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International Journal of Recent Scientific Research

Vol. 2, Issue, 2, pp.36-39, February, 2011

ISSN: 0976-3031

ONE POT SYNTHESIS OF BIGNELLI COMPOUNDS USING RECYCLABLE AND ECOFRIENDLY TASK SPECIFIC IONIC LIQUID
*1Rajendran,
1Department 2Research

A., 2Ramu, S. and 1Karthikeyan, C.

of Chemistry, Sir Theagaraya College, Chennai-21, Tamil Nadu, India. and Development Centre, Bharathiar University, Coimbatore, India.

Received 25th December, 2010; Accepted 15th January, 2011; Published online 15th February, 2011

Abstract
In recent years, the task specific ionic liquids (TSILS) are attracting increasing interest as a greener recyclable catalyst alternative to classical molecular solvents for environmentally benign organic synthesis. This paper deals with the synthesis of 3, 4-dihydropyrimidin-2(1H)-ones(DHPMs) popularly known as Bignelli compounds using ionic liquid [Et3 NH][HSO4 ] as catalyst. The reaction has been carried out thermally to provide neat product in excellent yields. Operational simplicity, mild reaction conditions, environmental and eco friendly, compatibility with various functional groups, higher yields than conventional methods and application of inexpensive and easily available reagents as catalysts are noted as the advantages of the present methodology for the synthesis of dihydropyrimidinones. 2010 IJRSR. All rights reserved.

Key words: Task specific ionic liquid, Bignelli compounds, Solventless reaction, One pot synthesis, Green chemistry

INTRODUCTION
Ionic liquids have emerged as a class of material, having properties that make them green solvents which had found application in a large number of organic transformations (Rajendran, 2010). More recently, the focus have been shifted to Task Specific Ionic Liquid (TSIL) i.e., ionic liquids having a functional group that catalyze or take part in reaction (Zhang Gao et al., 2005). There have been few reports where TSILs have been used as catalyst in organic synthesis (Shelton et al., 2009). Ionic liquids with acidic counter ions have been employed for esterification, Friedel crafts reaction, Diels Alder reaction, hydrogenation, etc., (Larock, 1999). The Bignelli reaction, which was discovered more than a century ago, is one of the most important reactions for the synthesis of dihydropyrimidinones based on acid catalyzed three component condensation of -dicarbonyl compounds, an aldehyde and urea or thiourea (Vasundhara Singh et al., 2010). The major drawback of this protocol is the low yield of product in the case of both substituted aromatic and aliphatic aldehydes (Ganeshpure et al., 2007). Several Lewis acid as well as Bronsted acids such as BF3OEt2, polyphosphate esters, lanthanum chloride, lanthanide triflate ferric chloride hexahydrate, indium chloride (Wang et al., 2006). Amberylyst-15, Nafion-H, KSF Clay and dry acetic acid under microwave irradiation had been used as promoters for this reaction (Kumar, 2009).

The application 3,4-dihydropyrimidin-2(1H)-ones (popularly known as Bignelli compounds) and their derivatives is increasing tremendously because of their therapeutic and pharmacological properties and also because of interesting biological activities of several marine alkaloids which contain the dihydropyrimidine nucleus involves one-potto multi step approaches (Shah et al.,2010). Most notable among them are batzelladine alkaloids, which have been found to be potent human immune deficiency virus (HIV) gp-120-CD4 inhibitors.

EXPERIMENTALS
Chemicals All the chemicals were of AR grade and used without further purification unless otherwise stated. These chemicals were obtained from S.D. fine chemicals, Mumbai. The proposed ionic liquid [Et3NH] HSO4 was synthesized according to procedure and reported in previous literature (Shah et al., 2009). General Procedure for the Synthesis of dihydro pyrimidinones: Representative procedure of one-pot synthesis of 5ethoxycarbonyl -6- methyl- 4-phenyl-3, 4-dihydro pyrimidine -2 (1H)-one. A mixture of ethylacetoacetate (25mmol), Benzaldehyde (25mmol), urea/thiourea (32.5mmol) and [Et3NH][HSO4] (0.4mmol) were taken in 25 ml round bottom flask fitted with a reflux condenser. The mixture was heated at 80oC and refluxed with various solvents (Table 1) for 1 hr in an oil bath when solid product separates out. To it was added ice cold water and
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*Corresponding author: annamalai_rajendran2000@yahoo.com

