Using magnetized water as a solvent for a green, catalyst-free, and efficient protocol for the synthesis of pyrano[2,3-c]pyrazoles and pyrano[4′,3′:5,6]pyrazolo [2,3-d]pyrimidines

Article abstract of DOI:10.1007/s11164-016-2680-y

A facile, eco-friendly, and highly efficient one-pot four-component protocol is demonstrated for the synthesis of the pyrano[2,3-c]pyrazole and pyrano[4′,3′:5,6]pyrazolo [2,3-d]pyrimidine derivatives using magnetized water as a new green solvent. Simplici

Full text of DOI:10.1007/s11164-016-2680-y

Res Chem Intermed
DOI 10.1007/s11164-016-2680-y
Using magnetized water as a solvent for a green,
catalyst-free, and efficient protocol for the synthesis
of pyrano[2,3-c]pyrazoles and pyrano[40,30:5,6]pyrazolo
[2,3-d]pyrimidines
Mohammad Bakherad1 Ali Keivanloo1
•
•
Mostafa Gholizadeh2 Rahele Doosti1
Mohaddese Javanmardi1
•
•
Received: 6 June 2016 / Accepted: 26 July 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A facile, eco-friendly, and highly efficient one-pot four-component pro-
tocol is demonstrated for the synthesis of the pyrano[2,3-c]pyrazole and
pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidine derivatives using magnetized water as a
new green solvent. Simplicity, short reaction time, high yield, easy work-up, and
absence of hazardous organic solvents are the main advantages of this method.
Keywords Magnetized water Á Catalyst-free Á Pyrano[2,3-c]pyrazoles Á
Pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines
Introduction
Designing biologically active compounds is a challenging point of view in
medicinal chemistry [1], and pyranopyrazoles have a critical role as biologically-
ctive molecules [2]. Because of their biological importance, there has been a
substantial interest in designing synthetic methods for the synthesis of pyranopy-
razole derivatives in water [3–5]. On the other hand, pyranopyrimidine, which is a
prominent member of the pyrimidine family, has acquired considerable attention
because of its broad biological activities [6]. A more obvious effect is often noticed
when a number of heterocyclic moieties occur in a specific molecule, because it can
have the properties of all the moieties and improve the pharmacological activities.
Important advances have recently been made to synthesize novel polycyclic
heterocycles by combining unlike structurally-diverse motifs [7]. In this regard, we
expected that it would be significant to combine the fused heterocycles in a
&
Mostafa Gholizadeh
m.bakherad@yahoo.com
1
2
School of Chemistry, Shahrood University of Technology, Shahrood 3619995161, Iran
Department of Chemistry, Ferdowsi University of Mashhad, Mashhad 91779, Iran
123

M. Bakherad et al.
molecular hybrid framework with both the pyranopyrazole and pyranopyrimidine
moieties. Up to the present time, a few examples have been reported for the
synthesis of pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines. Heravi et al. [8] have
developed a four-component reaction of hydrazines, ethyl acetoacetate, aldehydes,
and barbituric acid in the presence of DABCO for the synthesis of
pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines in refluxing water. Zhang et al. [9]
have reported a highly efficient protocol for the synthesis of pyrano[40,30:5,6]pyra-
zolo [2,3-d]pyrimidines using meglumine as a biodegradable and reusable catalyst.
Also Khodabakhshi et al. [10] have investigated the synthesis of
pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines using nano-titanium dioxide.
Multi-component reactions (MCRs), which are one-pot reactions in which at
least three different reagents merge through covalent bonds, have acquired
significance in synthetic organic chemistry. MCRs permit the generation of a
number of bonds in a single operation, and provide notable benefits such as
operational simplicity, convergence, facile automation, extraction, reduction in the
number of work-ups, and purification processes, and thus minimize waste
generation, rendering the transformations green [11–13]. Thus, the design of noble
MCRs with green methods has attracted much attention, in particular, in the areas of
organic synthesis, drug discovery, and material science [14, 15].
Furthermore, MCRs performed in water offer more desirable environmental
protections, and thus are regarded as clean and green reactions. The importance of
green chemistry methods is continuously growing. Substitute processes aid to save
resources, and can lower the costs. Replacement of the conventional solvents for
water, which is available in large amounts and is safe for one’s health, is an
appealing fundamental approach along these lines [16]. Water is an interesting
solvent. Biological processes are carried out in this medium. Some organic reactions
are speeded up by water, while the others are inhibited in it. Hydrophobicity,
hydrogen bonding, acidity, polarity, and entropy all have significant roles to play in
the impact of water on the organic reactions mediated in its presence. The varying
behavior of these properties can make water an appealing candidate as a solvent or
co-solvent from an industrial viewpoint, even before its potential environmental
advantages are taken into account. The reactivity and stereo-selectivity of these
reactions conducted under aqueous conditions have been reported to increase [17].
However, most chemical reactions cannot be done in water, as a solvent, since they
need the presence of reagents, catalysts, or energy. Therefore, if we can change the
physical properties of water, its reactivity toward organic reagents will be altered.
The change in the properties of water under the action of an applied magnetic field
is just a typical case. Vermeiren [18] has patented that an applied magnetic field can
affect the properties of water. It has been found that water gives rise to many
phenomena when exposed to a magnetic field, even if the magnetic flux density is
not high and the treatment time is short [19]. Water can be magnetized in the
presence of an external magnetic field, and due to the magnetization many
properties of water, such as density, penetration, specific heat, refractive index,
electric dipole-moment, average cluster size in the bulk water, vaporization
enthalpy, surface tension and viscosity, change compared with non-magnetic water
[20–22].
