An efficient one-pot synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives

Article abstract of DOI:10.1055/s-2008-1072716

An efficient, three-component, one-pot condensation reaction between phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl cyanoacetate for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives in excellent yields is reported. Ge

Full text of DOI:10.1055/s-2008-1072716

LETTER
1129
An Efficient One-Pot Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-dione
Derivatives
One-PotSynthes
a
1
H
-Py
m
razolo[1,2-
b
]phthala
i
zine-5
n
,10-dione
D
erivativ
G
e
s
hahremanzadeh, Ghazaleh Imani Shakibaei, Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti University, P. O. Box 19396-4716, Tehran, Iran
E-mail: a_bazgir@sbu.ac.ir
Received 21 January 2008
OH
CF3
Abstract: An efficient, three-component, one-pot condensation re-
OH
action between phthalhydrazide, aromatic aldehydes, and malono-
nitrile or ethyl cyanoacetate for the synthesis of 1H-pyrazolo[1,2-
b]phthalazine-5,10-dione derivatives in excellent yields is reported.
N
HO
N
O
OH
Key words: malononitrile, ethyl cyanoacetate, phthalhydrazide,
pyrazolo[1,2-b]phthalazine-5-dione
N
CONH2
N
H
H2NO2S
1
2
O
After the discovery of multicomponent reactions (MCR)
in 1850 by Strecker,1 the concept has stimulated substan-
tial interest in organic chemistry because it provides use-
ful products in a single step by the creation of several new
bonds in one pot. In drug discovery as well as ‘green
chemistry’, MCR are the preferred techniques due to high
throughput synthesis of compounds in a cost- and time-ef-
fective manner.2,3
N
N
NHAr
O
3
Figure 1
Multicomponent reactions of malononitrile or alkyl cy-
anoacetate, an aldehyde, and nucleophilic compounds
have recently attracted the interest of the synthetic com-
munity because the formation of different condensation
products can be expected depending on the specific con-
ditions and structure of the building blocks.15–19
Heterocycles containing the pyrazole ring are important
targets in synthetic and medicinal chemistry because this
fragment is a key moiety in numerous biologically active
compounds,4–7 among them such prominent drug mole-
cules as celecoxib (1), pyrazofurine (2), and many others.
Similarly, heterocycles containing a phthalazine moiety
are of interest because they show some pharmacological
and biological activities.8–10 For example, pyrazolo[1,2-
b]phthalazine-dione derivatives 3 were reported as anti-
inflammatory, analgesic, antihypoxic, and antipyretic
agents.8 Phthalazine derivatives were reported to possess
anticonvulsant,11 cardiotonic,12 and vasorelaxant13 activi-
ties (Figure 1).
Considering the above reports and in continuation of our
previous works on synthesis of heterocyclic compounds,20
we report the synthesis of 1H-pyrazolo[1,2-b]phthal-
azine-5,10-dione derivatives via the simple, efficient,
one-pot, and three-component condensation reaction of
malononitrile (4a) or ethyl cyanoacetate (4b), phthalhy-
drazide (5) and aldehydes 6a–g in the presence of a cata-
lytic amount of p-toluenesulfonic acid (PTSA) in ionic
So far, only a few methods have been reported for the syn-
thesis of pyrazolo[1,2-b]phthalazine-dione.14 Despite the
available methods, the development of new synthetic
methods for the efficient preparation of heterocycles con-
taining a phthalazine ring fragment is therefore an inter-
esting challenge.
liquid
1-butyl-3-methylimidazolium
bromide
{[bmim]Br} as solvent at 100 °C (Scheme 1).21
To achieve suitable conditions for the above transforma-
tion, we investigated the reaction of malononitrile (4a),
benzaldehyde (6a), and phthalhydrazide (5) in various
O
O
NH2
CN
NH
N
N
PTSA
Y
ArCHO
+
+
NH
[bmim]Br, 100 °C
Y
Ar
O
O
4a Y = CN
5
6a–g
7a–m
4b Y = CO2Et
Scheme 1
SYNLETT 2008, No. 8, pp 1129–1132
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072716; Art ID: D01908ST
© Georg Thieme Verlag Stuttgart · New York

