Scholarly article on topic 'Facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid'

Facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid Academic research paper on "Chemical sciences"

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{"Biginelli reaction" / " p-Dodecylbenzenesulfonic acid" / Dihydropyrimidinone / "Indeno[1 / 2-d]pyrimidine" / "2H-Indene-1 / 3-dione" / "One-pot synthesis"}

Abstract of research paper on Chemical sciences, author of scientific article — Krishnamoorthy Aswin, Syed Sheik Mansoor, Kuppan Logaiya, Prasanna Nithiya Sudhan, Rahim Nasir Ahmed

Abstract A facile method for synthesizing 3,4-dihydropyrimidin-2(1H)-ones and -thiones in the Biginelli reaction by condensation reaction of aldehydes, β-ketoesters and urea or thiourea with p-dodecylbenzenesulfonic acid as a recyclable catalyst under solvent-free conditions at 80°C is described. A series of indeno[1,2-d]pyrimidines was also synthesized under the same conditions by a Biginelli-like reaction of 2H-indene-1,3-dione with urea or thiourea and an aromatic aldehyde. All the products in both reactions were obtained in good to excellent yield by this simple, efficient procedure. The structures of all the synthesized compounds were established from advanced spectroscopic data.

Academic research paper on topic "Facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid"

Accepted Manuscript

Title: A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid

Author: Krishnamoorthy Aswin Syed Sheik Mansoor Kuppan Logaiya Prasanna Nithiya Sudhan R. Nasir Ahmed

PII: DOI:

Reference:

S1658-3655(14)00034-X http://dx.doi.org/doi:10.1016/j.jtusci.2014.03.005 JTUSCI 65

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Received date: Revised date: Accepted date:

25-11-2013

24-2-2014

21-3-2014

Please cite this article as: K. Aswin, S.S. Mansoor, K. Logaiya, P.N. Sudhan, R.N. Ahmed, A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid, Journal of Taibah University for Science (2014), http://dx.doi.org/10.1016/j.jtusci.2014.03.005

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A facile synthesis of 3,4-dihydropyrimidin-2(1#)-ones/thiones and indeno[1,2-d]pyrimidines catalyzed by ^-dodecylbenzenesulfonic acid Krishnamoorthy Aswin, Syed Sheik Mansoor*, Kuppan Logaiya, Prasanna Nithiya Sudhan, R. Nasir Ahmed

Bioactive Organic Molecule Synthetic Unit, Research Department of Chemistry, C. Abdul Hakeem College, Melvisharam - 632 509, Tamil Nadu. e-mail: smansoors2000@yahoo.co.in

Abstract: A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones (DHPMs) through Biginelli reaction by the condensation reaction of aldehydes, ^-ketoesters and urea/thiourea employing p-dodecylbenzenesulfonic acid (DBSA) as a recyclable catalyst under solvent-free condition at 80 oC is described. Furthermore, a series of indeno[1,2-d]pyrimidines have also been synthesized using the same conditions by the Biginelli-like reaction of 2H-indene-1,3-dione, with urea/thiourea and aromatic aldehyde. All the products in both reactions obtained in good to excellent yields by proceeding through a simple and efficient procedure. All the synthesized compounds structure has been established by advanced spectroscopic data.

Keywords: Biginelli reaction; p-dodecylbenzenesulfonic acid; dihydropyrimidinones; indeno[1,2-d]pyrimidines; 2H-indene-1,3-dione; one-pot synthesis

1. Introduction

Multi-component reactions (MCRs) are of increasing importance in organic and medicinal chemistry, because the strategies of MCR offer significant advantages over conventional linear-type syntheses [1]. Compared with conventional methods of organic synthesis, MCRs have the advantages of high-selectivity, good yields, milder reaction conditions, and simple work-up procedures, among others. Thus, a vast number of diverse compounds can be obtained in a parallel synthesis [2]. The development of new and efficient synthetic methodologies for the rapid construction of potentially bio-active compounds constitutes a major challenge for chemists in organic synthesis. MCRs allow the construction of several bonds in a single operation and are getting considerable importance as one of the most powerful emerging synthetic tools for the creation of molecular complexity and diversity [3].

The Biginelli synthesis is an easy and useful multicomponent reaction that is gaining increasing importance in organic and medicinal chemistry for its generation of multifunctionalized products, including 3,4-dihydropyrimidin-2(1#)-ones and their thione analogs and other related heterocyclic compounds [4]. Recently, appropriately functionalized dihydropyrimidine analog of novel 4-aryl-5-isopropoxycarbonyl-6-methyl-3,4-dihydropyrimidinones has emerged as anti-microbiological agent [5]. A novel 3,4-dihydropyrimidin-2(1#)-one has been reported as HIV-1 replication inhibitors with improved metabolic stability [6]. In addition, their special structure has been found in natural marine alkaloid batzelladines, which are the first low molecular weight natural products reported in the literature that inhibits the binding of HIVgp-120 to CD4 cell.

This could be a new path for the development of AIDS therapy [7-8]. In 1893, the Italian chemist Pietro Biginelli reported the cyclocondensation of ethyl acetoacetate, urea and an aryl aldehyde in the presence of an acid, furnishing 3,4-dihydropyrimidin-2(1#)-ones as products [9]. However, this reaction often requires harsh conditions and long reaction times and affords low yields, particularly when substituted aromatic and aliphatic aldehydes are employed. The scope of this reaction was gradually extended by the variation of all three building blocks, allowing access to a large number of multi functionalized dihydropyrimidines of medicinal use [10].

The most straightforward procedure for the preparation of dihydropyrimidinones and thiones is by condensation of ^-dicarbonyl compounds with an aromatic aldehyde and urea or thiourea in the presence of Lewis and Bronsted acid promoters such as silica immobilized nickel complex [11], cellulose sulfuric acid [12], lanthanum oxide [13], bioglycerol-based sulfonic acid functionalized carbon [14], ^-sulfonic acid calixarenes [15], copper(II) sulfamate [16], triphenylphosphine [17], melamine trisulfonic acid [18], montmorillonite KSF [19], natural catalyst [20], heteropoly acid supported on zeolite [21], In(OTf)3 [22], Ruthenium(III) chloride [23], silica sulfuric acid [24], Nafion-H [25], sulfonated carbon [26], lactic acid [27] and so on. The classical Biginelli reaction is considerably extended by use of 1-indanone [28]. However, some of these procedures require expensive reagents, strongly acidic conditions, long reaction times, high temperatures, or stoichiometric amounts of catalysts, or they result in environmental pollution or give unsatisfactory yields. Therefore, there is a need for new catalysts that are readily available or easy to prepare, inexpensive, and recoverable. Moreover, the

workup procedure should be simple. Therefore, to avoid these limitations, the introduction of a milder and more efficiently methods accompanied with higher yields are needed. In this regard, p-dodecylbenzenesulfonic acid (DBSA) has found many applications [29-34].

