and MeOH) and low boiling aprotic solvents
Table 1 Optimization of the reaction conditionsa
Entry
Solvent
Temperature (°C)
Time (min)
Yield (%)b
1
2
3
4
5
6
–
H2O
EtOH
MeOH
CH3CN
THF
90
60
40
120
120
120
120
54
88
43
48
54
42
refux
refux
refux
refux
refux
aReaction conditions: ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1 mmol), 2-aminopyridine
(1 mmol) and phenylglyoxal monohydrate (1 mmol), solvent 5 mL
bIsolated yields
1 3

F. Noruzian et al.
(CH3CN and THF) under refux conditions aforded the moderate yields of the prod-
uct 5a after 2 h (Table 1, entries 3–6).
With the optimized reaction conditions for the synthesis of amine substituted
ring-fused furopyrazoles, we explored the generality of this reaction. Our atten-
tion was focused on the use of commercially available aromatic amines such as
2-amino-4-methylpyridine (3b), 4-chloroaniline (3c), 2-amino-5-nitropyridine (3d)
and 2-amino-5-bromopyridine (3e). The reaction with 3b gave the corresponding
product 5b in high yield (84%) after 40 min. Interestingly, under similar reaction
conditions, the other amines 3c-e with ethyl acetoacetate, hydrazine hydrate and
phenylglyoxal monohydrate gave the corresponding 2,2′-bis(5-hydroxy-3-methyl-
1H-pyrazol-4-yl)-1-phenylethanone (6a) instead of the desired ring-fused furopyra-
zoles. It is suggested that 3-methyl-1H-pyrazol-5-ol (7a) generated in situ from the
condensation of hydrazine hydrate (2a) and ethyl acetoacetate (1) is more nucle-
ophilic than amine containing electron-withdrawing group (3c–e) and reacts with
intermediate 8a to aford product 6a (Scheme 1).
Thus, encouraged by the results, we further explored the scope and limitation of
the current method. With the optimal conditions in hand, one-pot, two-step dom-
ino reaction of phenyl hydrazine (2b, 1.0 mmol), ethyl acetoacetate (1, 1.0 mmol),
2-aminopyridine (3a, 1.0 mmol) and phenylglyoxal monohydrate (4, 1.0 mmol) was
investigated. Initially, the reaction of phenyl hydrazine (2b, 1.0 mmol) and ethyl ace-
toacetate (1, 1.0 mmol) in the presence of a catalytic amount of guanidine hydrochlo-
ride (10 mol%) as organocatalyst in water at refux condition was studied. The reac-
tion gave 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b) in high yield (90%) after 90 min
(Scheme 2). We also evaluated the amount of catalyst required for this reaction. It
was found that when we increased the amount of catalyst from 10 mol% to 15 mol%
and 20 mol%, the yield did not improve. Moreover, by decreasing the amount of
catalyst from 10 mol % to 5 mol%, the yield decreased from 90 to 75%. Also, under
the identical condition, the yield of the reaction was not afected in the presence of
Scheme 1 Synthesis of furopyrazole 5a–b and bis (pyrazole-5-ols) (6a)
1 3

“On-water”one-pot four-component synthesis of novel…
Scheme 2 One-pot synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b) and furopyrazole 5c–f
10 mol% catalyst after diferent time intervals (90 min, 120 min and 150 min). Thus,
10 mol% guanidine hydrochloride was chosen as a quantitative catalyst for this reac-
tion and 90 min was chosen as the reaction time. After determining the optimum
reaction condition, to established the synthesis of 7b, phenylglyoxal monohydrate
(4, 1.0 mmol) and various aryl amines (1.0 mmol) were added to the reaction mix-
ture for the synthesis of a series of novel furopyrazoles 5c–f (Scheme 2).
As indicated in Fig. 2, the various aromatic amines such as 2-aminopyridine,
2-amino-4-methylpyridine, 2-amino-5-bromopyridine and 2-amino-3-methylpyri-
dine (3f), aforded the corresponding furopyrazole 5c–f within 50–60 min in high
yields (75–85%).