1130
R. Ghahremanzadeh et al.
LETTER
solvents, ionic liquids (IL), and under solvent-free classi- Table 2 Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones
7a–m22
cal heating conditions. In refluxing various solvents or un-
der solvent-free conditions, the reaction was very slow
Product Ar
Y
Time (h) Yield (%)a
and the yield of product was very low. We found that the
best result was obtained in the presence of PTSA at
100 °C in [bmim]Br (Table 1).
7a
7b
7c
7d
7e
7f
Ph
CN
3
94
88
91
92
97
78
75
91
89
90
93
95
73
2-ClC6H4
4-ClC6H4
3-O2NC6H4
4-O2NC6H4
4-MeC6H4
4-MeOC6H4
Ph
CN
3.2
2.8
3.8
2.2
5
Table 1 Effect of Reaction Conditionsa
CN
Conditions
Time (h)
Yields (%)b
CN
[bmim]Br, 100 °C, PTSA
[bmim]Br, 100 °C
3
6
94
<40
65
CN
CN
[bmim]Br, 80 °C, PTSA
solvent-free, 100 °C, PTSA
EtOH (reflux), PTSA
DMF (reflux), PTSA
MeCN (reflux), PTSA
5
7g
7h
7i
CN
5
6
55
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3.5
5
10
10
10
<40
54
2-ClC6H4
4-ClC6H4
3-O2NC6H4
4-O2NC6H4
4-MeC6H4
7j
3.3
3
<40
7k
7l
a Malononitrile (1 mmol), benzaldehyde (1 mmol), phthalhydrazide
(1 mmol).
2.7
5
7m
a Isolated yields.
To explore the scope and limitation of this reaction, we
have extended the reaction of phthalhydrazide 5 with a
range of aromatic aldehydes 6a–g and malononitrile (4a)
or ethyl cyanoacetate (4b) under similar conditions {using
[bmim]Br and PTSA}, furnishing the respective 1H-pyra-
zolo[1,2-b]phthalazine-5,10-diones 7b–m in high yields.
The optimized results are summarized in Table 2. The re-
sults were excellent in terms of yields and product purity
using aromatic aldehydes carrying electron-donating or
electron-withdrawing substituents in the presence of PT-
SA, while without it for a long period of time (8 h) the
yields of products were low (<40%). Under the same con-
ditions {using [bmim]Br, PTSA}, this reaction almost
could not be observed when the aliphatic aldehyde was
used as a starting material.
fully supported by IR, 1H NMR and 13C NMR spectrosco-
py, mass spectrometry, and elemental analysis.
The formation of products 7a–m can be rationalized by
initial formation of intermediate 8 by standard Knoevena-
gel condensation of the malonitrile or ethyl cyanoacetate
4 and aldehyde 6. Then, the subsequent Michael-type ad-
dition of the phthalhydrazide (5) to the intermediate 8, fol-
lowed by cyclization and tautomerization affords the
corresponding products 7 (Scheme 2).
In summary, we have described an efficient and one-pot
synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones
via a cyclocondensation reaction of malonitrile or ethyl
cyanoacetate, phthalhydrazide, and aromatic aldehydes in
[bmim]Br. The novelty and synthetic usefulness of these
methodologies were demonstrated by the efficient synthe-
sis of phthalazine derivatives.
The nature of these compounds as 1:1:1 adducts was ap-
parent from their mass spectra, which displayed, in each
case, the molecular ion peak at appropriate m/z values.
Compounds 7a–m are stable solids whose structures are