In recent years, p-dodecylbenzenesulfonic acid (DBSA) has gained considerable popularity as an efficient Bronsted-acid surfactant combined catalyst for carrying out various organic transformations in water as well as under solvent-free conditions [29-34]. p-dodecylbenzenesulfonic acid has been used extensively as Bransted acid-surfactant-combined catalyst in Mannich-type reactions of aldehydes, amines, and ketones [29], ester, ether, thioether, and dithioacetal formation in water [30], organic synthesis inside particles in water [31], solvent-free esterification [32], for the synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles in aqueous media [33] and green synthesis of dibenzo[a,j]xanthenes [34]. However, there is no report on the use of p-dodecylbenzenesulfonic acid (DBSA) for the synthesis of 3,4-dihydropyrimidine derivatives and also indeno[1,2-d]pyrimidines.

In recent years, the target of science and technology has been shifting more towards environmentally friendly and has encouraged the application of solvent-free conditions. A move away from the use of solvents in organic synthesis has led in some cases to improved results and more benign synthetic procedures. Adopting the principles of Green Chemistry, we have established that using solvent-free conditions for synthesis of 1,4-dihydropyridines results in a dramatic improvement in yields [35].

As part of our continuing studies of organic processes on the development of environmentally friendly procedures for the synthesis of biologically active heterocyclic

molecules [36-39], we now describe the synthesis of 3,4-dihydropyrimidine derivatives using DBSA as an efficient novel catalyst under solvent-free condition at 80 oC.

By using the same procedure which we applied for the synthesis of 3,4-dihydropyrimidine derivatives, we have also synthesized a series of 4-aryl-3,4-dihydro-1#-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones by the Biginelli-like reaction of 2#-indene-1,3-dione, with urea/thiourea and aromatic aldehydes.

2. Experimental

2.1 Chemicals and analysis

Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were obtained using Bruker DRX-500 Avance at ambient temperature, using TMS as internal standard. FT-IR spectra were obtained as KBr discs on Shimadzu spectrometer. Mass spectra were determined on a Varion - Saturn 2000 GC/MS instrument. Elemental analysis was measured by means of Perkin Elmer 2400 CHN elemental analyzer flowchart. All yields refer to isolated products unless otherwise stated.

2.2 General procedure for the preparation of 3,4-dihydropyrimidinones / thiones

A mixture of aldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea/thiourea (1.5 mmol) and DBSA (5 mol%) under solvent-free condition was heated with stirring at 80 oC for appropriate time. The progress of the reaction was monitored by TLC. After cooling, the reaction mixture was poured into crushed ice with stirring. The crude product was

filtered, washed with cold water, dried and recrystallized from 95% ethanol or ethyl acetate to give pure products. After the separation of the product, CH2Cl2 (20 mL) was added, and the catalyst was removed by filtration. The recovered catalyst was washed two times with an aliquot of fresh CH2Cl2 (2*10 mL), then drying to ready for later run. The IR, NMR, 13C NMR, mass and elemental analysis data of the synthesized compounds are given below.

2.3 Spectral data for the synthesized compounds (4a-v)

2.3.1 5-Ethoxycarbonyl- 6-methyl-4-phenyl- 3,4- dihydropyrimidin-2(1H)-one (4a)

IR (KBr, cm-1): 3322 and 3213 (N-H str.), 1696 and 1664 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.33 (s, 3H, CH3), 3.92 (q, J = 7.2 Hz, 2H, OCH2CHs), 5.22 (s, 1H, CH), 7.20-7.43 (m, 5H, Ar-H), 7.88 (s,1H, NH-1), 9.48 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 14.1, 17.9, 54.2, 60.1, 100.3, 122.9, 125.7, 129.1, 142.9, 146.1, 154.9, 165.9 ppm; MS(ESI): m/z 261 (M+H)+; Anal. Calcd for CmH^Ob: C, 64.62; H, 6.15; N, 10.77 %. Found: C, 64.58; H, 6.13; N, 10.72 %.

2.3.2 5-Ethoxycarbonyl- 6-methyl-4-(2-nitroyphenyl)- 3,4- dihydropyrimidin-2(1H)-one (4b)

IR (KBr, cm-1): 3316 and 3207 (N-H str.), 1698 and 1659 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 1.05 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.24 (s, 3H, CH3), 3.94 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.20 (s, 1H, CH), 7.00-7.28 (m, 4H, Ar-H), 7.99 (s,1H, NH-1), 9.20 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSO-d6) S: 14.8, 17.0, 54.6, 60.7, 100.6, 122.7, 125.5, 129.3, 142.7, 146.3, 154.7, 165.7 ppm; MS(ESI): m/z 306 (M+H)+;

Anal. Calcd for C14H15N3O5: C, 55.08; H, 4.92; N, 13.77 %. Found: C, 55.00; H, 4.94; N, 13.70 %.

2.3.3 5-Ethoxycarbonyl- 6-methyl-4-(4-fluorophenyl)- 3,4- dihydropyrimidin-2(1H)-one (4c)

IR (KBr, cm-1): 3321 and 3211 (N-H str.), 1695 and 1663 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.92 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.22 (s, 1H, CH), 7.12 (d, 2H, J = 8.0 Hz, Ar-H), 7.34 (d, 2H, J = 8.0 Hz, Ar-H), 7.90 (s,1H, NH-3), 9.12 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 14.4, 17.8, 54.8, 60.0, 100.9, 122.5, 125.9, 129.7, 142.8, 146.7, 154.8, 166.2 ppm; MS(ESI): m/z 279 (M+H)+; Anal. Calcd for C14H15FN2O3: C, 60.43; H, 5.39; N, 10.07 %. Found: C, 60.30; H, 5.36; N, 10.09 %.

2.3.4 5-Ethoxycarbonyl- 6-methyl-4-(2-chlorophenyl)-3,4- dihydropyrimidin-2(1H)-one (4d)

IR (KBr, cm-1): 3312 and 3203 (N-H str.), 1686 and 1654 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 1.06 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.16 (s, 3H, CH3), 3.82 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.30 (s, 1H, CH), 7.16-7.38 (m, 4H, Ar-H), 8.00 (s,1H, NH-3), 9.30 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6: 14.2, 17.4, 54.4, 60.9, 100.2, 122.2, 126.1, 129.4, 143.2, 146.2, 155.5, 166.4 ppm; MS(ESI): m/z 295 (M+H)+; Anal. Calcd for C14H15ClN2O3: C, 57.05; H, 5.10; N, 9.52 %. Found: C, 57.00; H, 5.06; N, 9.46 %.

