Preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones using ZrO2 nanoparticles as a catalyst under solvent-free conditions

Article abstract of DOI:10.1515/hc-2017-0142

Zirconium oxide nanoparticles are an efficient catalyst for the preparation of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones via a three-component reaction of phthalhydrazide, aromatic aldehydes and malononitrile under solvent-free conditions.

Full text of DOI:10.1515/hc-2017-0142

Heterocycl. Commun. 2017; aop
Mohammad Piltan*
Preparation of 1H-pyrazolo[1,2-b]phthalazine-
5,10-diones using ZrO2 nanoparticles as a catalyst
under solvent-free conditions
https://doi.org/10.1515/hc-2017-0142
Received July 4, 2017; accepted August 10, 2017
Results and discussion
Abstract: Zirconium oxide nanoparticles are an efficient Initially, different reaction parameters for the synthe-
catalyst for the preparation of 1H-pyrazolo[1,2-b]phthala- sis of compound 4a by the three-component condensa-
zine-5,10-diones via a three-component reaction of tion reaction using benzaldehyde as a model reaction
phthalhydrazide, aromatic aldehydes and malononitrile were optimized. The scrutinized parameters were tem-
under solvent-free conditions.
perature, time of reaction solvents, including ethanol,
tetrahydrofuran, acetonitrile, dichloromethane and
water, and solvent-free conditions. The best results were
obtained under solvent-free conditions. When 10 mol%,
15 mol% and 20 mol% of ZrO2 nanoparticles were used,
the yields of 4a were 82%, 91% and 91%, respectively,
and the yields were much lower in any solvent. Only
20% of 4a was obtained in the absence of a catalyst.
Under optimized solvent-free conditions, the reaction
Keywords: aromatic aldehydes; multicomponent reac-
tion; nanoparticles; phthalhydrazide; solvent-free; zirco-
nium oxide.
Introduction
Multi-component reactions (MCRs) have become a pow- was conducted with 15 mol% of the catalyst at 100°C
erful, fast and convenient approach for the synthesis of for 45 min and furnished 4a with a 91% yield. The reac-
complex heterocyclic compounds from simple and readily tions with other aromatic aldehydes conducted using
available starting materials [1]. MCRs have advantages over this optimized procedure were also similarly effective.
classical reaction strategies including greater efficiency All reactions were completed within 35–45 min and
and shorter reaction time [2, 3]. Nanometer-sized particles afforded good yields of products 4b–g. The aromatic
have recently been considered as an alternative matrix for aldehydes substituted with either electron-donating
supporting catalytic reactions. Reusable nanoscale het- or electron-withdrawing groups underwent the reac-
erogeneous catalysts show high catalytic activity due to a tion smoothly and afforded the products in good yields.
high specific surface area and low-coordination sites [4].
As seen from Table 1, the method compares well with
1H-Pyrazolo[1,2-b]phthalazine-5,10-dione derivatives other known preparations of the model product 4a. The
containing fused hydrazine are an important class of suggested mechanism for the formation of products 4
pharmaceutical compounds that exhibit a wide spectrum involves generation of the intermediate compounds 5–7,
of biological activities [5–7]. Such compounds are rela- as shown in Scheme 2.
tively difficult to synthesize [8–17].
Therefore, the development of simple methods for
the synthesis of pyrazolo[1,2-b]phthalazine-5,10-diones is
important. In continuation of our efforts to develop a new
O
CHO
R
O
R
methodology for the synthesis of heterocyclic compounds
[18–21], we now report the use of ZrO2 nanoparticles as an
efficient catalyst for the preparation of 1H-pyrazolo[1,2-b]
phthalazine-5,10-diones 4a–g from phthalhydrazide, aro-
matic aldehydes and malononitrile (Scheme 1).
