Mild preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives with magnetic Fe3O4 nanoparticles coated by (3-aminopropyl)-triethoxysilane as catalyst under ambient and solvent-free conditions

Article abstract of DOI:10.1007/s11164-012-0969-z

An efficient, one-pot quantitative procedure for preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives from four-component condensation reaction of hydrazine monohydrate, phthalic anhydride, malononitrile or ethyl cyanoacetate, and aromatic aldehydes in the presence of magnetic Fe₃O₄ nanoparticles coated by (3-aminopropyl)-triethoxysilane as catalyst under mild, ambient, and solvent-free conditions is described. Simple procedure, high yield, short reaction time, and environmentally benign method are advantages of this protocol. The magnetic Fe₃O₄ nanoparticles coated by (3-aminopropyl)-triethoxysilane can be recovered and reused several times without loss of activity.

Full text of DOI:10.1007/s11164-012-0969-z

Res Chem Intermed
DOI 10.1007/s11164-012-0969-z
Mild preparation of 1H-pyrazolo[1,2-b]phthalazine-
5,10-dione derivatives with magnetic Fe3O4
nanoparticles coated by (3-aminopropyl)-
triethoxysilane as catalyst under ambient
and solvent-free conditions
•
Hamid Reza Shaterian Majid Mohammadnia
Received: 29 October 2012 / Accepted: 6 December 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract An efficient, one-pot quantitative procedure for preparation of 1H-pyr-
azolo[1,2-b]phthalazine-5,10-dione derivatives from four-component condensation
reaction of hydrazine monohydrate, phthalic anhydride, malononitrile or ethyl
cyanoacetate, and aromatic aldehydes in the presence of magnetic Fe3O4 nano-
particles coated by (3-aminopropyl)-triethoxysilane as catalyst under mild, ambient,
and solvent-free conditions is described. Simple procedure, high yield, short reac-
tion time, and environmentally benign method are advantages of this protocol. The
magnetic Fe3O4 nanoparticles coated by (3-aminopropyl)-triethoxysilane can be
recovered and reused several times without loss of activity.
Keywords Magnetic properties Á Four-component reaction Á Ambient conditions Á
Solvent-free Á Heterogeneous catalyst
Introduction
Multicomponent reactions (MCRs) have proven to be a valuable asset in organic
and medicinal chemistry [1–7]. Such protocols can be used for drug design and drug
discovery because of their simplicity, efficiency, and high selectivity [8, 9]. MCRs
can reduce the number of steps and present advantages such as low energy
consumption and little to no waste production, leading to desired environmentally
friendly processes. Synthesis of bioactive and complex molecules should be facile,
fast, and efficient with minimal workup in this methodology [6, 10].
Heterocycles containing the pyrazole ring are important targets in synthetic and
medicinal chemistry because this fragment is a key moiety in numerous biologically
H. R. Shaterian (&) Á M. Mohammadnia
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan,
PO Box 98135-674, Zahedan, Iran
e-mail: hrshaterian@chem.usb.ac.ir
123

