One-pot three-component synthesis of tetrahydrobenzo[b]pyrans catalyzed by cost-effective ionic liquid in aqueous medium☆

Jianguo Yang ,Shuo Liu ,Huanan Hu ,Shibin Ren ,Anguo Ying ,*

1 School of Pharmaceutical and Chemical Engineering,Taizhou University,Taizhou 318000,China

2 College of Chemistry,Nankai University,Tianjin 300071,China

ABSTRACT A simple and efficient method is proposed for the synthesis of tetrahydrobenzo[b]pyrans with aromatic aldehydes,active methylene compounds,and dimedone using basic ionic liquid catalyst in water.The procedure offers several advantages including short reaction time,good yield,easy procedure,and good recyclability of catalysts,which may be a practical alternative to conventional processes for preparation of 4-hpyrans.

?2015 The Chemical Industry and Engineering Society of China,and Chemical Industry Press.All rights reserved.

☆Supported by the Zhejiang Provincial Natural Science Foundation of China(LY15B060002),the National Natural Science Foundation of China(21106090,21272169,21471110),and the National Undergraduate Programs for Innovation and Entrepreneurship(201410350018).

Keywords:Tetrahydrobenzo[b]pyrans Ionic liquid Recyclability

1.Introduction

Tetrahydrobenzo[b]pyrans and their derivatives are an important class of heterocyclic compounds with useful biological and pharmacological properties.These compounds have been widely used as anticoagulant,antitumor,spasmolytic,antibacterial,diuretic,potassium channel activator and insulin-sensitizing activity[1–6].

Many methods for the synthesis of tetrahydrobenzo[b]pyrans derivatives have been reported.4H-benzo[b]pyrans is usually synthesized from α-cyano cinnamonitrile derivatives with dimedone catalyzed by acid or base[7].Recently,multicomponent reactions have emerged in the synthesis of tetrahydrobenzo[b]pyrans derivatives.Compared with conventional linear step synthesis,they can make the work easier,reduce time,save money,energy,and raw materials,resulting in both economic and environmental benefits[8,9].A number of methods have been reported using 5,5-dimethylcyclohexane-1,3-dione(dimedone),aromatic aldehydes and malononitrile in the presence of various catalysts,such as CeCl3·7H2O[10],N-methylimidazole[11],tetra-methyl ammonium hydroxide[12],MgO[13],amines[14],2,2,2-trifluoroethanol[15],TiO2[16],and starch solution[2].In addition,microwave[17],ultrasonic irradiation[18],and electrosynthesis[19]as subsidiary conditions also give satisfactory yields of pyrans.Each of these methods has its merits,while some still have one or more limitations,such as tedious work,poor product yield,long reaction time,effluent pollution,unavailability of catalyst,and large amount of organic solvents.Consequently,alternative efficient and environmentally friendly methods for synthesis of 4-hpyrans are needed.

Ionic liquids(ILs),due to their unique chemical and physical properties of nonvolatility,non flammability,thermal stability,and controlled miscibility[20],have been successfully used as catalysts for the preparation of tetrahydrobenzo[b]pyran derivates[21–24].However,the narrow range for applications,difficult recovery and high cost are still the drawbacks.

We have reported that some basic ionic liquids,[DABCO-PDO][X](Fig.1),can catalyze the Knoevenagel condensation reactions of aromatic aldehydes and α-aromatic-substituted methylene compounds[25].Promoted by our earlier study on one-pot three-component synthesis of tetrahydrobenzo[b]pyrans[26]and following our work on the catalytic activity of[DABCO-PDO][X][25,27],we herein report the ionic liquids,[DABCO-PDO][X],as efficient and recyclable catalysts for the preparation of tetrahydrobenzo-[b]pyran derivatives in water.

Fig.1.The structure of the ionic liquids[DABCO-PDO][X].

2.Experimental

NMR spectra were recorded with Bruker Advance DPX 400 MHz spectrometer(Bruker BioSpin Corporation,F?llanden,Switzerland)with chemical shift values(δ)in parts per million,relative to the internal standard of tetramethylsilane.Melting points were determined using YRT-3 apparatus(Reliant Instrument,Tianjin,China)without correction.All chemicals were purchased from Aladdin,Aldrich or Fluka(Buches SG,Switzerland).All reactions were monitored by thin layer chromatography(TLC).