Inter. J. Rece. Sci. Res., Vol. 2, Issue, 2, pp. 36-39, February, 2011

Table 1. Yield of 3,4-dihydropyrimidine-2-(1H)-one catalyzed by [Et3NH][HSO4] in various solvents

Entry 1 2 3 4 5 6 7
a c

Solventa CHCl3 THF EtOH CH3CN Toluene H2O EtOHc

Catalyst [Et3NH][HSO4] [Et3NH][HSO4] [Et3NH][HSO4] [Et3NH][HSO4] [Et3NH][HSO4] [Et3NH][HSO4] None

d

(%)Yieldd 35 56 93 91 90 15 26

Refluxed for 6hr; Refluxed for 24 hr; % Yield was determined with respect to starting aldehyde

Table 2. Synthesis of 3,4-dihydropyrimidine-2-(1H)-one catalyzed by [Et3NH][HSO4] in ethanol

Compound R1 R2 R3 X Time(min) %Yielda 1 CH3 OEt Ph O 3 92 2 CH3 OEt Ph S 3 92 3 CH3 OEt 4-Cl-C6 H4 O 3 88 4 CH3 OEt 4-Cl-C6 H4 S 3 87 5 CH3 OEt 4-OMe-C6H4 O 2 97 6 CH3 OEt 4-OMe-C6H4 S 2 96 7 CH3 OEt 2-OH-C6H4 O 4 97 8 CH3 OEt 2-OH-C6H4 S 4 97 9 CH3 OEt PhCH=CH2 O 5 79 10 CH3 OEt PhCH=CH2 S 5 79 11 CH3 OEt 4-NO2C6H4 O 1 90 12 CH3 OEt 4-NO2C6H4 S 1 90 1 13 All the products have been characterized by their H NMR, NMR and IR Spectral d analysis; % Yield was determined with respect to starting aldehyde

1. We started to study the three component Bignelli condensation catalyzed by [Et3NH][HSO4] and by examining the conditions required for the reaction involving Benzaldehyde, urea and ethylacetoacetate to afford great yield of dihydropyrimidinones. The summary of the results obtained is provided in Table I. Entries 1-6 show the effect of various solvents on the yield of the reaction. Although acetonitrile and toluene afforded the product in high yields we chose ethanol for its cheapness and environmental acceptability. Entry 3 describes the yields of five consecutive condensations leading to compound 1. Entry 7 shows the catalytic effect of [Et3NH][HSO4] in the three component condensation of benzaldehyde, urea and ethylacetoacetate. The reactions proceeded smoothly in refluxing ethanol and were completed within few minutes (Smith and March, 2001). From table-1, is clearly demonstrated that when the proposed ionic liquid is employed as catalyst in conjunction with ethanol as solvent produced greater yield of Bignelli compound (entry-3 in Table-1) than with other solvents. Not only that, when the same reaction is carried out without ionic liquid but with ethanol as solvent, it gave very poor yield (entry-7 in Table-1). This clearly proves the efficiency of the proposed ionic liquid in catalyzing the Bignelli condensation reaction. This procedure was followed for the synthesis of different dihydropyrimidinones and the results are listed in Table 2. Table 2 shows the generality of the present protocol which is equally effective for urea or thiourea and also for aromatic aldehydes. Under these conditions the yields were significantly better in comparison with the classical Bignelli procedure. Melting points of the products obtained in the aforementioned Bignelli reactions were determined on a glass disk with an electrical bath and are uncorrected. 1H (300 MHZ) and 13C NMR spectra were run in DMSO4-d6. FT-IR Spectra were taken as KBr discs /nujol. The results of this part of the work are displayed in table-3. After successful completion of the reaction, the remaining ionic liquid catalyst was separated from the reaction mixture by extraction with copious amount of water and reloaded with fresh reagents for at least half - a- dozen runs. No decrease in the yield was observed demonstrating that [Et3NH][HSO4] can be potentially reused as a catalyst in Bignelli condensation. The results of the reusability of the TSIL are presented in Table -4. Conclusion In summary a TSIL [Et3NH][HSO4] has been used as catalyst for bringing about Bignelli three component reactions. The reaction has been carried out thermally to provide DHPMs in excellent yields. Operational simplicity, mild reaction conditions, environmental and eco friendly, compatibility with various functional groups, high yields and application of inexpensive and easily available reagents as catalyst are the advantages of the present methodology for the three component one - pot

solid product was filtered out and purified by recrystallisation from ethanol to obtain pure product (scheme-1).
O O O

