Polyfunctionalized 4H-pyranshaveauniqueroleinmedicinal chemistry due to their wide range of biological and pharmacological activities ^{[1, 2]}. These compounds are utilized as anticancer agents,anti-coagulants,spasmolytics,and anti-anaphylactics ^{[3, 4]}. 4H-Pyran derivatives containing heterocyclic rings are extensively used for their pharmacological activities ^{[5, 6]}. Furthermore,4-phenyl-4H-pyrans have been identified as potent and specific IK_Ca channel blockers ^[7]. In addition,a number of 2-amino-4H-pyrans are valuable photoactive materials ^[8].

On the other hand,multicomponent reactions (MCRs) are efficient methods in heterocyclic scaffolds for the construction of diverse chemical libraries of drug-like molecules ^[9]. Synthetic strategies consisting MCRs have established themselves as a useful tool for the rapid introduction and development of molecular diversity ^[10]. MCRs increase the efficiency by combining several operational steps without isolation of intermediates or changing the reaction conditions ^{[11, 12]}. Because of their convergence and productivity,the MCRs have attracted noticeable attention from the combinatorial chemistry community ^[13].

Previously,2-amino-4H-pyrans were produced by the cyclization of arylidenemalononitriles with β-dicarbonyl compounds in the presence of bases such as piperidine ^[14],triethylamine ^[15], magnesium oxide ^[16],Mg/La ^[17],PEG1000-DAIL/EM ^[18],and nano ZnO ^[19]. Furthermore,diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates was synthesized with a low yield, utilizing ZnCl₂ as a catalyst,acetic anhydride as the solvent,and column chromatography as the purification method ^{[20, 21]}.

However,many of these methods require expensive reagents, acidic conditions,long reaction times,excess of reagents/catalyst,or toxic organic solvents and tedious workup,yet the yields are sometimes not ideal. In recent years,the use of heterogeneous catalysts has provided significant advantages in organic synthesis,for example,environmental compatibility,operational simplicity; also they are low cost,nontoxic,and easy to separate from the reaction mixtures ^{[22, 23]}. Furthermore,heterogeneous solid acids and especially those based on silica gel and other mesoporous high surface area support materials are beginning to show an influential role in the greening of fine and speciality chemicals manufacturing procedures ^{[24, 25, 26]}. In continuation of our recent work using heterogeneous solid acid nanoparticles in organic reactions ^{[27, 28, 29]}, we decided to investigate nano silica supported tin (II) chloride (SnCl₂/nano SiO₂) as a green catalyst for the practical and environmentally benign one-pot multicomponent synthesis of diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylates and 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylic acid ethylester (Scheme 1).

Scheme 1

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Scheme 1. SnCl2/nano SiO2 catalyzed synthesis of polyfunctionalized 4H-pyrans.

Nano silica gel supported tin (II) chloride was prepared according to the procedure reported in the literatures with some modification ^{[30, 31]}. In a typical procedure,tin (II) chloride dihydrate (0.28 g) was added to a suspension of nano particles of silica gel (3.075 g) in dichloromethane (DCM) (25.0 mL). The mixture was stirred at room temperature overnight. Then the solvent was removed under reduced pressure and the residue was heated at 100℃ under vacuum for 5 h to furnish SnCl₂/nano SiO₂. The prepared SnCl₂/nano SiO₂ has been structurally characterized by EDAX and SEM analysis.

A mixture of aldehyde (2 mmol),ethyl acetoacetate (4 mmol), and nano silica supported tin (II) chloride (0.15 mol%) was refluxed in ethanol (10 mL) for the appropriate time (monitored by TLC analysis). The hot reaction mixture was filtered to separate the catalyst and filtrate was solidified after cooling to room temperature. Then,ice water was added to mixture. The organic phase was extracted with dichloromethane,washed with water and dried with Na₂SO₄. The solvent was removed under reduced pressure. The crude products were purified by recrystallization (ethanol and water) with sufficient purity for spectral analysis.

A mixture of aldehyde (2 mmol),malononitrile (2 mmol),ethyl acetoacetate (2 mmol),and nano silica supported tin (II) chloride (0.15 mol%) was refluxed in ethanol (5 mL) for the appropriate time (monitored by TLC analysis). The hot reaction mixture was filtered to separate the catalyst and filtrate was solidified after cooling to room temperature. The solid product was consecutively washed with hexane (2 mL),ethyl acetate (2×0.5 mL),and dried.

