Chinese Chemical Letters  2014, Vol.25 Issue (12):1580-1582   PDF    
An environmentally friendly synthesis of 1,4-dihydropyrano [2,3-c]pyrazole derivatives catalyzed by tungstate sulfuric acid
Mahnaz Farahi, Bahador Karami , Iman Sedighimehr, Hamideh Mohamadi Tanuraghaj    
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
Abstract: An efficient three-component synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles via a reaction between 3-methyl-1-phenyl-2-pyrazolin-5-one, aromatic aldehydes and malononitrile using tungstate sulfuric acid as a catalyst was described. Mild conditions, good to excellent yields, easily available catalyst and easy work-up are the key features of this method.
Key words: 6-Amino-4-aryl-5-cyano-3-methyl-1-     phenyl-1,4-dihydropyrano[2,3-c]pyrazoles     3-Methyl-1-phenyl-2-pyrazolin-5-one     Aromatic aldehyde     Malononitrile     Tungstate sulfuric acid    
1. Introduction

There has been considerable interest in syntheses,reactions and biological activities of 4H-pyrane-containing molecules. Furthermore, 4H-pyrane derivatives also constitute a structural unit of some pharmaceutical agents,drug candidates,photoactive materials and natural products [1, 2]. These high profile applications and variety of biological activities have promoted extensive studies for the synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives [3].

Condensed pyrazoles are also biologically interesting compounds and their chemistry has recently received considerable attention [4]. Several pyrano[2,3-c]pyrazoles are reported to have useful biological effects,such as analgesic and anti-inflammatory activities [5]. Moreover,the biological activity of fused azoles has led to intensive research on their synthesis [6, 7]. Recently,the three component,one-pot condensation of 3-methyl-1-phenyl- 1H-pyrazol-5(4H)-one,aldehydes and malononitrile for the construction of 1,4-dihydropyrano[2,3-c]pyrazole derivatives has been reported using different conditions [8, 9].

Solid acids have been used as eco-friendly and reusable catalysts in various organic transformations. The solid acid catalysts were well received by the synthetic community because of their reusability,lack of toxicity,and easy work-up [10]. Recently,we found that anhydrous sodium tungstate (1) reacts with chlorosulfonic acid (2) to give tungstate sulfuric acid (3) (Scheme 1).

Scheme 1.Preparation of tungstate sulfuric acid (TSA).
2. Experimental

Catalyst preparation: Firstly,25 mL of dry n-hexane was taken in a 100 mL round bottom flask,equipped with ice bath and overhead stirrer,and 5.876 g (2 mmol) of anhydrous sodium tungstate was added to the flask,then 0.266 mL (4 mmol) of chlorosulfonic acid was added dropwise to the flask in 30 min. This solution was stirred for 1.5 h,the reaction mixture was slowly poured into 25 mL of chilled distilled water with agitation. The yellowish solid was filtered,washed with distilled water five times till the filtrate showed negative for chloride ion test,and dried at 120 ℃ for 5 h. The catalyst was obtained in 98% yield and decomposed at 285 ℃ [11].

General procedure for the preparation of 6-amino-4-aryl-5- cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles: A mixture of 3-methyl-1-phenyl-2-pyrazolin-5-one (1 mmol),aromatic aldehyde (1 mmol),malononitrile (1 mmol),and TSA (10 mol%) in ethanol (10 mL) was refluxed for an appropriate period of time. After the completion of the reaction (monitored by TLC analysis),the catalyst was separated by filtration. The solvent was removed under vacuum and the products 7 were purified by recrystallization from EtOH/H2O. 3. Results and discussion

Fig. 1(A) shows the XRD patterns of tungstate sulfuric acid (TSA). It was reported that high degree mixing of W-S in chlorosulfonic acid often led to the absence of XRD pattern for anhydrous sodium tungstate. The broad peak around 25.7° (2θ) (θ is the Bragg's angle) from the smaller inset could be attributed to insertion of W into the framework of chlorosulfonic acid.

