An Efficient and High-yielding One-pot Synthesis of 1 H-pyrazolo [ 1 , 2-b ] phthalazine-5 , 10-diones Catalyzed by Sodium Hydrogen Carbonate under Solvent-free Conditions

Sodium hydrogen carbonate, NaHCO 3 , efficiently catalyzes the one-pot, three-component reaction of phthalhydrazide, an aromatic aldehyde, and malononitrile or ethyl cyanoacetate under solvent-free conditions, to afford the corresponding 1H-pyrazolo[1,2-b]phthalazine-5,10-diones in high yields. Easy work up, inexpensive and readily available catalyst and avoiding the use of harmful organic solvents are other advantages of this simple procedure.


INTRODUCTION
The presence of pyrazole and phthalazine ring systems, either alone or as a fused ring with other heterocyclic moieties, in a number of pharmacologically significant molecules have made them prime targets for scientific research.Literature reports had already established pyrazoles and phthalazines as anticancer 1,2 , antifungal 3,4 , anti-inflammatory 5 , antiviral 6 , antidepressant 7 , antibacterial 8 , antipyretic 9 , and anticonvulsant 10 agents.Some substituted pyrazoles also act as inhibitors of COX-2 and B-Raf kinases 11,12 .On the other hand, pyrazoles are of interest as efficient analytical regents in the complexation of transitionmetal ions 13 and are the core structure of blockbuster drugs such as celecoxib, viagra, pyrazofurine, and many others [14][15][16][17] .In addition, recently, the titled compounds, 1H-pyrazolo[1,2-b]phthalazine-5,10diones containing two active pharmacophores pyrazole and phthalazine, attracted organic chemists because of their antiinflammatory, analgesic, antihypoxic, and antipyretic activities 18 .A perusal of literature reveals that there are only a few methods for the one-pot, three-component synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10diones which involve the cyclocondensation of phthalhydrazide, aldehyde, and malononitrile or ethyl cyanoacetate in the presence of P-TSA 19 , nano ZnO 20 , InCl 3 21 , and Al-KIT-6 22 as catalyst.Syntheses of these compounds using [bmim]OH or Et 3 N under microwave 23 or ultrasonic irradiation 24 , respectively, have also been reported.In addition, they can also be accessed by the one-pot, four-component reaction of phthalimide or phthalic anhydride, hydrazine hydrate, aldehyde, and an active methylene component [25][26][27][28] .Each of these methods has its own merit, however, many of them suffer from disadvantages such as the use of halogenated solvent or catalyst, long reaction time and using microwave irradiation for accelerated synthesis.Therefore, the development of a new greener and more convenient method using a new readily available catalyst with high catalytic activity for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10diones is highly desirable.

EXPERIMENTAL
All chemicals were available commercially and used without additional purification.Melting points were recorded using a Stuart SMP3 melting point apparatus.The FT-IR spectra of the products were obtained with KBr disks, using a Tensor 27 Bruker spectrophotometer.The 1 H NMR and 13 C-NMR spectra were recorded using a Bruker 400 spectrometer at 400 and 100 MHz frequencies, respectively.

General Procedure for the Synthesis of 1Hpyrazolo[1,2-b]phthalazine-5,10-diones 4a-m catalyzed by NaHCO 3
A mixture of phthalhydrazide (1 mmol), an aromatic aldehyde (1 mmol), malononitrile or ethyl cyanoacetate (1 mmol), and NaHCO 3 (1 mmol) was heated in an oil bath at 120 °C for 15-50 min.The reaction was monitored by TLC.Upon completion of the transformation, the reaction mixture was cooled to room temperature and warm water was added.This resulted in the precipitation of the product, which was collected by filtration.The crude product was washed with warm water repeatedly and then with warm ethanol to give compounds 4am in high yields.

RESULTS AND DISCUSSION
The one-pot synthesis of 1H-pyrazolo[1,2b]phthalazine-5,10-diones was achieved by the three-component cyclocondensation of phthalhydrazide, aromatic aldehydes and malononitrile or ethyl cyanoacetate using NaHCO 3 as catalyst.At first, the synthesis of compound 4a was selected as a model reaction to optimize the reaction conditions.The reaction was carried out by heating a mixture of phthalhydrazide (1 mmol), benzaldehyde (1 mmol), and malononitrile (1 mmol) under various conditions.We decided to investigate the efficiency of NaHCO 3 in the model reaction under solvent-free conditions, which offers   1.No product was obtained in the absence of the catalyst at 120 °C under solvent free conditions even after 120 min (entry 1), indicating that the catalyst is necessary for the reaction.We were pleased to see that the reaction was efficiently catalyzed by NaHCO 3 under solventfree conditions at elevated temperature leading to a high yield of product 4a.Then, the reaction was performed in the presence of various amounts of the catalyst and also in different temperatures under solvent-free conditions.As can be seen, the efficiency of the reaction is affected mainly by the amount of NaHCO 3 and reaction temperature.The best result was obtained when the reaction was run at 120 °C in the presence of 1 mmol of NaHCO 3 (entry 12).For showing the effect of solvent, the same model reaction was also carried out in different solvents including H 2 O, MeOH, EtOH, CH 3 CN and CH 2 Cl 2 in the presence of 1 mmol of the catalyst (entries 15-19).As shown, the yield of the reaction under solvent-free conditions was greater and the reaction time was considerably shorter than the conventional methods.Therefore, our optimized conditions are 1 mmol of NaHCO 3 at 120 °C under solvent free conditions.All subsequent reactions were carried out using these conditions.
Encouraged by the remarkable results obtained with the above reaction conditions, and to show the generality and scope of this new protocol, a range of 1H-pyrazolo[1,2-b]phthalazine-5,10diones were prepared in the presence of NaHCO 3 under optimized conditions, with the results shown in Table 2. Most of the reactions proceeded very efficiently and no side products were observed.As can be seen from Table 2, aromatic aldehydes bearing either electron donating or electron withdrawing substituents reacted successfully with phthalhydrazide and malononitrile or ethyl cyanoacetate to give the corresponding 1Hpyrazolo[1,2-b]phthalazine-5,10-dione products in high yields over short reaction time.
To show the merit of the present methodology, the results have been compared with the other methods reported for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.This comparison is shown in Table 3.As can be seen, our method gave the desired products in high yields over short reaction times.

CONCLUSION
In conclusion, we have successfully developed an easy and efficient method to prepare a variety of 1H-pyrazolo[1,2-b]phthalazine-5,10diones from the reaction of phthalhydrazide, aromatic aldehydes, and malononitrile or ethyl cyanoacetate in the presence of NaHCO 3 under solvent-free conditions.Short reaction times, simple performance and work-up procedure, high yields, low cost of the catalyst, and the absence of any hazardous organic solvents are some of advantages of this procedure.