2.3.5 5-Ethoxycarbonyl- 6-methyl-4-(3-bromophenyl)-3,4- dihydropyrimidin-2(1H)-one (4e)

IR (KBr, cm-1): 3319 and 3211 (N-H str.), 1695 and 1664 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 1.08 (t, J = 7.1 Hz , 3H, OCH2CH3), 2.18 (s, 3H, CH3), 3.78 (q, J = 7.1 Hz, 2H, OCH2CH3), 5.28 (s, 1H, CH), 7.03-7.25 (m, 4H, Ar-H), 7.92 (s,1H, NH-3), 9.04 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) S: 13.9, 17.5, 54.3, 60.2, 100.4, 122.4, 126.3, 129.0, 143.4, 146.4, 155.1, 165.6 ppm; MS(ESI): m/z 339.9 (M+H)+; Anal. Calcd for CHH15BrN2O3: C, 49.57; H, 4.43; N, 8.26 %. Found: C, 49.47; H, 4.45; N, 8.22 %.

2.3.6 5-Ethoxycarbonyl- 6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4f)

IR (KBr, cm-1): 3384 (O-H str.), 3314 and 3203 (N-H str.), 1690 and 1664 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.90 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.24 (s, 1H, CH), 7.22 (d, 2H, J = 8.0 Hz, Ar-H), 7.44 (d, 2H, J = 8.0 Hz, Ar-H), 7.82 (s,1H, NH-3), 9.12 (s, 1H, NH-1), 9.42 (s, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6) S: 14.2, 17.3, 54.1, 60.6, 100.6, 122.6, 126.2, 130.2, 143.6, 146.5, 155.3, 165.5 ppm; MS(ESI): m/z 277 (M+H)+; Anal. Calcd for C14H16N2O4: C, 60.87; H, 5.80; N, 10.14 %. Found: C, 60.89; H, 5.81; N, 10.10 %.

2.3.7 5-Ethoxycarbonyl- 6-methyl-4-(4-methoxyphenyl)-3,4- dihydropyrimidin-2(1H)-one (4g)

IR (KBr, cm-1): 3321 and 3215 (N-H str.), 1700 and 1670 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 1.07 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.18 (s, 3H, CH3), 3.64 (s, 3H, OCH3), 3.94 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.28 (s, 1H, CH), 7.09 (d, 2H, J = 8.2 Hz, Ar-H), 7.35 (d, 2H, J = 8.2 Hz, Ar-H), 7.92 (s,1H, NH-3), 9.04 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) S: 14.3, 18.0, 55.0, 60.4, 100.0, 121.9, 126.4, 130.3,

143.3, 146.2, 155.6, 166.3 ppm; MS(ESI): m/z 291 (M+H)+; Anal. Calcd for C15H18N2O4: C, 60.43; H, 5.39; N, 10.07 %. Found: C, 60.40; H, 5.34; N, 10.02 %.

2.3.8 5-Ethoxycarbonyl- 6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one (4h)

IR (KBr, cm-1): 3314 and 3206 (N-H str.), 1690 and 1659 (C = O str.); 1H NMR (500 MHz, DMSOd) 6: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.84 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.22 (s, 1H, CH), 7.07-7.33 (m, 4H, Ar-H), 8.18 (s,1H, NH-3), 9.12 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6: 14.1, 18.1, 55.2, 60.5, 99.7, 121.8, 126.6, 129.5, 143.5, 145.7, 154.6, 165.8 ppm; MS(ESI): m/z 306 (M+H)+; Anal. Calcd for C14H15N3O5: C, 55.08; H, 4.92; N, 13.77 %. Found: C, 55.09; H, 4.90; N, 13.74 %.

2.3.9 5-Ethoxycarbonyl-4-(2-furfuryl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4i)

IR (KBr, cm-1): 3376 and 3258 (N-H str.), 1706 and 1665 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 1.14 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.98 (q, J = 7.4 Hz , 2H, OCH2CH3), 5.12 (s, 1H, CH), 6.78 (d, J = 4.2 Hz, 1H), 7.00 - 7.08 (m, 2H), 7.22 (s, 1H, NH-3), 9.66 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6: 13.9, 17.7, 45.2, 60.4, 106.6, 111.4, 117.9, 138.5, 139.6, 142.3, 160.2, 171.3 ppm; MS(ESI): m/z 251 (M+H)+; Anal. Calcd for C12H14N2O4 : C, 57.59; H, 5.64; N, 11.19 %. Found: C, 57.48; H, 5.54; N, 11.22 %.

2.3.10 5-Ethoxycarbonyl-6-methyl-4-propyl-3,4-dihydropyrimidin-2(1H)-one (4j)

IR (KBr, cm-1): 3354 and 3240 (N-H str.), 1712 and 1658 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 1.07 (t, J = 7.4 Hz, 3H, OCH2CH3), 1.14-1.27 (m, 7H), 2.18 (s, 3H,

CH3), 3.99 (q, J = 7.4 Hz , 2H, OCH2CH3), 5.11 (s, 1H, CH), 7.29 (s, 1H, NH-3), 9.74 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 13.6, 14.5, 17.4, 18.2, 34.2, 46.1, 59.7, 109.6, 138.1, 160.2, 170.7 ppm; MS(ESI): m/z 227 (M+H)+; Anal. Calcd for C11H18N2O3 : C, 58.39; H, 8.02; N, 12.38 %. Found: C, 58.33; H, 8.00; N, 12.34 %.

2.3.11 4-Butyl-5-(ethoxycarbonyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4k)

IR (KBr, cm-1): 3354 and 3240 (N-H str.), 1712 and 1658 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 1.12 (t, J = 7.4 Hz, 3H, OCH2CH3), 1.15-1.42 (m, 9H), 2.26 (s, 3H, CH3), 3.94 (q, J = 7.4 Hz , 2H, OCH2CH3), 5.14 (s, 1H, CH), 7.22 (s, 1H, NH-3), 9.66 (s,

IH, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6: 13.8, 14.3, 18.1, 23.4, 26.8, 32.2, 46.3, 60.6, 111.4, 139.3, 162.2, 171.7 ppm; MS(ESI): m/z 241 (M+H)+; Anal. Calcd for C12H20N2O3 : C, 59.98; H, 8.39; N, 11.66 %. Found: C, 59.88; H, 8.37; N, 11.64 %.

2.3.12 5-Methoxycarbonyl- 6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (4l)

IR (KBr, cm-1): 3323 and 3214 (N-H str.), 1697 and 1665 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 2.18 (s, 3H, CH3), 3.52 (s, 3H, OCH3), 5.28 (s, 1H, CH), 7.02-7.59 (m, 4H, Ar-H), 7.98 (s,1H, NH-3), 9.22 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 14.5, 17.1, 55.1, 100.7, 122.0, 125.7, 129.8, 143.7, 145.9, 154.9, 165.7 ppm; MS(ESI): m/z 247 (M+H)+; Anal. Calcd for C13H14N2O3: C, 63.41; H, 5.69; N,

II.38 %. Found: C, 63.33; H, 5.66; N, 11.36 %.