All the ionic liquids were synthesized according to our previous methods[26].They were analyzed by1H NMR,13C NMR,and MS spectroscopic methods and the spectral data agreed with their structures(Fig.1).

A typical procedure for one-pot synthesis of tetrahydrobenzo[b]pyrans is as follows.

To a mixture of aromatic aldehyde(5 mmol),methyl active compound(5 mmol),and dimedone(5 mmol)in water(5 ml),[DABCO-PDO][CH3COO](0.5 mmol)was added,with stirring at 60°C.The reaction was monitored by TLC,in a solvent system of petroleum ether:ethyl acetate.After the reaction was completed,the reaction mixture was filtrated to obtain solid,which was recrystallized in 95%ethanol to give pure product.The ionic liquids was recovered from the remaining filtrate,then water was removed in vacuum at 80°C and reused several times without further purification.The product was characterized by melting point measurement and NMR.

Spectroscopic data of typical products are as follows.

2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 1,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 7.24–7.31(m,5H,Ph),4.56(s,2H,NH2),4.43(s,1H,CH),2.48(s,2H,CH2),1.61(s,2H,CH2),1.13(s,3H,CH3),1.06(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 195.8,162.3,158.1,144.6,128.1,127.9,127.8,120.1,113.5,58.3,50.2,39.8,35.9,32.4,28.5,27.6.MS(ESI):m/z 295[M+H]+,317[M+Na]+.IR(KBr)v:3392,3331,2182,1681,1216 cm?1.

2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 2,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 8.19(d,J=8.8Hz,2H,Ph),7.44(d,J=8.4Hz,2H,Ph),4.69(s,2H,NH2),4.54(s,1H,CH),2.51(s,2H,CH2),2.24–2.27(m,2H,CH2),1.15(s,3H,CH3),1.06(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 195.8,162.9,158.6,146.2,128.9,128.7,124.2,124.0,119.8,119.6,112.1,57.6,49.8,39.8,35.9,32.2,28.5,28.2.MS(ESI):m/z 340[M+H]+,362[M+Na]+.IR(KBr)v:3394,3325,2176,1681,1222 cm?1.

2-Amino-7,7-dimethyl-4-(3-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 3,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 8.10(d,J=8.4Hz,1H,Ph),8.06(s,1H,Ph),7.70(d,J=8.4Hz,1H,Ph),7.49–7.53(m,1H,Ph),4.74(s,2H,NH2),4.55(s,1H,CH),2.47–2.57(m,2H,CH2),2.20–2.30(m,2H,CH2),1.15(s,3H,CH3),1.07(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.2,163.8,157.8,150.4,143.1,136.4,130.2,125.8,121.6,119.8,119.2,59.2,49.8,39.6,35.7,32.2,28.3,27.6.MS(ESI):m/z 340[M+H]+,362[M+Na]+.IR(KBr)v:3392,3323,2182,1681,1216 cm?1.

2-Amino-4-(2-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 4,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 7.34(d,J=7.6Hz,1H,Ph),7.21–7.23(m,2H,Ph),7.14–7.18(m,1H,Ph),4.87(s,1H,CH),4.64(s,2H,NH2),2.47(s,2H,CH2),2.18–2.28(m,2H,CH2),1.14(s,3H,CH3),1.09(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.2,164.2,159.6,142.1,133.1,131.2,130.8,128.8,128.5,120.6,112.8,57.8,50.8,40.5,34.2,32.2,29.3,27.9.MS(ESI):m/z 329[M+H]+,351[M+Na]+.IR(KBr)v:3394,3323,2187,1681,1216 cm?1.

2-Amino-4-(3-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitril(Entry 5,Table 2):white solid.1H NMR(400 MHz,CDCl3):δ 7.21–7.25(m,1H,Ph),6.84(d,J=7.6Hz,1H,Ph),6.75–6.79(m,2H,Ph),4.61(s,2H,NH2),4.39(s,1H,CH),3.81(s,3H,OCH3),2.47(s,2H,CH2),2.25(d,J=2.4Hz,2H,CH2),1.13(s,3H,CH3),1.07(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.2,164.1,159.5,142.1,133.1,130.8,128.6,120.6,112.8,57.6,50.5,40.5,34.2,32.2,29.3,27.5.MS(ESI):m/z 325[M+H]+,347[M+Na]+.IR(KBr)v:3392,3328,2178,1681,1213 cm?1.