H. R. Shaterian, M. Mohammadnia
active pharmacological compounds [11–14] and drug molecules such as celecoxib
and pyrazofurine [15]. Pyrazolo[1,2-b]phthalazine-dione derivatives have been
reported to have anti-inflammatory, analgesic, antihypoxic, anticonvulsant, cardio-
tonic, vasorelaxant, antipyretic, antihyperglycemic, antibacterial, and antiviral
activities [16–18].
In continuation of our research on multicomponent reactions [19–21], herein we
describe the preparation of functionalized 1H-pyrazolo[1,2-b]phthalazine-5,10-
dione derivatives from four-component condensation reaction of hydrazine
monohydrate, phthalic anhydride, malononitrile or ethyl cyanoacetate, and aromatic
aldehydes in the presence of magnetic Fe3O4 nanoparticles coated by (3-
aminopropyl)-triethoxysilane (APTES-MNPs) as catalyst under ambient and
solvent-free conditions (Scheme 1).
Surface-functionalized iron oxide magnetic nanoparticles (MNPs) are a kind of
novel functional material which has been widely used in biotechnology and
catalysis. The presence of many hydroxyl groups on the surface of the MNPs leads
to reaction with 3-aminopropyltriethyloxysilane and formation of Si–O bonds which
support terminal –NH2 functional groups on the shell of the Fe3O4 core [22]. Such
surface modification provides Fe3O4 nanoparticles coated by (3-aminopropyl)-
triethoxysilane with basic character as catalyst. Due to the high magnetization of the
Fe3O4 core in the catalyst, it can be satisfactorily recovered by a simple external
magnet and could then be recycled and reused, which is important for green organic
synthesis. The Brønsted basic (–NH2) functionalized Fe3O4 core plays a crucial
catalytic role in the described transformation. APTES-MNPs core–shell nanopar-
ticles can be readily harvested upon applying an external magnetic field, providing
this protocol with an easy and simple workup.
Z
O
CHO
O
CN
X
N
N
APTES-MNPs (Catalyst)
X
H C
+
NH2NH2.H2O +
O
2
+
Solvent-free
Room Temperature
Z
NH2
O
O
(1)
(2)
(3)
(4)
(5)
-CN
Z = H, Br, Cl, F, CF3, CH3, OCH3, NO2
X
-CO2Et
APTES-MNPs
=
Scheme 1 Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
123

Preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Experimental
Chemicals and materials
All reagents were purchased from Merck and Aldrich and used without further
purification. APTES-MNPs was prepared according to the literature [22]. All yields
refer to isolated products after purification. Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker Avance DPX 300 MHz instrument. The spectra
were measured in dimethyl sulfoxide (DMSO)-d6 relative to tetramethylsilane
(TMS, 0 ppm). Infrared (IR) spectra were recorded on a JASCO FT–IR 460 plus
spectrophotometer. Melting points were determined in open capillaries with a
BUCHI 510 melting point apparatus. Thin-layer chromatography (TLC) was
performed on silica-gel Poly Gram SIL G/UV 254 plates.
General procedure for synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones
under solvent-free and ambient conditions
Hydrazine monohydrate (10 mmol) and phthalic anhydride (10 mmol) were mixed
at 100 °C until a white solid phthalhydrazide was formed (10 min). Then,
arylaldehydes (10 mmol), malononitrile or ethyl cyanoacetate (10 mmol), and
APTES-MNPs (10 mol%) as catalyst were stirred under ambient and solvent-free
conditions for the specific time. After completion of the reaction, the mixture was
diluted with dichloromethane and the catalyst was separated by an external magnet
to check for reusability. The solution containing the product was evaporated to give
a yellow solid. The solid was recrystallized with ethanol to give a pure yellow solid.
All of the desired product(s) were characterized by comparison of their physical
data with those of known compounds.
Spectroscopic data of new products are given below
3-Amino-1-(2,6-dichlorophenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phtha-
lazine-2-carbonitrile (5n): yellow powder; m.p. = 268–270 °C IR (KBr):
1
mmax = 3,398, 3,304, 2,200, 1,683, 1,595 cm-1; H NMR (300 MHz, DMSO-d6):
d = 6.89 (1H, s, CH), 7.09–7.11 (3H, m, Ar), 7.42–8.26 (6H, m, Ar and NH2) ppm;
13C NMR (75 MHz, DMSO-d6): d = 61.2, 62.6, 116.5, 122.4, 126.7, 127.5, 128.1,
128.2, 129.5, 129.8, 131.2, 132.7, 133.9, 135.0, 141.6, 151.3, 153.2, 156.7 ppm; MS
(EI, 70 eV) m/z (%) = 384 (M?, 17), 367 (18), 239 (100), 240 (74), 130 (14), 104
(25), 76 (19); Anal. Calcd. for C18H10Cl2N4O2: C, 56.12; H, 2.62; N, 14.54 %.
Found C, 56.13; H, 2.58; N, 14.56 %.
3-Amino-1-(2,4-dichlorophenyl)-5,10-dioxo-5,10-dihydro-1Hpyrazolo[1,2-b]phtha-
lazine-2-carbonitrile (5o): yellow powder; m.p. = 228–230 °C; IR (KBr):
1
mmax = 3,411, 3,374, 2,204, 1,675, 1,602 cm-1; H NMR (300 MHz, DMSO-d6):
d = 6.44 (1H, s, CH), 7.41–8.88 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 55.8, 59.2, 60.0, 115.5, 120.5, 126.6, 127.3, 128.0, 128.2, 128.8,
129.1, 132.2, 133.5, 133.8, 134.7, 151.2, 153.5, 156.6 ppm; MS (EI, 70 eV)
m/z (%) = 384 (M?, 16), 367 (16), 349 (12), 239 (100), 162 (24), 104 (27), 76 (16);
123