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Using magnetized water as a solvent for a green, catalyst-…
Based on the literature surveys carried out on magnetized water during the last
few years, most researchers have been interested in the study of magnetic field
effects on the properties of water [23, 24], especially the hydrogen bond distribution
[25–27]. On the other hand, various researchers have studied the effects of
magnetized water on the morphology of precipitated calcium carbonate [28], TiO2-
based varistors [29], synthesis of manganese oxide nano-crystals [30], crystalliza-
tion, and salt precipitations [31]. However, there is no report on the use of
magnetized water in organic reactions. Considering the above subjects, herein for
the first time, we report a green and catalyst-free protocol for the synthesis of the
biologically active pyrano[2,3-c]pyrazole and pyrano[40,30:5,6]pyrazolo [2,3-
d]pyrimidine derivatives using magnetized water as a solvent (Scheme 1).
Experimental
Reagents and solvents were purchased from Merck, Fluka or Aldrich. Melting
points were determined using an electro-thermal C14500 apparatus. The reaction
progress and the purity of compounds were monitored using TLC analytical silica
gel plates (Merck 60 F250). All the known compounds were identified by
1
comparison of their melting points and H NMR data with those in the authentic
1
samples. The H NMR (300 MHz) and 13C NMR (75 MHz) spectroscopies were
run on a Bruker Avance DPX-250 FT-NMR spectrometer. The chemical shift values
were given as d values against tetramethylsilane as the internal standard, and the J
values were given in Hz. Microanalysis was performed on a Perkin-Elmer 240-B
microanalyzer.
Preparation of magnetized water
Magnetized water was prepared using a static magnetic system of 6000 G [32] field
strength with a flow rate of 500 mL s-1 at different magnetization times (Fig. 1).
O
Ar
NC
CN
CN
4
N
magnetized water/ 25 oC
N
O
3
O
O
6
NH2
H
NH2NH2
+
Ar
O
magnetized water/ 50 oC
1
NH
Ar
N
O
O
O
N
H
O
7
N
H
O
H
2
HN NH
O
5
Scheme 1 Four-component synthesis of pyrano[2,3-c]pyrazoles 6 and pyrano[40,30:5,6]pyrazolo [2,3-
d]pyrimidines 7 in magnetized water
123

M. Bakherad et al.
Fig. 1 Pilot for solvent
magnetizing apparatus
As shown in Fig. 1, a centrifugal pump was used to circulate water in the system.
Water was treated in the system for 10 min, and then 100 mL of this magnetized
water was used in the current work.
General procedure for synthesis of dihydropyrano[2,3-c]pyrazoles (6a–x)
To a 10-mL round-bottomed flask equipped with a magnetic stirrer bar and
containing magnetized water (4 mL, with magnetization time of 10 min), were
added ethyl acetoacetate (1.0 mmol), hydrazine (1.0 mmol), an aldehyde
(1.0 mmol), and malononitrile (1.0 mmol). The reaction mixture was stirred at
room temperature, and monitored by thin layer chromatography (TLC) technique.
After completion of the reaction, the precipitate thus formed was filtered and
purified by recrystallization from ethanol to afford the desired product (Table 5).
General procedure for synthesis of pyrano[40,30:5,6]pyrazolo [2,3-
d]pyrimidine derivatives (7a–t)
To a 10-mL round-bottomed flask equipped with a magnetic stirrer bar and
containing magnetized water (4 mL, with magnetization time of 10 min), were
added ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1.0 mmol), an aldehyde
(1.0 mmol), and barbituric acid (1.0 mmol). The reaction mixture was stirred at
50 °C, and the reaction progress was monitored by TLC using chloroform as the
eluent. After completion of the reaction, the precipitate formed was filtered and
purified by recrystallization from ethanol to afford the desired product (Table 7).
6-Amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (6a)
1H NMR (300 MHz, DMSO-d6) d 1.82 (s, 3H, CH3), 4.63 (s, 1H, CH), 6.90 (s, 2H,
NH2), 7.21–7.28 (m, 3H, Ph-H), 7.34–7.38 (m, 2H, Ph-H), 12.13 (s, 1H, NH); 13C
NMR (75 MHz, DMSO-d6) d 9.7, 36.1, 57.1, 97.6, 120.7, 126.7, 127.4, 128.4,
135.5, 144.4, 154.7, 160.8; Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N, 22.21;
found: C, 66.85; H, 4.90; N, 22.03.
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Using magnetized water as a solvent for a green, catalyst-…
6-Amino-3-methyl-4-(4-N,N-dimethylamino-phenyl)-1,4-dihydropyano[2,3-
c]pyrazole-5-carbonitrile (6f)
1H NMR (300 MHz, DMSO-d6) d 1.80 (s, 3H, CH3), 2.87 (s, 6H, NCH3), 4.46 (s,
1H, CH), 6.66 (d, 2H, J 8.4 Hz, Ar-H), 6.77 (s, 2H, NH2), 6.97 (d, 2H, J 8.4 Hz, Ar-
H), 12.05 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d 10.2, 35.8, 58.4, 98.6,
112.7, 121.4, 128.4, 132.5, 135.7, 135.9, 149.7, 155.2, 160.9; Anal. Calcd for
C16H17N5O: C, 65.07; H, 5.80; N, 23.71; found: C, 64.90; H 5.71; N 23.87.
