Catalysis Communications 12 (2011) 11531156

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Catalysis Communications
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c a t c o m

Short Communication

Sulfated tungstate: An alternative, eco-friendly catalyst for Biginelli reaction

Suresh D. Salim, Krishnacharya G. Akamanchi
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India

a r t i c l e

i n f o

a b s t r a c t
Sulfated tungstate catalyzed simple, one pot, solvent free and environmentally benign process for synthesis of dihydropyrimidinones via Biginelli reaction is described. It was found that the catalyst is reusable and exhibited remarkable activity. 2011 Elsevier B.V. All rights reserved.

Article history: Received 18 December 2010 Received in revised form 20 February 2011 Accepted 22 February 2011 Available online 28 February 2011 Keyword: Sulfated tungstate Biginelli reaction Dihydropyrimidinones

1. Introduction Recently we have synthesized and characterized sulfated tungstate and demonstrated its effectiveness as catalyst in amide bond formation between carboxylic acid and amine [1]. It has several advantages such as mild acidity, noncorrosive nature, safe, easy to handle and store, stability at temperature and provides experimental simplicity. Biginelli reaction, a more than a century old reaction came into prominence after the discovery and development of dihydropyridines based calcium channel modulator drugs such as nifedipine used in cardiovascular diseases [2]. Dihydropyrimidines can be regarded as aza-analogs of dihydropyridines of the nifedipine type drugs. This important class of heterocyclic compounds has attracted medicinal chemists due to pharmacological and biological properties such as antihypertensive, -1a-antagonism, neuropeptide Y(NPY) antagonism, antibacterial, antiviral, antitumour, antioxidant and antiinammatory [35]. Batzelladine alkaloids containing dihydropyrimidines core have been found to show potent anti-HIV activity [6]. Biginelli reaction provides dihydropyrimidinones or dihydropyrimidinthiones in one step through multicomponent one pot reaction of aldehyde, -ketoester, urea/thiourea. Classically this reaction was carried out in alcoholic solution of Brnsted acids such as HCl, H2SO4 acetic acid, and which usually gave very low yields [7,8]. With the awareness of environmental issues and importance of this reaction many improvements have been attempted by way of use of catalysts such as Brnsted acids like p-toluenesulfonic acid [9], silica-sulfuric acid [10], KHSO4 [11], triuoroacetic acid, triuoromethanesulfonic acid [12], chloroacetic acid [13] and Lewis acids like BF3Et2O/Cu

(OAc)2 [14], Yb(OTf)3 [15], Mn(OAc)3 [16], Yb(III)-resin [17], sulfated zirconia [18], FeCl3 [19], Bi(OTf)3 [20], CeCl37H2O [21], Cu(NH2SO3)2 [22], and TaBr5 [23]. Other variants reported for this reaction are the use of catalyst such as triphenylphosphine [24], hexaaquaaluminium (III) tetrauoroborate [25], microwave heating [26], sonication [27], organocatalysts [28] and ionic liquids [29]. Additionally a fair amount of research has been geared towards making this important reaction more environmentally benign by use of solid acid catalysts such as Montmorillonite KSF [30], bentonite clay [31], zeolites [32], H3PMo12O40 [33] and H3PW12O40 [34]. In the present work we describe successful application of our recently introduced sulphated tungstate a mild, solid acid, as an alternative environmentally benign, cheap and easy to prepare catalyst for Biginelli reaction. 2. Experimental 2.1. Materials and methods General H NMR spectra were recorded on JEOL MY-60 operating at 60 MHz instrument, chemical shifts are expressed in parts per million downeld from TMS in units. IR spectra were recorded on FTIR RX1 Perkin-Elmer instrument. Melting points were determined with Veego melting point apparatus having stirred parafn bath. Silica gel # 60120 was used for column chromatography and Thin Layer Chromatography (TLC) was performed using Merck Silica gel 60 F254 plates. All other chemicals were of laboratory grade and used as received. 2.2. Catalyst preparation The catalyst was prepared by adding anhydrous sodium tungstate (0.1 mol) gradually to a stirred solution of chlorosulfonic acid (0.2 mol) in chloroform (150 ml) contained in a 250 ml round bottom
1

Corresponding author. Tel.: +91 22 33611111/2222; fax: +91 22 33611020. E-mail address: kgap@rediffmail.com (K.G. Akamanchi). 1566-7367/$ see front matter 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.catcom.2011.02.018