H. R. Shaterian, M. Mohammadnia
Anal. Calcd. for C18H10Cl2N4O2: C, 56.12; H, 2.62; N, 14.54 %. Found C, 56.17; H,
2.58; N, 14.50 %.
3-Amino-1-(2,3-dichlorophenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phtha-
lazine-2-carbonitrile (5p): yellow powder; m.p. = 265–268 °C; IR (KBr):
1
mmax = 3,415, 3,372, 2,211, 1,686, 1,660 cm-1; H NMR (300 MHz, DMSO-d6):
d = 6.52 (1H, s, CH), 7.35–8.27 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 61.3, 62.7, 116.5, 122.3, 126.7, 127.3, 128.0, 128.2, 129.5, 129.9,
131.1, 131.7, 133.9, 135.0, 141.7, 151.3, 153.2, 156.6 ppm; MS (EI, 70 eV)
m/z (%) = 384 (M?, 17), 349 (12), 240 (80), 239 (100), 162 (0), 104 (31), 76 (21);
Anal. Calcd. for C18H10Cl2N4O2: C, 56.12; H, 2.62; N, 14.54 %. Found C, 56.17; H,
2.59; N, 14.52 %.
3-Amino-1-(2-methoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phtha-
lazine-2-carbonitrile (5q): yellow powder; m.p. = 248–251 °C IR (KBr):
1
mmax = 3,383, 3,255, 2,201, 1,681, 1,560 cm-1; H NMR (300 MHz, DMSO-d6):
d = 3.73 (3H, s, OCH3), 6.34 (1H, s, CH), 6.90 (1H, t, J = 7.18 Hz), 7.03 (1H, d,
J = 7.91 Hz, Ar), 7.29 (2H, t, J = 7.72 Hz, Ar), 7.97–8.27 (6H, m, Ar) ppm; 13C
NMR (75 MHz, DMSO-d6) d = 55.8, 58.9, 60.6, 111.6, 115.9, 120.6, 125.8, 126.6,
127.2, 127.3, 128.5,128.6, 129.3, 133.7, 134.6, 150.9, 153.2, 155.5, 155.6 ppm; MS
(EI, 70 eV) m/z (%) = 346 (M?, 20), 329 (72), 315 (13), 239 (100), 240 (16), 162
(9), 104 (13); Anal. Calcd. for C19H14N4O3: C, 65.89; H, 4.07; N, 16.18 %. Found
C, 65.87; H, 4.11; N, 16.21 %.
3-Amino-1-(3-methoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phtha-
lazine-2-carbonitrile (5r): yellow powder; m.p. = 258–260 °C; IR (KBr):
1
mmax = 3,422, 3,362, 2,192, 1,680, 1,654 cm-1; H NMR (300 MHz, DMSO-d6):
d = 3.62 (3H, s, CH3), 6.08 (1H, s, CH), 6.87–7.23 (4H, m, Ar), 7.94–8.36 (6H, m,
Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-d6): d = 61.3, 62.7, 116.5, 122.3,
126.5, 127.1, 127.7, 129.0, 129.5, 129.9, 131.1, 131.7, 134.2, 135.0, 141.7, 151.2,
153.5, 154.2, 157.2; MS (EI, 70 eV) m/z (%) = 346 (M?, 70), 329 (56), 240 (83),
239 (100), 184 (19), 104 (17); Anal. Calcd. for C19H14N4O3: C, 65.89; H, 4.07; N,
16.18 %. Found C, 65.84; H, 4.11; N, 16.14 %.
3-Amino-1-(2,4,6-trimethoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile (5s): yellow powder: m.p. = 257–260 °C IR (KBr):
1
mmax = 3,416, 3,328, 2,190, 1,635, 1,575 cm-1; H NMR (300 MHz, DMSO-d6):
d = 3.65 (3H, s, OCH3), 3.74 (6H, s, OCH3), 6.05 (1H, s, CH), 6.76 (2H, s, Ar),
7.97 (2H, s, NH2), 8.05 (3H, s, Ar), 8.25 (1H, s, Ar) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 56.0, 59.9, 61.2, 63.3, 104.2, 110.6, 116.1, 120.4, 125.6, 126.6,
127.2, 128.7, 128.9, 133.6, 134.0, 134.5, 137.2, 150.5, 152.9, 153.8, 156.7 ppm; MS
(EI, 70 eV) m/z (%) = 406 (M?, 28), 389 (32), 244 (50), 239 (100), 229 (32), 162
(18), 104 (14); Anal. Calcd. for C21H18N4O5: C, 62.06; H, 4.46; N, 13.79 %. Found
C, 62.02; H, 4.42; N, 13.75 %.
3-Amino-1-(2,5-dimethoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]-
phthalazine-2-carbonitrile (5t): yellow powder; m.p. = 257–260 °C IR (KBr):
1
mmax = 3,420, 3,348, 2,180, 1,681, 1,595 cm-1; H NMR (300 MHz, DMSO-d6):
d = 3.66 (3H, s, OCH3), 3.67 (3H, s, OCH3), 6.29 (1H, s, CH), 6.82–6.98 (3H, m,
Ar), 7.95–8.28 (6H, m, Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 55.4, 56.3, 59.0, 60.4, 112.9, 113.3, 113.8, 116.0, 126.6, 127.0, 127.2, 128.5,
123

Preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
128.7, 133.6, 134.6, 150.6, 151.0, 153.3, 153.4, 156.6 ppm; MS (EI, 70 eV)
m/z (%) = 376 (M?, 23), 359 (43), 345 (25), 329 (24), 239 (100), 214 (29), 199
(39); Anal. Calcd. for C20H16N4O4: C, 63.82; H, 4.28; N, 14.89 %. Found C, 63.78;
H, 4.24; N, 14.84 %.
3-Amino-1-(2-methylphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]phtha-
lazine-2-carbonitrile (5u): yellow powder; m.p. = 248–250 °C, IR (KBr):
1
mmax = 3,366, 3,302, 2,210, 1,661, 1,601 cm-1; H NMR (300 MHz, DMSO-d6):
d = 2.45 (3H, s, CH3), 6.30 (1H, s, CH), 7.25–7.30 (4H, m, Ar), 7.95–8.24 (6H, m,
Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-d6): d = 18.65, 61.0, 62.4, 122.0,
126.7 127.1, 127.7, 128.0, 128.2, 128.5, 128.7, 130.4, 133.7, 134.7, 135.2,
136.5,153.5, 154.2, 156.6 ppm; MS (EI, 70 eV) m/z (%) = 330 (M?, 70), 315 (14),
240 (56), 239 (100), 184 (10), 169 (8), 104 (10); Anal. Calcd. for C19H14N4O2: C,
69.08; H, 4.27; N, 16.96 %. Found C, 69.04; H, 4.31; N, 16.92 %.
3-Amino-1-(4-trifluoromethylphenyl)-5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile (5v): yellow powder; m.p. = 268–270 °C, IR (KBr):
1
mmax = 3,359, 3,284, 2,195, 1,659, 1,594 cm-1; H NMR (300 MHz, DMSO-d6):
d = 6.24 (1H, s, CH), 7.7 (4H, s, Ar), 7.97–8.26 (6H, m, Ar and NH2) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 55.8, 60.3, 60.6, 111.6, 115.8, 120.6, 125.4, 126.6,
127.2, 127.6, 128.2, 128.4, 128.9, 133.8, 134.6, 143.1, 150.8, 153.7, 156.6 ppm; MS
(EI, 70 eV) m/z (%) = 384 (M?, 25), 367 (34), 240 (70), 239 (100), 104 (30), 76
(19), 57 (2); Anal. Calcd. for C19H11F3N4O2: C, 59.38; H, 2.88; N, 14.58 %. Found
C, 59.35; H, 2.84; N, 14.52 %.
Ethyl
o[1,2-b]phthalazine-2-carboxylate (5w): yellow powder; m.p. = 260–262 °C, IR
(KBr): mmax = 3,446, 3,332, 1,707, 1,659, 1,645 cm-1 1H NMR (300 MHz,
3-amino-5,10-dihydro-1-(2,6-dichlorophenyl)-5,10-dioxo-1H-pyrazol-
;
DMSO-d6): d = 0.96 (3H, t, J = 6.7 Hz, CH3), 3.91 (2H, q, J = 6.5 Hz, OCH2),
6.52 (1H, s CH), 7.22–8.27 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 13.9, 55.8, 58.6, 63.3, 80.2, 124.2, 126.7, 127.2, 127.3, 128.0, 128.1, 128.8,
129.5, 131.3, 133.8, 134.7, 150.3, 153.1, 156.7, 163.8 ppm; MS (EI, 70 eV)
m/z (%) = 431 (M?, 8), 286 (100), 258 (45), 240 (93), 239 (60), 173 (12), 104 (15);
Anal. Calcd. For C20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72 %. Found C, 55.60; H,
3.52; N, 9.74 %.
Ethyl
o[1,2-b]phthalazine-2-carboxylate (5x): yellow powder; m.p. = 228–230 °C, IR
(KBr): mmax = 3,452, 3,340, 1,700, 1,660, 1,620 cm-1 1H NMR (300 MHz,
3-amino-5,10-dihydro-1-(2,4-dichlorophenyl)-5,10-dioxo-1H-pyrazol-
;
DMSO-d6): d = 0.95 (3H, t, J = 6.7 Hz, CH3), 3.91 (2H, q, J = 6.6 Hz, OCH2),
6.42 (1H, s, CH), 7.62–8.28 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 14.0, 58.7, 62.7, 81.0, 120.1, 124.8, 126.6, 127.2, 127.3, 128.4, 128.7,
128.8, 132.6, 133.7, 134.7, 143.2, 148.9, 153.02, 156.7, 163.8 ppm; MS (EI, 70 eV)
m/z (%) = 431 (M?, 11), 286 (100), 258 (44), 241 (14), 240 (91), 173 (11), 104
(14); Anal. Calcd. for C20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72 %. Found C,
55.60; H, 3.52; N, 9.64 %.
Ethyl
o[1,2-b]phthalazine-2-carboxylate (5y): yellow powder; m.p. = 260–263 °C IR
(KBr): mmax = 3,446, 3,333, 1,707, 1,647, 1,629 cm-1 1H NMR (300 MHz,
3-amino-5,10-dihydro-1-(2,3-dichlorophenyl)-5,10-dioxo-1H-pyrazol-
;
DMSO-d6): d = 0.95 (3H, t, J = 6.8 Hz, CH3), 3.90 (2H, q, J = 6.7 Hz, OCH2),
123