6-Amino-3-methyl-4-(2-chlorophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (6h)
1H NMR (300 MHz, DMSO-d6) d 1.85 (s, 3H, CH3), 5.16 (s, 1H, CH), 7.03 (s, 2H,
NH2), 7.26–7.28 (m, 1H, Ar-H), 7.33–7.43 (m, 2H, Ar-H), 7.50 (dd, 1H, J 6.9,
0.9 Hz, Ar-H), 12.21 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d 9.8, 34.1, 56.3,
96.8, 120.3, 127.7, 128.5, 129.4, 130.6, 131.9, 135.3, 140.8, 154.9, 162.2; Anal.
Calcd for C14H11ClN4O: C, 58.65; H, 3.87; N, 19.54; found: C, 58.46; H, 3.79; N,
19.73.
6-Amino-3-methyl-4-(2,3,4-trimethoxy-phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (6p)
1H NMR (300 MHz, DMSO-d6) d 1.80 (s, 3H,CH3), 3.68 (s, 3H, OCH3), 3.73 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 4.74 (s, 1H, CH), 6.75–6.79 (m, 2H, Ar-H), 12.01
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d 9.9, 31.0, 56.1, 57.3, 60.6, 61.3,
98.4, 121.5, 123.8, 130.1, 135.5, 141.9, 151.5, 152.5, 155.4, 161.4; Anal. Calcd for
C17H18N4O4: C, 59.64; H, 5.30; N, 16.37; found: C, 59.84; H, 5.21; N, 16.54.
6-Amino-3-methyl-4-(4-hydroxy-,3,5-dimethoxy-phenyl)-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (5q)
1H NMR (300 MHz, DMSO-d6) d 1.85 (s, 3H, CH3), 3.81 (s, 6H, OCH3), 4.52 (s,
1H, CH), 6.42 (s, 2H, NH2), 6.84 (s, 2H, Ar-H), 8.28 (s, 1H, OH), 12.08 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6) d 9.8, 36.2, 55.9, 57.3, 97.6, 104.8, 120.8,
134.3, 134.4, 135.6, 147.7, 147.8, 154.6, 160.7; Anal. Calcd for C16H16N4O4: C,
58.53; H, 4.91; N, 17.06; found: C, 58.35; H, 4.80; N 17.25.
6-Amino-3-methyl-4-(furan-2-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(6r)
1H NMR (300 MHz, DMSO-d6) d 1.98 (s, 3H, CH3), 4.78 (s, 1H, CH), 6.18 (d, 1H,
J 3.0 Hz, furan-H), 6.37–6.39 (m, 1H, furan-H), 6.96 (s, 2H, NH2), 7.54 (t, 1H,
J 0.9 Hz, furan-H), 12.17 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d 10.0, 30.2,
54.4, 95.5, 106.1, 110.7, 121.0, 136.1, 136.3, 142.7, 155.2, 156.1, 161.9; Anal.
Calcd for C12H10N4O2: C, 59.50; H, 4.16; N, 23.13; found: C, 59.70; H, 4.24; N,
23.32.
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M. Bakherad et al.
6-Amino-3-methyl-4-(2-chloroquinolin-3-yl)-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (6u)
1H NMR (300 MHz, DMSO-d6) d 1.79 (s, 3H, CH3), 5.21 (s, 1H, CH), 7.11 (s, 2H,
NH2), 7.63–7.68 (m, 1H, quinolin-H), 7.79–7.84 (m, 1H, quinolin-H), 7.95 (d, 1H,
J 8.4 Hz, quinolin-H), 8.08 (d, 1H, J 8.4 Hz, quinolin-H), 8.40 (s, 1H, quinolin-H),
12.21 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d 10.1, 34.1, 56.3, 96.5, 120.9,
127.7, 127.9, 128.4, 131.3, 135.8, 136.0, 140.0, 146.6, 149.6, 155.5, 161.9; Anal.
Calcd for C17H12ClN5O: C, 60.45; H, 3.58; N, 20.73; found: C, 60.66; H, 3.69; N,
20.90.
4-(4-Hydroxyphenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-
d]pyrimidine-5,7 (1H,4H)-dione (7b)
1H NMR (300 MHz, DMSO-d6) d 2.26 (s, 3H, CH3), 5.30 (s, 1H, CH), 6.58 (d, 2H,
J 8.4 Hz, Ar-H), 6.87 (d, 2H, J 8.4 Hz, Ar-H), 9.94 (s, 2H, NH); Anal. Calcd for
C15H12N4O4: C, 57.69; H, 3.87; N, 17.94; found: C, 57.88; H, 3.96; N, 17.78.
4-(4-Methoxyphenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-
d]pyrimidine-5,7 (1H,4H)-dione (7d)
1H NMR (300 MHz, DMSO-d6) d 2.21 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 5.37 (s,
1H, CH), 6.77 (d, 2H, J 8.4 Hz, Ar-H), 6.95 (d, 2H, J 8.4 Hz, Ar-H), 10.15 (s, 2H,
NH); Anal. Calcd for C16H14N4O4 : C, 58.89; H, 4.32; N, 17.17; found: C, 59.05; H,
4.23; N, 17.33.