However, when the reaction was performed with 4-chloroaniline (3c) or 2-amino-
5-nitropyridine
(3d),
2,2′-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-phenylethanone (6b) was obtained instead of the expected furopyrazole deriva-
tives. Accordingly, the reaction occurred via initial formation of intermediate 8b
from the reaction of 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b) and phenylglyoxal
monohydrate followed by Michael addition of 7b to 8b to give product 6b because
of the higher nucleophilicity of 7b than amines bearing strong electron-withdrawing
group (3c–d) (Scheme 3).
It should be noted that the purifcation of the title compounds is very easy. After
cooling the reaction mixture to room temperature, the solid that separated out was
fltered. The crude product was stirred for 5 min in boiling CH3CN and the resulting
precipitate was fltered to give the pure product. In another study, one-pot three-
component reaction of 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b), phenylglyoxal
monohydrate (4) and aromatic amines 3a–f in the absence of catalyst in water under
refux conditions was examined (Scheme 4). In this process, the same products
5c–f and 6b as well as yields were obtained after 50–60 min. As a result, guani-
dine hydrochloride as catalyst in the synthesis of compounds 5c–f and 6b is only
Fig. 2 One-pot, two-step synthesis of furopyrazole 5c–f
1 3

F. Noruzian et al.
Scheme 3 Synthesis of bis (pyrazole-5-ols) (6b)
Scheme 4 One-pot three-component synthesis of compounds 5c–f and 6b
Scheme 5 Proposal mechanism for the synthesis of compound 10
efective for the frst step of the reaction, in which phenyl hydrazine reacts with ethyl
acetoacetate, and has no efect on the second step.
In order to expand the scope of the current method, the reaction of hydrazine
hydrate (2a, 1.0 mmol), ethyl acetoacetate (1, 1.0 mmol), 2-aminopyridine (3a,
1.0 mmol) and benzaldehyde (1.0 mmol) was examined to synthesize 3-methyl-
4-(phenyl(pyridin-2-ylamino)methyl)-1H-pyrazol-5-ol (9). Unfortunately, the
attempt to replace phenylglyoxal monohydrate with benzaldehyde failed and
4,4′-(phenylmethylene)bis(3-methyl-1H-pyrazol-5-ol) (10) was obtained instead
of compound 9. Therefore, it might be concluded that 4-benzylidene-3-methyl-
1H-pyrazol-5(4H)-one (8) is initially formed as an intermediate. Then, the inter-
mediate is attacked by 3-methyl-1H-pyrazol-5(4H)-one to give the product 10,
which might be due to the higher nucleophilicity of the 3-methyl-1H-pyrazol-
5(4H)-one than 2-aminopyridine (Scheme 5). Also, we examined the reaction of
2-aminopyridine and benzaldehyde in the presence of guanidine hydrochloride
1 3

“On-water”one-pot four-component synthesis of novel…
under solvent-free condition at 90 °C for 20 min. Then, 3-methyl-1H-pyrazol-
5-ol (7a) was added to the reaction mixture and stirred at 90 °C for 15 min. As a
result, compound 10 obtained instead of the desired product 9.
The plausible reaction mechanism of formation of compounds 5a–f is
described in Scheme 6. The reaction proceeds through the in situ formation of
1H-pyrazol-5-ol 7 by the condensation of hydrazine 2 and ethyl acetoacetate 1.
The last one reacts with the phenylglyoxal monohydrate with loss of a water mol-
ecule leading to the formation of intermediate 11. Next, the Michael addition of
amine to intermediates 11 provide to intermediate 12 and subsequent intramolec-
ular cyclization and dehydration, to aford fnal the corresponding furopyrazole 5.
Conclusion
In summary, we have developed a protocol for the facile preparation of novel
fused 1H-furo[2,3-c]pyrazole-4-amines in high yields by a one-pot four-compo-
nent domino protocol involving Knoevenagel condensation, Michael addition,
cyclization and dehydration sequences in an aqueous medium under refux con-
ditions. In this process, the replacement of the amine bearing electron-donating
group or weak electron-withdrawing group moiety with amine bearing strong
electron-withdrawing group led to the formation of bis(pyrazole-5-ol) com-
pounds. The advantages of this method include environmental acceptability, easy
work-up, easy product separation and purifcation, short reaction time, no additive
catalyst, and fnally compliance with green chemistry protocols. Moreover, our
products are expected to be of pharmacological interest and may act as potential
drug candidates similar to the pyrazoles. To the best of our knowledge, this is the
frst report on the synthesis of novel 1H-furo[2,3-c]pyrazole-4-amine derivatives.