CN
ZrO2 NPs
NH
NH
N
N
+
+
CN
Solvent-free
CN
O
NH2
O
1
2
4a–g
4a: R = H
3a–g
4e: R = 4-Cl
4f: R = 4-NO2
4g: R = 2-NO
4b: R = 2-Me
4c: R = 3-Me
4d: R = 3-MeO
2
*Corresponding author: Mohammad Piltan, Department of
Chemistry, Faculty of Science, Islamic Azad University, Sanandaj
Branch, Sanandaj 618, Iran, e-mail: mohammadpiltan@yahoo.com
Scheme 1ꢀSynthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones
4a–g.
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2ꢀ ꢀM. Piltan: 1H-Pyrazolo[1,2-b]phthalazine-5,10-diones
Table 1ꢀComparison of the results of different preparations of 4a.
Entry
Catalyst
Conditions
Time (min)
Yield (%) [Ref]
1
p-TSA (30 mol%)
TBBDA/PBBS
Et3N (20 mol%)
[Bmim]OH (20 mol%)
CuI NPs
APTES-MNPs (10 mol%)
NiCl26H2O
[Bmim]Br/100°C
EtOH, 100°C
EtOH, 50°C, ultrasound
MW, 100 W, 45°C
Solvent-free, 70°C
Solvent-free, rt
EtOH, reflux
180
15/40
60
94 [8]
2
89/65 [9]
90 [10]
3
4
4
96 [11]
5
27
19
180
240
40
91 [12]
7
92 [14]
8
87 [16]
9
AL-KIT-6
ZrO2 NPs
EtOH, 60°C
Solvent-free, 100°C
93 [17]
10
91 (present work)
General procedure for the preparation of 1H-pyrazolo[1,2-
b]phthalazine-5,10-diones 4a–g
R
O
O
CN
CN
ZrO2 NPs
1
N
A mixture of phthalhydrazide (1 mmol), aromatic aldehyde (1 mmol),
malononitrile (1 mmol) and ZrO2 nanoparticles (15 mol%) was stirred
at 100°C under solvent-free conditions for 35–45 min. After comple-
tion of the reaction, the resultant precipitate was crystallized from
MeOH to afford pure product 4.
2 + 3
NH CN
CN
R
6
5
Cyclization
O
R
3-Amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-
b]phthalazine-2-carbonitrile (4a)ꢀYellow powder; yield 0.29 g
Tautomerization
N
N
4
CN
1
(91%); mp 276–278°C; IR: 3361, 3292, 3248, 2198, 1659, 1567 cm−1; H
NMR: δ 6.12 (s, 1H, CH), 7.31–7.46 (m, 5H, ArH), 7.92–8.26 (m, 6H, ArH
and NH2); 13C NMR: δ 61.8, 62.8, 116.3, 126.6, 126.7, 127.1, 128.2, 128.5,
128.7, 129.1, 133.7, 134.6, 138.4, 149.8, 153.6, 156.8; EI-MS: m/z 316. Anal.
Calcd for C18H12N4O2 (316.32): C 68.35, H 3.82, N 17.71. Found: C 68.28,
H 3.75, N 17.78.
NH
O
7
Scheme 2ꢀA plausible mechanism for the formation of compounds 4.
3-Amino-1-(2-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4b)ꢀYellow pow-
der; yield 0.29 g (88%); mp 247–249°C; IR: 3383, 3300, 2207, 1659,
Conclusions
1
1603 cm−1; H NMR: δ 2.43 (3H, s, CH3), 6.30 (1H, s, CH), 7.17–7.28
The reaction between phthalhydrazide, malononitrile and
aromatic aldehydes in the presence of nano-ZrO2 offers
a simple one-pot access to pyrazolo[1,2-a][1,2,4]triazole-
1,3-dione derivatives of potential synthetic and pharma-
cological interest. The simplicity, easy workup, as well as
the safety and reusability of the catalyst are advantages of
this method.