4-(4-N,N-dimethylaminophenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-
pyrano[2,3-d] pyrimidine-5,7(1H,4H)-dione (7f)
1H NMR (300 MHz, DMSO-d6) d 2.21 (s, 3H, CH3), 2.83 (s, 6H, NCH3), 5.35 (s,
1H, CH), 6.85 (d, 2H, J 8.1 Hz, Ar-H), 7.65 (d, 2H, J 8.1 Hz, Ar-H), 10.14 (s, 2H,
NH); 13C NMR (75 MHz, DMSO-d6) d 9.9, 30.1, 44.6, 95.5, 109.2, 111.4, 111.7,
127.8, 130.1, 139.7, 143.5, 154.7, 162.4; Anal. Calcd for C17H17N5O3: C, 60.17; H,
5.05; N, 20.64; found: C, 60.36; H, 5.14; N, 20.82.
4-(2,6-Dichlorophenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-
d]pyrimidine-5,7 (1H,4H)-dione (7j)
1H NMR (300 MHz, DMSO-d6) d 2.09 (s, 3H, CH3), 5.29 (s, 1H, CH), 7.45–7.47
(m, 1H, Ar-H), 7.49–7.53 (m, 2H, Ar-H), 10.23 (s, 2H, CH); 13C NMR (75 MHz,
DMSO-d6) d 11.1, 30.3, 88.8, 127.8, 129.0, 129.2, 131.3, 132.0, 134.1, 151.6, 152.4,
156.6, 160.8; Anal. Calcd for C15H10Cl2N4O3: C, 49.34; H, 2.76; N, 15.34; found:
C, 49.55; H, 2.63; N, 15.50.
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Using magnetized water as a solvent for a green, catalyst-…
4-(4-Bromophenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-
d]pyrimidine-5,7 (1H,4H)-dione (7k)
1H NMR (300 MHz, DMSO-d6) d 2.21 (s, 3H, CH3), 5.37 (s, 1H, CH), 7.0 (d, 2H,
J 8.4 Hz, Ar-H), 7.39 (d, 2H, J 8.4 Hz, Ar-H), 10.14 (s, 2H, NH); Anal. Calcd for
C15H11BrN4O3: C, 48.02; H, 2.96; N, 14.93; found: C, 48.19; H, 2.88; N, 15.09.
4-(4-Nitrophenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-
d]pyrimidine-5,7(1H,4H)-dione (7n)
1H NMR (300 MHz, DMSO-d6) d 2.24 (s, 3H, CH3), 5.48 (s, 1H, CH), 7.30 (d, 2H,
J 8.4 Hz, Ar-H), 8.10 (d, 2H, J 8.4 Hz, Ar-H): 11.50 (s, 2H, NH); Anal. Calcd for
C15H11N5O5: C, 52.79; H, 3.25; N, 20.52; found: C, 52.98; H, 3.33; N, 20.68.
1,4-Bis(3-methyl-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-d]pyrimidine-
5,7(1H,4H)-dione) benzene (7o)
1H NMR (300 MHz, DMSO-d6) d 2.31 (s, 3H, CH3), 5.42 (s, 1H, CH), 6.93 (s, 2H,
Ar-H), 11.51 (s, 2H, NH); 13C NMR (75 MHz, DMSO-d6) d 9.9, 30.8, 96.0, 105.4,
126.1, 127.1, 128.1, 139.0, 143.7, 145.6, 159.2, 161.1; Anal. Calcd for C24H18N8O6:
C, 56.03; H, 3.53; N, 21.78; found: C, 56.24; H, 3.63; N, 21.56.
4-(3,5-Dimethoxy-4-hydroxyphenyl)-3-methyl-6,8-dihydropyrazolo[40,30:5,6]-
pyrano[2,3-d] pyrimidine-5,7(1H,4H)-di one (7q)
1H NMR (300 MHz, DMSO-d6) d 2.22 (s, 3H, CH3), 3.82 (s, 6H, OCH3), 5.34 (s,
1H, CH), 6.32 (s, 2H, Ar-H), 7.16 (s, 1H, OH), 10.18 (s, 2H, NH); 13C NMR
(75 MHz, DMSO-d6) d 10.0, 55.9, 91.4, 105.7, 124.2, 132.7, 133.7, 143.3, 147.4,
148.0, 150.5, 156.2, 160.67; Anal. Calcd for C17H16N4O6: C, 54.84; H, 4.33; N,
15.05; found: C, 54.65; H, 4.25; N, 15.22.
3-Methyl-4-(furan-2-yl)-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-d]pyrimidine-
5,7(1H,4H)-dione (7r)
1H NMR (300 MHz, DMSO-d6) d 2.01 (s, 3H, CH3), 4.99 (s, 1H, CH), 7.21 (t, 1H,
J 7.2 Hz, furan-H), 7.37 (d, 1H, J 8.1 Hz, furan-H), 7.69–7.75 (m, 1H, furan-H),
11.21 (s, 2H, NH); 13C NMR (75 MHz, DMSO-d6) d 10.0, 27.7, 79.3, 102.2, 105.9,
110.1, 133.0, 138.8, 140.9, 155.7, 160.5, 163.8; Anal. Calcd for C13H10N4O4: C,
54.55; H, 3.52; N, 19.57; found: C, 54.73; H, 3.60; N, 19.75.