Scheme 6 Proposed mechanism pathway for the formation of 5a–f
1 3

F. Noruzian et al.
Experimental section
General information
All commercially available chemicals and reagents were used without further puri-
fcation. Melting points were determined with an Electrothermal model 9100 appa-
ratus and are uncorrected. IR spectra were recorded on a Shimadzu 4300 spectro-
1
photometer. The H and 13C NMR spectra were recorded in DMSO-d6 on Bruker
DRX-300 Avance spectrometers. Chemical shifts (δ) are reported in parts per mil-
lion and are referenced to the NMR solvent. Mass spectra of the products were
obtained with an HP (Agilent technologies) 5973 mass selective detector. Elemental
analyses were carried out by a CHN–O–Rapid Heraeus elemental analyzer (Welles-
ley, MA).
General procedure for the synthesis of compounds 5a–b and 6a
Hydrazine hydrate (1.0 mmol), ethylacetoacetate (1.0 mmol), aromatic amine
(1.0 mmol), phenylglyoxal monohydrate (1.0 mmol) and 5 mL of H2O were placed
in a 50 mL round bottom fask over a magnetic stirrer and the contents were refuxed
for appropriate times (40–55 min). The progress of the reaction was monitored by
TLC. After completion of the reaction, the reaction mixture was allowed to cool
at room temperature and the resulting solid (crude product) fltered and dried. The
crude product was stirred for 5 min in boiling CH3CN and the resulting precipitate
was fltered. The products 5a, 5b and 6a thus obtained were found to be pure upon
1H and 13C-NMR, mass spectra, elemental analyses, and TLC examination.
General procedure for the synthesis of compounds 5c–f and 6b
Phenyl hydrazine (1.0 mmol), ethylacetoacetate (1.0 mmol), guanidine hydrochlo-
ride (10% mol) and 5 mL of H2O were placed in a 50 mL round bottom fask over
a magnetic stirrer and the contents were refuxed for 90 min (the progress of the
reaction was monitored by TLC). Then, aromatic amine (1.0 mmol), phenylglyoxal
monohydrate (1.0 mmol) were added to the reaction mixture and the contents were
refuxed for appropriate times (50–60 min). The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the reaction mixture was allowed to
cool at room temperature and the resulting solid (crude product) fltered and dried.
The crude product was stirred for 5 min in boiling CH3CN and the resulting pre-
cipitate was fltered. The products 5c–f and 6b thus obtained were found to be pure
upon 1H and 13C-NMR, mass spectra, elemental analyses, and TLC examination.
3‑Methyl‑5‑phenyl‑N‑(pyridin‑2‑yl)‑1H‑furo[2,3‑c]pyrazol‑4‑amine (5a)
Light pink powder; m.p.=324–325 °C; IR (KBr, cm−1): 3417, 3113, 3030, 2885,
1636, 1617, 1578, 1530, 1505, 1450, 1384, 1340, 1276, 1244, 1154, 1112, 1059; 1H
1 3

“On-water”one-pot four-component synthesis of novel…
NMR (300 MHz, DMSO-d6): δ=1.50 (s, 3H, CH3), 6.62 (t, 1H, J=6.6 Hz, Ar–H),
7.00–7.11 (m, 4H, Ar–H), 7.35 (d, 1H, J=9.0 Hz, Ar–H), 7.52 (d, 2H, J=7.8 Hz,
Ar–H), 7.59 (d, 1H, J=6.6 Hz, Ar–H), 9.92 (br, 1H, NH), 11.55 (br, 1H, NH);
13C NMR (75 MHz, DMSO-d6): δ=10.87, 91.28, 95.45, 112.45, 112.93, 117.12,
125.11, 125.24, 127.02, 127.65, 128.77, 135.37, 142.33, 160.10, 164.61; MS m/z
(%): 291 (M+1) (100), 290 (M)+, 289, 275, 233, 218, 205, 154, 128, 103, 78; Anal.
calcd. for C17H14N4O: C, 70.34; H, 4.82; N, 19.31. Found: C, 70.43; H, 4.75; N,
19.37.