H. R. Shaterian, M. Mohammadnia
6.51 (1H, s CH), 7.21–8.26 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 13.9, 55.6, 58.6, 63.4, 80.2, 124.2, 126.6, 127.2, 128.0, 128.1, 128.4, 128.7,
129.5, 131.3, 133.7, 134.7, 150.2, 153.0, 156.7, 163.8 ppm; MS (EI, 70 eV)
m/z (%) = 431 (M?, 7), 286 (100), 258 (39), 240 (94), 239 (73), 173 (11), 104 (15);
Anal. Calcd. for C20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72 %. Found C, 55.63; H,
3.52; N, 9.74 %.
Ethyl 3-amino-5,10-dihydro-1-(2-methoxyphenyl)-5,10-dioxo-1H-pyrazolo[1,2-
b]phthalazine-2-carboxylate (5z): yellow powder; m.p. = 205–208 °C IR (KBr):
1
mmax = 3,444, 3,329, 1,700, 1,660, 1,622 cm-1; H NMR (300 MHz, DMSO-d6):
d = 0.98 (3H, t, J = 8.9 Hz, CH3), 3.62 (3H, s, CH3), 3.90 (2H, q, J = 9.0 Hz,
OCH2), 6.27(1H, s, CH), 7.16–8.28 (10H, m, Ar and NH2) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 14.0, 55.7, 58.4, 62.4, 80.7, 111.4, 120.0, 126.6, 126.8,
127.2, 128.4, 128.6, 128.8, 131.1, 133.5, 134.6, 150.2, 152.6, 156.5, 156.9,
164.1 ppm; MS (EI, 70 eV) m/z (%) = 393 (M?, 20), 376 (33), 320 (34), 286 (100),
258 (33), 240 (79), 104 (17); Anal. Calcd. for C21H19N3O5: C, 64.12; H, 4.87; N,
10.68 %. Found C, 64.18; H, 4.84; N, 10.70 %.
Ethyl 3-amino-5,10-dihydro-1-(4-trifluoromethylphenyl)-5,10-dioxo-1H-pyraz-
olo[1,2-b]phthalazine-2-carboxylate (5aa): yellow powder; m.p. = 222–225 °C;
1
IR (KBr): mmax = 3,430, 3,325, 1,692, 1,661, 1,625 cm-1; H NMR (300 MHz,
DMSO-d6): d = 1.01 (3H, t, J = 7.1 Hz, CH3), 3.96 (2H, q, J = 7.0 Hz, CH2), 6.1
(1H, s, CH), 7.62–8.28 (10H, m, Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 14.1, 58.7, 62.7, 81.0, 124.8, 126.6, 127.2, 127.8, 128.2, 128.6, 128.8, 132.6,
133.6, 134.6, 143.2, 144.4, 149.8, 153.2, 156.3, 156.8, 163.8 ppm; MS (EI, 70 eV)
m/z (%) = 431 (M?, 14), 286 (100), 258 (52), 240 (91), 173 (11), 104 (14), 76 (8);
Anal. Calcd. for C21H16F3N3O4: C, 58.47; H, 3.74; N, 9.74 %. Found C, 58.44; H,
3.78; N, 9.70 %.
Results and discussion
First, to optimize conditions, the solvent-free reaction of hydrazine monohydrate,
phthalic anhydride, 4-chlorobenzaldehyde, and malononitrile in the presence of
different amount of APTES-MNPs as catalyst under ambient and solvent-free
conditions was selected as a model. The reaction was carried out with different
amounts of APTES-MNPs as catalyst (5, 10, 15 mol%) (Table 1). As shown in
Table 1, 10 mol% of APTES-MNPs as catalyst afforded 3-amino-5,10-dioxo-1-(4-
chlorophenyl)-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile in 15 min
with 93 % yield (Table 1).
Next, using these optimized reaction conditions, the scope and efficiency of these
procedures were explored for synthesis of a wide variety of substituted 1H-
pyrazolo[1,2-b]phthalazines in the presence of APTES-MNPs. Interestingly, a
variety of aromatic aldehydes including ortho-, meta-, and para-substituted aryl
aldehyde participated well in this reaction and gave the corresponding products in
good to excellent yield (Table 2). As seen from Table 2, both aromatic aldehydes
carrying electron-donating or electron-withdrawing substituent act well under these
123

Preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Table 1 Optimization of amount of APTES-MNPs as catalyst in four-component synthesis of 3-amino-
5,10-dioxo-1-(4-chlorophenyl)-5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile from reaction
of phthalic anhydride, hydrazine monohydrate, malononitrile, and 4-chlorobenzaldehyde under solvent-
free and ambient conditions
Entry
Catalyst (mol%)
Time (min)
Yield (%)a
1
2
3
a
5
10
15
18
15
14
81
93
93
Yields refer to isolated pure product
Table 2 Four-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives from the
reaction of phthalic anhydride, hydrazine, malononitrile or ethyl cyanoacetate, and aldehydes in the
presence of APTES-MNPs as catalyst
Entry Aldehyde
X
Product Time (min) Yield
(%)
Melting point Report. m.p
(°C)/Lit. m.p (°C) [Ref]
1
CN
5a
5b
5c
19
15
16
92
93
90
274–276/(276–278) [23]
258–259/(259–261) [23]
267–268/(266–267) [24]
CHO
2
CN
CN
CHO
Cl
3
4
5
CHO
Cl
CN
CN
5d
5e
15
17
93
89
272–273/(270–272) [23]
266–267/(263–265) [24]
CHO
Cl
CHO
F
6
7
CN
CN
5f
14
15
91
92
266–267/(265–266) [24]
263–265/(265–267) [24]
CHO
NO2
5g
CHO
Br
123