Fig. 1.(A): The powder X-Ray diffraction pattern of the tungstate sulfuric acid. (B): FT-IR spectra of TSA and sodium tungstate.

The FT-IR spectra of anhydrous sodium tungstate and TSA are shown in Fig. 1(B). The spectrum of tungstate sulfuric acid shows the characteristic bonds of anhydrous sodium tungstate and chlorosulfonic acid. The adsorption bands in 3406,1820,1725, 1702,1620,1290,1060,1005 and 860 cm-1 in the catalyst spectrum reveal both bonds in anhydrous sodium tungstate and the -OSO3H group. Hence titration of catalyst with NaOH (0.1mol/L) was conducted. Catalyst (1 mmol) was dissolved in 100 mL of water and titrated with NaOH (0.1 mol/L) using phenolphthalein as an indicator. Itwas found that for 1 mmol of catalyst,4 mmol of NaOH was utilized. This result shows that each complex contains two acidic groups. TheXRF data of tungstate sulfuric acid indicates the presence of WO4 and SO3 in this catalyst (Table 1).

Table 1
XRF data of TSA.

In continuation of our interest in using solid catalysts in the synthesis of heterocycles [11, 12, 13],in this work,we describe a simple and green strategy based on the condensation of 3-methyl- 1-phenyl-2-pyrazolin-5-one (4),aromatic aldehydes (5) and malononitrile (6) using TSA as a powerful,recyclable and safe catalyst for the preparation of novel and known 6-amino-4-aryl-5- cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles (7) (Scheme 2).

Scheme 2.TSA-catalyzed synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles 7.

To determine the suitable reaction conditions,a solvent-free reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one,benzaldehyde and malononitrile was performed at room temperature. A low conversion was observed. Then,the reaction was heated for 4 h, but again full conversion was not achieved. So,we studied the effect of solvent,temperature and various catalytic amount of the TSA catalyst on the model reaction (Table 2).

Table 2
Optimization of the reaction conditions.

As can be seen,the best results were obtained by performing the reaction in the presence of 10 mol% of TSA in refluxing ethanol. Then the generality of the procedure was evaluated using various aromatic aldehydes under optimized reaction conditions. It was found that both,electron rich and electron poor aryl aldehydes reacted well in this process to afford the corresponding products in good to excellent yields (Table 3).

Table 3
Synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3- c]pyrazoles by TSA.

We propose the possible following mechanism for the reaction. One molecule of malononitrile is firstly condensed with the aromatic aldehyde activated by the strong solid acid TSA to afford a-cyanocinnamonitrile derivative 8. Then nucleophilic attack of the active methylene of 4-8 gives the intermediate 9 followed by tautomerization to produce 10. Cyclization of 10 by the nucleophilic attack of the OH group in the cyano moiety gives 11 and subsequently products 7 (Scheme 3).

As an eco-friendly procedure,the recovery and reusability of the catalyst are quite preferable. The recovered TSA from the model reaction was regenerated by washing with ethylacetate and dried at 100 ℃ for 1 h. The recycled catalyst can be used at least four consecutive times in the model reaction,albeit in gradually decreased yields.

From these results,we identified the best conditions for the synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4- dihydropyrano[2,3-c]pyrazoles with the TSA catalyst. Comparison of this method with others in the synthesis of 6-Amino-5-cyano-3- methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole (7a) as a model reaction is shown in Table 4. These results show that this catalyst compared favorably in the synthesis of 1,4-dihydropyrano[ 2,3-c]pyrazole derivatives with the other reported catalysts and methods.

Table 4
Comparison of the results for the synthesis of 7a by the other catalysts.
4. Conclusion

In summary,the reaction between 3-methyl-1-phenyl-2- pyrazolin-5-one,aromatic aldehydes and malononitrile using tungstate sulfuric acid as a catalyst provides a simple and efficient one-pot entry for the synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives. The use of a green and recyclable catalyst,high yield of products,and a simple workup procedure make the present method a valuable contribution in accord with green chemistry principles.

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