Mild basic ionic liquids catalyzed new four-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones

Article abstract of DOI:10.1016/j.molliq.2012.06.007

A new four-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives using three weak basic ionic liquids such as 1,8-diazabicyclo[5.4.0] -undec-7-en-8-ium acetate, pyrrolidinium formate, and pyrrolidinium acetate as efficient catalysts for condensation reaction of hydrazine monohydrate, phthalic anhydride, malononitrile or ethyl cyanoacetate, and aromatic aldehydes under ambient and solvent-free conditions in excellent yields is described.

Full text of DOI:10.1016/j.molliq.2012.06.007

Journal of Molecular Liquids 173 (2012) 55–61
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Mild basic ionic liquids catalyzed new four-component synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-diones
⁎
Hamid Reza Shaterian , Majid Mohammadnia
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, PO Box 98135-674, Zahedan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new four-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives using three weak
basic ionic liquids such as 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate, pyrrolidinium formate, and
pyrrolidinium acetate as efficient catalysts for condensation reaction of hydrazine monohydrate, phthalic
anhydride, malononitrile or ethyl cyanoacetate, and aromatic aldehydes under ambient and solvent-free con-
ditions in excellent yields is described.
Received 27 February 2012
Received in revised form 7 June 2012
Accepted 8 June 2012
Available online 21 June 2012
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Ionic liquids
Phthalic anhydride
Malononitrile
Aldehyde
Catalyst
Solvent-free
1. Introduction
with a frequency of 50 kHz and an output power of 350 W [20], and
c) using 1-butyl-3-methylimidazolium hydroxide ([Bmim]OH) under
Multi-component 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 simplic-
ity, efficiency, and high selectivity [8,9]. This environmentally friendly
process can reduce the number of steps and synthesis 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 active and drug molecules [11–15].
Pyrazolo[1,2-b]phthalazine-dione derivatives were reported as anti-
inflammatory, analgesic, antihypoxic, anticonvulsant, cardiotonic, vaso-
relaxant, antipyretic anti-hyperglycemic, anti-bacterial, and anti-viral
compounds [16–18]. Thus, the development of new synthetic methods
for the efficient preparation of heterocycles containing phthalazine ring
is an interesting challenge in green organic synthesis.
Only three reported methods for preparation of this class of com-
pounds have been reported via the three-component reactions (3-CRs)
of phthalhydrazide, malononitrile or ethyl cyanoacetate, and aromatic
aldehydes a) in the presence of a catalytic amount of p-toluenesulfonic
acid (p-TSA) in ionic liquid, 1-butyl-3-methylimidazolium bromide
[bmim]Br, as solvent at 100 °C [19], b) using triethylamine (0.02 g, 20%
mol) as catalyst in EtOH (5 ml) at 50 °C for 60 min under ultrasonication
irradiation in a single-mode microwave synthesis system at 100 W
power and 45 °C [21].
In continuation of our research on ionic liquids and their applica-
tions as catalyst in organic synthesis [22–24], herein, we reported
an efficient method for a new and novel four-component synthesis
of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives using weak
basic ionic liquids such as 1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium
acetate (DBU[CH3COO]), pyrrolidinium formate ([Pyrr][HCOO]) and
pyrrolidinium acetate ([Pyrr][CH3COO]) (Fig. 1) as catalysts for con-
densation reaction of hydrazine monohydrate, phthalic anhydride,
malononitrile or ethyl cyanoacetate, and aromatic aldehydes under
ambient and solvent-free conditions for the first time (Scheme 1).
Literature survey showed us that a few papers were published on
these ionic liquids. DBU[CH3COO] was used in aza-conjugated addition
of amines to various electron deficient alkenes [25]. The volumetric
properties of [Pyrr][HCOO] was studied [26]. [Pyrr][CH3COO] was
applied in Knoevenagel condensation [27].
2. Experimental
All reagents were purchased from Merck and Aldrich and used
without further purification. The weak basic ionic liquids such as
1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate (DBU[CH3COO]),
pyrrolidinium formate ([Pyrr][HCOO]) and pyrrolidinium acetate
([Pyrr][CH3COO]) as catalysts were prepared according to the reported
procedure [25–28]. All yields refer to isolated products after purification.
