JOURNAL OF CHEMICAL RESEARCH 2015 483
Table
2
Synthesis of pyrazolo[1,2-b]phthalazine derivatives using
reflux for 10 min. Then the appropriate aldehyde (1.0 mmol) and
malononitrile (1.0 mmol) were added, and the mixture was refluxed
for the specified time to complete the reaction (Table 2). The progress
of the reaction was monitored by TLC (ethyl acetate/n-hexane).
After the reaction was complete, the mixture was allowed to cool to
room temperature. The residue that had precipitated during this time
was separated from the solution by filtration, and recrystallised from
ethanol to afford the pure product 5.
potassium carbonate
M.p./°C
Found
265–268 274–276
260–263 270–272
Entry R
Product Time/min Yield/%
Lit.
1
8
1
2
3
4
5
6
7
8
9
H
5a
5b
5c
5d
5e
5f
50
50
50
70
50
70
60
80
80
50
95
92
90
86
96
85
86
86
90
92
9
4-Cl
2-Cl
4-NO2
4-Br
1
8
258–260 258–259
260–262 264–266
263–265 265–267
1
2
0
7
5
3
-Amino-1-phenyl-5,10-dihydro-5,10-dioxo-1H-pyrazolo[1,2-b]
1
-1
phthalazine-2-carbonitrile (5a): IR (KBr) n /cm 3361, 3260, 3100,
2198, 1659, 1567, 1439, 1384; HNMR (400 MHz, DMSO-d ): δ 6.12
1
max
4-CH3
250–254 253–255
1
6
1
2,4-Cl2
5g
5h
5i
259–261 259–261
247–250 248–250
(s, 1H, CH), 7.31–7.45 (m, 5H, ArH), 7.96–8.26 (m, 6H, ArH and NH ).
2
1
8
2-OCH3
3-Amino-1- (4-methylphenyl)-5,10-dihydro-5,10-dioxo-1H-
1
4
-1
4-OCH3
4-F
259–261 259–261
264–267 263–265
pyrazolo[1,2-b]phthalazine-2-carbonitrile (5f): IR (KBr) nmax/cm
1
0
1
10
5j
3414, 3290, 2208, 1615, 1566, 1470, 1389, 1361, 1198; H NMR (400
MHz, DMSO-d ): δ 2.28 (s, 3H, CH ), 6.07 (s, 1H, CH), 7.14–7.33 (m,
6
3
4
H, ArH), 7.94–8.25 (m, 6H, ArH and NH ).
2
free conditions. The best results were obtained in ethanol
under reflux conditions. To find the optimum temperature, the
mixture was heated at different temperatures. It was observed
that the reaction did not proceed at room temperature. At
reflux conditions, the reaction proceeded smoothly and almost
complete conversion to the product was observed.
3
-Amino-1-(2,4-dichlorophenyl)-5,10-dioxo-5,10-dihydro-1H-
-
1
pyrazolo[1,2-b]phthalazine -2-carbonitrile (5g): IR (KBr) nmax/cm
3
MHz, DMSO-d ): δ 6.34 (s, 1H, CH), 7.31–8.78 (m, 9H, ArH and NH ).
1
411, 3372, 2206, 1666, 1616, 1582, 1468, 1383, 1101; H NMR (400
6
2
3
-Amino-1-(2-methoxyphenyl)-5,10-dioxo-5,10-dihydro-1H-
-1
pyrazolo[1,2-b]phthalazine-2-carbonitrile (5h): IR (KBr) nmax/cm
Hence, the best reaction conditions for the synthesis of
3
480, 3354, 3183, 2192, 1649, 1614, 1509, 1466, 1405, 1262, 1151;
3
2
-amino-1-phenyl-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-
-carbonitrile 5a was found to be through a one-pot, four-
1
H NMR (400 MHz, DMSO-d ): δ 3.63 (s, 3H, OCH ), 6.28 (s, 1H,
6
3
CH), 6.90–7.28 (m, 4H, ArH), 7.97–8.27 (m, 6H, ArH and NH ).
2
component reaction of phthalic anhydride, hydrazine hydrate,
benzaldehyde and malononitrile in the presence of K CO (0.1
g on a 1 mmol scale) in ethanol under reflux conditions and the
product 5a was obtained in 95% after 50 min.
Paper 1503379 doi: 10.3184/174751915X14382558688543
Published online: 7 August 2015
2
3
With the optimal reaction conditions in hand, the scope of this
four-component reaction was examined by using other aldehydes.
