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 To appear in: 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 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid ip t Krishnamoorthy Aswin, Syed Sheik Mansoor*, Kuppan Logaiya, Prasanna Nithiya Sudhan, R Nasir Ahmed Research Department of Chemistry, cr Bioactive Organic Molecule Synthetic Unit, C Abdul Hakeem College, Melvisharam – 632 509, Tamil Nadu us e-mail: smansoors2000@yahoo.co.in an Abstract: A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones (DHPMs) through Biginelli reaction by the condensation reaction of aldehydes, β-ketoesters and M 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 d]pyrimidines have also been synthesized using the same conditions by the Biginelli-like te reaction of 2H-indene-1,3-dione, with urea/thiourea and aromatic aldehyde All the Ac ce p 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 Page of 35 Introduction Multi-component reactions (MCRs) are of increasing importance in organic and medicinal chemistry, because the strategies of MCR offer significant advantages over ip t conventional linear-type syntheses [1] Compared with conventional methods of organic synthesis, MCRs have the advantages of high-selectivity, good yields, milder reaction cr conditions, and simple work-up procedures, among others Thus, a vast number of us 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 an 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 te d molecular complexity and diversity [3] M importance as one of the most powerful emerging synthetic tools for the creation of The Biginelli synthesis is an easy and useful multicomponent reaction that is Ac ce p gaining increasing importance in organic and medicinal chemistry for its generation of multifunctionalized products, including 3,4-dihydropyrimidin-2(1H)-ones and their thione analogs and other related heterocyclic compounds [4] Recently, appropriately functionalized dihydropyrimidine analog of novel 4-aryl-5-isopropoxycarbonyl-6methyl-3,4-dihydropyrimidinones has emerged as anti-microbiological agent [5] A novel 3,4-dihydropyrimidin-2(1H)-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 Page of 35 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(1H)-ones as ip t products [9] However, this reaction often requires harsh conditions and long reaction times and affords low yields, particularly when substituted aromatic and aliphatic cr aldehydes are employed The scope of this reaction was gradually extended by the us variation of all three building blocks, allowing access to a large number of multi an functionalized dihydropyrimidines of medicinal use [10] The most straightforward procedure for the preparation of dihydropyrimidinones M and thiones is by condensation of β-dicarbonyl compounds with an aromatic aldehyde d and urea or thiourea in the presence of Lewis and Brønsted acid promoters such as silica te immobilized nickel complex [11], cellulose sulfuric acid [12], lanthanum oxide [13], bioglycerol-based sulfonic acid functionalized carbon [14], p-sulfonic acid calixarenes Ac ce p [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 Page of 35 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 ip t applications [29–34] In recent years, p-dodecylbenzenesulfonic acid (DBSA) has gained considerable cr popularity as an efficient Bronsted-acid surfactant combined catalyst for carrying out us various organic transformations in water as well as under solvent-free conditions [29–34] p-dodecylbenzenesulfonic acid has been used extensively as Brønsted acid−surfactant- an combined catalyst in Mannich-type reactions of aldehydes, amines, and ketones [29], ester, ether, thioether, and dithioacetal formation in water [30], organic synthesis inside M particles in water [31], solvent-free esterification [32], for the synthesis of 6-amino-4- d aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles in aqueous media the use of te [33] and green synthesis of dibenzo[a,j]xanthenes [34] However, there is no report on p-dodecylbenzenesulfonic acid (DBSA) for the synthesis of Ac ce p 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 Page of 35 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- ip t dihydropyrimidine derivatives, we have also synthesized a series of 4-aryl-3,4-dihydro1H-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2- cr d]pyrimidine-5-ones by the Biginelli-like reaction of 2H-indene-1,3-dione, with us urea/thiourea and aromatic aldehydes an Experimental 2.1 Chemicals and analysis H NMR (500 MHz) and 13C NMR (125 MHz) spectra were obtained using Bruker DRX- d M Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies te 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 Ac ce p 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 Page of 35 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 13 C NMR, mass and elemental analysis data of the synthesized compounds are given below us 2.3 Spectral data for the synthesized compounds (4a-v) cr The IR, 1H NMR, ip t two times with an aliquot of fresh CH2Cl2 (2×10 mL), then drying to ready for later run 2.3.1 5-Ethoxycarbonyl- 6-methyl-4-phenyl- 3,4- dihydropyrimidin-2(1H)-one (4a) an IR (KBr, cm-1): 3322 and 3213 (N–H str.), 1696 and 1664 (C = O str.); 1H NMR (500 MHz, DMSO-d6) δ: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.33 (s, 3H, CH3), 3.92 (q, J = 9.48 (s, 1H, NH-3) ppm; 13 M 7.2 Hz, 2H, OCH2CH3), 5.22 (s, 1H, CH), 7.20–7.43 (m, 5H, Ar-H), 7.88 (s,1H, NH-1), C NMR (125 MHz, DMSO-d6) δ: 14.1, 17.9, 54.2, 60.1, te d 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 C14H16N2O3: C, 64.62; H, 6.15; N, 10.77 % Found: C, 64.58; H, 6.13; Ac ce p 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, DMSO-d6) δ: 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; 13 C NMR (125 MHz, DMSO-d6) δ: 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)+; Page of 35 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 ip t (4c) IR (KBr, cm-1): 3321 and 3211 (N–H str.), 1695 and 1663 (C = O str.); 1H NMR (500 cr MHz, DMSO-d6) δ: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.92 (q, J = us 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; 13 C NMR (125 MHz, 166.2 ppm; an DMSO-d6) δ: 14.4, 17.8, 54.8, 60.0, 100.9, 122.5, 125.9, 129.7, 142.8, 146.7, 154.8, MS(ESI): m/z 279 (M+H)+; Anal Calcd for C14H15FN2O3: C, 60.43; H, M 5.39; N, 10.07 % Found: C, 60.30; H, 5.36; N, 10.09 % d 2.3.4 5-Ethoxycarbonyl- 6-methyl-4-(2-chlorophenyl)-3,4- dihydropyrimidin-2(1H)-one te (4d) IR (KBr, cm-1): 3312 and 3203 (N–H str.), 1686 and 1654 (C = O str.); 1H NMR (500 Ac ce p MHz, DMSO-d6) δ: 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; 13 C NMR (125 MHz, DMSO-d6) δ: 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) Page of 35 IR (KBr, cm-1): 3319 and 3211 (N–H str.), 1695 and 1664 (C = O str.); 1H NMR (500 MHz, DMSO-d6) δ: 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), 13 C NMR (125 MHz, DMSO-d6) δ: 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 ip t 9.04 (s, 1H, NH-1) ppm; cr (M+H)+; Anal Calcd for C14H15BrN2O3: C, 49.57; H, 4.43; N, 8.26 % 2.3.6 us 49.47; H, 4.45; N, 8.22 % Found: C, 5-Ethoxycarbonyl- 6-methyl-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)- an one (4f) IR (KBr, cm-1): 3384 (O–H str.), 3314 and 3203 (N–H str.), 1690 and 1664 (C = O str.); H NMR (500 MHz, DMSO-d6) δ: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.22 (s, 3H, M d CH3), 3.90 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.24 (s, 1H, CH), 7.22 (d, 2H, J = 8.0 Hz, Ar- OH) ppm; 13 te 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, C NMR (125 MHz, DMSO-d6) δ: 14.2, 17.3, 54.1, 60.6, 100.6, 122.6, Ac ce p 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, DMSO-d6) δ: 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; NMR (125 MHz, DMSO-d6) δ: 13 C 14.3, 18.0, 55.0, 60.4, 100.0, 121.9, 126.4, 130.3, Page of 35 143.3, 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 ip t (4h) IR (KBr, cm-1): 3314 and 3206 (N–H str.), 1690 and 1659 (C = O str.); 1H NMR (500 cr MHz, DMSO-d6) δ: 1.08 (t, J = 7.2 Hz , 