The NMR spectra were recorded on a Bruker Avance DPX 300 MHz
⁎
Corresponding author. Tel.: +98 541 2446565; fax: +98 541 2431067.
E-mail address: hrshaterian@chem.usb.ac.ir (H.R. Shaterian).
0167-7322/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.molliq.2012.06.007

56
H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 173 (2012) 55–61
H
N
3-Amino-1-(2,4-dichlorophenyl)-5, 10-dioxo-5, 10-dihydro-
H
1Hpyrazolo[1,2-b]phthalazine-2-carbonitrile (Table 3, entry 15):
Yellow powder ; mp=228–230 °C; IR(KBr): νmax =3411, 3374, 2204,
CH3
O
O
O
CH3COO
N
1675, 1602 cm−1 1H NMR (300 MHz, DMSO-d6): δ=6.44 (1H, s,
;
N
N
H
O
H
H
H
CH),7.41–8.88 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz, DMSO-
d6): δ=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); anal. calcd for C18H10Cl2N4O2: C, 56.12; H,
2.62; N, 14.54%. Found: C, 56.17; H, 2.58; N, 14.50%.
[Pyrr][HCOO]
[Pyrr][CH3COO]
DBU[CH3COO]
Fig. 1. The molecular structures of ionic liquids.
instrument. The spectra were measured in DMSO-d6 relative to TMS
(0.00 ppm). Elemental analyses for C, H, and N were performed using a
Heraeus CHN-O-Rapid analyzer. IR spectra were recorded on a JASCO
FT-IR 460 plus spectrophotometer. Mass spectra were recorded on an
Agilent technologies 5973 network mass selective detector (MSD) oper-
ating at an ionization potential of 70 eV. Melting points were determined
in open capillaries with a BUCHI 510 melting point apparatus. TLC was
performed on silica-gel Poly Gram SIL G/UV 254 plates.
3-Amino-1-(2,3-dichlorophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (Table 3, entry 16):
Yellow powder; mp=265–268 °C; IR (KBr): νmax=3415, 3372,
2211, 1686, 1660 cm−1
;
1H NMR (300 MHz, DMSO-d6): δ=
6.52(1H, s, CH), 7.35- 8.27 (9H, m, Ar and NH2) ppm; 13C NMR
(75 MHz, DMSO-d6): δ=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%.
2.1. General procedure for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,
10-diones under solvent-free and ambient conditions
3-Amino-1-(2-methoxyphenyl)-5, 10-dioxo-5, 10-dihydro-1H-
pyrazolo[1,2-b] phthalazine-2-carbonitrile (Table 3, entry 17):
Yellow powder; mp=248–251 °C IR (KBr): νmax=3383, 3255,
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 ionic liquids containing DBU
[CH3COO] (10 mol%) or [Pyrr][HCOO] (12 mol%), or [Pyrr][CH3COO]
(12 mol%) as weak basic catalyst was added and stirred under ambi-
ent and solvent-free conditions for the specific time. After completion
of the reaction, 5 mL of water was added to the mixture. The ionic
liquid was dissolved in water, and filtered for separation of the
crude product. The separated product was washed twice with water
(2×5 mL). The solid product was purified by recrystallization proce-
dure in ethanol. All of the desired products were characterized by
comparison of their physical data with those of known compounds.
For recycling the catalysts, after washing solid products with water
completely, the water containing ionic liquid (IL is soluble in water)
was evaporated under reduced pressure and ionic liquid was recov-
ered and reused.
2201, 1681, 1560 cm−1 1H NMR (300 MHz, DMSO-d6): δ=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): δ=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]phthalazine-2-carbonitrile (Table 3, entry 18):
Yellow powder; mp=258–260 °C; IR(KBr): νmax=3422, 3362,
2192, 1680, 1654 cm−1 1H NMR (300 MHz, DMSO-d6): δ=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): δ=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%.