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S.D. Salim, K.G. Akamanchi / Catalysis Communications 12 (2011) 11531156 Table 1 Effect of different amounts of sulfated tungstate and solvents on formation of (I)a. Entry 1 2 3 4 5 6 7
a

ask placed in an ice bath. After completion of addition the mixture was stirred further for 1 h. A yellowish-white solid was obtained. It was ltered and repeatedly washed with deionized water until a neutral ltrate was obtained. The absence of chloride ions was detected by AgNO3 test. Then the catalyst was dried in an oven for 2 h at 100 C. 2.3. General procedure for sulfated tungstate mediated synthesis of dihydropirimidinones To a stirred slurry of aldehyde (10 mmol), -ketoester (10 mmol) and urea/thiourea (15 mmol) was added sulfated tungstate (10 wt.%) and heated at 80 C. Progress of the reaction was monitored by TLC using petroleum ether (6080 C): ethyl acetate as eluent. Upon completion of the reaction, the reaction mixture was diluted with ethanol (20 mL) and the reaction mass was stirred and allowed to cool, slurry was ltered to remove catalyst and washed with ethanol (3 10 mL). Combined ltrate and washings were concentrated under reduced pressure to obtain a solid residue. The solid residue was slurried in water (3 15 mL) and ltered, the cake was washed with hexane (3 15 mL) and recrystallized from ethanol to give pure product. All products are known compounds and were characterized by IR 1 and H NMR spectroscopic data and melting points and compared with reported values. 3. Result and discussion To evaluate the feasibility of sulphated tungstate for Biginelli reaction a model reaction (Scheme 1) with a building block ratio of 1:1:1.5 of benzaldehyde, ethyl acetoacetate, and urea respectively to give 5-ethoxycarbonyl-4-phenyl-6-methyl-3,4-dihydropyridin-2 (1H)-one (I), was conducted under different conditions both in the absence and in the presence of sulphated tungstate and results are given in Table 1. In the absence of sulphated tungstate only 20% yield of the product was obtained even after heating at 80 C for 12 h with recovery of starting material (entry 1, Table 1) whereas in the presence of sulfated tungstate (5 wt.%), under the same conditions yield increased to 60% (entry 2, Table 1). Building upon this result further studies were conducted and it was found that 10 wt.% of sulfated tungstate was optimum for this reaction and gave a product of 92% yield in just 1 h (entry 3, Table 1). The reaction was also examined in solvents such as EtOH, H2O, CHCl3 and toluene. In the presence of solvents reaction was sluggish and formation of byproducts was observed (entries 47, Table 1). The reaction temperature was also optimized, below 80 C the reaction proceeded slow giving a relatively low yield and no improvement was observed above 80 C. All further studies were carried out under solvent free conditions with 10 wt.% catalyst at 80 C. Catalytic efciency of sulfated tungstate among the other solid acid catalysts for the preparation of the dihydropyrimidinone was evaluated and comparative data are presented in Table 2. Among the solid acid catalysts Montmorillonite KSF, silica-sulfuric acid,

Sulfated tungstate amount (wt.%) Nil 5 10 10 10 10 10

Condition/solvent 80 C/solvent free 80 C/solvent free 80 C/solvent free Reux/ ethanol Reux/ water Reux/chloroform Reux/toluene

Time (h)/yieldb (%) 12/20 12/60 1/92 8/45 8/60 8/32 8/51

Reactions carried out at 10 mmol scale with molar ratio of benzaldehyde: ethyl acetoacetate:urea = 1:1:1.5, b isolated yield.

zeolite[HY(Si/Al = 2.43, H56(SiO2)136(AlO2)56], BFOEt2/Cu(OAc)2, and H3PMo12O40 and Yb(III)-resin, sulfated tungstate was found to be superior in terms of catalyst amount as well as yield and time of reaction. Results of H3PW12O40 and sulfated zirconia were comparable and gave slightly higher yield however required higher amount of the catalysts and in the sulphated zirconia case reaction time was longer (entries 7and 8, Table 2). Scope and generality of this protocol were demonstrated by subjecting a broad range of building block combinations such as aromatic aldehydes carrying either electron-donating or electronwithdrawing substituent, aliphatic aldehyde, different -ketoesters and urea/thiourea. All the building block combination reacted very well, giving moderate-to-excellent yields of the desired products under optimized reaction conditions, except in the case of aliphatic aldehyde which needed higher reaction temperature of 120 C, results are highlighted in Table 3. The structural variations in the aldehydes had no signicant effect on the yield and with aldehydes bearing sensitive functional groups like NO2, Cl and OCH3 the reaction proceeded smoothly to afford the corresponding products in excellent yields (entries 48, 11, and 12, Table 3). The reaction proceeded comparatively faster with aldehyde conatining p-methoxy group and required only 30 min to give corresponding dihydropyrimidinones in excellent yields (entries 5 and 11, Table 3). Sulfated tungstate also worked well even with an acid-sensitive aldehyde such as furfural without leading to the formation of any side products (entry 9, Table 3). Longer reaction times (180 min) were needed for the reaction of di-chloroaldehyde (entry 7, Table 3). Thiourea has been also used with success to provide the corresponding dihydropyrimidin-2-(1H)-thiones in high yields (entries 1012, Table 3). It is well known that for Biginelli reaction, aromatic aldehyde works very well, but aliphatic aldehyde works hard, however it is noteworthy that sulfated tungstate catalyzed the reaction with aliphatic aldehyde. Reaction was very slow and practically did not give any product at 80 C but the reaction got accelerated with rising reaction temperature and at 120 C gave 65% yield in 1 h (entry 13, Table 3). Sulfated tungstate was recovered by adding ethanol to the stirred reaction mixture followed by ltration and analysed by EDAX which showed the presence of sulfur indicating that sulfur has not leached