2.3.13 5-Methoxycarbonyl- 6-methyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4m)

IR (KBr, cm-1): 3313 and 3204 (N-H str.), 1690 and 1656 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 2.24 (s, 3H, CH3), 3.62 (s, 3H, OCH3), 5.14 (s, 1H, CH), 7.16 (d, 2H, J = 8.0 Hz, Ar-H), 7.25 (d, 2H, J = 8.0 Hz, Ar-H), 7.89 (s,1H, NH-3), 9.18 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, CDCl3) S: 13.8, 17.4, 54.9, 100.7, 122.8, 126.1,

129.2, 142.6, 145.8, 155.3, 166.4 ppm; MS(ESI): m/z 277 (M+H)+; Anal. Calcd for C14H16N2O4: C, 60.87; H, 5.80; N, 10.14 %. Found: C, 60.77; H, 5.75; N, 10.08 %.

2.3.14 5-Methoxycarbonyl- 6-methyl-4-(4-chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one (4n)

IR (KBr, cm-1): 3316 and 321 (N-H str.), 1696 and 1656 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 2.11 (s, 3H, CH3), 3.66 (s, 3H, OCH3), 5.33 (s, 1H, CH), 7.07 (d, 2H, J = 8.0 Hz, Ar-H), 7.35 (d, 2H, J = 8.0 Hz, Ar-H), 8.00 (s,1H, NH-3), 9.22 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) S: 14.0, 17.5, 54.5, 100.7, 122.5, 126.5,

130.3, 142.8, 146.0, 155.5, 166.6 ppm; ppm; MS(ESI): m/z 281 (M+H)+; Anal. Calcd for C13H13ClN2O3: C, 55.62; H, 4.63; N, 9.98 %. Found: C, 55.55; H, 4.65; N, 9.95 %.

2.3.15 5-Methoxycarbonyl- 6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4o)

IR (KBr, cm-1): 3377 (O-H str.), 3318 and 3219 (N-H str.), 1692 and 1670 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 2.24 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 5.18 (s, 1H, CH), 7.13 (d, 2H, J = 8.2 Hz, Ar-H), 7.39 (d, 2H, J = 8.2 Hz, Ar-H), 7.78 (s, 1H, NH-3), 9.29 (s, 1H, NH-1), 9.55 (s, 1H, OH) ppm; 13C NMR (125 MHz, DMSOd) S: 14.2, 17.7, 54.7, 100.7, 122.5, 126.0, 129.6, 142.9, 146.3, 154.4, 165.5 ppm; MS(ESI): m/z 263 (M+H)+; Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.34; N, 10.68 %. Found: C, 59.44; H, 5.30; N, 10.62 %.

2.3.16 5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-thione (4p)

IR (KBr, cm-1): 3328 and 3209 (N-H str.), 1702 (C = O str.), 1202 (C = S str.); 1H NMR (500 MHz, DMSO-d6) 6: 1.03 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.17 (s, 3H, CH3), 4.02 (q, J= 7.4 Hz , 2H, OCH2CH3), 5.11 (s, 1H, CH), 7.21-7.41 (m, 4H, Ar-H), 7.16 (s, 1H, NH-3), 9.57 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6: 14.4, 18.0, 54.6, 60.1, 99.9, 122.4, 125.9, 129.8, 143.0, 154.6, 165.7, 174.7 ppm; MS(ESI): m/z 277 (M+H)+; Anal. Calcd for C14H16N2O2S : C, 60.87; H, 5.79; N, 10.14 %. Found: C, 60.83; H, 5.73; N, 10.13 %.

2.3.17 5-Ethoxycarbonyl-6-methyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-thione (4q)

IR (KBr, cm-1): 3323 and 3206 (N-H str.), 1697 (C = O str.), 1209 (C = S str.); 1H NMR (500 MHz, DMSOd) 6: 1.20 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.19 (s, 3H, CH3), 3.58 (s, 3H, OCH3), 3.99 (q, J = 7.4 Hz, 2H, OCH2CH3), 5.26 (s, 1H, CH), 7.11 (s, 1H, NH-3), 7.01 (d, 2H, J = 8.0 Hz, Ar-H), 7.36 (d, 2H, J = 8.0 Hz, Ar-H), 9.56 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 14.6, 17.2, 54.2, 60.8, 99.5, 122.2, 126.3, 129.6, 143.3, 155.8, 166.0, 175.5 ppm; MS(ESI): m/z 307 (M+H)+; Anal. Calcd for C15H18N2O3S: C, 58.82; H, 5.88; N, 9.15 %. Found: C, 58.72; H, 5.85; N, 9.12 %.

2.3.18 5-Ethoxycarbonyl-6-methyl-4-(2-thienyl)-3,4-dihydropyrimidin-2(1H)-thione (4r) IR (KBr, cm-1): 3368 and 3244 (N-H str.), 1688 (C = O str.), 1258 (C = S str.); 1H NMR (500 MHz, DMSOd) 6: 1.12 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3), 4.06 (q, J = 7.4 Hz , 2H, OCH2CH3), 5.18 (s, 1H, CH), 6.95 - 7.01 (m, 2H), 7.22 (s, 1H, NH-3), 7.41 (d, J = 4.2 Hz, 1H), 9.66 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6:

14.3, 17.8, 53.2, 59.7, 104.6, 121.4, 126.9, 129.5, 138.6, 142.4, 164.2, 175.7 ppm; MS(ESI): m/z 283 (M+H)+; Anal. Calcd for C12H14N2O2S2 : C, 51.04; H, 5.00; N, 9.92 %. Found: C, 51.00; H, 4.95; N, 9.95 %.

2.3.19 5-Methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-thione (4s) IR (KBr, cm-1): 3310 and 3201 (N-H str.), 1686 (C = O str.), 1196 (C = S str.); 1H NMR (500 MHz, DMSOd) S: 2.11(s, 3 H, CH3), 3.66 (s, 3H, OCH3), 5.19 (s, 1H, CH), 7.00-7.28 (m, 4H, Ar-H): 7.43 (s, 1H, NH-3), 9.26 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) S: 13.7, 17.1, 54.4, 100.1, 122.2, 126.4, 129.6, 143.5, 155.4, 165.4, 174.9 ppm; MS(ESI): m/z 263 (M+H)+; Anal. Calcd for C13H14N2O2S : C, 59.54; H, 5.34; N, 10.69 %. Found: C, 59.44; H, 5.32; N, 10.64 %.