3-Methyl-4-(2-chloroquinoline-3-yl)-6,8-dihydropyrazolo[40,30:5,6]-pyrano[2,3-
d]pyrimidine-5,7(1H,4H)-dione (7t)
1H NMR (300 MHz, DMSO-d6) d 2.30 (s, 3H, CH3), 5.19 (s, 1H, CH), 7.49-7.58
(m, 1H, quinolin-H), 7.69–7.96 (m, 3H, quinolin-H), 8.04 (s, 1H, quinolin-H), 10.85
(s, 2H, NH); 13C NMR (75 MHz, DMSO-d6) d 9.9, 26.7, 105.5, 125.1, 126.3, 127.2,
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M. Bakherad et al.
130.9, 131.1, 138.6, 139.3, 144.7, 149.7, 153.6, 154.1, 159.0, 163.0; Anal. Calcd for
C18H12ClN5O3: C, 56.63; H, 3.17; N, 18.34; found: C, 56.80; H, 3.26; N, 18.16.
Results and discussion
Choosing a suitable reaction medium is very important in a successful organic
synthesis. In this work, the four-component reaction of ethyl acetoacetate
(1.0 mmol), hydrazine hydrate (1.0 mmol), malononitrile (1.0 mmol), and ben-
zaldehyde (1.0 mmol) was taken initially as a model reaction for the synthesis of
6-amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 6a at
25 °C in different solvents and in the absence of any catalyst (Table 1). The target
product was not formed in non-polar solvents (Table 1, entries 1 and 2), and even
methanol and ethanol, as polar protic solvents, were unable to produce the desired
product 6a in an acceptable yield (Table 1, entries 5 and 6). It was found that water
is a suitable solvent with respect to reaction yield (Table 1, entry 7). This effect can
be ascribed to the existence of powerful hydrogen bond interactions at the organic
phase-water interface, which stabilizes the reaction intermediate [33]. According to
the results obtained in the Table 1, we tried to optimize the reaction conditions
using magnetized water, which could help to reduce the reaction time and improve
the yield of the target product.
Magnetized water was prepared using a static magnetic system of 6000 G field
strength with a flow rate of 500 mL s-1 at different magnetization times (Fig. 1). As
shown in Fig. 1, the equipment was connected from one end to a liquid pump and
from the other end to the pipelines of a water reservoir. The water had to flow
through a static magnetic gap and come back to the water reservoir. Therefore, the
water could pass through the field for many times in a closed cycle.
Doubly distilled water, which was deionized by a Millipore Q-Plus 185 system,
was used in the experiments. After magnetizing water, the elementary constituents
of the resulting magnetized water were measured. The Ca, Si, Na, K, and nitrate
contents of magnetized water were 0.01, 0.005, 0.007, 0.002, and 1 mg L-1
,
respectively. Therefore, there were no metallic and magnetic elements present in the
magnetized water.
Meanwhile, we measured the changes in the values for pH, viscosity, refractive
index, dielectric constant, and electric conductivity of magnetized water relative to
Table 1 Synthesis of
compound 6a in different
solvents
Entry
Solvent
Yield (%)a
1
2
3
4
5
6
7
Benzene
Toluene
CH3CN
THF
–
–
Reaction conditions: hydrazine
hydrate 1 (1.0 mmol), ethyl
acetoacetate 3 (1 mmol),
5
5
benzaldehyde 2a (1.0 mmol),
malononitrile 4 (1.0 mmol),
solvent (3 mL), 25 °C for 4 h
MeOH
EtOH
10
10
30
H2O
a
Isolated yield
123

Using magnetized water as a solvent for a green, catalyst-…
those for normal water (Table 2). As shown in Table 2, the magnetic field applied
decreased the values for pH and viscosity of water, and increased the values for
refraction index, dielectric constant, and electric conductivity of it after magneti-
zation. Pang et al. [23] have reported the measurement of the electromagnetic
properties of magnetized water. They have found that the applied magnetic field
increases the values for refraction index, dielectric constant, and electric conduc-
tivity of water. According to the mechanism and theory of magnetization of water
proposed by Pang, the macroscopic properties of magnetized water are due to the
variations in the microscopic structure of water, for example, the distribution of
molecules and electrons, displacement and polarization of molecules and atoms, and
dipole moments of the transitional and vibrational states of molecules, under the
action of an applied magnetic field. In Pang’s theory, the increase in the dielectric
constant and electric conductivity of water under the influence of an external
magnetic field is due to the increase in the shift speed of the charged particles, for
example, hydronium and OH- ions from one water molecule of to another under the
action of an external magnetic field. Obviously, the greater the shift speed, the
stronger is the magnetic field, and the longer is the magnetization time. This directly
results in an increase in the electric conductivity of magnetized water.
Then, the above model reaction was carried out in different magnetized waters.
As indicated in Table 3 (entries 1–3), the magnetization time seems to play an
important role in achieving a high-yield product 6a. With increase in the water
magnetization time from 5 to 15 min, the pH value for the magnetized water
decreased, and the reaction product 6a was obtained in a shorter time and with more
yield. The best product yield was found to be in the water magnetized in 10 min,
and for a reaction time of 10 min (Table 3, entry 2). Increasing the reaction time did
not improve the product yield (Table 3, entry 4). Further optimization studies
revealed that the magnetized water volume did not have a pivotal effect on the
outcome of the reaction (Table 2, entries 5–8). Although satisfactory yields were
obtained with several magnetized water volumes tested, it turned out that the
reactions proceeded with higher yields in 4 mL of magnetized water (Table 3, entry
2). Also, the above four-component reaction was carried out in an aqueous solution
of pH 5.5 to establish the real efficacy of magnetized water. As shown in Table 3,
only a low product yield was obtained even after the reaction time was prolonged to
2 h (Table 3, entry 9).