O
O
N
NH
NH
NH
N
CN
Y
CN
– H2O
H
O
ArCHO
+
Y
Ar
O
O
Y
Ar
4
6
8
NH
Ar
O
NH2
Ar
N
N
N
Y
Y
N
O
O
7
Scheme 2
Synlett 2008, No. 8, 1129–1132 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 1H-Pyrazolo[1,2-b]phthalazine-5,10-dione Derivatives
1131
and residue recrystallized from MeOH to afford the pure
product 7a. Yellow powder (94%); mp 276–278 °C. IR
(KBr): nmax = 3359, 3190, 2197, 1690, 1658 cm–1. MS (EI,
70 eV): m/z (%) = 316 (20) [M+], 299 (42), 239 (100). 1H
NMR (300 MHz, DMSO-d6): d = 6.13 (1 H, s, CH), 7.29–
7.47 (5 H, m, ArH), 7.93–8.26 (4 H, m, ArH), 8.09 (2 H, s,
NH2) ppm. 13C NMR (75 MHz, DMSO-d6): d = 62.4, 63.6,
116.1, 127.2, 127.3, 127.7, 128.7, 128.9, 129.2, 134.1,
135.1, 138.7, 151.2, 154.2, 157.1 ppm. Anal. Calcd (%) for
C18H12N4O2: C, 68.35; H, 3.82; N, 17.71. Found: C, 68.41;
H, 3.87; N, 17.78.
Acknowledgment
We gratefully acknowledge the financial support from the Research
Council of Shahid Beheshti University.
References and Notes
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1345.
(22) Selected Characterization Data
3-Amino-1-(2-chlorophenyl)-5,10-dihydro-5,10-dioxo-
1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (7b)
Yellow powder (88%); mp 259–262 °C. IR (KBr): nmax
=
3370, 3176, 2207, 1695, 1658 cm–1. MS (EI, 70 eV): m/z
(%) = 350 (17) [M+], 333 (44), 239 (100). 1H NMR (300
MHz, DMSO-d6): d = 6.46 (1 H, s, CH), 7.33–7.62 (4 H, m,
ArH), 7.87–8.30 (4 H, m, ArH), 8.15 (2 H, s, NH2) ppm. 13
NMR (75 MHz, DMSO-d6): d = 60.2, 61.0, 116.2, 127.2,
127.8, 128.3, 128.8, 129.2, 130.2, 130.4, 131.7, 134.3,
C
135.2, 135.8, 151.6, 154.0, 157.1 ppm. Anal. Calcd (%) for
C18H11ClN4O2: C, 61.64; H, 3.16; N, 15.97. Found: C, 61.57;
H, 3.11; N, 15.91.
3-Amino-1-(4-chlorophenyl)-5,10-dihydro-5,10-dioxo-
1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (7c)
Yellow powder (91%); mp 270–272 °C. IR (KBr): nmax
=
3375, 3264, 2200, 1662, 1655 cm–1. MS (EI, 70 eV): m/z
(%) = 350 (8) [M+], 333 (27), 239 (100). 1H NMR (300 MHz,
DMSO-d6): d = 6.15 (1 H, s, CH), 7.41–7.53 (4 H, m, ArH),
7.93–8.26 (4 H, m, ArH), 8.13 (2 H, s, NH2) ppm. 13C NMR
(75 MHz, DMSO-d6): d = 61.3, 62.7, 116.4, 127.1, 127.7,
128.9, 129.3, 133.3, 134.2, 135.1, 137.9, 151.2, 154.1, 157.1
ppm. Anal. Calcd (%) for C18H11ClN4O2: C, 61.64; H, 3.16;
N, 15.97. Found: C, 61.56; H, 3.09; N, 15.92.
Ethyl 3-Amino-5,10-dihydro-1-(3-nitrophenyl)-5,10-
dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carboxylate (7k)
Yellow powder (93%); mp 239–240 °C. IR (KBr): nmax
=
3360, 3249, 1693, 1651, 1613 cm–1. MS (EI, 70 eV): m/z
(%) = 408 (23) [M+], 286 (100), 240 (40), 162 (85). 1H NMR
(300 MHz, DMSO-d6): d = 0.99 (3 H, t, 3JHH = 9.2 Hz, CH3),
3.94 (2 H, q, 3JHH = 7.8 Hz, OCH2), 6.22 (1 H, s, CH), 7.56–
8.30 (10 H, m, NH2 and ArH), 8.26–8.27 ppm. 13C NMR (75
MHz, DMSO-d6): d = 14.51, 59.19, 63.10, 81.12, 122.58,
123.12, 127.14, 127.69, 129.09, 129.49, 129.99, 134.17,
134.56, 135.05, 142.61, 147.95, 150.52, 153.93, 157.39,
164.31 ppm. Anal. Calcd (%) for C20H16N4O6: C, 58.82; H,