The data in Table 2 show that, in all cases, the reactions gave
the corresponding products in good to excellent yield. Different
substituted aryl aldehydes were employed under the optimised
reaction conditions. Satisfactorily, aryl aldehydes bearing
electron-donating as well as electron-withdrawing substituents
afforded the corresponding 3-amino-1-aryl-5,10-dioxo-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitriles 5a–j in high yields.
The products are known and their structures were
characterised by comparing their physical and spectral data with
References
1
2
3
4
M. S. Singh and S. Chowdhury, RSC Adv., 2012, 2, 4547.
A. Dhakshinamoorthy and H. Garcia, Chem. Soc. Rev., 2014, 43, 5750.
A. Majumder, R. Gupta and A. Jain, Green Chem. Lett. Rev., 2013, 6, 151.
Macromolecules, 2014, 47, 1285.
5
6
R. P. Jain and J. C. Vederas, Bioorg. Med. Chem. Lett., 2004, 14, 3655.
L. Zhang, L. P. Guan, X. Y. Sun, C. X. Wei, K. Y. Chai and Z. S. Quan,
Chem. Biol. Drug Des., 2009, 73, 313.
7
J. Sinkkonen, V. Ovcharenko, K.N. Zelenin, I.P. Bezhan, B.A. Chakchir, F.
Al-Assar and K. Pihlaja, Eur. J. Org. Chem., 2002, 2046.
D.S. Raghuvanshi and K.N. Singh, Tetrahedron Lett., 2011, 52, 5702.
R. Ghahremanzadeh, G. Imani Shakibaei and A. Bazgir, Synlett, 2008, 8,
1129.
8
9
8
-19
those of authentic samples. Note that all the products were
purified by a simple process of crystallisation and filtration; no
chromatography was involved.
10
M.R. Nabid, S.J.T. Rezaei, R. Ghahremanzadeh and A. Bazgir, Ultrason.
Sonochem., 2010, 17, 159.
In conclusion, a straightforward, facile and less time
consuming method has been described for preparing 3-amino-1-
aryl-5,10-dioxo-1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile
derivatives through a one-pot, four-component reaction of
phthalic anhydride, hydrazine hydrate, aromatic aldehydes and
malononitrile using K CO as the cost effective catalyst. The
1
1
M.V. Reddy and Y.T. Jeong, Tetrahedron Lett., 2013, 54, 3546.
12
13
N.M. Shah, M.P. Patel and R.G. Patel, J. Heterocyclic Chem., 2012, 49,
1310.
14
S.H. Song, J. Zhong, Y.H. He and Z. Guan, Tetrahedron Lett., 2012, 53,
7075.
2
3
simplicity, easy work-up, the avoidance of using hazardous
and expensive solvents and catalysts are the most significant
advantages over previously reported methods.
1
5
H.R. Shaterian, M. Mohammadnia, J. Mol. Liq., 2012, 173, 55.
16 L. Torkiana, M. Dabiri, P. Salehi and M. Bararjanian, Helv. Chim. Acta,
011, 94, 1416.
17
2
J. Safaei-Ghomi, H. Shahbazi-Alavi, A. Ziarati, R. Teymuri and M.R.
Saberi, Chinese Chem. Lett., 2014, 25, 401.
H.R. Shaterian and M. Mohammadnia, Res. Chem. Intermed., 2014, 40,
Experimental
18
All reagents were commercially available and used without further
purification. Melting points were measured using an Electrothermal
type 9100 melting point apparatus. The IR spectra were recorded on a
Shimadzu FTIR 4300 spectrophotometer as KBr disks. NMR spectra
were determined on a Bruker AC 400 MHz spectrometer for DMSO-d6
solutions.
3
71.
19 E. Mosaddegh and A. Hassankhani, Tetrahedron Lett., 2011, 52, 488.
2
014, 7, 60.
2
2
2
1
2
3
Z. Karimi-Jaberi and B. Pooladian, Synth. Commun., 2013, 43, 1188.
Z. Karimi-Jaberi and B. Pooladian, Sci. World J., 2012, 208796.
M. Misra, R. Sharma, R. Kant, P. R. Maulik and R. P. Tripathi, Tetrahedron
Lett., 2011, 67, 740.
L. Shen, S. Cao, J. Wu, H. Li, J. Zhang, M. Wu and X. Qian, Tetrahedron
Synthesis of pyrazolo[1,2-b]phthalazine derivatives 5; general
procedure
2
4
A mixture of phthalic anhydride (1.0 mmol), hydrazine hydrate
(
1.0 mmol), and K CO (0.1 g) in ethanol (5 mL) was stirred under
Satyanarayana, J. Sulfur Chem., 2015, 36, 105.
2
3