3‑Methyl‑N‑(4‑methylpyridin‑2‑yl)‑5‑phenyl‑1H‑furo[2,3‑c]pyrazol‑4‑amine (5b)
White powder; m.p.=332–334 °C; IR (KBr, cm−1): 3219, 3169, 3055, 2913, 1644,
1623, 1561, 1524, 1498, 1382, 1346, 1270, 1243, 1220, 1166, 1112, 1058; 1H NMR
(300 MHz, DMSO-d6): δ=1.49 (s, 3H, CH3), 2.10 (s, 3H, CH3), 6.45–6.47 (dd, 1H,
J=1.2, 7.2 Hz, Ar–H), 6.95–7.11 (m, 4H, Ar–H), 7.45–7.51 (m, 3H, Ar–H), 9.93
(br, 1H, NH), 11.47 (br, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ=10.86, 21.23,
91.44, 112.30, 114.88, 115.37, 124.36, 126.90, 127.46, 128.70, 135.52, 135.64,
140.20, 141.96, 145.08, 164.71; MS m/z (%): 304 (M)+ (100), 289, 275, 247, 232,
219, 205, 169, 152, 128, 115, 92, 78, 65; Anal. calcd. for C18H16N4O: C, 71.05; H,
5.26; N, 18.42. Found: C, 70.97; H, 5.30; N, 18.54.
3‑Methyl‑1,5‑diphenyl‑N‑(pyridin‑2‑yl)‑1H‑furo[2,3‑c]pyrazol‑4‑amine (5c)
Light pink powder; m.p.=310–312 °C; IR (KBr, cm−1): 3430, 3062, 2920, 1595,
1500, 1445, 1389, 1359, 1309,1231, 1029; 1H NMR (300 MHz, DMSO-d6): δ=1.52
(s, 3H, CH3), 6.65 (t, 1H, J=6.6 Hz, Ar–H), 6.99–7.26 (m, 9H, Ar–H, NH), 7.39
(d, 1H, J=12.0 Hz, Ar–H), 7.57–7.60 (m, 3H, Ar–H), 7.75 (d, 1H, J=6.9 Hz,
1
Ar–H); H NMR (300 MHz, DMSO-d6 +D2O): δ=1.65 (s, 3H, CH3), 6.86 (t,
1H, J=6.6 Hz, Ar–H), 7.15–7.41 (m, 8H, Ar–H), 7.54 (d, 1H, J=8.7 Hz, Ar–H),
7.66–7.69 (m, 3H, Ar–H), 7.90 (d, 1H, J=6.9 Hz, Ar–H); 13C NMR (75 MHz,
DMSO-d6): δ=23.25, 112.72, 117.05, 120.48, 120.93, 125.70, 125.89, 125.91,
127.05, 127.88, 128.94, 129.43, 135.14, 138.86, 140.41, 142.71, 144.85, 145.74,
148.62; MS m/z (%): 366 (M)+ (100), 346, 292, 261, 233, 231, 218, 205, 187, 185,
155, 128, 105, 91, 77; Anal. calcd. for C23H18N4O: C, 75.41; H, 4.91; N, 15.30.
Found: C, 75.34; H, 4.99; N, 15.33.
3‑Methyl‑N‑(3‑methylpyridin‑2‑yl)‑1,5‑diphenyl‑1H‑furo[2,3‑c]pyrazol‑4‑amine (5d)
Pink powder; m.p.=330–331 °C; IR (KBr, cm−1): 3413, 3061, 2948, 2917, 1597,
1
1548, 1500, 1449, 1347, 1309, 1255, 1031; H NMR (300 MHz, DMSO-d6):
δ=1.52 (s, 3H, CH3), 2.32 (s, 3H, CH3), 6.56 (t, 1H, J=6.6, Ar–H), 6.87 (d, 1H,
J=6.6 Hz, Ar–H), 6.95–7.25 (m, 7H, Ar–H, NH); 7.57–7.60 (m, 5H, Ar–H); 13C
NMR (75 MHz, DMSO-d6): δ=13.01, 16.99, 112.68, 112.75, 120.86, 123.19,
124.21, 125.84, 126.53, 127.14, 127.74, 128.86, 129.40, 135.26, 138.80, 142.30,
145.19, 145.77, 148.62, 148.64; MS m/z (%): 380 (M)+ (100), 351, 310, 275, 260,
1 3

F. Noruzian et al.
247, 245, 231, 219, 208, 190, 168, 128, 105, 92, 77; Anal. calcd. for C24H20N4O: C,
75.79; H, 5.26; N, 14.73. Found: C, 75.84; H, 5.15; N, 14.77.