2.3.20 5-Methoxycarbonyl-6-methyl-4-(4-chlorophenyl)-3,4-dihydropyrimidin-2(IH)-thione (4t)

IR (KBr, cm-1): 3321 and 3212 (N-H str.), 1689 (C = O str.), 1206 (C = S str.); 1H NMR (500 MHz, DMSOd) S: 2.18 (s, 3 H, CH3), 3.55 (s, 3H, OCH3), 5.21 (s, 1H, CH), 7.13 (d, 2H, J = 8.2 Hz, Ar-H), 7.33 (d, 2H, J = 8.2 Hz, Ar-H), 7.55 (s, 1H, NH-3), 9.33 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSO-d6) S: 14.3, 17.7, 54.0, 100.5, 122.1, 126.1, 129.4, 143.0, 155.2, 165.3, 175.2 ppm; MS(ESI): m/z 297 (M+H)+; Anal. Calcd for C13H13QN2O2S : C, 52.62; H, 4.38; N, 9.44 %. Found: C, 52.55; H, 4.33; N, 9.44 %.

2.3.21 5-Methoxycarbonyl-6-methyl-4-(2-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-thione (4u)

IR (KBr, cm-1): 3311 and 3202 (N-H str.), 1698 (C = O str.), 1208 (C = S str.); 1H NMR (500 MHz, DMSOd) S: 2.26 (s, 3 H, CH3), 3.58 (s, 3H, OCH3), 5.28 (s, 1H, CH), 7.18-7.40 (m, 4H, Ar-H), 7.63 (s, 1H, NH-3), 9.17 (s, 1H, NH-1) ppm; 13C NMR (125

MHz, DMSO-d6) 6: 14.4, 18.2, 54.7, 100.4, 122.0, 126.6, 129.5, 143.2, 154.9, 166.5, 174.3 ppm; MS(ESI): m/z 308 (M+H)+; Anal. Calcd for C13H13N3O4S : C, 50.81; H, 4.23; N, 13.68 %. Found: C, 50.75; H, 4.20; N, 13.66 %.

2.3.22 5-Methoxycarbonyl-6-methyl-4-(4-fluorophenyl)-3,4-dihydropyrimidin-2(1H)-thione (4v)

IR (KBr, cm-1): 3314 and 3213 (N-H str.), 1688 (C = O str.), 1206 (C = S str.); 1H NMR (500 MHz, DMSOd) 6: 2.14 (s, 3 H, CH3), 3.44 (s, 3H, OCH3), 5.27 (s, 1H, CH), 7.10 (d, 2H, J = 8.0 Hz, Ar-H), 7.30 (d, 2H, J = 8.0 Hz, Ar-H), 7.53 (s, 1H, NH-3), 9.24 (s, 1H, NH-1) ppm; 13C NMR (125 MHz, DMSOd) 6: 14.4, 17.8, 54.5, 100.8, 121.9, 126.0, 129.0, 143.1, 154.7, 166.7, 175.8 ppm; MS(ESI): m/z 281 (M+H)+; Anal. Calcd for C13H13FN2O2S : C, 55.71; H, 4.64; N, 10.00 %. Found: C, 55.66; H, 4.60; N, 10.03 %.

2.4 General procedure for the preparation of 4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones

A mixture of aldehyde (1 mmol), 2H-indene-1,3-dione (1 mmol), urea (1.5 mmol), and DBSA (5 mol%) under solvent-free condition was heated to 80 oC, with stirring, for 2.5 -

3.5 h to complete the reaction (monitored by TLC). After cooling to room temperature, the reaction was quenched with 20 ml of H2O and stirred for 10 min. The pure product was isolated by filtration, followed by washing with EtOAc. The IR, 1H NMR, 13C NMR, mass and elemental analysis data of the synthesized compounds are given below.

2.5 Spectral data of the synthesized compounds (6a-l)

2.5.1 4-Phenyl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-dione (6a)

IR (KBr, cm-1): 3388 and 3268 (N-H str.), 1688 and 1661 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 5.11 (s, 1H, CH), 7.07-7.30 (m, 5H, Ar-H), 7.51-7.67 (m, 4H, Ar-H), 7.81 (s,1H, NH-1), 9.40 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 48.1, 107.2, 126.1, 126.6, 127.4, 128.3, 128.8, 129.3, 134.2, 134.6, 136.4, 142.3, 142.7, 155.9, 189.1 ppm; MS(ESI): m/z 277 (M+H)+; Anal. Calcd for C17H12N2O2: C, 73.91; H, 4.35; N, 10.14 %. Found: C, 73.83; H, 4.28; N, 10.13 %.

2.5.2 4-(3-Nitrophenyl)-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-dione (6b)

IR (KBr, cm-1): 3380 and 3275 (N-H str.), 1685 and 1669 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 5.17 (s, 1H, CH), 7.11-7.28 (m, 4H, Ar-H), 7.49-7.62 (m, 4H, Ar-H), 7.83 (s,1H, NH-1), 9.33 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 48.3, 107.5, 126.4, 126.9, 127.6, 128.6, 128.9, 129.4, 134.4, 134.7, 136.5, 142.5, 142.9,

156.2, 188.7 ppm; MS(ESI): m/z 322 (M+H)+; Anal. Calcd for C17H11N3O4: C, 63.55; H, 3.43; N, 13.08 %. Found: C, 63.43; H, 3.40; N, 13.01 %.

2.5.3 4-(4-Chlorophenyl)-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-dione (6c)

IR (KBr, cm-1): 3384 and 3264 (N-H str.), 1680 and 1663 (C = O str.); 1H NMR (500 MHz, DMSOd) S: 5.20 (s, 1H, CH), 7.15 (d, 2H, J = 8.2 Hz, Ar-H), 7.32 (d, 2H, J =

8.2 Hz, Ar-H), 7.55-7.68 (m, 4H, Ar-H), 7.85 (s,1H, NH-1), 9.38 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 48.4, 107.3, 126.2, 126.7, 127.7, 128.5, 128.9, 129.3,

134.3, 134.6, 136.2, 142.3, 142.6, 156.4, 188.8 ppm; MS(ESI): m/z 311 (M+H)+; Anal. Calcd for C17H11QN2O2: C, 65.71; H, 3.54; N, 9.02 %. Found: C, 65.65; H, 3.50; N,

9.03 %.