H. R. Shaterian, M. Mohammadnia
Table 2 continued
Entry Aldehyde
X
Product Time (min) Yield
(%)
Melting point Report. m.p
(°C)/Lit. m.p (°C) [Ref]
8
CN
5h
16
89
271–273/(270–272) [24]
CHO
Br
Cl
9
COOEt 5i
23
88
211–212/(211–213) [24]
CHO
10
11
COOEt 5j
COOEt 5k
21
22
89
91
235–236/(235–237) [24]
238–239/(239–240) [23]
CHO
NO2
CHO
NO2
CHO
12
13
COOEt 5l
21
22
89
90
242–244/(241–243) [23]
206–207/(205–206) [24]
NO2
COOEt 5m
CHO
Br
14
15
CN
CN
5n
5o
14
15
92
91
269–271
The product prepared for
the first time
CHO
Cl
Cl
228–229
The product prepared for
the first time
CHO
Cl
Cl
16
CN
5p
16
93
267–268
The product prepared for
the first time
CHO
Cl
Cl
123

Preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
Table 2 continued
Entry Aldehyde
X
Product Time (min) Yield
(%)
Melting point Report. m.p
(°C)/Lit. m.p (°C) [Ref]
17
CN
5q
14
16
90
92
248–250
The product prepared for
the first time
CHO
OCH3
18
19
CN
CN
5r
259–261
The product prepared for
the first time
CHO
OCH3
CHO
5s
5t
17
16
91
93
258–259
The product prepared for
the first time
H3CO
OC
OCH3
CHO
20
CN
259–260
The product prepared for
the first time
OC
H3CO
H3C
21
22
CN
CN
5u
5v
16
16
92
90
248–251
The product prepared for
the first time
CHO
265–267
The product prepared for
the first time
CHO
CF3
23
24
COOEt 5w
COOEt 5x
22
21
89
88
262–264
The product prepared for
the first time
CHO
Cl
Cl
230–232
The product prepared for
the first time
CHO
Cl
Cl
25
COOEt 5y
23
89
262–263
The product prepared for
the first time
CHO
Cl
Cl
123