3‑Methyl‑N‑(4‑methylpyridin‑2‑yl)‑1,5‑diphenyl‑1H‑furo[2,3‑c]pyrazol‑4‑amine (5e)
Yellowish powder; m.p.=270–272 °C; IR (KBr, cm−1): 3444, 3069, 2979, 2910,
1
1596, 1503, 1452, 1359, 1216, 1027; H NMR (300 MHz, DMSO-d6): δ=1.50 (s,
3H, CH3), 2.12 (s, 3H, CH3), 6.50 (d, 1H, J=6.9 Hz, Ar–H), 6.98–7.25 (m, 8H,
Ar–H, NH), 7.55–7.64 (m, 5H, Ar–H); 13C NMR (75 MHz, DMSO-d6): δ=13.03,
21.27, 112.11, 114.99, 115.38, 116.65, 117.31, 118.91, 120.74, 124.78, 124.87,
125.69, 126.95, 127.81, 128.88, 129.38, 134.83, 136.71, 144.90, 148.56; MS m/z
(%): 380 (M)+ (100), 351, 310, 275, 260, 247, 245, 232, 219, 190, 169, 119, 105, 92,
77; Anal. calcd. for C24H20N4O: C, 75.79; H, 5.26; N, 14.73. Found: C, 75.68; H,
5.20; N, 14.80.
N‑(5‑Bromopyridin‑2‑yl)‑3‑methyl‑1,5‑diphenyl‑1H‑furo[2,3‑c]pyrazol‑4‑amine (5f)
White powder; m.p.=313–315 °C; IR (KBr, cm−1): 3430, 3065, 2918, 1594, 1531,
1
1492, 1440, 1405, 1326, 1223, 1102, 1052; H NMR (300 MHz, DMSO-d6):
δ=1.52 (s, 3H, CH3), 7.02–7.26 (m, 8H, Ar–H), 7.39 (d, 1H, J=9.6 Hz, Ar–H),
7.56–7.61 (m, 4H, Ar–H), 7.95 (br, 1H, NH); 13C NMR (75 MHz, DMSO-d6):
δ=15.13, 106.65, 113.05, 118.35, 121.18, 122.47, 124.77, 125.93, 127.08, 128.16,
128.48, 129.02, 129.42, 134.73, 143.44, 143.67, 150.83, 152.87, 161.31; MS m/z
(%): 446 (M+2)+ (100), 444 (M)+, 380, 365, 339, 313, 311, 283, 285, 260, 247,
231, 218, 204, 185, 158, 156, 128, 105, 92, 77; Anal. calcd. for C23H17BrN4O: C,
62.02; H, 3.82; N, 12.58. Found: C, 62.08; H, 3.75; N, 12.64.
2,2‑Bis(5‑hydroxy‑3‑methyl‑1H‑pyrazol‑4‑yl)‑1‑phenylethanone (6a)
Yellowish powder; m.p.=260–262 °C; IR (KBr, cm−1): 3371, 3023, 2896, 1691,
1600, 1529, 1446, 1364, 1291, 1241, 1172, 1076; 1H NMR (300 MHz, DMSO-d6):
δ=1.73 (s, 6H, 2×CH3), 3.11 (2×OH exchanged with water of DMSO-d6), 5.13 (s,
1H, methine-H), 7.15–7.25 (m, 3H, Ar–H), 7.56 (d, 2H, J=7.5 Hz, Ar–H), 10.55
(br, 2H, 2×NH); 13C NMR (75 MHz, DMSO-d6): δ=10.77, 38.08, 100.40, 128.56,
128.73, 132.70, 137.17, 138.93, 160.56, 197.35; MS m/z (%): 312 (M)+, 311, 310,
293, 281, 216, 207, 185, 175, 157, 128, 112, 105 (100), 98, 91, 77; Anal. calcd. for
C16H16N4O3: C, 61.53; H, 5.12; N, 17.94. Found: C, 61.59; H, 5.22; N, 18.01.
