Chinese Chemical Letters  2015, Vol.26 Issue (11): 1385-1388   PDF    
Preparation of 2-amino-5,7-dimethoxy-4-aryl/alkyl-4H-chromene-3-carbonitriles using Na2O-Al2O3-P2O5 glass-ceramic system
Saeid Jabbarzarea , Majid Ghashangb    
a Advanced Materials Research Center, Materials Engineering Department, Najafabad Branch, Islamic Azad University, Najafabad, Iran;
b Department of Chemistry, Faculty of Sciences, Najafabad Branch, Islamic Azad University, Najafabad, Iran
Abstract: A highly efficient and environmentally benign protocol for the synthesis of 2-amino-5,7-dimethoxy-4- aryl/alkyl-4H-chromene-3-carbonitrile derivatives by one-pot three-component coupling reacting of aromatic aldehydes, malononitrile and 3,5-dimethoxy phenol under reflux condition has been developed in aqueous EtOH media using Na2O-Al2O3-P2O5 glass-ceramic system.
Key words: Na2O-Al2O3-P2O5 glass-ceramic system     2-Amino-4H-chromene     3,5-Dimethoxy phenol     2-Amino-5,7-dimethoxy-4-aryl/alkyl-4Hchromene-     3-carbonitriles    
1. Introduction

Heterocyclic compounds containing chromene moieties are of considerable interest as they are a class of natural and synthetic compounds that possess a great variety of biological and pharmaceutical activities [1, 2, 3, 4, 5]. These scaffolds are more privileged when they joined with rigid hetero ring systems and/or other chemical functional groups. Obviously,functionalization of chromene derivatives have played an ever increasing role in the synthetic approaches to promising compounds in the field of medicinal chemistry [1, 2, 3, 4, 5]. On the other hand,functionalized chromenes appear as an important structural component in both biologically active and natural compounds [1, 2, 3, 4, 5]. For example some of interesting molecules with chromene framework joined with different functional groups displaying rich medicinal chemistry and numerous applications such as anti-inflammatory, antioxidant,anti-HIV,antibacterial,and analgesic properties [6, 7, 8, 9, 10, 11]. Amongst of them chromenes with cyano-functionality has potential applications in the treatment of rheumatoid, psoriasis and cancer [12]. In addition they are applicable as laser dyes [13],optical brighteners [14] and Pigments [15].

Consequently,several methods have been reported for the preparation of chromene derivatives involve multi-component reaction of aldehydes,malononitrile and β-keto esters,diverse enolizable C-H activated acidic compounds,phenols and a- and β-naphthols [16, 17, 18, 19, 20, 21]. To achieve this aim several methods using different homogeneous [16, 17, 18, 19] and heterogeneous [20, 21, 22, 23] catalysts were explored. These methods have the advantages of high yields,and mild reaction conditions and some disadvantages of using toxic solvents and expensive catalysts. However the discovery of new synthetic methodologies that facilitate the preparation of organic compounds is of great interest. One approach to address this challenge involves the development of new synthesized environmentally friendly catalysts to catalyze the reaction.

Therefore,as a part of our incessant efforts on the using of heterogeneous catalysts in multi-component reactions,the scope of the present work was extended for the multi-component condensation reaction of aldehydes,3,5-dimethoxy phenol and malononitrile to afford 2-amino-5,7-dimethoxy-4-aryl/alkyl-4Hchromene- 3-carbonitriles using Na2O-Al2O3-P2O5 glass-ceramic system as a green,environmentally friendly catalyst (Scheme 1).

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Scheme. 1.Preparation of 2-amino-5,7-dimethoxy-4-aryl/alkyl-4H-chromene-3-carbonitriles using Na2O-Al2O3-P2O5 glass–ceramic system.
2. Experimental

All reagents were purchased from Merck and Aldrich and used without further purification. Field Emission Scanning Electron Microscope (FE-SEM) images were obtained on HITACHI S-4160. N2 adsorption measurements of the catalyst were carried out using micro metrics adsorption equipment (Quantachrome instrument, model Nova 2000,USA),N2 (99.99%) as the analysis gas and the catalyst samples were slowly heated to 120 ℃ for 3 h under nitrogen atmospheric. The NMR spectra were recorded on a Bruker Avance DPX 400 MHz instrument. The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm). 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.