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.84 (q, J = 9.12 (s, 1H, NH-1) ppm; 13 us 7.2 Hz, 2H, OCH2CH3), 5.22 (s, 1H, CH), 7.07–7.33 (m, 4H, Ar-H), 8.18 (s,1H, NH-3), C NMR (125 MHz, DMSO-d6) δ: 14.1, 18.1, 55.2, 60.5, an 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; M N, 13.74 % d 2.3.9 5-Ethoxycarbonyl-4-(2-furfuryl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4i) te IR (KBr, cm-1): 3376 and 3258 (N–H str.), 1706 and 1665 (C = O str.); 1H NMR (500 MHz, DMSO-d6) δ: 1.14 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.22 (s, 3H, CH3), 3.98 (q, J = Ac ce p 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; 13 C NMR (125 MHz, DMSO-d6) δ: 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) δ: 1.07 (t, J = 7.4 Hz, 3H, OCH2CH3), 1.14-1.27 (m, 7H), 2.18 (s, 3H, Page of 35 21 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 ip t The possibility of recycling the catalyst was examined using the model reaction cr for the synthesis of 3,4-dihydropyrimidin-2(1H)-one under the optimized conditions us 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 an 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 M recycled catalyst was used for further runs, the yields ranged from 94% to 88% d te 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 Ac ce p 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), 2Hindene-1,3-dione (5), and urea (3a) at a mol ratio of 1:1:1.5 in the presence of 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) Page 21 of 35 22 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 2Hindene-1,3-dione to give the corresponding products in good yields We also found that ip t this condensation reaction was complete within 2.5 - 3.5 h cr Conclusions us In conclusion, we describe here an efficient method for the synthesis of 3,4-dihydro pyrimidinones/thiones by DBSA catalyzed reaction of aldehydes, ethylacetoacetoacetate an 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 and environmentally acceptable M easily These environmentally friendly features make the catalytic procedure a practically method for the synthesis of 3,4-dihydro d pyrimidinones/thiones A series of 4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5- te diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones have also been Ac ce p synthesized using the same conditions by the Biginelli-like reaction of 2H-indene-1,3dione, 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 Page 22 of 35 23 References [1] A Dömling, I Ugi, Multicomponent reactions with isocyanides, Angewandte Chemie International Edition 39 (2000) 3168-32110 X.-M Wang, H.-L Ye, Z.-J.Qaun, X.-C Wang, One-pot synthesis of ip t [2] benzoquinoline and coumarin derivatives using Meldrum’s acid in three- M D Burke, S L Schreiber, A planning strategy for diversity- oriented us [3] cr component reactions, Research on Chemical Intermediates 39 (2013) 2357-2367 synthesis, Angewandte Chemie International Edition 43 (2004) 46-58 C O Kappe, 100 Years of the Biginelli dihydropyridine synthesis, Tetrahedron an [4] 49 (1993) 6937-6963 S Chitra, D Devanathan, K Pandiarajan, Synthesis and in vitro microbiological M [5] d evaluation of novel 4-aryl-5-isopropoxycarbonyl-6-methyl-3,4- 367-371 J Kim, T.Ok, C Park, W So, M Jo, Y Kim, A novel 3,4-dihydropyrimidin- Ac ce p [6] te dihydropyrimidinones, European Journal of Medicinal Chemistry 45 (2010) 2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability, Bioorganic and Medicinal Chemistry Letters 22 (2012) 2522-2526 [7] A D Patil, N V Kumar, W C Kokke, M F Bean, A J Freyer, C D Brossi, S Mai, A Truneh, D J Faulkner, B Carte, A.L.Breen, R.P.Hertzberg, R K Johnson, J W Westly, B C M Potts, Novel Alkaloids from the Sponge Batzella sp.: Inhibitors of HIV gpl20-Human CD4 Binding, Journal of Organic Chemistry 60 (1995) 1182-1188 Page 23 of 35 24 [8] B B.Snider, J Chen, A D Patil, A Freyer, Synthesis of the Tricyclic Portions of Batzelladines A, B and D Revision of the Stereoehemistry of Batzelladines A and D, Tetrahedron Letters 37 (1996) 6977-6980 P Biginelli, Aldehyde-urea derivatives of