2,2‑Bis(5‑hydroxy‑3‑methyl‑1‑phenyl‑1H‑pyrazol‑4‑yl)‑1‑phenylethanone (6b)
Pink powder; m.p.=273–275 °C; IR (KBr, cm−1): 3417, 3062, 2907, 2865, 2782,
1679, 1621, 1566, 1498, 1406, 1368, 1312, 1204, 1136, 1010; 1H NMR (300 MHz,
DMSO-d6): δ=1.94 (s, 6H, 2×CH3), 5.24 (s, 1H, methine-H), 6.88 (t, 1H,
J=7.2 Hz, Ar–H), 7.08–7.35 (m, 11H, Ar–H), 7.81–7.86 (m, 3H, Ar–H), 10.91 (br,
2H, 2×OH); 13C NMR (75 MHz, DMSO-d6): δ=11.72, 32.09, 118.75, 125.07,
128.60, 129.21, 129.35, 133.89, 135.95, 136.28, 137.33, 148.06, 163.39, 207.86;
1 3

“On-water”one-pot four-component synthesis of novel…
MS m/z (%): 368, 292, 290, 261, 236, 213, 187 (100), 185, 173, 157, 141, 128, 115,
105, 91, 77; Anal. calcd. for C28H24N4O3: C, 72.41; H, 5.17; N, 12.06. Found: C,
72.33; H, 5.19; N, 12.11.
Acknowledgements The authors thank the Research Council of Payame Noor University and Islamic
Azad University, Qaemshahr Branch for fnancial support.
References
1. G. Varvounis, Adv. Heterocycl. Chem. 98, 143 (2009)
2. H.H. Fahmy, A.M. Srour, M.A. Esmail, M.A. Khater, R.A. Serrya, M.A. El-Manawaty, Res. Chem.
Intermed. 42, 6881 (2016)
3. S. Archana, R. Ranganathan, M. Dinesh, P. Arul, A. Ponnuswamy, P. Kalaiselvi, S. Chellammal, G.
Subramanian, Res. Chem. Intermed. 43, 2471 (2017)
4. B.J. Bradbury, M.J. Pucci, Curr. Opin. Pharmacol. 8, 574 (2008)
5. K.A. Kumar, M. Govindaraju, Int. J. Chem. Tech. Res. 8, 313 (2015)
6. S.G. Kucukguzel, S. Senkardes, Eur. J. Med. Chem. 97, 786 (2015)
7. F. Manetti, C. Brullo, M. Magnani, F. Mosci, B. Chelli, E. Crespan, S. Schenone, A. Naldini, O.
Bruno, M.L. Trincavelli, G. Maga, F. Carraro, C. Martini, F. Bondavalli, M. Botta, J. Med. Chem.
51, 1252 (2008)
8. N.K. Lokanath, K.A. Kumar, Res. Chem. Intermed. 44, 5635 (2018)
9. P.C. Tsai, I.J. Wang, Dyes Pigments 64, 259 (2005)
10. V. Kumar, R. Aggarwal, P. Tyagi, S. Singh, Eur. J. Med. Chem. 40, 922 (2005)
11. B. Yang, Y. Lu, C. Chen, J. Cui, M. Cai, Dyes Pigments 83, 144 (2009)
12. K.S. Gudmundsson, B.A. Johns, Z. Wang, E.M. Turner, S.H. Allen, G.A. Freeman, F. Lesleboyd,
C.D. Sexton, D.W. Sellseth, K.R. Moniri, K.L. Greeh, Bioorg. Med. Chem. 13, 5346 (2005)
13. S.H. Hwang, K.M. Wagner, C. Morisseau, J.Y. Liu, H. Dong, A.T. Wecksler, B.D. Hammock, J.
Med. Chem. 54, 3037 (2011)
14. G. Szabo, J. Fischer, A. Kis-Varga, K. Gyires, J. Med. Chem. 51, 142 (2008)
15. S. Chimichi, M. Boccalini, M.M. Hassan, G. Viola, F. Dall Ácqua, M. Curini, Tetrahedron 62, 90
(2006)
16. H.A. Abdel-Aziz, A.A.I. Mekawey, Eur. J. Med. Chem. 44, 4985 (2009)
17. K. Manna, Y.K. Agrawal, Bioorg. Med. Chem. Lett. 19, 2688 (2009)
18. A. Hall, A. Billinton, S.H. Brown, N.M. Clayton, A. Chowdhury, G.M.P. Giblin, P. Goldsmith, T.G.
Hayhow, D.N. Hurst, I.R. Kilford, A. Naylor, B. Passingham, L. Winyard, Bioorg. Med. Chem. Lett.