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] phthalazine-2-carbonitrile (Table 3, entry 14):
Yellow powder ; mp=268–270 °C. IR (KBr): νmax=3398, 3304,
2200, 1683, 1595 cm−1 1H NMR (300 MHz, DMSO-d6): δ=6.89
;
3-Amino-1-(2,4,6-trimethoxyphenyl)-5,10-dioxo-5,10-dihydro-
1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (Table 3, entry 19):
Yellow powder: mp=257–260 °C. IR (KBr): νmax=3416, 3328,
(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): δ=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, 670 eV) m/z (%)=
2190,1635,1575 cm−1
;
1H NMR(300 MHz, DMSO-d6):δ=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): δ=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,
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%.
Z
O
CHO
O
CN
X
Ionic liquids (Catalyst)
N
N
X
NH2NH2.H2O +
+
O
H2C
+
Solvent-free
Room Temperature
Z
NH2
O
O
Z = H, Br, Cl, F, CF3, CH3 , OCH3, NO2
X= -CN, -CO2Et
Ionic Liquids=1,8-diazabicyclo[5.4.0]-undec-7-en-8-ium acetate (DBU[CH3COO]), pyrrolidinium formate ([Pyrr][HCOO]),
and pyrrolidinium acetate ([Pyrr][CH3COO])
Scheme 1. Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives.

H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 173 (2012) 55–61
57
Table 1
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%.
Preparation of 3-amino-5,10-dioxo-1-(4-chlorophenyl)-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile in the presence of different catalysts.
Entry Conditions
Time Yield
(h)
(%)a
3-Amino-1-(2,5-dimethoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b] phthalazine-2-carbonitrile (Table 3, entry 20):
Yellow powder; mp=257–260 °C. IR (KBr): νmax =3420, 3348,
1
2
3
4
5
6
7
8
P2O5/SiO2 (0.08 g), EtOH (Reflux)
P2O5/SiO2 (0.1 g), (Solvent-free, 100 °C)
P2O5/Al2O3 (0.08 g), EtOH (Reflux)
P2O5/Al2O3 (0.08 g), (solvent-free, 100 °C)
H3PO4/Al2O3 (0.08 g), EtOH (Reflux)
H3PO4/Al2O3 (0.10 g), (Solvent-free, 100 °C)
Cellulose sulfate (0.10 g), EtOH (Reflux)
Cellulose sulfate (0.10 g), (solvent-free, 100 °C)
Starch sulfate (0.080 g), EtOH (Reflux)
Starch sulfate (0.10 g), (solvent-free, 100 °C)
Silica sulfuric acid (0.080 g), EtOH (Reflux)
Silica sulfuric acid (0.10 g), (solvent-free, 100 °C)
Alumina sulfuric acid (0.080 g), EtOH (Reflux)
Alumina sulfuric acid (0.10 g), (solvent-free, 100 °C)
Et3N (0.023 g, 0.22 mmol), EtOH room temperature
Et3N (0.023 g, 0.22 mmol), EtOH (reflux)
Et3N (0.023 g, 0.22 mmol), (solvent-free, 70 °C)
Et3N (0.46 g, 0.44 mmol), EtOH (reflux)
DABCO (0.022 g, 0.178 mmol), EtOH, room temperature
DABCO (0.022 g, 0.178 mmol), EtOH (reflux)
DABCO (0.022 g, 0.178 mmol), (solvent-free, 70 °C)
1,8-Diazabicyclo[5.4.0]-undec-7-en-8-ium acetate
(DBU[CH3COO], 0.021 g), (solvent-free, room temperature)
Pyrrolidinium formate ([Pyrr][HCOO], 0.014),
(solvent-free, room temperature)
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
24
6
40
25
30
42
30
30
30
10
25
20
25
15
40
10
15
50
30
60
20
75
50
2180, 1681, 1595 cm−1 1H NMR (300 MHz, DMSO-d6): δ=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): δ=55.4, 56.3, 59.0, 60.4, 112.9, 113.3,
113.8, 116.0, 126.6, 127.0, 127.2, 128.5, 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%.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3-Amino-1-(2-methylphenyl)-5, 10-dioxo-5, 10-dihydro-1H-
pyrazolo[1,2-b] phthalazine-2-carbonitrile (Table 3, entry 21):
Yellow powder; mp=248–250 °C, IR(KBr): νmax =3366, 3302,
2210, 1661, 1601 cm− 1 1H NMR (300 MHz, DMSO-d6): δ=
;
20
1.5
4
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):
δ=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
6 min 93
8 min 93
8 min 94
23
24
Pyrrolidinium acetate ([Pyrr][CH3COO], 0.016),
(solvent-free, room temperature)
C
19H14N4O2: C, 69.08; H, 4.27; N, 16.96%. Found: C, 69.04; H,
4.31; N, 16.92%.