[Et3NH]H 4 SO
NH2

O R 2

R 3 N H X

R1

R2

H2N

R3CHO

EtOH,

R1 N H

Where R1= - CH3; R2 = - OEt; R3 = - Ph / -4-Cl-C6H4 / 4-OMe-C6H4 / - 2-OH-C6H4 / - PhCH=CH2 / - 4-NO2C6H4 ; and X = O / S

RESULTS AND DISCUSSION

In continuation with our studies toward exploring the use of ionic liquid [Et3NH] HSO4 we herein report the use of [Et3NH] HSO4 as catalyst for one pot three component Bignelli reaction under thermal heating (Shelke et al., 2009). The optimal reaction conditions were fixed and the products were characterized by FT-IR, 1H-NMR and 13CNMR studies (Sahoo et al., 2006). The catalytic behavior and the suitability of the proposed ionic liquid are highlighted. The ionic liquid was recovered and reused for more than half a dozen times without the potential loss in the activity (Shah et al., 2009). The present scope and potential economic impact of the reaction are demonstrated by the synthesis of Bignelli compounds. Remaining challenges and future perspectives of the new transformation are discussed (Wang et al., 2006). The results of one pot synthesis of 3,4dihydropyrimidine-2-(1H)-ones (Bignelli compounds) catalyzed by the proposed task specific ionic liquid [Et3NH][HSO4] in various solvents are presented in Table
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Inter. J. Rece. Sci. Res., Vol. 2, Issue, 2, pp. 36-39, February, 2011

Table 3. Melting point and spectral characteristics of various Bignelli compounds

Entry Compound Name m.p. 214-217oC FT-IR
1

H-NMR(300 MHz, CDCl3 DMSOd6) 8.20 (s, IH,NH),7.22-7.33(m,5H,ArH),6.02 (br,s,1H,NH),5.38(d,1H,J=2.7 Hz,-CH-),3.61 (t,2H, -COCH2 CH3),3.74 (q,3H, COCH2 -CH3 ) 9.46 (br, s, IH, NH),7.227.33(m,5H,Ar-H),6.56 (br,s,1H,NH),5.17(d,1H,J=3.6 Hz,-CH),3.61 (t,2H, -COCH2 -CH3 ),3.74 (q,3H, COCH2 -CH3) 8.59 (s, IH,NH),8.19(d,2H,J=7.6 Hz Ar-H))7.88(br, s, 1H,NH),7.50 (d,2H,J=7.6 Hz, Ar-H),5.27 (d,1H,J=2.3Hz,-CH-) (t,2H, -COCH2 CH3),3.74 (q,3H, COCH2 -CH3 ) 8.59 (s, IH,NH),8.19(d,2H,J=7.6 Hz Ar-H))7.88(br, s, 1H,NH),7.50 (d,2H,J=7.6 Hz, Ar-H),5.27 (d,1H,J=2.3Hz,-CH-) (t,2H, -COCH2 CH3),3.74 (q,3H, COCH2 -CH3 ), 8.59 (s, IH,NH),8.19(d,2H,J=7.6 Hz Ar-H))7.88(br, s, 1H,NH),7.50 (d,2H,J=7.6 Hz, Ar-H),5.27 (d,1H,J=2.3Hz,-CH-) (t,2H, -COCH2 CH3),3.74 (q,3H, COCH2 -CH3), 3.70(s.3H,-OCH3 ) 8.59 (s, IH,NH),8.19(d,2H,J=7.6 Hz Ar-H))7.88(br, s, 1H,NH),7.50 (d,2H,J=7.6 Hz, Ar-H),5.27 (d,1H,J=2.3Hz,-CH-) 3.72(t,2H, COCH2 -CH3),3.74 (q,3H, COCH2 CH3), 3.70(s.3H,-OCH3) 8.39 (br, s, IH,NH),7.00(d,2H,J=8.1 Hz, Ar-H),6.91(br, s, 1H,OH),6.53 (d,2H,J=8.1 Hz, Ar-H),5.02 (s,1H,-CH)3.89 (q,2H,J=7.1Hz,-OCH2),2.22 (s,3H,-CH3),1.10 (t,3H,J=7.1Hz,-CH3), 3.72(t,2H, -COCH2 -CH3),3.74 (q,3H, COCH2 -CH3), 3.70(s.3H,-OCH3) 8.77 (br, s, IH,NH),8.0 (br, s, IH,OH),7.00(d,2H,J=8.1 Hz, ArH),6.91(br, s, 1H,NH),6.63 (d,2H,J=8.1 Hz, Ar-H),5.08 (d,1H,J=2.7,-CH-)3.89 (q,2H,J=7.1Hz,-OCH2),2.22 (s,3H,CH3),1.10 (t,3H,J=7.1Hz, -CH3), 3.72(t,2H, -COCH2-CH3),3.74 (q,3H, COCH2 -CH3 ). 8.99 (br, s, IH,NH),7.68(m,5H, Ar-H )6.32(d,1H,J=14.6 Hz Ar-CH=CH-) 6.16(dd,1H,J=14.5Hz, Ar-CH=CH),5.21 (d,1H,J=3.9Hz,-CH-)4.03(q,2H,OCH2),2.18( s,3H,-CH3),1.03(t,3H,CH3) 8.99 (br, s, IH,NH),7.68(m,5H, Ar-H )6.32(d,1H,J=14.6 Hz Ar-CH=CH-) 6.16(dd,1H,J=14.5Hz, Ar-CH=CH),5.21 (d,1H,J=3.9Hz,-CH-)4.03(q,2H,OCH2),2.18( s,3H,-CH3),1.03(t,3H,CH3) 8.59 (s, IH,NH),8.19(d,2H,J=7.6 Hz Ar-H))7.88(br, s, 1H,NH),7.50 (d,2H,J=7.6 Hz, Ar-H),5.27 (d,1H,J=2.3Hz,-CH-) (t,2H, -COCH2 CH3),3.74 (q,3H, COCH2 -CH3 ) 8.59 (s, IH,NH),8.19(d,2H,J=7.6 Hz Ar-H))7.88(br, s, 1H,NH),7.50 (d,2H,J=7.6 Hz, Ar-H),5.27 (d,1H,J=2.3Hz,-CH-) (t,2H, -COCH2 CH3),3.74 (q,3H, COCH2 -CH3 )