2.5.4 4-(2-Chlorophenyl)-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-dione (6d)

IR (KBr, cm-1): 3373 and 3273 (N-H str.), 1682 and 1666 (C = O str.); 1H NMR (500 MHz, DMSO-d6) 6: 5.15 (s, 1H, CH), 7.09-7.34 (m, 4H, Ar-H), 7.48-7.64 (m, 4H, Ar-H), 7.80 (s,1H, NH-1), 9.41 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) 6: 47.9, 107.4, 126.0, 126.8, 127.3, 128.2, 128.8, 129.5, 134.5, 134.8, 136.4, 142.1, 142.7, 155.8, 188.6 ppm; MS(ESI): m/z 311.4 (M+H)+; Anal. Calcd for C17H11QN2O2: C, 65.71; H, 3.54; N, 9.02 %. Found: C, 65.62; H, 3.48; N, 8.96 %.

2.5.5 4-Phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6e)

IR (KBr, cm-1): 3406 and 3280 (N-H str.), 1672 (C = O str.), 1194 (C = S str.); 1H NMR (500 MHz, DMSO-d6) 6: 5.24 (s, 1H, CH), 7.13-7.34 (m, 5H, Ar-H), 7.55-7.67 (m, 4H, Ar-H), 7.91 (s,1H, NH-1), 9.16 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) 6: 46.3, 105.2, 124.2, 125.3, 126.2, 127.6, 128.4, 129.3, 134.0, 135.6, 136.2, 142.3, 144.5,

183.3, 188.7 ppm; MS(ESI): m/z 293 (M+H)+; Anal. Calcd for C17H12N2OS: C, 69.86; H, 4.11; N, 9.59 %. Found: C, 69.80; H, 4.06; N, 9.57 %.

2.5.6 4-(4-Nitrophenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6f) IR (KBr, cm-1): 3411 and 3277 (N-H str.), 1677 (C = O str.), 1187 (C = S str.); 1H NMR (500 MHz, DMSO-d6) 6: 5.20 (s, 1H, CH), 7.05 (d, 2H, J = 8.0 Hz, Ar-H), 7.29 (d, 2H, J = 8.0 Hz, Ar-H), 7.57-7.70 (m, 4H, Ar-H), 7.98 (s,1H, NH-1), 9.22 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 46.7, 104.8, 124.5, 125.5, 126.4, 127.8, 128.6, 129.5,

134.4, 135.3, 136.3, 141.9, 144.3, 183.5, 189.1 ppm; MS(ESI): m/z 338 (M+H)+; Anal. Calcd for C17H11N3O3S: C, 60.53; H, 3.26; N, 12.46 %. Found: C, 60.44; H, 3.22; N, 12.40 %.

2.5.7 4-(4-Methylphenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6g)

IR (KBr, cm-1): 3405 and 3274 (N-H str.), 1669 (C = O str.), 1189 (C = S str.); 1H NMR (500 MHz, DMSOd) S: 2.16 (s, 3H, CH3), 5.23 (s, 1H, CH), 7.11 (d, 2H, J = 8.1 Hz, Ar-H), 7.31 (d, 2H, J = 8.1 Hz, Ar-H), 7.54-7.67 (m, 4H, Ar-H), 7.97 (s,1H, NH-1), 9.21 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 17.1, 46.2, 105.3, 124.4, 125.4, 126.3, 127.7, 128.5, 129.4, 134.5, 135.5, 136.5, 141.9, 144.4, 183.4, 189.3 ppm; MS(ESI): m/z 307 (M+H)+; Anal. Calcd for C18H14N2OS: C, 70.59; H, 4.58; N, 9.15 %. Found: C, 70.53; H, 4.51; N, 9.10 %.

2.5.8 4-(2-Chlorophenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6h)

IR (KBr, cm-1): 3413 and 3283 (N-H str.), 1678 (C = O str.), 1190 (C = S str.); 1H NMR (500 MHz, DMSOd) S: 5.17 (s, 1H, CH), 7.02-7.25 (m, 4H, Ar-H), 7.49-7.61 (m, 4H, Ar-H), 7.90 (s,1H, NH-1), 9.17 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 46.6, 104.9, 124.6, 125.6, 126.5, 127.5, 128.7, 129.6, 134.7, 135.7, 136.4, 141.8, 144.2, 183.2, 188.7 ppm; MS(ESI): m/z 327 (M+H)+; Anal. Calcd for C17H11QN2OS: C, 62.49; H, 3.37; N, 8.58 %. Found: C, 62.44; H, 3.35; N, 8.53 %.

2.5.9 4-(3-Nitrophenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6i) IR (KBr, cm-1): 3401 and 3287 (N-H str.), 1675 (C = O str.), 1193 (C = S str.); 1H NMR (500 MHz, DMSOd) S: 5.16 (s, 1H, CH), 7.04-7.30 (m, 4H, Ar-H), 7.50-7.71 (m, 4H, Ar-H), 7.97 (s,1H, NH-1), 9.19 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) S: 46.4, 105.2, 124.7, 125.7, 126.4, 127.6, 128.8, 129.8, 134.6, 135.2, 136.6, 142.4, 144.6, 183.0, 189.0 ppm; MS(ESI): m/z 338 (M+H)+; Anal. Calcd for C17H11N3O3S: C, 60.53; H, 3.26; N, 12.46 %. Found: C, 60.47; H, 3.20; N, 12.44 %.

2.5.10 4-(3-Bromophenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6j)

IR (KBr, cm-1): 3410 and 3279 (N-H str.), 1670 (C = O str.), 1185 (C = S str.); 1H NMR (500 MHz, DMSO-d6) 6: 5.20 (s, 1H, CH), 7.11-7.29 (m, 4H, Ar-H), 7.53-7.72 (m, 4H, Ar-H), 7.95 (s,1H, NH-1), 9.21 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSOd) 6: 46.3, 104.8, 124.4, 125.2, 126.7, 127.7, 128.4, 129.7, 134.1, 135.1, 136.2, 142.6, 144.0, 183.6, 189.2 ppm; MS(ESI): m/z 371.9 (M+H)+; Anal. Calcd for CnHnBr^OS: C, 55.00; H, 2.96; N, 7.55 %. Found: C, 54.93; H, 2.93; N, 7.51 %.

2.5.11 4-(4-Methoxyphenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6k)

IR (KBr, cm-1): 3403 and 3286 (N-H str.), 1680 (C = O str.), 1186 (C = S str.); 1H NMR (500 MHz, DMSO-d6) 6: 3.60 (s, 3H, OCH3), 5.23 (s, 1H, CH), 7.10 (d, 2H, J = 8.2 Hz, Ar-H), 7.37 (d, 2H, J = 8.2 Hz, Ar-H), 7.48-7.66 (m, 4H, Ar-H), 7.91 (s,1H, NH-1), 9.23 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 46.6, 55.3, 105.2, 124.5, 125.3, 126.6, 127.5, 128.6, 129.7, 134.3, 135.3, 136.5, 142.2, 144.5, 183.7, 188.8 ppm; MS(ESI): m/z 323 (M+H)+; Anal. Calcd for C18H14N2O2S: C, 67.08; H, 4.35; N, 8.70 %. Found: C, 67.02; H, 4.31; N, 8.63 %.