2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitril(Entry 6,Table 2):white solid.1H NMR(400 MHz,CDCl3):δ 7.17(d,J=8.4Hz,2H,Ph),6.84(d,J=8.4Hz,2H,Ph),4.53(s,2H,NH2),4.38(s,1H,CH),3.79(s,3H,OCH3),2.46(s,2H,CH2),2.23(d,J=5.2Hz,2H,CH2),1.13(s,3H,CH3),1.06(s,3H,CH3);1C NMR(100 MHz,CDCl3):δ 195.8,162.1,158.6,137.1,128.2,120.3,113.8,58.6,55.2,49.8,40.5,34.2,32.6,28.3,27.2.MS(ESI):m/z 325[M+H]+,347[M+Na]+.IR(KBr)v:3382,3245,2184,1681,1213 cm?1.

2-Amino-4-(2-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitril(Entry 7,Table 2):white solid.1H NMR(400 MHz,CDCl3):δ 7.18–7.22(m,1H,Ph),7.11–7.13(m,1H,Ph),6.87–6.91(m,2H,Ph),4.73(s,1H,CH),4.46(s,2H,NH2),3.86(s,3H,OCH3),2.46(s,2H,CH2),2.23(d,J=8.4Hz,2H,CH2),1.14(s,3H,CH3),1.07(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.2,163.2,158.5,142.2,133.1,130.6,127.6,120.5,113.2,56.6,50.3,40.7,34.2,32.2,28.3,27.4.MS(ESI):m/z 325[M+H]+,347[M+Na]+.IR(KBr)v:3386,3229,2176,1680,1215 cm?1.

2-Amino-4-(4-hydroxy-3,5-dimethoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 8,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 6.46(s,2H,Ph),5.47(s,1H,CH),4.62(s,2H,NH2),4.34(s,1H,OH),3.88(s,6H,OCH3),2.43–2.53(m,2H,CH2),2.22–2.31(m,2H,CH2),1.14(s,3H,CH3),1.09(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.1,163.1,157.6,138.5,128.2,127.1,125.2,120.3,113.8,57.6,55.7,49.9,39.5,34.6,32.2,28.1,27.4.MS(ESI):m/z 371[M+H]+,393[M+Na]+.IR(KBr)v:3386,3229,2176,1680,1215 cm?1.

2-Amino-7,7-dimethyl-5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 9,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 7.15(d,J=4.4Hz,1H,Ph),7.01(d,J=3.2Hz,1H,Ph),6.91–6.93(m,1H,Ph),4.80(s,1H,CH),4.63(s,2H,NH2),2.45(s,2H,CH2),2.30(s,2H,CH2),1.14(s,3H,CH3),1.09(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.1,162.2,157.5,136.1,127.6,125.4,123.2,120.1,113.7,53.6,50.8,39.7,33.8,32.1,28.6,27.5.MS(ESI):m/z 301[M+H]+,323[M+Na]+.IR(KBr)v:3383,3240,2172,1681,1218 cm?1.

2-Amino-7,7-dimethyl-4-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 10,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 8.40(d,J=8.4Hz,1H,Ph),7.85(d,J=8.0Hz,1H,Ph),7.74(d,J=8.0Hz,1H,Ph),7.59–7.61(m,1H,Ph),7.57(s,1H,Ph),7.48–7.52(m,1H,Ph),7.25–7.43(m,1H,Ph),5.23(s,1H,CH),4.53(s,2H,NH2),2.53–2.60(m,2H,CH2),2.17–2.28(m,2H,CH2),1.15(s,3H,CH3),1.09(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 195.8,162.6,155.6,135.8,133.2,132.8,128.7,127.6,127.4,125.4,125.2,125.0,123.6,120.4,113.6,54.5,51.8,40.2,34.8,32.2,28.2,27.4.MS(ESI):m/z 345[M+H]+,367[M+Na]+.IR(KBr)v:3394,3236,2186,1682,1217 cm?1.