2.1. Preparation of Na2O-Al2O3-P2O5 glass-ceramic system

The glass was prepared via mixing of equal molar of Na2O,P2O5 and Al2O3 as starting materials. The mixing materials were melted at 1000 ℃ for 2 h in alumina crucible and afterwards the melt was allowed to cool to room temperature. The resulting glass was grinded using a high-energy planetary ball mill at rotational speed of 600 rpm and a ball-to-powder weight ratio of 1:7. The glass was grinded in air atmosphere for 3 h.

2.2. General procedure for the synthesis of 2-amino-5,7-dimethoxy- 4-aryl/alkyl-4H-chromene-3-carbonitriles

A mixture of aldehydes (1 mmol),3,5-dimethoxyphenol (1 mmol),malononitrile (1 mmol),and glass sample (0.1 g) in H2O/EtOH (7 mL/3 mL) was refluxed (80 ℃) for an appropriate time. The progress of the reaction was monitored using TLC. After completion of the reaction,the reaction mixture was dissolved in hot ethanol. The catalyst was removed by simple filtration. Solvent was concentrated and the crude product were purified by recrystallization from EtOH. The spectral data of compounds a-i are given below:

2-Amino-5,7-dimethoxy-4-phenyl-4H-chromene-3-carbonitrile (a): Melting point: 212-214 ℃; 1HNMR(400 MHz,DMSO-d6): δ 3.77(s,3H,OCH3),3.83 (s,3H,OCH3),4.64 (s,1H,CH),6.19 (s,1H), 6.37 (s,1H),6.94 (s,2H,NH2),7.22-7.34 (m,5H); 13C NMR (100 MHz,DMSO-d6): δ 44.7,55.5,56.6,57.3,101.1,112.3,114.9, 119.3,128.6,128.7,128.9,141.5,155.8,157.6,162.8,163.4. Cacld. for C18H16N2O3: C,70.12; H,5.23; N,9.09; Found: C,70.25; H,5.33; N,9.18.

2-Amino-5,7-dimethoxy-4-p-tolyl-4H-chromene-3-carbonitrile (b): Melting point: 217-219 ℃; 1H NMR (400 MHz,DMSOd6): δ 2.28 (s,3H,CH3),3.80(s,3H,OCH3),3.89 (s,3H,OCH3),4.58 (s, 1H,CH),6.21 (s,1H),6.41 (s,1H),6.96 (s,2H,NH2),7.07 (d,2H, J = 7.7 Hz),7.18 (d,2H,J = 7.7 Hz); 13C NMR (100 MHz,DMSO-d6): δ 21.2,46.9,55.5,55.9,58.0,101.2,111.8,115.0,120.1,126.8,129.3, 139.8,140.7,155.6,157.3,162.8,164.0. Cacld. for C19H18N2O3: C, 70.79; H,5.63; N,8.69; Found: C,70.95; H,5.81; N,8.80.

2-Amino-5,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)-4H-chromene- 3-carbonitrile (c): Melting point: 231-233 ℃; 1H NMR (400 MHz,DMSO-d6): d 3.67 (s,3H,OCH3),3.72(s,3H,OCH3),3.79 (s,6H,OCH3),3.81 (s,3H,OCH3),4.52 (s,1H,CH),6.20 (s,1H),6.40 (s,1H),6.69 (s,2H) 6.83 (s,2H,NH2); 13C NMR (100 MHz,DMSOd6): δ 43.3,55.6,56.8,58.0,61.6,100.7,109.2,112.4,114.9,119.1, 139.7,141.2,153.1,156.0,158.9,162.8,163.4. Cacld. for C21H22N2O6: C,63.31; H,5.57; N,7.03; Found: C,63.39; H, 5.5.68; N,7.11.