a
Yields refer to pure isolated product. Based on the reaction of hydrazine monohydrate
(1 mmol), phthalic anhydride (1 mmol), malononitrile (1 mmol), and 4-chlorobenzaldehyde
(1 mmol), the product was characterized by comparison of their physical data (melting
points, IR, 1H and 13C NMR) with the known compound [19].
3-Amino-1-(4-trifluromethylphenyl)-5,10-dioxo-5,10-dihydro-
1H-pyrazolo[1,2-b] phthalazine-2-carbonitrile (Table 3, entry 22):
Yellow powder : mp=268–270 °C, IR (KBr): νmax=3359, 3284,
2195, 1659, 1594 cm−1 1H NMR (300 MHz, DMSO-d6): δ=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): δ=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%.
1707, 1647, 1629 cm−1 1H NMR (300 MHz, DMSO-d6): δ=0.95
;
(3H, t, J=6.8 Hz, CH3), 3.90 (2H, q, J=6.7 Hz, OCH2), 6.51(1H, s
CH), 7.21–8.26 (9H, m, Ar and NH2) ppm; 13C NMR (75 MHz,
DMSO-d6): δ=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-(2,6-dichlorophenyl)-5,10-dioxo-
1H-pyrazolo[1,2-b]phthalazine-2-carboxylate (Table 3, entry 23) :
Yellow powder; mp=260–262 °C, IR(KBr): νmax=3446, 3332,
1707, 1659, 1645 cm−1
;
1H NMR (300 MHz, DMSO-d6): δ=0.96
Ethyl 3-amino-5,10-dihydro-1-(2-methoxyphenyl)-5,10-dioxo-
1H-pyrazolo[1, 2-b]phthalazine-2-carboxylate (Table 3, entry 26):
Yellow powder; mp=205–208 °C. IR (KBr): νmax=3444, 3329,
(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): δ=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
1700, 1660, 1622 cm−1 1H NMR (300 MHz, DMSO-d6): δ=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): δ=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 (%)=
C
20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72%. Found: C, 55.60;
H, 3.52; N, 9.74%.
Ethyl 3-amino-5,10-dihydro-1-(2,4-dichlorophenyl)-5,10-dioxo-
1H-pyrazolo[1,2-b] phthalazine-2-carboxylate (Table 3, entry 24):
Yellow powder; mp=228–230 °C, IR (KBr): νmax =3452, 3340,
Table 2
1700, 1660, 1620 cm−1 1H NMR (300 MHz, DMSO-d6): δ=0.95
;
Optimization amount of A: DBU[CH3COO], B: [Pyrr][HCOO] C: [Pyrr][CH3COO] as catalysts
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 the reaction of phathalic anhydride,
hydrazine monohydrate, malononitrile, and 4-chlorobenzaldehyde under solvent-free
and ambient conditions.
(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): δ=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
Entry
Catalyst (mol%)
Time (min)
Yield (%)a
A
B
C
A
B
C
A
B
C
C
20H15Cl2N3O4: C, 55.57; H, 3.50; N, 9.72%. Found: C, 55.60; H, 3.52;
1
2
3
4
5
5
5
8
6
6
5
14
11
8
15
11
8
80
93
94
94
80
86
93
93
81
86
94
94
N, 9.64%.
10
12
17
10
12
17
10
12
17
Ethyl 3-amino-5,10-dihydro-1-(2,3-dichlorophenyl)-5,10-dioxo-
1H-pyrazolo[1,2-b]phthalazine-2-carboxylate (Table 3, entry 25):
Yellow powder; mp=260–263 °C. IR (KBr): νmax =3446, 3333,
7
7
a
Yields refer to pure isolated yields.