18, 3392 (2008)
19. L.C. Chou, L.J. Huang, J.S. Yang, F.Y. Lee, C.M. Teng, S.C. Kuo, Bioorg. Med. Chem. 15, 1732
(2007)
20. A. Yazdani-Elah-Abadi, R. Morekian, N. Simin, M. Lashkari, J. Chem. Res. 42, 219 (2018)
21. S. Bondock, W. Khalifa, A.A. Fadda, Eur. J. Med. Chem. 46, 2555 (2011)
22. G. Broggini, L. Garanti, G. Molteni, G. Zecchi, Tetrahedron Asymmetry 10, 487 (1999)
23. L. De Benassuti, L. Garanti, G. Molteni, Tetrahedron Asymmetry 15, 1127 (2004)
24. Y.M. Zhu, L.N. Qin, R. Liu, S.J. Ji, H. Katayama, Tetrahedron Lett. 48, 6262 (2007)
25. V.S. Tangeti, G.V. SivaPrasad, J. Panda, K.R. Varma, Synth. Commun. 46, 878 (2016)
26. Z. Zhang, J. Han, S. Zhu, Tetrahedron 67, 8496 (2011)
27. M.A. El-Borai, H.F. Rizk, M.R. Sadek, M.M. El-Keiy, Green Sustain. Chem. 6, 88 (2016)
28. H.A. Shindy, Color. Technol. 123, 298 (2007)
29. C.J. Li, L. Chen, Chem. Soc. Rev. 35, 68 (2006)
30. D.N. Kommi, D. Kumar, K. Seth, A.K. Chakraborti, Org. Lett. 15, 1158 (2013)
31. D.N. Kommi, D. Kumar, R. Bansal, R. Chebolu, A.K. Chakraborti, Green Chem. 14, 3329 (2012)
32. D.N. Kommi, D. Kumar, A.K. Chakraborti, Green Chem. 15, 756 (2013)
33. A. Chanda, V.V. Fokin, Chem. Rev. 109, 725 (2009)
34. R.N. Butler, A.G. Coyne, Chem. Rev. 110, 6302 (2010)
35. R. Breslow, Acc. Chem. Res. 24, 317 (1991)
1 3

F. Noruzian et al.
36. R. Breslow, K. Groves, M.U. Mayer, Pure Appl. Chem. 70, 1933 (1998)
37. S. Otto, J.B.F.N. Engberts, Pure Appl. Chem. 72, 1365 (2000)
38. S.S. Pawar, U. Phalgune, A. Kumar, J. Org. Chem. 64, 7055 (1999)
39. A. Dandia, V. Parewa, A.K. Jain, K.S. Rathore, Green Chem. 13, 2135 (2011)
40. A. Dandia, V. Parewa, S.L. Gupta, K.S. Rathore, J. Mol. Catal. A Chem. 373, 61 (2013)
41. A. Dandia, R. Sharma, A. Indora, V. Parewa, Chem. Select 3, 8285 (2018)
42. A. Dandia, S. Bansal, R. Sharma, V. Parewa, Chem. Select 3, 9785 (2018)
43. A. Dandia, S. Khan, R. Sharma, S. Parihar, V. Parewa, Chem. Select 2, 9684 (2017)
44. A. Dandia, V. Parewa, S. Kumari, S. Bansal, A. Sharma, Green Chem. 18, 2488 (2016)
45. A. Olyaei, Z. Shafe, M. Sadeghpour, Tetrahedron Lett. 59, 3567 (2018)
46. A. Olyaei, M. Saraei, R. Khoeiniha, Synlett 29, 1589 (2018)
47. A. Olyaei, M. Vaziri, R. Razeghi, Tetrahedron Lett. 54, 1963 (2013)
48. R. Khoeiniha, A. Olyaei, M. Saraei, Synth. Commun. 48, 155 (2018)
49. R. Khoeiniha, A. Olyaei, M. Saraei, J. Heterocycl. Chem. 54, 1746 (2017)
50. A. Olyaei, S. Javarsineh, M. Sadeghpour, Chem. Heterocycl. Compd. 54, 934 (2018)
51. A. Olyaei, M.S. Shahsavari, M. Sadeghpour, Res. Chem. Intermed. 44, 943 (2018)
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional afliations.
1 3