(4H, m, Ar), 7.96–8.25 (6H, m, Ar and NH2); 13C NMR: δ 20.1, 61.2,
62.9, 122.0, 126.7, 127.2, 127.7, 128.1, 128.3, 128.5, 129.0, 130.3, 133.8,
134.8, 135.2, 136.5, 153.7, 154.2, 156.9; EI-MS: m/z 330. Anal. Calcd
for C19H14N4O2 (330.35): C 69.09, H 4.27, N 16.95. Found: C 68.95, H
4.25, N 16.96.
3-Amino-1-(3-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-pyra-
zolo[1,2-b]phthalazine-2-carbonitrile (4c)ꢀYellow powder; yield
0.29 g (89%); mp 250–252°C; IR: 3361, 3259, 2194, 1658, 1570 cm−1; 1H
NMR: δ 2.25 (3H, s, CH3), 6.08 (1H, s, CH), 7.11–7.22 (4H, m, Ar), 7.97–
8.26 (6H, m, Ar and NH2); 13C NMR: δ 21.0, 61.2, 62.8, 122.0, 122.3, 127.0,
127.4, 127.9, 128.4, 128.6, 128.9, 131.4, 134.2, 134.7, 135.8, 136.4, 154.1,
154.4, 157.3; EI-MS: m/z 330.
Experimental
Melting points were determined on an Electrothermal 9100 appa-
ratus and are not corrected. Infrared (IR) spectra were recorded in
KBr pellets on a Shimadzu 460 spectrometer. H NMR (400 MHz)
Anal. Calcd for C19H14N4O2 (330.35): C 69.09, H 4.27, N 16.95.
Found: C 69.12, H 4.18, N 16.85.
1
and 13C NMR (100 MHz) spectra were recorded on a Bruker AVANCE
400 spectrometer using DMSO-d6 as a solvent. Electron impact mass
spectra were obtained at 70 eV on a Finnigan MAT 8430 mass spectro-
meter. Elemental analyses for C, H and N were obtained on a Heraeus
CHNO Rapid analyzer. All commercially available chemicals and rea-
gents were used without further purification. In all experiments, ZrO2
(5–25 nm, Plasma Chem GmbH) was used.
3-Amino-1-(3-methoxyphenyl)-5,10-dioxo-5,10-dihydro-
1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
(4d)ꢀYellow
powder; yield 0.30 g (87%); mp 247–249°C; IR: 3363, 3260, 2189,
1
1655, 1567 cm−1; H NMR: δ 3.76 (s, 3H, OCH3); 6.15 (s, 1H), 6.90 (d,
3Jꢁꢁ=ꢁꢁ8.0 Hz, 1H), 6.96–6.99 (m, 2H), 7.26 (t, 3Jꢁꢁ=ꢁꢁ7.5 Hz, 1H), 7.65–7.99
(m, 2H), 8.09–8.12 (m, 3H, NH2, CH), 8.25–8.28 (m, 1H); 13C NMR:
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ꢂ3
M. Piltan: 1H-Pyrazolo[1,2-b]phthalazine-5,10-dionesꢂ
[7] Al’-Assar, F.; Zelenin, K. N.; Lesiovskaya, E. E.; Bezhan, I. P.;
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δ 55.7, 61.2, 62.6, 112.8, 114.5, 119.2, 124.3, 126.8, 127.2, 128.9, 129.1,
129.2, 129.6, 134.3, 137.6, 150.6, 153.2, 157.1, 160.0; EI-MS: m/z 346.
Anal. Calcd for C18H11N5O4 (346.35): C 65.89, H 4.07, N 16.18. Found:
C 65.78, H 4.15, N 16.24.