2.5.12 4-(2-Methylphenyl)-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-one (6l)

IR (KBr, cm-1): 3404 and 3276 (N-H str.), 1674 (C = O str.), 1189 (C = S str.); 1H NMR (500 MHz, DMSO-d6) 6: 2.21 (s, 3H, CH3), 5.19 (s, 1H, CH), 7.06-7.30 (m, 4H, Ar-H), 7.49-7.63 (m, 4H, Ar-H), 7.90 (s,1H, NH-1), 9.18 (s, 1H, NH-3) ppm; 13C NMR (125 MHz, DMSO-d6) 6: 17.4, 46.8, 104.9, 124.6, 125.6, 126.3, 127.9, 128.5, 129.5, 134.5,

135.7, 136.2, 142.3, 144.3, 183.3, 189.4 ppm; MS(ESI): m/z 307 (M+H)+; Anal. Calcd for C18H14N2OS: C, 70.59; H, 4.58; N, 9.15 %. Found: C, 70.55; H, 4.54; N, 9.13 %.

3. Results and discussion

Dihydropyrimidines show a diverse range of biological activities. We are interested in studying Biginelli reaction with the aim to develop an operationally simple method for the synthesis of a large range of DHPMs. Different analogues were synthesized by varying aldehydes with ethylacetoacetate or methylacetoacetate and urea or thiourea. We started our study of the one-pot three-component Biginelli condensation using DBSA as the catalyst (Scheme 1), by examining the conditions for the reaction using benzaldehyde, ethylacetoacetate and urea to afford the corresponding DHPM product.

One important aspect of green chemistry is the elimination of solvents in chemical processes or the replacement of hazardous solvents with relatively benign solvents [40]. Our initial work started with screening of solvent and catalyst loading so as to identify optimal reaction conditions for the synthesis of DHPM derivatives. A range of solvents like acetonitrile, dioxane, acetic acid, water and ethanol were examined (Table 1, enries 1-5). The reaction without any solvent at 80 oC was more successful (Table -1, entry 6). We also evaluated the amount of DBSA required for the reaction. It was found that when decreasing the amount of the catalyst from 5 mol% to 3 mol%, the yield decreased from 94 to 73% (entry 7). But, when increasing the amount of the catalyst from 5 mol% to 10 mol%, there is no change in the yield (Table 1, entry 8). The use of 5 mol% of DBSA maintaining the yield at 94%, so this amount is sufficient to promote the reaction. In the

presence of more than this amount of the catalyst, neither the yield nor the reaction time were improved (Table 1, entry 8). Thus, the best result was obtained with 5 mol% of DBSA under solvent-free condition at 80 oC (Table 1, entry 6).

<Table 1>

In order to investigate the scope of these conditions, we have undertaken the synthesis of different derivatives of 3,4-dihydropyrimidin-2(1#)-one/thione from a variety of substrates from aldehydes, either ethylacetoacetate or methylacetoacetate and either urea or thiourea in the presence of DBSA as catalyst. The results are presented in Table 2. All the reactions, consisting of those involving ortho-, meta-, and para-substituted benzaldehydes, proceeded smoothly and afforded the corresponding 3,4-dihydropyrimidin-2(1H)-one in moderate to high yields. Electronic effects can be observed. The electron-donating group substituted benzaldehydes required prolonged reaction time to give the yields, while electron-withdrawing group substituted ones gave evidently increasing yields. ort^o-Substituted benzaldehydes, whether the substituent is electron-donating group or electron-withdrawing group, afforded the corresponding 3,4-dihydropyrimidin-2(1#)-one in relatively lower yields, indicating an obvious steric effect. Thiourea exhibited behavior similar to that of urea (Scheme 1).

<Scheme 1> <Table 2>

To explore the advantages of this DBSA-catalyzed synthesized of 3,4-dihydropyrimidin-2(1H)-one, we compared the results we obtained under the optimized conditions with results reported in the literature by other catalysts (Table 3). Among the solid acid catalysts copper(II) sulfamate, zeolite-supported HPA, nafion-H, p-sulfonic

acid calixarenes, triphenyl phosphine, silica sulfuric acid, bioglycerol based carbon, montmorillonite KSF, cellulose sulfuric acid, quartz or granite and Ruthenium(III) chloride, DBSA was found to be superior in terms of yield and time of reaction.

<Table 3>

The possibility of recycling the catalyst was examined using the model reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-one under the optimized conditions. Upon completion of the reaction, the mixture was poured into crushed ice with stirring. The crude product was filtered, washed with cold water and recrystallized from hot ethanol. The catalyst was recovered as described in the experimental section and the recycling ability of the catalyst was tested for further runs. As shown in Figure 1, the recycled catalyst was used for further runs, the yields ranged from 94% to 88%.

<Figure 1>

During the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones, we found that several compounds are synthesized smoothly in the presence of DBSA as catalyst. Therefore, we applied the same reaction conditions to carry out the synthesis of a new series of 4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones. A mixture of benzaldehyde (1a), 2H-indene-1,3-dione (5), and urea (3a) at a mol ratio of 1:1:1.5 in the presence of 5 mol% DBSA under solvent-free condition was heated at 80 oC of for 2.5 h. To our delight, the desired product 6a was obtained in 91% yield (Scheme 2). Encouraged by the result, a series of aldehydes were selected to undergo the condensation (Table 4).

<Scheme 2> <Table 4>

As shown in Table 4, aromatic aldehydes bearing functional groups (for example -H, -CH3, -OCH3, -Cl, -F, -NO2, and -Br) react smoothly with urea/thiourea and 2H-indene-1,3-dione to give the corresponding products in good yields. We also found that this condensation reaction was complete within 2.5 - 3.5 h.

4. Conclusions

In conclusion, we describe here an efficient method for the synthesis of 3,4-dihydro pyrimidinones/thiones by DBSA catalyzed reaction of aldehydes, ethylacetoacetoacetate or methylacetoacetoacetate, and urea or thiourea under solvent-free condition at 80 oC. The reaction presented here has several advantages: it is one-pot, and can be handled easily. These environmentally friendly features make the catalytic procedure a practically and environmentally acceptable method for the synthesis of 3,4-dihydro pyrimidinones/thiones. A series of 4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones have also been synthesized using the same conditions by the Biginelli-like reaction of 2H-indene-1,3-dione, with urea or thiourea and aromatic aldehydes.

Acknowledgement

The authors gratefully acknowledge University Grants Commission, Government of India, New Delhi for financial support (Major Research Project : F. No. 40-44 / 2011(SR)). The authors also gratefully wish to thank both the referees for their helpful and critical suggestions.