2-Amino-4-(1H-indol-3-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(Entry 11,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 8.10(s,1H,NH),7.40(d,J=8.0Hz,1H,Ph),7.35(d,J=8.0Hz,1H,Ph),7.21(s,1H,Ph),7.14–7.18(m,1H,Ph),7.05–7.09(m,1H,Ph),4.75(s,1H,CH),4.54(s,2H,NH2),2.43–2.55(d,2H,CH2),2,15–2,25(m,2H,CH2),1.12(s,3H,CH3),0.97(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 195.9,161.6,155.4,136.8,127.6,123.6,122.2,120.4,119.8,118.2,113.6,110.9,108.6,54.5,51.8,40.2,34.8,32.2,28.2,27.4.MS(ESI):m/z 334[M+H]+,356[M+Na]+.IR(KBr)v:3396,3237,2176,1681,1214 cm?1.

Ethyl 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate(Entry 12,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 7.27–7.29(m,2H,Ph),7.20–7.24(m,2H,Ph),7.10–7.14(m,1H,Ph),6.18(m,2H,NH2),4.72(s,1H,CH),3.99–4.09(m,2H,CH2),2.45(s,2H,CH2),2.16–2.27(m,2H,CH3),1.16–1.20(m,3H,CH3),1.12(s,3H,CH3),0.99(s,3H,CH3);1C NMR(100 MHz,CDCl3):δ 196.2,172.3,162.4,156.1,144.4,128.1,127.2,124.1,113.6,68.3,62.4,51.2,38.8,36.9,32.4,28.5,27.6,14.6.MS(ESI):m/z 342[M+H]+,364[M+Na]+.IR(KBr)v:3382,3246,2185,1682,1219 cm?1.

Ethyl 2-amino-4-(4- fluorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate(Entry 13,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 7.22–7.26(m,2H,Ph),6.88–6.93(m,2H,Ph),6.19(s,2H,NH2),4.70(s,1H,CH),4.03–4.08(m,2H,CH2),2.44(s,2H,CH2),2.16–2.27(m,2H,CH2),1.15–1.19(m,3H,CH3),1.12(s,3H,CH3),0.99(s,3H,CH3);13C NMR(100 MHz,CDCl3):δ 196.2,171.2,162.3,159.6,156.1,142.4,132.3,121.1,113.9,68.6,62.5,50.8,38.5,36.9,32.3,28.3,27.6,14.6.MS(ESI):m/z 360[M+H]+,382[M+Na]+.IR(KBr)v:3386,3225,2179,1681,1216 cm?1.

Ethyl 2-amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate(Entry 14,Table 2):yellow solid.1H NMR(400 MHz,CDCl3):δ 7.19(d,J=8.4Hz,2H),6.76(d,J=8.4Hz,2H),6.17(s,2H),4.66(s,1H),3.99–4.10(m,2H),3.77(s,3H),2.44(s,2H),2.16–2.27(m,2H),1.17–1.21(m,3H),1.11(s,3H),0.99(s,3H);13C NMR(100 MHz,CDCl3):δ 196.1,171.8,162.5,158.2,156.2,137.3,129.4,115.6,113.6,69.4,62.1,50.6,38.4,37.2,32.4,28.3,27.6,14.5.MS(ESI):m/z 372[M+H]+,394[M+Na]+.IR(KBr)v:3396,3241,2189,1682,1216 cm?1.

3.Results and Discussion

The reaction of benzaldehyde,malononitrile and dimedone was selected as the model to test the catalytic activity of the ILs(Table 1).The reaction did not proceed in the absence of ionic liquid(Entry 1).The model reaction proceeded smoothly in the presence of[DABCOPDO][X],leading to 71–95%yields of product(Entries 2–5).Among the four ILs tested,[DABCO-PDO][CH3COO]was the most effective,giving an excellent yield of 95%.Then we optimized the amount of[DABCOPDO][CH3COO],with the reaction in the presence of 5,10,15 and 20%(by mole)in water at 60 °C(Entries 2,6–8).The best catalyst loading was 10%(by mole).The reaction temperature of 40°C reduced the yield significantly,while the temperature of 80°C was not more effective on the yield(Entries 2,9,10).In addition,no significant changewas found with the organic solvents.Consequently,the reaction conditions of10%(by mole)[DABCO-PDO][CH3COO]as the catalystat60°C in water were subjected to further examination.