1-hydroxy, 1-amino-, and 1-hydrazino-substituted 2,3-dihydro-
1H-pyrazolo[1,2-a]pyridazine-5,8-diones and 2,3-dihydro-
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3-Amino-1-(4-chlorophenyl)-5,10-dihydro-5,10-dioxo-1H-pyra-
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one derivatives under solvent-free conditions. RSC Adv. 2014,
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1
0.33 g (93%); mp 273–275°C; IR: 3362, 3256, 2188, 1661, 1652 cm−1; H
NMR: δ 6.17 (1H, s, CH), 7.43–7.54 (4H, m, Ar), 7.94–8.18 (6H, m, Ar and
NH2); 13C NMR: δ 61.7, 62.6, 116.7, 126.8, 127.7, 128.2, 128.7, 129.3, 129.4,
133.3, 134.0, 134.7, 137.4, 150.2, 154.1, 157.3; EI-MS: m/z 350. Anal. Calcd
for C18H11N4O2Cl (350.77): C 61.64, H 3.16, N 15.97. Found: C 61.53, H
3.13, N 16.03.
[10] Nabid, M. R.; Rezaei, S. J. T.; Ghahremanzadeh, R.; Bazgir, A.
Ultrasoundassisted one-pot, three-component synthesis of
1H-pyrazolo[1,2-b]phthalazine-5,10-diones. Ultrason. Sono-
chem. 2010, 17, 159–161.
[11] Raghuvanshi, D. S.; Singh, K. N. A highly efficient green synthesis
of 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives and their
photophysical studies. Tetrahedron Lett. 2011, 52, 5702–5705.
[12] Safaei-Ghomi, J.; Shahbazi-Alavi, H.; Ziarati, A.; Tey-
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1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives with CuI
nanoparticles as catalyst under solvent-free conditions. Chin.
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[13] Reddy, M. V.; Jeeong, Y. T. InCl3-catalyzed green synthesis of
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conditions. Tetrahedron Lett. 2013, 54, 3546–3549.
[14] Shaterian, H. R.; Mohammadnia, M. Mild preparation of
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives with mag-
netic Fe3O4 nanoparticles coated by (3-aminopropyl)-triethox-
ysilane as catalyst under ambient and solvent-free conditions.
Res. Chem. Intermed. 2014, 40, 371–383.
3-Amino-1-(4-nitrophenyl)-5,10-dioxo-5,10-dihydro-1H-pyra-
zolo-[1,2-b]phthalazine-2-carbonitrile
(4f)ꢀYellow
powder;
yield 0.35 g (96%); mp 226–228°C; IR: 3371, 3301, 3079, 2185, 1662,
1554 cm−1; 1H NMR: δ 6.30 (s, 1H); 7.81 (d, 3Jꢁꢁ=ꢁꢁ8.6 Hz, 2H), 7.97–8.09 (m,
3
3H), 8.22 (brs, 2H, NH2), 8.24 (d, Jꢁꢁ=ꢁꢁ8.6 Hz, 2H), 8.26–8.29 (m, 1H);
13C NMR δ 61.5, 62.9, 116.5, 126.1, 127.9, 128.1, 128.8, 129.1, 129.4, 134.5,
134.9, 146.4, 147.6, 150.8, 154.0, 157.2; EI-MS: m/z 361. Anal. Calcd for
C18H11N5O4 (361.32): C 59.84, H 3.07, N 19.38. Found: C 60.13, H 3.13, N
19.23.
3-Amino-1-(2-nitrophenyl)-5,10-dioxo-5,10-dihydro-1H-pyra-
zolo-[1,2-b]phthalazine-2-carbonitrile (4g)ꢀYellow powder; yield
1
0.34 g (95%); mp 261–263°C; IR: 3380, 3165, 2192, 1694, 1655 cm−1; H
NMR: δ 6.64 (1H, s, CH), 7.59–8.28 (10H, m, Ar and NH2); 13C NMR δ
61.1, 62.8, 106.5, 124.1, 126.8, 127.3, 128.1, 128.9, 129.2, 129.7, 133.4, 134.0,
134.6, 135.0, 148.4, 151.8, 154.2, 157.0; EI-MS: m/z 361. Anal. Calcd for
C18H11N5O4 (361.32): C 59.84, H 3.07, N 19.38. Found: C 59.98, H 3.15, N
19.16.
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Acknowledgments: We gratefully acknowledge financial
support from the Research Council of Islamic Azad Uni-
versity, Sanandaj Branch.
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