Diethyl 4-(3-methoxyphenyl)-2,6-dimethl-4H-pyran-3,5-dicarboxylate (4h): Yellow crystal; 85%; mp: 91-94℃,FT-IR (KBr, cm^-1):ν 3020 (C-H),1682 (C＝O);¹H NMR (400 MHz,CDCl₃):δ 1.42 (t,3H,J= 6.8 Hz),1.72 (s,3H),3.81 (s,2H),3.90 (s,1H),4.10 (q, 2H,J= 6.8 Hz),6.58-7.17 (CH aromatic);¹³C NMR (400 MHz, CDCl₃):δ 14.5,17.6,48.1,52.8,64.2,106.4,112.5,116.7,120.7, 128.8,141.1,155.6,162.3,166.9. Anal. calcd. for C₂₀H₂₃O₆:C, 66.85; H,6.40. Found: C,66.79; H,6.48.

Ethyl-6-amino-5-cyano-4-(4-bromophenyl)-2-methyl-4H-pyran-3-carboxylate (5e): Orange crystal; 95%; mp: 264-265℃,FT-IR (KBr,cm^-1 ):ν 3401,3319 (NH₂),2210 (CN),1692(C＝O);¹H NMR (400 MHz,DMSO-d₆):δ 1.10 (t,3H,J= 7.2 Hz),2.28 (s,3H),2.48 (s, 1H),3.94 (q,2H,J= 7.2 Hz),4.27 (s,NH₂),6.93-7.4 (CH aromatic);¹³C NMR (400 MHz,DMSO-d₆):δ 15.3,18.6,36.6,60.9,63.4,111.5, 116.8,120.6,133.9,135.8,156.7,159.1,160.3,165.9. Anal. calcd. for C₁₆H₁₆O₄N₂: C,53.03; H,4.14; N,7.73. Found: C,52.91; H,4.10; N,7.80.

Ethyl-6-amino-5-cyano-4-(3-methoxyphenyl)-2-methyl-4H-pyran-3-carboxylate (5h):Yellow crystal; 83%,mp: 264-265℃,FT-IR (KBr,cm^-1):ν 3405,3315 (NH₂),2206 (CN),1706 (C＝O);¹H NMR (400 MHz,DMSO-d₆):δ 1.61 (t,3H,J= 6.8 Hz),2.12 (s,3H),3.83 (s, 3H),3.97 (s,1H),4.10 (s,NH₂),4.45 (q,2H,J= 6.8 Hz),6.51-7.85 (CH aromatic);13C NMR (400 MHz,DMSO-d₆):δ 11.2,17.2,40.1, 57.9,61.1,63.8,105.5,111.2,117.9,119.8,123.4,130.7,141.8, 158.2,159.9,162.5,170.2. Anal. calcd. for C₁₇H₁₈O₄N₂: C,64.96; H, 5.73; N,8.91. Found: C,64.87; H,5.66; N,8.97.

According to literature reports,utilities of the heterogeneous solid-supported materials as new environmentally friendly catalysts for the synthesis of biologically active molecules have increased. Hence,we describe a simple and efficient method for the synthesis of polyfunctionalized 4H-pyrans using the environmental friendly and reusable nano silica supported tin (II) chloride as a catalyst herein. The catalyst was prepared by reacting of tin (II) chloride with silica under favorable conditions (Scheme 2). In order to study the morphology and dimension of SnCl₂/nano SiO₂,SEM image of SnCl₂/nano SiO₂ was obtained and shown in Fig. 1.

Scheme 2

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Scheme 2. Reaction of SnCl2 with silicagel.

These results show that the size of commercial silicagel and synthesized SnCl₂/nano SiO₂ are till about 20 nm (Fig. 1). In the EDAX pattern of SnCl₂/nano SiO₂(Fig. 2),Sn,Cl,Si and O elements are indicated. This analysis is detecting that SnCl₂ is supported in nano silicagel.

Fig. 1

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Fig. 1. SEM photograph of (a) nano-SiO2 and (b) SnCl2/nano SiO2.

Fig. 2

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Fig. 2. The EDAX spectrum of SnCl2/nano SiO2.

To identify the structure of this catalyst,we studied IR spectra of SnCl₂/nano SiO₂(Fig. 3). In the IR spectrum of SnCl₂/nano SiO₂,the Sn-Cl,Sn-O,Si-OH and Si-O-Si resonances were observed in 1559,563,3347 and 1061 cm^-1,respectively. Based on these results,we suggest the following structure for SnCl₂/nano SiO₂.