58
H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 173 (2012) 55–61
Table 3
Four component synthesis of 1H-pyrazolo [1,2-b] phthalazine-5,10-dione derivatives from the reaction of phathalic anhydride, hydrazine monohydrate, malononitrile or ethyl
cyanoacetate, and aldehydes in the presence of A: DBU[CH3COO], B: [Pyrr][HCOO] C: [Pyrr][CH3COO] as catalysts.
Entry
Aldehyde
X
Time (min)
Yield (%)
Melting Point Report. m.p. (°C)
/Lit. m.p. (°C) [Ref]
A
B
C
A
B
C
1
2
3
CN
CN
CN
12
14
14
94
93
94
275–276/(276–278) [19]
257–259/(259–261) [19]
266–268/(266–267) [20]
7
6
8
7
9
8
93
93
94
93
93
94
4
5
CN
CN
6
6
8
7
8
7
93
94
93
92
94
93
272/(270–272) [19]
265–266/(263–265) [20]
6
7
CN
CN
5
8
7
8
8
91
92
94
92
94
91
265–267/(265–266) [20]
263–264/(265–267) [20]
10
8
9
CN
8
7
9
93
90
93
88
92
89
271/(270–272) [20]
COOEt
12
13
14
210–211/(211–213) [20]
10
11
COOEt
COOEt
10
11
12
11
12
11
91
90
91
89
92
89
234–235/(235–237) [20]
238/(239–240) [19]
12
13
14
COOEt
COOEt
CN
10
14
6
10
15
6
10
14
6
92
89
94
90
89
92
91
89
93
241–242/(241–243) [19]
203–204/(205–206) [20]
269–271
The product was prepared for the first time
15
16
CN
CN
5
5
6
5
6
5
91
94
90
93
91
94
228–229
The product was prepared for the first time
267–268
The product was prepared for the first time
17
18
CN
CN
6
5
7
6
7
7
90
92
90
90
91
91
248–250
The product was prepared for the first time
259–261
The product was prepared for the first time
19
CN
4
4
5
94
93
94
258–259
The product was prepared for the first time
20
21
CN
CN
9
10
11
10
12
89
87
89
86
90
87
259–260
The product was prepared for the first time
11
248–251
The product was prepared for the first time
22
CN
11
11
11
94
94
94
265–267
The product was prepared for the first time
23
24
COOEt
COOEt
14
13
14
13
14
13
88
90
89
89
89
90
262–264
The product was prepared for the first time
230–232
The product was prepared for the first time
25
COOEt
10
11
11
93
92
93
262–263
The product was prepared for the first time

H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 173 (2012) 55–61
59
Table 3 (ccoonnttiinnuueedd))
Entry
Aldehyde
X
Time (min)
Yield (%)
Melting Point Report. m.p. (°C)
/Lit. m.p. (°C) [Ref]
A
B
C
A
B
C
26
27
COOEt
COOEt
14
13
13
88
86
86
206–208
The product was prepared for the first time
15
16
16
93
90
93
220–221
The product was prepared for the first time
28
n-Heptanal
CN
8 h
–
–
Trace
–
–
–
aYields refer to the isolated pure products. The desired pure products were characterized by comparison of their physical data (melting points, IR, 1 H and 13 C NMR) with those of
known compounds.
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%.