Table 1 Optimization of catalyst/organic solvent in Michael addition reaction①

With the optimal reaction conditions we explored a wide range of aromatic aldehydes and active methylene compounds,and the results are presented in Table 2.The reactions proceeded smoothly and good to excellent yields of desired products were obtained within 1 h,while little byproducts from Knoevenagel condensation were monitored by thin layer chromatography.The effects of substituents on the aromatic ring in the reaction were studied.The aromatic aldehydes bearing electron-donating groups such as OMe and OH,reacted much slower with malononitrile and dimedone than other aromatic aldehydes substituted with NO2and Cl(Entries 2–8).The heterocyclic alde-hydes and fused ring aldehydes such as 2-thienyl,3-indolyl aldehydes and 1-naphthaldehyde were also demonstrated to be efficient reagents for this reaction(Entries 9–11).

Table 2 One-pot synthesis of various 4H-benzo[b]pyran derivatives via a three-component condensation in aqueous media①

Encouraged by the good results from the reactions of malononitrile,we extended the substrate scope and ethyl 2-cyanoacetate was tested(Entries 12–14).The reactions can also give heterocyclic compounds in good yields.

In order to demonstrate the industrial applicability of this methodology,the aqueous one-pot synthesis of 4H-benzo[b]pyrans via the reaction of benzaldehyde,malononitrile and dimedone catalyzed by[DABCO-PDO][CH3COO]was carried out on a larger scale(100 mmol).The reaction was completed in 0.5 h.A good yield of 96%was achieved for the product.On the same scale,the recyclability of the catalytic system was investigated using the same model reaction.Upon the completion of reaction,the product was isolated by filtration and the filtrate was dried to remove water at 80°C under vacuum.The recovered ionic liquid was reused in subsequent reactions.As shown in Fig.2,no significant decrease in yields is observed after six times.

The high activity of[DABCO-PDO][CH3COO]catalyzing synthesis of 4H-benzo[b]pyrans could be rationalized by a proposed mechanism(Fig.3).The lone pair electrons on the N atom of the IL can take hydrogen atom away from active methylene compounds to form active carbon anion.Meanwhile,the hydrogen bonding interactions between the hydroxyl groups of the IL with the carbonyl group of the aldehyde increases the electrophilicity of aldehyde carbon atom.Then A forms through Knoevenagel condensation.The lone pair electrons on the N atom of the IL can also take hydrogen atom away from dime done,which can readily react with A,leading to the Michael addition product B,followed by tautomerism,intramolecular O-cyclization and proton transfer reactions under dual activities of the IL to give the desired product.

Fig.2.Recyclability of[DABCO-PDO][CH3COO]as a catalyst for the one-pot three component reaction of benzaldehyde,malononitrile and dimedone.

Table 3 provides13C NMR data of benzaldehyde and the mixture of[DABCO-PDO][CH3COO]and benzaldehyde to prove the catalytic role of the hydrogen bond.The chemical shift of carbonyl carbon atom in benzaldehyde is 192.19 while it is 192.32 in the mixture.The offset of 0.13 indicates the possible formation of hydrogen bond.

For comparison with other methodologies in terms of catalytic efficiency,we carried out the reaction of benzaldehyde,malononitrile and dimedone.As shown in Table 4,the ionic liquid[Ch][OH],synthesized by our group,gave good yields in a long time and the temperature was higher than[DABCO-PDO][CH3COO](Entry 1).Under ultrasound irradiation conditions,good yield of product was obtained in a short time(Entries 2–3).We also tried the[DABCOPDO][CH3COO]catalyzed synthesis of tetrahydrobenzo[b]pyran under ultrasound irradiation condition at room temperature and obtained a better result than the cited references(Entry 5).All of the results demonstrate that the present catalytic system is very efficient for the preparation of tetrahydrobenzo[b]pyrans.

Table 3 13C NMR data of benzaldehyde and benzaldehyde-IL mixture

Table 4 Comparison of the present catalytic system with some reported protocols in the model reaction between benzaldehyde,malononitrile and dimedone

4.Conclusions

We successfully used a basic and cost-effective ionic liquid for onepot three-component synthesis of tetrahydrobenzo[b]pyrans in aqueous solution.Compared with the ionic liquid[Ch][OH]synthesized previously,this protocol reduces the requirement of reaction conditions and promotes the reaction effects.This catalytic system is being investigated in our lab to find much better conditions.

Acknowledgments

We are also grateful for the financial supports for this research by Key Disciplines of Applied Chemistry of Zhejiang Province,Taizhou University.

Fig.3.Proposed mechanism for the synthesis of tetrahydrobenzo[b]pyrans promoted by[DABCO-PDO][CH3COO].