2-Amino-5,7-dimethoxy-4-(4-methoxyphenyl)-4H-chromene- 3-carbonitrile (d): Melting point: 220-222 ℃; 1H NMR (400 MHz, DMSO-d6): δ 3.76 (s,3H,OCH3),3.77(s,3H,OCH3),3.83 (s,3H, OCH3),4.63 (s,1H,CH),6.22 (s,1H),6.43 (s,1H),6.90 (s,2H,NH2), 6.97 (d,2H,J = 7.6),7.29 (d,2H,J = 7.6); 13C NMR (100 MHz,DMSOd6): δ 43.6,54.9,56.3,57.0,58.4,102.0,112.0,114.5,114.9,120.6, 128.6,142.9,156.2,157.0,162.4,163.9,164.7. Cacld. for C19H18N2O4: C,67.44; H,5.36; N,8.28; Found: C,67.57; H,5.49; N,8.35.

2-Amino-5,7-dimethoxy-4-o-tolyl-4H-chromene-3-carbonitrile (e): Melting point: 196-198 ℃; 1HNMR (400 MHz,DMSO-d6): d 2.35 (s,3H,CH3),3.77(s,3H,OCH3),3.84 (s,3H,OCH3),4.72 (s,1H, CH),6.24 (s,1H),6.45 (s,1H),6.95 (s,2H,NH2),7.06-7.21 (m,4H); 13C NMR (100 MHz,DMSO-d6): d 20.8,43.6,54.7,56.8,57.8,101.9, 110.9,115.4,120.4,122.9,126.8,129.7,131.2,132.8,140.1,156.1, 157.8,162.8,163.7. Cacld. for C19H18N2O3: C,70.79; H,5.63; N, 8.69; Found: C,70.88; H,5.74; N,8.81.

4-(4-tert-Butylphenyl)-2-amino-5,7-dimethoxy-4H-chromene- 3-carbonitrile (f): Melting point: 219-221 ℃; 1H NMR (400 MHz,DMSO-d6): δ 1.27 (s,9H,C(CH3)3),3.74(s,3H,OCH3), 3.81 (s,3H,OCH3),4.69 (s,1H,CH),6.23 (s,1H),6.42 (s,1H),6.89 (s, 2H,NH2),7.07 (d,2H,J = 7.9),7.22 (d,2H,J = 7.9); 13C NMR (100 MHz,DMSO-d6): δ 31.4,34.7,44.6,55.5,57.6,58.8,102.3, 112.8,115.4,121.0,125.4,126.8,142.5,153.5,156.1,158.2,162.8, 163.9. Cacld. for C22H24N2O3: C,72.50; H,6.64; N,7.69; Found: C, 72.63; H,6.78; N,7.89.

2-Amino-4-(4-chlorophenyl)-5,7-dimethoxy-4H-chromene-3- carbonitrile (g): Melting point: 234-236 ℃; 1H NMR (400 MHz, DMSO-d6): δ 3.77(s,3H,OCH3),3.86 (s,3H,OCH3),4.81 (s,1H,CH), 6.27 (s,1H),6.46 (s,1H),6.98 (s,2H,NH2),7.36 (d,2H,J = 8.0),7.47 (d,2H,J = 8.0); 13C NMR (100 MHz,DMSO-d6): δ 44.9,55.7,57.6, 58.3,102.6,113.1,115.8,121.6,123.7,128.5,142.3,148.0,155.6, 158.2,162.8,163.8. Cacld. for C18H15ClN2O3: C,63.07; H,4.41; N, 8.17; Found: C,63.21; H,4.53; N,8.25.

2-Amino-5,7-dimethoxy-4-(4-nitrophenyl)-4H-chromene-3- carbonitrile (h): Melting point: 245-247 ℃; 1H NMR (400 MHz, DMSO-d6): δ 3.82 (s,3H,OCH3),3.91(s,3H,OCH3),5.28 (s,1H,CH), 6.25 (s,1H),6.44 (s,1H),7.01 (s,2H,NH2),7.41 (d,2H,J = 8.0),8.11 (d,2H,J = 8.0); 13C NMR (100 MHz,DMSO-d6): δ 46.7,55.6,57.9, 58.2,102.7,113.2,115.7,121.5,123.8,128.6,142.5,148.7,155.9, 158.6,162.9,163.9. Cacld. for C18H15N3O5: C,61.19; H,4.28; N, 11.89; Found: C,61.31; H,4.45; N,11.98.