3.95; N, 13.72. Found: C, 58.88; H, 3.89; N, 13.66.
(16) Wang, X.-S.; Zhang, M.-M.; Jiang, H.; Yao, C.-S.; Tu, S.-J.
Tetrahedron 2007, 63, 4439.
(17) Maggi, R.; Ballini, R.; Sartori, G.; Sartorio, R. Tetrahedron
Lett. 2004, 45, 2297.
(18) Magedov, I. V.; Manpadi, M.; Evdokimov, N. M.; Elias, E.
M.; Rozhkova, E.; Ogasavara, M. A.; Bettale, J. D.;
Przheval’ski, N. M.; Rogelj, S.; Kornienko, A. Bioorg. Med.
Chem. Lett. 2007, 17, 3872.
Ethyl 3-Amino-5,10-dihydro-1-(4-nitrophenyl )-5,10-
dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carboxylate (7l)
(19) Wang, X.-S.; Shi, D.-Q.; Wei, X.-Y.; Zong, Z.-M. J. Chem.
Yellow powder (95%); mp 241–243 °C. IR (KBr): nmax
=
Res. 2004, 679.
3386, 3210, 1694, 1655, 1630 cm–1. MS (EI, 70 eV): m/z
(%) = 408 (13) [M+], 286 (81), 240 (17), 162 (100). 1H NMR
(300 MHz, DMSO-d6): d = 1.03 (3 H, t, 3JHH = 6.8 Hz, CH3),
3.95 (2 H, q, 3JHH = 6.7Hz, OCH2), 6.18 (1 H, s, CH), 7.73–
8.29 (10 H, m, NH2 and ArH) ppm. 13C NMR (75 MHz,
DMSO-d6): d = 14.61, 59.27, 63.04, 81.18, 123.59, 125.58,
127.16, 127.73, 129.02, 129.25, 133.04, 134.22, 135.12,
147.34, 147.77, 153.81, 157.32, 164.26 ppm. Anal. Calcd
(%) for C20H16N4O6: C, 58.82; H, 3.95; N, 13.72. Found: C,
58.75; H, 3.90; N, 13.78.
(20) (a) Sayyafi, M.; Seyyedhamzeh, M.; Khavasi, H. R.; Bazgir,
A. Tetrahedron 2008, in press. (b) Dabiri, M.; Arvin-
Nezhad, H.; Bazgir, A. Tetrahedron 2007, 63, 1770.
(c) Dabiri, M.; Delbari, A. S.; Bazgir, A. Synlett 2007, 821.
(d) Dabiri, M.; Delbari, A. S.; Bazgir, A. Heterocycles 2007,
71, 543. (e) Amini, M. M.; Shaabani, A.; Bazgir, A. Catal.
Commun. 2006, 7, 843. (f) Bazgir, A.; Seyyedhamzeh, M.;
Yasaei, Z.; Mirzaei, P. Tetrahedron Lett. 2007, 48, 8790.
(21) Typical Procedure for the Preparation of 3-Amino-5,10-
dihydro-5,10-dioxo-1-phenyl-1H-pyrazolo[1,2-
b]phthalazin-2-carbonitrile (7a)
Ethyl 3-Amino-5,10-dihydro-5,10-dioxo-1-p-tolyl-1H-
pyrazolo[1,2-b]phthalazine-2-carboxylate (7m)
A mixture of malononitrile (1 mmol), phthalhydrazide (1
mmol), benzaldehyde (1 mmol), PTSA (0.3 mmol), and
[bmim]Br (0.30 g) was heated at 100 °C for 3 h (TLC). After
cooling, the reaction mixture was washed with H2O (15 mL)
Yellow powder (73%); mp 204–206 °C. IR (KBr): nmax
=
3447, 3333, 1706, 1658, 1624 cm–1. MS (EI, 70 eV): m/z
(%) = 377 (27) [M+], 286 (100), 240 (25), 162 (10). 1H NMR
Synlett 2008, No. 8, 1129–1132 © Thieme Stuttgart · New York

1132
R. Ghahremanzadeh et al.
LETTER
128.93, 129.18, 129.34, 134.05, 135.11, 137.23, 137.26,
150.13, 153.49, 157.22, 164.55. Anal. Calcd (%) for
C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.88;
H, 5.01; N, 11.19.
(300 MHz, DMSO-d6): d = 1.04 (3 H, t, 3JHH = 8.9 Hz, CH3),
2.25 (3 H, s, CH3), 3.96 (2 H, q, 3JHH = 9.0 Hz, OCH2), 6.04
(1 H, s, CH), 7.07–7.38 (4 H, m, ArH), 7.69 (2 H, br s, NH2),
7.92–8.27 (4 H, m, ArH). 13C NMR (75 MHz, DMSO-d6):
d = 14.66, 21.17, 59.12, 63.45, 82.17, 127.11, 127.71,
Synlett 2008, No. 8, 1129–1132 © Thieme Stuttgart · New York

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