Scheme 1. Biginelli reaction of benzaldehyde, ethyl acetoacetate, and urea.

S.D. Salim, K.G. Akamanchi / Catalysis Communications 12 (2011) 11531156 Table 2 Effect of different acidic catalysts for formation of (I). Entry 1 2 3 4 5 6 7 8 9
a

1155

Catalyst Montmorillonite KSF Silica-sulfuric acid Zeolite [HY(Si/Al = 2.43, H56(SiO2)136(AlO2)56] BF3.OEt2/Cu(OAc)2 H3PMo12O40 H3PW12O40 Yb(III)-resin Sulfated zirconia Sulfated tungstate

Amount (wt.%) 15 35d 15 Stoichiometry 11c 18c 80 15.15 10

Molar ratioa 1:1:1.5 1:1:1.5 1:0.8:1.0 1:1:1.5 1:1:1.5 1:1:1.5 1:1:1.5 1:1:1.5 1:1:1.5

Condition/solvent 100 C/solvent free Reux/ethanol Reux/toluene 65 C/acetic acid Reux/acetic acid 80 C/solvent free 120 C/solvent free 60 C/solvent free 80 C/solvent free

Time (h)/yieldb (%) 48/77 6/91 12/80 18/71 5/80 1/93 48/80 4/ 94 1/ 92

Reference [30] [10] [32] [14] [33] [34] [17] [18] This work

Molar ratio of benzaldehyde: ethyl acetoacetate:urea, b isolated yield, c for ready comparison mole ratio of catalyst was converted into wt.%.

Table 3 Substrate scope.

O O R H + R1 O O O CH3 + H2N X NH2 sulfated tungstate/ solvent-free 80 oC R1O H3 C

R NH N H X
Yield (%) 92 90 92 90 96 90 84 88 86 90 97 79 65b Time (min) 60 60 60 60 30 60 180 80 100 60 30 90 65 References

Entry

Substrate/product R R1 C2H5 C2H5 CH3 CH3 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 X O O O O O O O O O S S S O

1 2 3 4 5 6 7 8 9 10 11 12 13
a

C6H5 4-CH3-C6H4 C6H5 4-Cl-C6H4 4-OCH3-C6H4 3,4-(OCH3)2 C6H4 3,4-Cl2-C6H4 3-NO2-C6H4 2-furyl C6H5 4-OCH3-C6H4 3-NO2-C6H4 i-C4H9

[33] [33] [33] [35] [33] [32] [27] [33] [33] [33] [33] [22] [29]

Reaction conditions: aromatic aldehyde (10 mmol); -ketoester (10 mmol); urea or thiourea (15 mmol); sulfated tungstate (10 wt.%), temperature 80 C. All products are known 1 and were identied by their melting point, IR and H NMR spectra according to literature. b Reaction carried out 120 C.

out. For reusability experiments recovered catalyst was dried in oven at 120 C for 1 h prior to use and results are given in Table 4. The results indicate that the catalyst was reusable four times without any signicant loss of activity. In order to prove that the reaction is heterogeneous, a standard leaching experiment was conducted. The reaction was preceded for 10 min in the presence of catalyst and catalyst was removed by ltration and reaction was allowed to proceed without catalyst. There was no change in yield even after 8 h of heating at 80 C, indicating that no homogeneous catalyst was involved. 4. Conclusion In conclusion the present work describes a simple and highly efcient protocol for preparation of dihydropyrimidinones using sulfated tungstate as catalyst. The attractive features of this protocol are its green-ness with respect to solvent free reaction, recyclability of
Table 4 Reusability studya. Run no. Fresh First recycle Second recycle Third recycle Fourth recycle
a

catalyst, mild reaction conditions, short reaction times and high yield. It is noteworthy that reaction occurs with aliphatic aldehydes as well which otherwise are hard to react.

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