2-Amino-5,7-dimethoxy-4-(3-nitrophenyl)-4H-chromene-3- carbonitrile (i): Melting point: 243-245 ℃; 1H NMR (400 MHz, DMSO-d6): δ 3.79 (s,3H,OCH3),3.89 (s,3H,OCH3),5.17 (s,1H,CH), 6.23 (s,1H),6.43 (s,1H),6.98 (s,2H,NH2),7.42 (d,1H,J = 8.1),7.76 (t, 1H,J = 8.1),8.19-8.23(m,2H); 13CNMR(100MHz,DMSO-d6): δ 46.4, 55.4,57.8,58.2,102.5,113.0,115.4,121.1,122.5,125.1,127.8,130.1, 141.4,148.1,155.6,158.0,162.8,163.7. Cacld. for C18H15N3O5: C, 61.19; H,4.28; N,11.89; Found: C,61.29; H,4.47; N,12.01.

3. Results and discussion

Na2O-Al2O3-P2O5 glass-ceramic system was prepared via a simple thermal melting method. The procedure is new and the method is green and environmentally friendly. Field emission scanning electronic microscopy (FE-SEM) was used to study the morphology of the surface of Na2O-Al2O3-P2O5 glass-ceramic system (Fig. 1). The analysis of the obtained picture shows clearly that the system has high tendency to agglomerate owing to its relatively large specific surface area,which were associated with Vander Waals interactions. The specific surface area of the glass- ceramic was measured by BET method and was determined as 34 m2 g-1.

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Fig. 1.FE-SEM micrographs of Na2O-Al2O3-P2O5 glass–ceramic system.

The catalytic activity of Na2O-Al2O3-P2O5 glass-ceramic system was examined on the condensation reaction of 3,5-dimethoxy phenol (1 mmol),malononitrile (1 mmol) and benzaldehyde (1 mmol) as a tentative experiment in different condition including solvent,temperature and catalyst dosage (Table 1). The progress of the reaction was monitored using TLC. After completion of the reaction a work-up afforded the product 2-amino-5,7-dimethoxy- 4-phenyl-4H-chromene-3-carbonitrile in low yields at room temperature and did not give the product in non-polar solvents (Table 1,entries 1-7). Investigation of the procedure at higher temperatures showed that a significant change was observed in the relative yields,and reaction times decrease under these conditions (Table 1,entries 8 and 9). It is noteworthy to mention that the best result was obtained in aqueous EtOH medium. In another experiment,the effect of different catalyst dosages was examined and it was found that the yield of the reaction is increased with increasing of the quantity of the catalyst (Table 1,entries 11,12). The optimal catalyst amount was found to be 0.1 g. The use of lesser amounts of the catalyst afforded lower product yield. On the other hand,the use of higher quantities of the catalyst did not provide any significant advantage in the increasing of the reaction yield.

Table 1
Optimization of the reaction conditions in the synthesis of 2-amino-5,7-dimethoxy-4-phenyl-4H-chromene-3-carbonitrile.

To study the scope and limitations of this procedure,a series of experiments were carried out using a variety of aromatic aldehydes. The results have been shown in Table 2. The reactions worked well with almost all the aldehydes. However,aromatic aldehydes bearing electron withdrawing groups showed better reactivity and the reactions were completed in shorter time.

Table 2
Preparation of 2-amino-5,7-dimethoxy-4-aryl/alkyl-4H-chromene-3-carbonitriles using Na2O-Al2O3-P2O5 glass–ceramic system.
4. Conclusion

In summary,a high yielding one-pot condensation reaction of 3,5-dimethoxy phenol,aromatic aldehydes and malononitrile for the synthesis of 2-amino-5,7-dimethoxy-4-aryl/alkyl-4H-chromene- 3-carbonitriles using Na2O-Al2O3-P2O5 glass-ceramic system was developed. Na2O-Al2O3-P2O5 glass-ceramic system prepared via a simple melting method has been used in catalytic quantities. Various aromatic aldehydes afforded the corresponding products in high yields.

Acknowledgment

The authors are indebted to the Najafabad Branch,Islamic Azad University for financial support of this research.

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