Table 2 Comparison between some properties of doubly distilled water and those for magnetized water
Entry
Physicochemical properties
Doubly distilled water
Magnetized water
1
2
3
4
5
pH
6.9
5.5
Viscosity (l Pa s)
965.42 1.20
1.3310
995.63 4.40
1.3320
Refractive index
Electric dipole-moment (Debye)
Electric conductivity (S m-1)
1.85
0.1 9 10-6
[1.85
0.2 9 10-6
Conditions: Magnetization time (10 min), temperature (25 °C)
123

M. Bakherad et al.
Table 3 Optimization of the reaction conditions for the synthesis of pyrano[2,3-c]pyrazole 6a
Entry
Solvent (mL)
Magnetization
time (min)
pH
Reaction time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
Magnetized water (4)
Magnetized water (4)
Magnetized water (4)
Magnetized water (4)
Magnetized water (2)
Magnetized water (3)
Magnetized water (5)
Magnetized water (6)
Distilled water (4)
5
6.0
5.5
5.5
5.5
5.5
5.5
5.5
5.5
5.5
15
10
7
85
97
97
96
94
96
92
92
35
10
15
10
10
10
10
10
–
15
10
10
10
10
120
Reaction conditions: ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1.0 mmol), benzaldehyde
(1.0 mmol), and malononitrile (1.0 mmol), at 25 °C
a
Isolated yield
Some experiments have shown that when the magnetic exposure is stopped, the
magnetic effect of the magnetized water left behind does not disappear immediately,
and can be maintained for a very long period of time. This phenomenon is called the
memory effect of magnetized water [34, 35]. According to Pang and Deng [36] the
memory effect for magnetized water increases with increase in the applied magnetic
field. Coey and Cass [37] have reported that the memory of a magnetic treatment
can be maintained for up to 200 h. Thus we examined the memory effect, i.e., how
long the water magnetization effect remains after completion of the magnetic
exposure. We carried out the model reaction in magnetized water at different times
after completion of the magnetic exposure. After a magnetic exposure of 10 min,
magnetized water was left standing for different time periods, and the reaction
yields were tabulated in Table 4. As shown in Table 4, the product yield decreases
gradually with increasing time and becomes finally the same as that of pure water
after 8 h. We found that water kept its magnetization property for up to 4 h, and a
reaction performed in water magnetized for some time was as satisfactory as that
performed in a freshly-magnetized water, with high yield.
Table 4 Synthesis of
Entry
Time after completion of magnetic
exposure (h)
Yield (%)a
pyrano[2,3-c]pyrazole 6a at
different times after water
magnetization
1
2
3
4
5
0 (freshly-magnetized water)
97
97
90
70
40
2
4
6
8
123

Using magnetized water as a solvent for a green, catalyst-…
With these results in hand, we focused on the general applicability of the
developed one-pot protocol by screening a number of aldehydes with different
substituents (Table 5). A broad scope of different aldehydes was tested, and
pyrano[2,3-c]pyrazoles were obtained in good to excellent yields. The nature of the
functional group present on the aromatic ring of the aldehyde used exerted a slight
influence on the reaction time. Furthermore, the steric effects of the substituents at
the ortho positions of the aromatic aldehydes had no obvious impact on the reaction
yield (Table 5, entries 1–17). Notably, the heteroaryl aldehydes such as furan-2-
carbaldehyde, thiophene-2-carbaldehyde, pyridine-4-carbaldehyde, and 2-chloro
quinolone-3-carbaldehyde were also well-tolerated to afford their corresponding
products in high isolated yields (Table 5, entries 18–21). It is pertinent to note that
aliphatic aldehydes were not found to be appropriate starting materials in many
Table 5 Synthesis of pyrano[2,3-c]pyrazoles 6
Entry
Ar
Product
Time (min)
Yield (%)a
MP (°C) (lit.) [ref.]
1
Ph
6a
6b
6c
6d
6e
6f
10
12
12
15
15
20
20
20
15
20
10
15
10
10
15
10
20
10
15
10
10
20
25
20
98
87
93
95
90
87
92
88
90
88
90
86
87
95
94
90
88
94
97
96
92
86
90
93
240–242 (242–244) [38]
210–212 (208–210) [3]
197–199 (197–198) [39]
211–213 (210–212) [40]
248–250 (249–250) [38]
217–219 (219–220) [40]
232–234 (234–235) [38]
244–246 (245–246) [38]
227–229 (229–230) [38]
189–191 (188–190) [41]
246–248 (249–250) [40]
241–242 (243–244) [38]
230–232 (232–233) [40]
249–250 (248–249) [38]
238–240 (240–242) [42]
224–225 (223–225) [40]
210–212
2
2-OH-C6H4
3
4-Me-C6H4
4
4-MeO-C6H4
2-MeO-C6H4
4-Me2N-C6H4
4-Cl-C6H4
5
6
7
6g
6h
6i
8
2-Cl-C6H4
9
2,4-Cl2C6H3
2,6-Cl2C6H3
4-Br-C6H4
10
11
12
13
14
15b
16
17
18
19
20
21
22
23
24
6j
6k
6l
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
4-CHO-C6H4
2,3,4-(OMe)3-C6H2
3,5-(OMe)2-4-OH-C6H2
20-Furanyl
20-thiophenyl
40-Pyridinyl
2-Chloro quinolone-3-yl
CH3–
6m
6n
6o
6p
6q
6r
6s
228–230 (230–232) [40]
222–224 (224–226) [40]
215–217 (216–217) [40]
235–237
6t
6u
6v
6w
6x
155–157 (155–158) [43]
163–165 (166–168) [44]
184–186 (186–188) [45]
(CH3)2CH–
(CH3)2CHCH2–
Reaction conditions: Hydrazine hydrate (1.0 mmol), ethyl acetoacetate (1.0 mmol), malononitrile
(1.0 mmol), aldehyde (1.0 mmol), and magnetized water (4 mL), magnetization time (10 min) at 25 °C
a
Isolated yield
b
Disubstituted product
123

