Reusable silica supported poly phosphoric acid catalyzed three-component synthesis of 2 H -indazolo[2,1-b ]phthalazine-trione derivatives

An efficient synthesis of 2 H -indazolo[2,1-b]phthalazine-1,6,11(13 H )-trione derivatives from the three-component condensation reaction of phthalhydrazide, dimedone, and aromatic aldehydes under solvent-free conditions in good to excellent yields and short reaction times using reusable silica supported poly phosphoric acid (PPA–SiO 2 ) as heterogeneous acid catalyst has been investigated.


Introduction
2][3] Among the various heterogeneous catalysts, particularly, silica supported reagents have advantages of low cost, ease of preparation, and catalyst recycling.These catalysts are generally less expensive, eco-friendly, high reactive, easy to handle and recoverable.][3] In the past few decades, the synthesis of new heterocyclic compounds has been a subject of great interest due to their wide applicability.Heterocyclic compounds occur very widely in nature and are essential to life.Among a large variety of heterocyclic compounds, heterocycles containing the phthalazine moiety are of interest because they show some pharmacological and biological activities. 4Phthalazine derivatives were reported to possess anticonvulsant, 5 cardiotonic, 6 and vasorelaxant 7 activities.
Recently the synthesis of 2H-indazolo[2,1-b]phthalazine-triones has been reported by Bazgir et al using p-TSA as expensive and non recyclable catalyst. 8In continuation of our interest in heterogeneous catalysts as well as solvent-free organic reactions, 3 a simple, new, and efficient protocol for the preparation of 2H-indazolo[2,1-b]phthalazine-trione derivatives using a catalytic amount of recyclable PPA-SiO 2 under solvent-free conditions is described (Scheme 1).PPA-SiO 2 is safe, easy to handle, environmentally benign with fewer disposals problems.PPA-SiO 2 was prepared from the reaction of silica gel with poly phosphoric acid.9a PPA-SiO 2 has been used in some organic reactions, such as: conversion of carbonyl compounds into oxathioacetals and dithioacetals, 9a synthesis of amidoalkyl naphthols, 9b one-pot Knoevenagel condensation, Michael addition and cyclo-dehydration of dimedone and aldehydes.9c

Results and Discussions
To choose optimum conditions, first, the effect of temperature on the rate of the reaction was studied for the preparation of 2,2-dimethyl-13-phenyl-2,3-dihydro-1H-indazolo[2,1-b]phthalazine-4,6,11(13H)-trione from the three-component condensation reaction of phthalhydrazide, dimedone, and benzaldehyde under solvent-free conditions (Table 1).At 80 o C, the reaction proceeded smoothly and almost complete conversion of product was observed.Further increase in temperature to, 100 and 120 o C increased the rate of reaction.Therefore, we kept the reaction temperature as 100 o C (giving short reaction time and high yield).
Next, the study set out to determine optimal amount of PPA-SiO 2 , the reaction was carried out by varying amount of the catalyst (Table 1).Maximum yield was obtained with 0.1 g (0.05 mmol H + ) 9 of the catalyst.Further increase in amount of PPA-SiO 2 in the mentioned reaction did not has any significant effect on the product yield.a Yields refer to the isolated pure product b The molar ratio of phthalhydrazide, dimedone, and benzaldehyde was chosen 1/1/1.2.
The generality of this reaction was examined using several types of aldehydes.In all cases, the reactions gave the corresponding products in good to excellent yield (Table 2).This methodology offers significant improvements with regard to the scope of this transformation, simplicity in operation and green aspects by avoiding expensive or corrosive catalysts.We also have prepared 5 new analogues of this class of compounds in high yields (Table 2, Entries 9-13).a Yields 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. 8The reaction was carried out under thermal solvent-free conditions in an oil bath at 100 o C; The molar ratio of aldehyde / phthalhydrazide / dimedone / PPA-SiO 2 is ((12 / 10 / 10 / 0.5 (1 g)) The suggested mechanism of the PPA-SiO 2 catalyzed transformations is shown in Scheme 2. As reported in the literature the Knoevenagel type coupling of arylaldehyde with active methylene compounds such as dimedone give 2-benzylidene-5,5-dimethylcyclohexane-1,3-dione (I). 10 Then, the subsequent 1,4-conjugate addition of phthalhydrazide to the intermediate (I) followed by cyclization affords the corresponding products.

Scheme 2
The reusability of the catalyst was tested in the synthesis of 2,2-dimethyl-13-phenyl-2,3dihydro-1H-indazolo[2,1-b]phthalazine-4,6,11(13H)-trione, as shown in Figure 1.The catalyst was recovered after each run, washed three times with acetone, dried in an oven at 100 o C for 30 min prior to use and tested for its activity in the subsequent run.The catalyst was tested for 5 runs.It was seen that the catalyst displayed very good reusability (Figure 1).

Conclusions
In summary, an efficient protocol for the one-pot preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives from the three-component condensation reaction of phthalhydrazide, dimedone, and aromatic aldehydes using a commercially available, environmental friendly and reusable PPA-SiO 2 as catalyst was described.The reactions were carried out under thermal solventfree conditions with short reaction time and produced the corresponding products in good to excellent yields.Also the catalyst could be successfully recovered and recycled at least for five runs without significant loss in activity.The one-pot nature and the use of heterogeneous solid acid as an eco-friendly catalyst make it an interesting alternative to multi-step approaches.Also, five new analogues of this class of compounds were prepared in high yields.

Experimental Section
General Procedures.All reagents were purchased from Merck and Aldrich and used without further purification.All yields refer to isolated products after purification.PPA-SiO 2 was prepared according to the reported procedure. 9Products were characterized by comparison of spectroscopic data (IR, 1 H NMR, 13 C NMR spectra) and melting points with authentic samples.Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer.The NMR spectra were recorded on a Bruker Avance DPX 300 MHz instrument.The spectra were measured in CDCl 3 relative to TMS (0.00 ppm).IR spectra were recorded on a JASCO FT-IR 460plus spectrophotometer.All of the compounds were solid and solid state IR spectra were recorded using the KBr disk technique.Mass spectra were recorded on an Agilent technologies 5973 network mass selective detector (MSD) operating 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 polygram SIL G/UV 254 plates.