13

C-NMR (300 MHz, CDCl3 DMSO-d6 ) =165.7,152.0,148.5,144.5,128. 3,127.2,126.0,98.9,53.7,50.7,1 7.7 =171.3,166.7,158.8,140.5,112 8.9,127.7,127.0,126.5,103.6,1 5.2,50.1,17.0 =165.4,152.0,150.5,146.5,127. 8,124.2,96.9,54.5,50.0,17.7

Ethyl-6-methyl-2oxo-4-phenyl-3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2thioxo-4-phenyl3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2oxo-4-(4chloro)phenyl-3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2thioxo-4-(4chloro)phenyl-3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2oxo-4-(4methoxy)phenyl3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2thioxo-4-(4methoxy)phenyl3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2oxo-4-(4hydroxy)phenyl3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2thioxo-4-(4hydroxy)phenyl3,4dihydropyrimidine5-carboxylate

3245,1698,1638 cm-1 (KBr) 3425,2916,1695,16 -1 66,1462,1377cm (nujol)

242-245oC

240--246o C

3353,3210,2955,16 90,1528,1350 cm-1 (nujol)

252--254o C

3353,3210,2955,16 90,1528,1350 cm-1 (nujol)

=165.4,152.0,150.5,146.5,127. 8,124.2,96.9,54.5,50.0,17.7

226--228o C

3400,3210,2922,16 70,1460,1240 cm-1 (nujol)

=160.7,159.9,150.3,144.5,110. 6,108.2,107.9,100.1,60.2,55.9, 55.5,53.1,16.9,15.2

236--238 C

3400,3210,2922,16 70,1460,1240 cm-1 (nujol)

=160.7,159.9,150.3,144.5,110. 6,108.2,107.9,100.1,60.2,55.9, 55.5,53.1,16.9,15.2

227--229 C

3520,3220,2917,16 83cm-1 (nujol)

=164.3,152.6,147.63,135.9,12 9.4,129.1,116.1,107.4,62.3,49. 6,16.2,15.5

227--230o C

3402,2927,1462,13 77cm-1 (nujol)

=172.5,166.7,154.6,153.3,130. 1,129.4,128.8,119.1,119.0,109 .7,54.4,50.2,16.1.