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Table 1 Synthesis of 3,4-dihydropyrimidin-2(1#)-one: Solvent screening and catalyst loadinga.

Entry Solvent Temperature (oC) Amount of catalyst (mol %) Time (h) Yield (%)b

1 Acetonitrile Reflux 5 5.0 68

2 Dioxane Reflux 5 5.0 63

3 Acetic acid Reflux 5 5.0 71

4 Water Reflux 5 5.0 60

5 Ethanol Reflux 5 5.0 58

6 Solvent-free 80 5 3.0 94

7 Solvent-free 80 3 3.0 73

8 Solvent-free 80 10 3.0 94

aReaction conditions: benzaldehyde (1 mmol), ethylacetoacetate (1 mmol), and urea (1.5 mmol) were refluxed in the presence of DBSA with various solvents (5 ml) and also heated at 80 oC under solvent-free conditions.

bIsolated yields

Table 2 DBSA - catalyzed synthesis of 3,4-dihydropyrimidin-2(1#)-ones and -thionesa

Entry R1 R X Product Time Yield Mp (oC)

(h) (%)b -

Reported

1 C6H5 OEt O 4a 3.0 94 200 - 202 202 -

203 [22]

2 2-NO2-C6H4 OEt O 4b 2.5 81 205 - 207 206 -

208 [13]

3 4-F-C6H4 OEt O 4c 2.5 93 176 - 178 174 -

176 [13]

4 2-Cl-C6H4 OEt O 4d 2.5 84 212 - 214 213 -

216 [18]

5 3-Br-C6H4 OEt O 4e 2.5 88 183 - 185 182 -

184 [16]

6 4-OH-C6H4 OEt O 4f 2.5 93 195 - 198 196 -

197 [25]

7 4-OCH3-C6H4 OEt O 4g 3.0 86 202 - 204 203 -

204 [22]

8 3- NO2-C6H4 OEt O 4h 2.5 90 224 - 226 226 -

228 [22]

9 2-Furfuryl OEt O 4i 3.0 89 202 - 204 205 -

206 [20]

10 «-C3H7 OEt O 4j 3.0 87 155 - 157 157 -

158 [24]

11 n-C4H9 OEt O 4k 3.0 88 155 - 157 156 -

158 [27]

12 C6H5 OMe O 4l 3.0 89 212 - 214 210 -

213 [18]

13 4-OCH3-C6H4 OMe O 4m 3.0 86 191 - 194 190 -

192 [18]

14 4- CI-C6H4 OMe O 4n 2.5 94 205 - 206 204 -

206 [18]

15 4- OH-C6H4 OMe O 4o 2.5 90 240 - 242 241 -

242 [16]

16 C6H5 OEt S 4p 3.0 88 208 - 210 210 -

211 [25]

17 4-OCH3-C6H4 OEt S 4q 3.0 85 155 - 157 154 -

156 [13]

18 2-Thienyl OEt S 4r 3.0 85 215 - 217 214 -

216 [27]

19 C6H5 OMe S 4s 3.0 87 220 - 222 -

20 4- CI-C6H4 OMe S 4t 2.5 89 184 - 186 -

21 2- NO2-C6H4 OMe S 4u 2.5 81 194 - 196 -

22 4-F-C6H4 OMe S 4v 2.5 94 208 - 210 -

aReaction conditions: aldehydes (1 mmol), ethylacetoacetate (1 mmol), and urea/thiourea (1.5 mmol) heating at 80 oC in the presence of DBSA under solvent-free condition bIsolated yield.

Table 3 Comparison of catalytic activity of DBSA with other catalysts reported in the literature for the synthesis of 3,4-dihydropyrimidinones Entry Catalyst

Conditions

Time (h) Yield (%

1 Copper(II) Sulfamate [16] Acetic acid/100 oC 6.0 79

2 Zeolite-supported HPA [21] CH3CN/Reflux 10.0 84

3 Nafion-H [25] EtOH/Reflux 4.0 94

4 ^-Sulfonic acid calixarenes [15] EtOH/Reflux 8.0 81

5 Triphenyl phosphine [17] Solvent-free/100 oC 10.0 70

6 Silica sulfuric acid [24] EtOH/Reflux 6.0 91

7 Bioglycerol based carbon [14] CH3CN/75-80 oC 6.0 91

8 Montmorillonite KSF [19] Solvent-free/100 oC 48.0 77

9 Cellulose sulfuric acid [12] H2O/100 oC 5.0 80

10 Quartz [20] EtOH/Reflux 3.0 68

11 Granite [20] EtOH/Reflux 3.5 64

12 RuCl3 [23] Solvent-free/100 oC 0.5 91

13 DBSA Solvent-free/80 oC 3.0 94 Present

Table 4 DBSA - catalyzed synthesis of various substituted 4-aryl-3,4-dihydro-1#-

indeno[1,2-^]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-

d]pyrimidine-5-onesa

Entry R1 X Product Time (h) Yield (%)b

Mp (oC)

1 C6H5 O 6a 2.5 91

208 - 210

2 3-NO2-C6H4 O 6b 2.5 90

216 - 218

3 4-Cl-C6H4 O 6c 2.5 92

196 - 198

4 2-Cl-C6H4 O 6d 3.0 88

184 - 186

5 C6H5 S 6e 3.0 89

212 - 214

6 4-NO2-C6H4 S 6f 2.5 92

220 - 222

7 4-CH3-C6H4 S 6g 3.5 88

200 - 202

8 2-Cl-C6H4 S 6h 3.5 87

190 - 192

9 3-NO2-C6H4 S 6i 3.0 90

198 - 200

10 3-Br-C6H4 S 6j 3.0 91

204 - 206

11 4-OCH3-C6H4 S 6k 3.5 88

226 - 228

12 2-CH3-C6H4 S 6l 3.5 87

202 - 204

aReaction conditions: substituted benzaldehydes (1 mmol), 2#-indene-1,3-dione (1 mmol) and urea/thiourea (1.5 mmol) heating at 80 oC in the presence of DBSA under solvent-free condition bIsolated yield.

R1-CHO +

h2n^^nh2

H3C" O

DBSA (5 mol%)

CH2(CH2)10CH3

Solvent-free, 80 oC

Rff ^¡T NH

H3C' "N^^X H

r = ch3c2h5 x = o, s

Scheme - 1 DBSA - catalyzed synthesis of 3,4-dihydropyrimidin-2(1#)-ones/thiones

Scheme - 2 DBSA - catalyzed synthesis of various substituted 4-aryl-3,4-dihydro-1#-indeno[1,2-Jjpyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones

>: 9088-

251658240

Figure 1: Recycling of catalyst DBSA for the synthesis of 3,4-dihydropyrimidin-2(1#)-one

12 3 4

Number of Runs