Introduction

Recently, science and technology are shifting emphasis toward environmentally friendly and green organic processes [1]. In this regard, bio-supported and solid heterogeneous catalysts for the synthesis of fine chemicals have attracted considerable interest for both environmental and economical reasons [2]. Cellulose and its derivatives have some unique properties which make them attractive alternatives for conventional synthetic organic or inorganic supports for catalytic applications [3]. Cellulose-SO3H has been widely studied as a biodegradable catalyst and a renewable resource, whichis easily separated from reaction mixtures with simple filtration and can be reused several times without any considerable loss of its activities [4]. Cellulose-SO3H shows excellent catalytic properties which are attributed to the high thermal stability and strong acidity sites of sulfonic acid functional groups on this bio-polymer [4].

Phthalazine derivatives have been reported to possess anticonvulsant [5], cardiotonic [6] and vasorelaxant [7] activities. A number of methods have been reported via the three-component reactions (3-CRs) of phthalhydrazide, dimedone, and aromatic aldehydes under solvent-free conditions [8–13].

In continuation of our research toward the development of new green routes for the synthesis of heterocyclic compounds using green reaction mediums [14–17], we now report an efficient method for the four-component synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives using cellulose-SO3H as a recyclable solid acid catalyst under solvent-free conditions (Scheme 1).

Scheme 1
scheme 1

Preparation of 2H-indazolo[2,1-b]phthalazine-trione

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Experimental

General

All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated products after purification. Cellulose-SO3H was prepared according to the literature [4] and 0.08 g of the catalyst has 4 mol% of H+ [4]. The NMR spectra were recorded on a Bruker Avance DPX 300 MHz instrument. The spectra were measured in DMSO-d 6 relative to TMS (0.00 ppm). IR spectra were recorded on a JASCO FT-IR 460 plus spectrophotometer. Mass spectra were recorded on an Agilent technologies 5973 network mass selective detector (MSD) operating at an ionization potential of 70 eV. TLC was performed on silica-gel Poly Gram SIL G/UV 254 plates.

General procedure for the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives

Hydrazinium hydroxide (1.2 mmol) and phthalic anhydride (1 mmol) were mixed at 80 °C until a white solid phthalhydrazide was formed (10 min). Then, dimedone (1 mmol), aromatic aldehyde (1 mmol), and cellulose-SO3H (0.08 g, 4 mol%) were added to this solid state mixture. The reaction mixture was melted at 80 °C. The completion of reaction was monitored on TLC. The 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives were synthesized. After satisfactory completion, the reaction mass was cooled to 25 °C, then the solid residue was dissolved in hot EtOH and the catalyst was filtered off. The filtrate solution was concentrated and the solid crude product was purified by recrystallization in aqueous EtOH (25 %).

The desired pure products were characterized by comparison of their physical data (melting points, IR, 1H and 13C NMR) with those of known compounds [9–11, 18].

Results and discussion

To choose optimum conditions, first we tried to prepare 2H-indazolo[2,1-b]phthalazine-trione from the reaction of benzaldehyde (1 mmol), dimedone (1 mmol) phthalic anhydride (1 mmol) and hydrazinium hydroxide (1.2 mmol) as a model under solvent-free conditions at different temperatures (60, 70, 75, 80, 90 °C) in the presence of cellulose-SO3H (0.05 g, 2.5 mol%). The best result was obtained at 80 °C. Next, the model was examined with different amounts of cellulose-SO3H (0.05, 0.06, 0.07, 0.08, 0.09 g) at 80 °C. The highest yield and short reaction time was obtained at 80 °C and 0.08 g (4 mol%) of the catalyst.

Using these optimized reaction conditions, the scope and efficiency of these procedures were explored for the synthesis of a wide variety of substituted 2H-indazolo[2,1-b]phthalazine-triones. Interestingly, a variety of aldehydes including ortho-, meta-, and para- substituted aryl aldehydes participated well in this reaction and gave the 2H-indazolo[2,1-b]phthalazine-trione derivatives in good to excellent yield (Table 1). As can be seen from Table 1, both aromatic aldehydes carrying electron-donating or electron-withdrawing substituents act well in these reaction conditions. Aliphatic aldehydes such as n-heptanal and n-octanal were intact in the mentioned reaction (Table 1, Entries 13, 14).

Table 1 Preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives via the four-component condensation reaction from hydrazinium hydroxide, phthalic anhydride, dimedone, and aromatic aldehydes using cellulose-SO3H as catalyst
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According to a literature survey [11], the suggested mechanism for the formation of the products is shown in Scheme 2. First, the reaction occurs via initial nucleophilic addition of phthalic anhydride (1) to hydrazinium hydroxide (2) and followed by dehydration to form phthalhydrazide in the absence of the catalyst under thermal solvent-free conditions. Next, intermediate (6) was formed by standard Knoevenagel condensation of aldehyde (4) and dimedone (5) in the presence of cellulose-SO3H. Subsequent Michael addition of the phthalhydrazide (3) to (6) in the presence of the catalyst followed by cyclization affords the corresponding product (7) (Scheme 2).

Scheme 2
scheme 2

The proposed mechanism for one-pot synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives

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In order to show the accessibility of the present work (4-CRs) in comparison with the three-component reported results in the literature such as H2SO4 [18], PMA-SiO2 [11], Mg(HSO4)2 [9] and TMSCl [19], we summarize some of the results for the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione in Table 2, which shows that cellulose-SO3H is the most efficient catalyst reaction time and temperature, and exhibits broad applicability in terms of the obtained yield.

Table 2 Comparison results of cellulose-SO3H with other catalyst for the preparation of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione
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We also studied the reusability of the catalysts in the reaction of benzaldehyde, dimedone, phthalic anhydride, and hydrazinium hydroxide under solvent-free conditions at 80 °C. In this procedure, after completion of the reaction, the reaction mixture was cooled to room temperature, and the crude solid was dissolved in hot ethanol. The mixture was filtered for separation of the catalyst. The catalyst was washed twice with (2 × 5 mL) hot ethanol. The recovered catalyst was dried in 60 °C and was used for the subsequent catalytic runs without any loss of its activities (Fig. 1).

Fig. 1
figure 1

Reusability of the catalysts in the reaction of benzaldehyde, dimedone and phthalic anhydride, hydrazinium hydroxide under solvent-free conditions (Table 1, Entry 1)

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Conclusions

We have developed a green and straightforward protocol for the synthesis of 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-trione via the four-component condensation reaction from hydrazinium hydroxide, phthalic anhydride, dimedone, and aromatic aldehydes using cellulose-SO3H as a bio-supported catalyst under solvent-free conditions. This procedure provides several advantages such as cleaner reactions, easier workup, and reduced reaction times, as well as a reusable catalyst, and is an eco-friendly promising strategy.