Ethyl-6-methyl-2oxo-4-styryl-3,4dihydropyrimidine5-carboxylate

237--238o C

2920,1683,1644,14 62 cm-1 (nujol)

=166.1,154.6,148.5,137.2,130. 0,127.6,127.2,126.1,125.0,97. 8,60.2,51.8,17.7,15.2.

10

10

Ethyl-6-methyl-2thioxo-4-styryl-3,4dihydropyrimidine5-carboxylate

240--242o C

2920,1683,1644,14 62 cm-1 (nujol)

=166.1,154.6,148.5,137.2,130. 0,127.6,127.2,126.1,125.0,97. 8,60.2,51.8,17.7,15.2.

11

11

Ethyl-6-methyl-2oxo-4-(4nitro)phenyl-3,4dihydropyrimidine5-carboxylate Ethyl-6-methyl-2thioxo-4-(4nitro)phenyl-3,4dihydropyrimidine5-carboxylate

236--238o C

3353,3210,2955,16 90,1528,1350 cm-1 (nujol)

=165.4,152.0,150.5,146.5,127. 8,124.2,96.9,54.5,50.0,17.7

12

12

236--238o C

3353,3210,2955,16 90,1528,1350 cm-1 (nujol)

=165.4,152.0,150.5,146.5,127. 8,124.2,96.9,54.5,50.0,17.7

synthesis of dihydropyrimidinones. This work was also proved to be a very efficient and selective protocol for the synthesis of Bignelli compounds as it involves a simple
38

work-up procedure, absence of by-products, recyclability of the catalyst and using greener chemicals that are environmentally and ecologically benign. Also, it is

Inter. J. Rece. Sci. Res., Vol. 2, Issue, 2, pp. 36-39, February, 2011

demonstrated that simple non acidic ionic liquids do not catalyze this reaction. Acknowledgements The authors immensely thank the UGC, New Delhi for the financial support rendered for the major research project [F. No. 35-147 / 2008 (SR]. The authors also thank the principal and the management of Sir Theagaraya College, Chennai-21, Tamil Nadu for their constant encouragement and support given.

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Shah, T.B. Gupta, A, Patel, M.R. Chaudhari, V.S. Patel, H. and Patel, V.C. 2010. Synthesis and in vitro study of biological activity of heterocyclic N-Mannich base of 3,4-dihydropyrimidine-2(1H)-thiones, Indian journal of Chemistry, 49B: 578-586. Shah, T.B. Gupta, A. Patel, M.R. Chaudhari, V.S. Patel, H. and Patel, V.C. 2009. Synthesis and in vitro study of biological activity of heterocyclic N-Mannich bases, Indian journal of Chemistry, 48B: 88-96. Shelke, K.F. Sapkal, S.B. Madje, B.R. Shingate, B.B. Shingare, M.S. 2009. Ionic liquid promoted an efficient synthesis of 5 arylidene 2, 4thiazolidinedione, Bulletin of the Catalysis Society of India, 8: 30 34. Shelton, R.A. Arends, I. and Hanefeld, U. 2009. Green Chemistry and Catalysis, Wiley-VCH, New York, N.Y. Smith, M.B. March, J. 2001. Advanced Organic Chemistry, Reactions, Mechanisms and Structure; John Wiley & Sons: New York, 1218 1224. Vasundhara, S. Skhbir, K. Rajni, R. Goverdhan, L.K. and Jasvinder, S. 2010. Acidic task specific ionic liquid catalyzed synthesis of dihydropyrimidinones, Indian journal of Chemistry, 49B: 611-616. Wang, C. Guo, L. Li, H. Wang, Y. Weng, J. and Wu, L. 2006. Preparation of simple ammonium ionic liquids and their application in the cracking of dialkoxypropanes, Green Chem. 8: 603 607. Zhang Gao, L.E. Chen, Z.C. Hu, Y. and Zheng, Q.G. 2005. Organic reactions in Ionic Liquids: Ionic liquid promoted Three component Condensation of Benzotriazole with Aldehyde and Alcohol, Chinese Chemical Letters, 16 (2): 155-158.

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