3. Results and discussions
First, the four component reaction of hydrazine monohydrate,
phthalic anhydride, 4-chlorobenzaldehyde, and malononitrile was chosen
as model. We tried to prepare 3-amino-5,10-dioxo-1-(4-chlorophenyl)-
5,10-dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile in the pres-
ence of Brønsted acidic heterogeneous catalysts such as P2O5/SiO2, P2O5/
Al2O3, H3PO4/Al2O3, cellulose sulfate, starch sulfate, silica sulfuric acid, alu-
mina sulfuric acid in ethanol under reflux and also under solvent-free
conditions at 100 °C. The reaction produce desired product in low yield
and starting materials were observed intact even after 24 h (Table 1,
entries 1–14). Thus, acid catalyst did not show any significant catalytic
activities in the mentioned reaction. But, in basic catalytic conditions
such as Et3N, and DABCO the desired product was obtained in good
yield under reflux conditions in ethanol (Table 1, entries 15–21). We
Ethyl 3-amino-5,10-dihydro-1-(4-trifuloromethylphenyl)-5,10-
dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carboxylate (Table 3, entry
27): Yellow powder; mp=222–225 °C; IR (KBr): νmax=3430,
3325, 1692, 1661, 1625 cm−1 1H NMR (300 MHz, DMSO-d6):
;
δ=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 (10 H, m, Ar and NH2) ppm; 13C NMR
(75 MHz, DMSO-d6): δ=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%.
Scheme 2. Suggested mechanism for the formation of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.

60
H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 173 (2012) 55–61
aldehyde such as n-heptanal instead of benzaldehydes in the reaction.
The all starting materials in the reaction almost were intact with for-
mation only trace product without any side products even after 10 h
(Table 3, entry 28). Our observation about aliphatic aldehydes can
be confirmed with other catalysts reported in the literature [19–21].
According to the literature [20], the suggested mechanism for the
formation of the products using DBU[CH3COO] is shown in Scheme 2.
First the standard Knoevenagel condensation of arylaldehydes (1)
with malononitrile (2) in the presence of catalytic amount of the
weak basic ionic liquid was afforded benzylidenemalononitrile (3).
Then, condensation of hydrazine monohydrate (4) with phthalic
anhydride (5) via dehydration afforded phthalhydrazide (6). The
second cycle involves 1,4-conjugated addition of the phthalhydrazide
to benzylidenemalononitrile (3) in the basic catalytic media, followed
cyclization and tautomerism affords the corresponding product (9)
(Scheme 2).
We also investigated the recycling of the ionic liquids under
solvent-free conditions using a model reaction of hydrazine mono-
hydrate, phthalic anhydride, 4-chlorobenzaldehyde, and malononitrile
for the preparation of 3-amino-5,10-dioxo-1-(4-chlorophenyl)-5,10-
dihydro-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile in the presence
of DBU[CH3COO] or [Pyrr][HCOO], [Pyrr][CH3COO] (Table 3, Entry 4).
After completion of the reaction, water was added and the precipitated
mixture was filtered off for separation of crude products. After washing
the solid products with water completely, the water containing ionic
liquid (IL is soluble in water) was evaporated under reduced pressure
and ionic liquid was recovered and reused (Fig. 2). The recovered
catalysts were reused four runs without any loss of their activities.
In order to show the accessibility of the present work (4-CRs) in
comparison with the three-component reported results in the lit-
erature such as p-toluenesulfonic acid (p-TSA) as catalyst in ionic
liquid, 1-butyl-3-methylimidazolium bromide [bmim]Br, as solvent
at 100 °C [19], triethylamine (0.02 g, 20% mol) as catalyst in ethanol
as solvent at 50 °C for 60 min under ultrasound conditions with a fre-
quency of 50 kHz and an output power of 350 W [20], and 1-butyl-3-
methylimidazolium hydroxide, [Bmim]OH, under irradiation in a
single-mode microwave synthesis system at 100 W power and 45 °C
[21], we summarized some of the results for the preparation of 1H-
pyrazolo[1,2-b] phthalazines in Table 4. The results show that present
weak basic ionic liquids such as DBU[CH3COO], [Pyrr][HCOO], and
[Pyrr][CH3COO] under ambient and solvent-free conditions are the
most efficient catalysts with respect to the low reaction times and
the high yields.
Fig. 2. The recycling of DBU[CH3COO], [Pyrr][HCOO] and [Pyrr][CH3COO]as catalysts
under solvent-free conditions using a model reaction of phathalic anhydride, hydrazine
monohydrate, malononitrile, and 4-chlorobenzaldehyde.
also used three mild basic ionic liquids such as DBU[CH3COO], [Pyrr]
[HCOO], and [Pyrr][CH3COO] under ambient and solvent-free conditions
for the mentioned reaction. We observed the reaction was completed
after 12–14 min with 93–94 yield%. Thus, these reusable ionic liquids
were chosen for continuation this research (Table 1, entries 22–24).