H. R. Shaterian, M. Mohammadnia
Table 2 continued
Entry Aldehyde
X
Product Time (min) Yield
(%)
Melting point Report. m.p
(°C)/Lit. m.p (°C) [Ref]
26
COOEt 5z
22
22
90
206–208
The product prepared for
the first time
CHO
OCH3
27
COOEt 5aa
89
220–221
The product prepared for
the first time
CHO
CF3
n-Heptanal
28
CN
–
10 h
Trace
–
a
Yields refer to the isolated pure products. The desired pure products were characterized by comparison
of their physical data (melting points, IR, 1H and 13C NMR) with those of known compounds
reaction conditions. In addition, malononitrile acts well in comparison with ethyl
cyanoacetate in the mentioned reaction. Furthermore, we examined aliphatic
aldehyde such as n-heptanal instead of benzaldehydes in the reaction. All starting
materials in the reaction were almost intact with formation of only trace product
without any side-products after 10 h (Table 2, entry 28). Our observation is
confirmed with other catalysts reported in the literature [23–25].
According to the literature survey [23], the suggested mechanism for the
formation of the products using APTES-MNPs is shown in Scheme 2. First the
standard Knoevenagel condensation product of arylaldehydes (1) with malono-
nitrile (2) in the presence of the basic APTES-MNPs as catalyst was afforded,
benzylidenemalononitrile (6). Then, condensation of hydrazine monohydrate (3)
with phthalic anhydride (4) via dehydration afforded phthalhydrazide (7). The
second cycle involves 1,4-conjugated addition of the phthalhydrazide to
benzylidenemalononitrile (6) in the basic catalytic media, followed by cyclization
and tautomerism, affording the corresponding product (5) (Scheme 2).
We also investigated recycling of the APTES-MNPs as catalyst under solvent-
free conditions using the model reaction of hydrazine monohydrate, phthalic
anhydride, 4-chlorobenzaldehyde, and malononitrile (Table 2, entry 4). After
completion of the reaction, the reaction mixture was dissolved in dichloromethane.
Then, APTES-MNPs as catalyst were separated by an external magnet for
subsequent experiments to check their reusability under similar reaction condi-
tions. The results showed that APTES-MNPs are a stable catalyst in reaction
media and can be reused several times without significant loss of catalytic activity
(Fig. 1).
To show the accessibility of the present work (4-CRs) in comparison with results
reported in the literature such as for p-toluenesulfonic acid (p-TSA) as catalyst [23],
triethylamine (0.02 g, 20 mol%) as catalyst under ultrasound conditions at
123

Preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives
APTES-MNPs
O
+
NC
X
Ar
H
1
2
NC
H
OH
H
X
Ar
O
O
-H2O
O
-H2O
NH
N
+
NH2.NH2.H2O
3
O
H
7
O
4
NC
H
O
NH2
Ar
X
Ar
6
N
X
APTES-MNPs
N
O
5
O
N
O
NH
Ar
NH
N
N
X
X
N
Ar
O
8
O
9
Scheme 2 Suggested mechanism for the formation of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones
96
95
93
92
100
90
80
70
60
50
40
30
20
10
0
90
89
87
1
2
3
4
5
6
7
Reaction cycles
Fig. 1 Recycling of APTES-MNPs as catalyst
frequency of 50 kHz and output power of 350 W [24], 1-butyl-3-methylimidazo-
lium hydroxide ([Bmim]OH) [25], and triethylamine (360 mol%) [26], we
summarize some of the results for the preparation of 1H-pyrazolo[1,2-b]phthala-
zines in Table 3. The results show that APTES-MNPs are the most efficient catalyst
with respect to reaction time and in terms of yield.
123

H. R. Shaterian, M. Mohammadnia
Table 3 Comparison of the results for APTES-MNPs with [Bmim]OH, Et3N, and p-TSA for synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-diones
Entry Catalyst
Conditions
Time (min) Yield (%) [Ref]
1
2
3
4
5
p-TSA (30 mol%)
[Bmim]Br/100 °C
180
60
94 [23]
Et3N (20 mol%)
EtOH/50 °C/ultrasound
MW, 100 W, 45 °C
Triethylamine (360 mol%) DMF (20 ml), refluxed
90 [24]
[Bmim]OH (20 mol%)
4
96 [25]
180
15
72 [26]
APTES-MNPs (10 mol%) Solvent-free, room temperature
93 (present work)
Conclusions
In this research, APTES-MNPs were used for mild preparation of 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione derivatives under solvent-free and ambient conditions for
the first time. The attractive features of this protocol are the simple procedure,
cleaner reaction, and use of recyclable nanocatalyst. Satisfactory yields of products
and easy workup make this a useful protocol for green synthesis of this class of
compounds.
Acknowledgments We are grateful to the University of Sistan and Baluchestan Research Council for
partial support of this research.
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