Fig. 3

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Fig. 3. The IR spectrum of SnCl2/nano SiO2.

We would like to report the preparation of polyfunctionalized 4H-pyran using reactions involving arylaldehydes,ethylacetoacetate,and malononitrile (Scheme 1). We chose the reaction of benzaldehyde 1,ethylacetoacetate 2 and malononitrile 3 as a model system for the optimization study.

Initially,a series of comparative experiments were performed to compare the effectiveness of SnCl₂/nano SiO₂ versus other catalysts in the formation of polyfunctionalized 4H-pyran. In some cases,data for other catalysts were taken from the literature. The results are shown in Table 1. SnCl₂/nano SiO₂ was assessed to be the most efficient of all tested catalysts,in terms of reaction time and yield (Table 1,entry 11). As shown in Table 1,the yield for products 4a and 5a is high in the presence of SnCl₂/SiO₂ as a catalyst (Table 1,entry 9). Also it indicates the yields of products in the presence of SnCl₂/nano SiO₂(Table 1,entry 10) are higher than those catalyzed by SnCl₂/SiO₂. We believe that the heterogeneous nanoparticles have higher surface-to-volume ratio,which provides a larger number of active sites per unit area in comparison to their heterogeneous counterparts. Also,as shown in Table 1 no product was obtained in the absence of the catalyst (Table 1,entry 13).

Table 1

Table 1 Literature results for the synthesis of 4a and 5a with various catalysts.

Table 1 Literature results for the synthesis of 4a and 5a with various catalysts.

In the next step,the synthesis of 4a and 5a was separately carried out in different solvents such as water,ethanol,methanol, tetrahydrofuran (THF),acetonitrile and dichloromethane (DCM) under stirring and reflux. The results are summarized in Fig. 4. In the presence of water the products were obtained in low yield 55%-60%.

Fig. 4

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Fig. 4. Effect of solvents on the activity of SnCl2/nano SiO2 catalyst.

Unfortunately,when the reactions were carried out in THF and DCM,the desired product was only obtained in 30%,25% yields respectively. Obviously,the protic solvents such as ethanol were more suitable than aprotic solvents (Fig. 4). In solvent-free conditions the reaction did not give the desired product.

In continuation of our research,we used a diverse of aldehydes to investigate these three-component reactions under the optimized conditions. We observed various aldehydes could be introduced with high efficiency and produced products in high yields. Also aldehydes bearing electron-withdrawing group such as NO₂,Cl in the para-position reacted very smoothly,while reactants with electron-donating group decreased both the rate of reaction and yield of the corresponding products as shown in Table 2.

Table 2

Table 2 Synthesis of polyfunctionalized 4H-pyrans catalyzed by SnCl2/nano SiO2(0.15 mol%)a.

Table 2 Synthesis of polyfunctionalized 4H-pyrans catalyzed by SnCl2/nano SiO2(0.15 mol%)a.

As an environmentally-friendly methodology,the reuse and recovery of the SnCl₂/nano SiO₂ are highly desirable. In order to study the reusability of nano silicagel supported tin (II) chloride as a catalyst,eight batches of the experiments were carried out for the preparation of products 4a and 5a (Fig. 5). The catalyst was filtered off and washed with an excess of ethanol and reused in a new reaction.

Fig. 5

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Fig. 5. Repeated use of SnCl2/nano SiO2 for the synthesis of 4H-pyran derivetives 4a and 5a.

The characterization of the fresh SnCl₂/nano SiO₂ and after eight times of reuse showed the same particle size by SEM (Fig. 6). Interestingly,the shape and size of the nanoparticles remained unchanged before and after reaction. We believe that,this is also the possible reason for the extreme stability of the SnCl₂/nano SiO₂ presented herein.

Fig. 6

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Fig. 6. SEM images of SnCl2/nano SiO2 before use (a) and after eight times reuse (b).

This paper describes SnCl₂/nano SiO₂ as a heterogeneous,easy to prepare,inexpensive,and efficient catalyst for the synthesis of polyfunctionalized 4H-pyrans. The distinguished advantages of this procedure are novelty,operational simplicity,high yields and the ease of isolation. The products were obtained in excellent yields and the reaction times were significantly shorter than the available methods. The present approach demonstrates a simple and effective method using SnCl₂/nano SiO₂ as novel nano-scale materials.

The authors are grateful to University of Kashan for supporting this work by Grant No. 159196/XV.