Next, to optimize the catalytic amount of the basic ionic liquids, the re-
action of hydrazine monohydrate (1 mmol) and phthalic anhydride
(1 mmol) were mixed at 100 °C until a white solid phthalhydrazide was
formed (10 min). Then, 4-chlorobenzaldehyde (1 mmol), malononitrile
(1 mmol), and ionic liquids containing DBU[CH3COO] or [Pyrr][HCOO],
or [Pyrr][CH3COO] as weak basic catalyst were mixed under solvent-free
and ambient conditions. The reaction was carried out with different
amount of DBU[CH3COO] (5, 10, 12, 17 mol %), [Pyrr][HCOO] (5, 10, 12,
17 mol %), and [Pyrr][CH3COO] (5, 10, 12, 17 mol%) as catalyst (Table 2).
As it was shown from Table 2, DBU[CH3COO] (10 mol %), [Pyrr]
[HCOO] (12 mol %) and [Pyrr][CH3COO] (12 mol %) as basic catalysts
afforded 3-amino-1-(4-chlorophenyl)-5,10-dioxo-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile in 6, 8, and 8 min with 93%,
93%, and 94% of yield respectively.
Using these optimized reaction conditions, the scope and efficien-
cy of these procedures were explored for the synthesis of a wide
variety of substituted 1H-pyrazolo[1,2-b]phthalazines in the presence
of three mentioned ionic liquids. Interestingly, a variety of aromatic
aldehydes including ortho-, meta-, and para- substituted arylaldehyde
participated well in this reaction and gave the corresponding prod-
ucts in good to excellent yield (Table 3). As seen from Table 3,
both aromatic aldehydes carrying electron-donating or electron-
withdrawing substituent act well in this reaction conditions. In addi-
tion, malononitrile acts well in comparison with ethyl cyanoacetate
in the mentioned reaction. Furthermore, we examined aliphatic
4. Conclusion
In this research, three mild basic ionic liquids DBU[CH3COO]
or [Pyrr][HCOO], or [Pyrr][CH3COO] were used for preparation of
1H-pyrazolo[1,2-b]phthalazine-5,10-diones under ambient and solvent-
free conditions for the first time. The attractive features of this protocol
are simple procedure, cleaner reaction, use of inexpensive and reusable
ionic liquids as catalysts. Satisfactory yields of products, as well as a
simple reactions, isolation, and purification of the products make it a
useful protocol for the synthesis of these classes of compounds.
Table 4
Comparison the results of DBU[ CH3COO ], Pyrr[HCOO] and Pyrr [CH3COO] with [Bmim]
OH, Et3N, and p-TSA in the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.
Entry
Catalyst
(mol%)
Conditions
Time
(min)
Yield (%)
[Ref]
Acknowledgments
1
p-TSA
[bmim]Br/100 °C
180
94 [19]
(30 mol%)
We are thankful to the University of Sistan and Baluchestan Research
Council for the partial support of this research.
2
3
Et3N (20 mol%)
[Bmim]OH
(20 mol%)
EtOH /50 °C /ultrasound
MW, 100 W ,45 °C
60
4
90 [20]
96 [21]
References
4
5
6
DBU[ CH3COO ]
(10 mol%)
Pyrr[HCOO]
(12 mol%)
Pyrr[CH3COO]
(12 mol%)
solvent-free,
room temperature
solvent-free,
room temperature
solvent-free,
room temperature
6
8
8
93
(Present work)
93
(Present work)
94
[1] J. Zhu, H. Bienayme, Multicomponent Reactions, Wiley-VCH, Weinheim, Germany,
2005.
[2] A. Dömling, Chemical Reviews 106 (2006) 17–89.
[3] S. Jimenez-Alonso, H. Chavez, A. Estevez-Braan, A. Ravelo, G. Feresin, A. Tapia,
Tetrahedron 64 (2008) 8938–8942.