M. Bakherad et al.
reported procedures due to the formation of unwanted by-products via various side-
reactions such as the aldol condensation and Cannizzaro reaction. Fortunately, the
magnetized water-catalyzed transformations were not found to be limited to the
aliphatic aldehydes, and gave the pyranopyrazole products in high yields (Table 5,
entries 22–24).
The excellent efficiency of magnetized water, as a promoting medium, in the
synthesis of pyrano[2,3-c]pyrazoles motivated us to explore their efficacy for the
synthesis of pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidine derivatives. In order to
optimize the reaction conditions, the reaction of ethyl acetoacetate (1.0 mmol),
hydrazine hydrate (1.0 mmol), benzaldehyde (1.0 mmol), and barbituric acid
(1.0 mmol) was chosen as a model reaction in water and magnetized water in order
to establish the effectiveness of magnetized water at various temperatures, and the
results obtained are tabulated in Table 6 (Scheme 1). As shown in Table 6, only a
low yield of product 7a was formed in water and an aqueous solution with pH 5.5 at
50 °C (Table 6, entries 1 and 2). Then we tried to optimize the reaction conditions
with different magnetized water. As indicated in Table 6 (entries 3–5), with increase
in the time of water magnetization from 5 to 15 min, the reaction product 7a was
obtained in a shorter time and with more yield. The best product yield was found
to be in water magnetized in 10 min, and for a reaction time of 10 min at 50 °C
(Table 6, entry 4). It was found that at 25 °C, the reaction proceeded slowly, giving
a low product yield (Table 6, entry 6). The increase in the reaction temperature up
to 50 °C did not improve the yield (Table 6, entry 7). In addition, to demonstrate the
efficiency and practicability of this method in the synthesis of these types of
molecules, the model reaction was carried out in a scale of 50 mmol. As expected,
the desired product could be obtained with 97 % yield in 10 min (Table 6, entry 8).
Using the optimized reaction condition, several pyrano[40,30:5,6]pyrazolo [2,3-
d]pyrimidine derivatives were prepared (Table 7). As it is evident in this table, all
reactions proceeded efficiently, and the desired products were produced in high to
Table 6 The synthesis of pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidine 7a under various conditions
Entry
Solvent
Magnetization
time (min)
pH
Temp.
(°C)
Reaction time
(min)
Yield
(%)a
1
2
3
4
5
6
7
8b
Distilled water
–
6.9
5.5
6.0
5.5
5.5
5.5
5.5
5.5
50
50
50
50
50
25
70
50
120
120
20
25
30
84
96
96
57
96
97
Distilled water
–
Magnetized water
Magnetized water
Magnetized water
Magnetized water
Magnetized water
Magnetized water
5
10
15
10
10
10
10
10
40
10
10
Reaction conditions: Ethyl acetoacetate (1.0 mmol), hydrazine hydrate (1.0 mmol), benzaldehyde
(1.0 mmol), barbituric acid (1.0 mmol), and solvent (5 ml)
a
Isolated yield
b
50 mmol scale
123

Using magnetized water as a solvent for a green, catalyst-…
Table 7 Synthesis of pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines 7
Entry
Ar
Product
Time (min)
Yield (%)a
MP (°C) (lit.) [ref.]
1
Ph
7a
7b
7c
7d
7e
7f
5
5
98
92
90
92
97
87
94
90
94
92
88
92
94
97
92
85
86
92
88
93
217–219 (218–220) [9]
264–266 (263–265) [10]
201–203 (200–201) [9]
226–228 (228–230) [10]
231–233 (230–231) [9]
258–260 (260–262) [10]
220–222 (222–223) [9]
224–226 (223–225) [9]
234–236 (233–234) [9]
194–196
2
4-OH-C6H4
3
4-Me-C6H4
10
5
4
4-MeO-C6H4
2-MeO-C6H4
4-Me2N-C6H4
4-Cl-C6H4
5
10
12
5
6
7
7g
7h
7i
8
2-Cl-C6H4
10
10
12
10
8
9
2,4-Cl2C6H3
2,6-Cl2C6H3
4-Br-C6H4
10
11
12
13
14
15b
16
17
18
19
20
7j
7k
7l
209–211 (211–212) [9]
208–210 (208–209) [9]
264–266 (266–267) [9]
233–235 (233–234) [9]
165–167
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
4-CHO-C6H4
2,3,4-(OMe)3-C6H2
3,5-(OMe)2-4-OH-C6H2
20-Furanyl
7m
7n
7o
7p
7q
7r
7s
5
5
17
15
20
15
15
5
195–197 (193–194) [9]
240–242
173–175 (176–177) [9]
246–248 (247–248) [9]
271-273
20-Pyridinyl
2-Chloro quinolone-3yl
7t
Reaction conditions: Hydrazine hydrate (1.0 mmol), ethylacetoacetate (1.0 mmol), aldehyde (1.0 mmol),
barbituric acid (1.0 mmol), and magnetized water (5 mL), magnetization time (10 min), at 50 °C
a
Isolated yield
b
Disubstituted product
excellent yields in relatively short reaction times without formation of any by-
product. The reactions proceeded rapidly for aromatic aldehydes with the electron-
withdrawing or electron-donating groups at different positions of the ring (Table 7,
entries 1–17), and heteroaryl aldehydes (Table 7, entries 18–20), and the desired
products were isolated in excellent yields without any side product formation in
short reaction times.