(Present work)

H.R. Shaterian, M. Mohammadnia / Journal of Molecular Liquids 173 (2012) 55–61
61
[4] D.F. Tejedor, G. Tellado, Chemical Society Reviews 36 (2007) 484–491.
[5] R.V.A. Orru, M. de Greef, Synthesis 10 (2003) 1471–1499.
[17] Y. Nomoto, H. Obase, H. Takai, M. Teranishi, J. Nakamura, K. Kubo, Chemical &
Pharmaceutical Bulletin 38 (1990) 2179–2183.
[6] L. Weber, Drug Discovery Today 7 (2002) 143–147.
[18] N. Watanabe, Y. Kabasawa, Y. Takase, K. Miyazaki, H. Ishihara, K. Kodama, H.
Adachi, Journal of Medicinal Chemistry 41 (1998) 3367–3372.
[19] R. Ghahremanzadeh, G.I. Shakibaei, A. Bazgir, Synlett 8 (2008) 1129–1132.
[20] M.R. Nabid, S.J. Tabatabaie, R. Gahremanzadeh, A. Bazgir, Ultrasonics Sonochemistry
17 (2010) 159–161.
[21] D.S. Raghuvanshi, K.N. Singh, Tetrahedron Letters 52 (2011) 5702–5705.
[22] H.R. Shaterian, M. Arman, F. Rigi, Journal of Molecular Liquids 158 (2011) 145–150.
[23] H.R. Shaterian, M. Ranjbar, K. Azizi, Journal of Molecular Liquids 162 (2011) 95–99.
[24] H.R. Shaterian, M. Ranjbar, Journal of Molecular Liquids 160 (2011) 40–49.
[25] A.G. Ying, L. Liu, G.F. Wu, G. Chen, X.Z. Chen, W.D. Ye, Tetrahedron Letters 50
(2009) 1653–1657.
[7] A. Domling, I. Ugi, Angewandte Chemie International Edition 39 (2000) 3169–3210.
[8] A. Nefzi, J.M. Ostresh, R.A. Houghten, Chemical Reviews 97 (1997) 449–472.
[9] L.A. Thompson, Current Opinion in Chemical Biology 4 (2000) 324–337.
[10] A. Dömling, Current Opinion in Chemical Biology 6 (2002) 306–313.
[11] N.K. Terrett, A.S. Bell, D. Brown, P. Ellis, Bioorganic & Medicinal Chemistry Letters
6 (1996) 1819–1824.
[12] J. Elguero, In: in: A.R. Katrizky, C.W. Rees, E.F.V. Scriven (Eds.), Comprehensive
Heterocyclic Chemistry II, Elsevier-Oxford, 1996.
[13] S.K. Singh, P.G. Reddy, K.S. Rao, B.B. Lohray, P. Misra, S.A. Rajjak, Y.K. Rao, A.
Venkatewarlu, Bioorganic & Medicinal Chemistry Letters 14 (2004) 499–504.
[14] M.J. Genin, C. Biles, B.J. Keiser, S.M. Poppe, S.M. Swaney, W.G. Tarpley, Y. Yagi, D.L.
Romero, Journal of Medicinal Chemistry 43 (2000) 1034–1040.
[26] M. Anouti, M. Caillon-Caravanier, Y. Dridi, J. Jacquemin, C. Hardacre, D. Lemordant,
Journal of Chemical Thermodynamics 41 (2009) 799–808.
[15] F. Al'-Assar, K.N. Zelenin, E.E. Lesiovskaya, I.P. Bezhan, B.A. Chakchir, Pharmaceutical
Chemistry Journal 36 (2002) 598–603.
[27] A.M. Dumas, A. Seed, A.K. Zorzitto, E. Fillion, Tetrahedron Letters 48 (2007)
7072–7074.
[16] S. Grasso, G. De Sarro, A. De Sarro, N. Micale, M. Zappala, G. Puja, M. Baraldi, C. De
Micheli, Journal of Medicinal Chemistry 43 (2000) 2851–2859.
[28] M. Anouti, M. Caillon-Caravanier, Y. Dridi, H. Galiano, D. Lemordant, The Journal
of Physical Chemistry B 112 (2008) 13335–13343.