Interestingly, all the starting materials were soluble in magnetized water so that
at the beginning of the reaction, a solution that looked nearly transparent was
observed. All the products obtained were found to be insoluble in magnetized water,
and with the reaction progress, they sedimented slowly in the reaction mixture
(Fig. 2).
A comparative study of the reaction conditions for the synthesis of pyrano[2,3-
c]pyrazoles (Table 8, entries 1–7) and pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines
(Table 8, entries 8–11) using the methods given in Table 8 and reported in the
present article demonstrate that the present protocol is indeed superior to several of
the other protocols. As shown in Table 8, most of the listed methodologies suffer
123

M. Bakherad et al.
Fig. 2 Progress of the reaction between ethyl acetoacetate, hydrazine hydrate, 4-nitrobenzaldehyde, and
barbituric acid in magnetized water without any catalysts (a beginning of the reaction, b after 10 min of
reaction at 50 °C, c the end of the reaction)
Table 8 Comparison of reaction conditions of magnetized water with the most recent reported catalyst
for the synthesis of pyrano[2,3-c]pyrazoles and pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines
Entry Catalyst (mol%)
Product Conditions
Time Yield
(min) (%) [ref.]
1
2
b-Cyclodextrin (10)
6a
6a
H2O/80 °C
H2O/90 °C
15
24
92 [3]
92 [4]
Cetyltrimethyl ammonium chloride
(30)
3
4
5
6
7
Cocamidopropyl betaine (0.02)
Imidazole (50)
6a
6a
6a
6a
6a
H2O/60 °C
H2O/80 °C
H2O/rt
4
20
15
5
90 [43]
89 [46]
30 [38]
94 [47]
97
Meglumine (10)
Piperidine (5)
H2O/rt
Present work (no catalyst)
Magnetized water/
25 °C
H2O/reflux
7
8
DABCO (20)
7a
7a
7a
7a
20
15
60
5
99 [8]
95 [9]
55 [10]
96
9
Meglimine (10)
H2O/rt
10
11
Nano-titanium dioxide (10)
Present work (no catalyst)
H2O/reflux
Magnetized water/
50 °C
from some limitations such as the prolonged reaction times, elevated temperatures,
and use of catalysts.
The plausible mechanism for the synthesis of pyrano[2,3-c]pyrazole 6a from
ethyl acetoacetate, hydrazine, benzaldehyde, and malononitrile in magnetized water
is shown in Scheme 2.
Pyrazolone I was formed by the condensation of ethyl acetoacetate and
hydrazine, and was converted to its corresponding enolate form II in the presence of
magnetized water. Magnetized water plays a major role in its promoting activity for
the formation of phenylidenemalononitrile III, which is readily prepared in situ by
123

Using magnetized water as a solvent for a green, catalyst-…
H
H
O
H
H
O
O
O
H
H
N
H
H
N
OEt
O
N
O
+
N
H2N NH2
H
I
H
II
O
H
H
O
H
H
O
O
H
H
O
H
H
H
H
H
H
O
O
H
H
CN
H
O
HO
+
CN
H
NC
CN
Ph
H
-H2O
Ph
CN
Ph
CN
4
III
H
O
H
H
O
H
Ph
Ph
O
Ph
H
H
CN
CN
NH
CN
N
N
N
N
C
N
N
O
NH2
N
H
O
H
H
O
6a
O
H
H
H
H
Scheme 2 Plausible mechanism for synthesis of pyrano[2,3 c]pyrazole 6a
the Knoevenagel condensation of benzaldehyde 2a with the highly active CH acidic
malononitrile 4. Finally, the Michael-type addition of 3-methyl-1H-pyrazol-5(4H)-
one II to phenylidenemalononitrile III followed by cyclization and tautomerization
yielded pyrano[2,3-c]pyrazole 6a.
Conclusion
In conclusion, we reported a highly efficient, catalyst-free, and green method for the
one-pot
four-component
synthesis
of
pyrano[2,3-c]pyrazole
and
pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidine derivatives using magnetized water as
an inexpensive new solvent. The merits for the presented methodology are its
efficiency, generality, green solvent, wide scope of substrates, high yield, short
reaction time, cleaner reaction profile, and simple work-up procedure, which make
it a useful and attractive process for the synthesis of pyranopyrazoles and
pyrano[40,30:5,6]pyrazolo [2,3-d]pyrimidines. We would like to state that this
method involves an environmentally-friendly procedure, and that it is the first
123

M. Bakherad et al.
reported procedure for the organic synthesis in magnetized water. Moreover, the
presented method can be used in a large scale synthesis.
Acknowledgments We gratefully acknowledge the financial support of the Research Council of the
Shahrood University of Technology.
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Using magnetized water as a solvent for a green, catalyst-…
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