aceto- and oxaloacetic acids, Gazzetta ip t [9] Chimica Italiana 23, 360 (1893) B R P Kumar, G Sankar, R B N Baig, S Chandrashekaran, Novel Biginelli cr [10] us dihydropyrimidines with potential anticancer activity: A parallel synthesis and CoMSIA study, European Journal of Medicinal Chemistry 44 (2009) 4192- [11] an 4198 R K Sharma, D Rawat, Silica immobilized nickel complex: An efficient and M reusable catalyst for microwave-assisted one-pot synthesis of dihydropyrimidin A Rajack, K Yuvaraju, C Praveen, Y L N Murthy, A facile synthesis of te [12] d ones, Inorganic Chemistry Communications 17 (2012) 58-63 3,4-dihydropyrimidinones/thiones and novel N-dihydro pyrimidinone- Ac ce p decahydroacridine-1,8-diones catalyzed by cellulose sulfuric acid, Journal of Molecular Catalysis A: Chemical 370 (2013) 197-204 [13] A Kuraitheerthakumaran, S Pazhamalai, M Gopalakrishnan, Microwaveassisted multicomponent reaction for the synthesis of 3,4-dihydropyrimidin2(1H)-ones and their corresponding 2(1H)-thiones using lanthanum oxide as a catalyst under solvent-free conditions Arabian Journal of Chemistry (2011) doi:10.1016/j.arabjc.2011.06.005 [14] K Konkala, N M Sabbavarapu, R Katla, N Y V Durga, T.V K Reddy, L.A P D Bethala, R.B.N Prasad, Revisit to the Biginelli reaction: a novel and Page 24 of 35 25 recyclable bioglycerol-based sulfonic acid functionalized carbon catalyst for onepot synthesis of substituted 3,4-dihydropyrimidin-2-(1H)-ones, Tetrahedron Letters 53 (2012) 1968-1973 D L da Silva, S A Fernandes, A A Sabino, A de Fatima, p-Sulfonic acid ip t [15] calixarenes as efficient and reusable organocatalysts for the synthesis of 3,4- cr dihydropyrimidin-2(1H)-ones/-thiones, Tetrahedron Letters 52 (2011) 6328– [16] us 6330 C.-J Liu, J.-D Wang, Copper(II) Sulfamate: An Efficient Catalyst for the One- an Pot Synthesis of 3,4-Dihydropyrimidine-2(1H)-ones and thiones, Molecules 14 (2009) 763-770 A Debache, M Amimour, A Belfaitah, S Rhouati, B Carboni, A one-pot M [17] d Biginelli synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones catalyzed by [18] te triphenylphosphine as Lewis base, Tetrahedron Letters 49 (2008) 6119–6121 F Shirini, M A Zolfigol, J Albadi, Melamine trisulfonic acid: A new, efficient Ac ce p and recyclable catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)ones/thiones in the absence of solvent, Chinese Chemical Letters 22 (2011) 318321 [19] F Bigi, S Carloni, B Frullanti, R Maggi, G Sartori, A revision of the Biginelli reaction under solid acid catalysis Solvent-free synthesis of dihydropyrimidines over montmorillonite KSF, Tetrahedron Letters 40 (1999) 3465–3468 [20] A M Elmaghraby, I A Mousa, A A Harb and M Y Mahgoub, Three component reaction: An efficient synthesis and reactions of 3,4- Page 25 of 35 26 dihydropyrimidin-2(1H)-ones and thiones using new natural catalyst, Organic Chemistry (2013), Article ID 706437 http://dx.doi.org/10.1155/2013/706437 [21] M Moosavifar, An appropriate one-pot synthesis of dihydropyrimidinones ip t catalysed by heteropoly acid supported on zeolite: An efficient and recyclable catalyst for the Biginelli reaction, Comptes Rendus Chimie 15 (2012) 444-447 R Ghosh, S Maiti, A Chakraborty, In(OTf)3-catalysed one-pot synthesis of 3,4- cr [22] us dihydropyrimidin-2(lH)-ones, Journal of Molecular Catalysis A: Chemical 217 (2004) 47-50 S K De, R A Gibbs, Ruthenium(III) chloride-catalyzed one-pot synthesis of an [23] 3,4-dihydro-pyrimidin-2-(1H)-ones under solvent-free conditions, Synthesis P Salehi, M Dabiri, M A Zolfigol, M A B Fard, Silica sulfuric acid: an d [24] M (2005) 1748-1750 te efficient and reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin2(1H)-ones, Tetrahedron Letters 44 (2003) 2889-2891 H X Lin, Q J Zhao, B Xu, X H Wang, A green synthesis of Ac ce p [25] dihydropyrimidinones by Biginelli reaction over Nafion-H catalyst, Chinese Chemical Letters 18 (2007) 502-504 [26] M Moghaddas, A Davoodnia, M M Heravi, N Tavakoli-Houseini, Sulfonated carbon catalyzed Biginelli reaction for one-pot synthesis of 3,4-dihydropyrimidin2(1H)-ones and –thiones, Chinese Journal of Catalysis 33 (2012) 706-710 Page 26 of 35 27 [27] Suresh, A Saini, D Kumar, J S Sandhu, Multicomponent eco-friendly synthesis of 3,4-dihydropyrimidine-2-(1H)-ones using an organocatalyst Lactic acid, Green Chemistry Letters and Reviews (2009) 29-33 R Kaur, M Bansal, B Kaur, T Mishra, A Bhatia, Synthesis of 4-aryl-4,5- ip t [28] dihydro-1H-indeno[1,2-d]pyrimidines by Biginelli condensation and their K Manabe, S Kobayashi, Mannich-type reactions of aldehydes, amines, and us [29] cr antibacterial activities, Journal of Chemical Sciences 123 (2011) 443–451 ketones in a colloidal dispersion system created by a Brønsted acid-surfactant- [30] an combined catalyst in water, Organic Letters (1999) 1965-1967 K Manabe, S Iimura, X M Sun, S Kobayashi, Dehydration reactions in water M Brønsted acid-surfactant-combined catalyst for ester, ether, thioether, and K Manabe, Y Mori, T Wakabayashi, S Nagayama, S Kobayashi, Organic Ac ce p [31] te (2002) 11971-11978 d dithioacetal formation in water, Journal of American Chemical Society 124 synthesis inside particles in water:  Lewis acid-surfactant-combined catalysts for Organic reactions in water using colloidal dispersions as reaction media, Journal of American Chemical Society 122 (2000) 7202-7207 Page 27 of 35 28 [32] L Gang, L Xinzong, W Eli, Solvent-free esterification catalyzed by surfactantcombined catalysts at room temperature, New Journal of Chemistry 31 (2007) [33] ip t 348-351 T.-S Jin, R.-Q Zhao, T.-S Li, An one-pot three-component process for the cr synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3- [34] us c]pyrazoles in aqueous media, ARKIVOC (xi) (2006) 176-182 D Prasad, A Preetam, M Nath, Microwave-assisted green synthesis of an dibenzo[a, j]xanthenes using p-dodecylbenzenesulfonic acid as an efficient Bronsted acid catalyst under solvent-free conditions, Comptes Rendus Chimie 15 [35] M (2012) 675–678 S S Mansoor, K Aswin, K Logaiya, P N Sudhan, S Malik, Silica-supported d perchloric acid (HClO4–SiO2): a mild, reusable and highly efficient heterogeneous te catalyst for multicomponent synthesis of 1,4-dihydropyridines via unsymmetrical Ac ce p Hantzsch reaction, Research on Chemical Intermediate 40 (2014) 357–369 [36] K Aswin, S S Mansoor, K Logaiya, S P N Sudhan, Melamine trisulfonic acid as an efficient catalyst for the synthesis of 2,6-dimethyl-4-substituted-1,4dihydropyridine-3,5-diethyl/dimethylcarboxylate derivatives via Hantzsch reaction in solvent free condition, Journal of King Saud University - Science 25 (2013) 191–199 [37] K Aswin, K Logaiya, S P N Sudhan, S S Mansoor, An efficient one-pot synthesis of 1,4-dihydropyridine derivatives through Hantzsch reaction catalysed by Melamine trisulfonic acid, Journal of Taibah University for Science (2012) 1-9 Page 28 of 35 29 [38] S S Mansoor, K Aswin, K Logaiya, S P N.Sudhan, H Ramadoss, Melamine trisulfonic acid : A new, efficient and reusable catalyst for the synthesis of some fused pyranopyrrole derivatives, Journal of Saudi Chemical Society (2012), [39] ip t http://dx.doi.org/10.1016/j.jscs.2012.12.009 S S Mansoor, K Aswin, K Logaiya, S P N Sudhan, An efficient one-pot cr multi component synthesis of polyhydroquinoline derivatives through Hantzsch http://dx.doi.org/10.1016/j.arabjc.2012.10.017 J Safari, Z Zarnegar, M Heydarian, Practical, ecofriendly, and highly efficient an [40] us reaction catalysed by Gadolinium triflate, Arabian Journal of Chemistry (2012), synthesis of 2-amino-4H-chromenes using nanocrystalline MgO as a reusable M heterogeneous catalyst in aqueous media, Journal of Taibah University for Ac ce p te d Science (2013) 17-25 Page 29 of 35 31 Table Synthesis of 3,4-dihydropyrimidin-2(1H)-one: Solvent screening and catalyst Amount of catalyst (mol %) Acetonitrile Reflux Dioxane Reflux Acetic acid Reflux Water Reflux 5 Ethanol Reflux Solvent-free 80 Solvent-free 80 Solvent-free 80 5.0 68 5.0 63 5.0 71 5.0 60 5.0 58 3.0 94 3.0 73 10 3.0 94 an M Yield (%)b Reaction conditions: benzaldehyde (1 mmol), ethylacetoacetate (1 mmol), and urea (1.5 d a Time (h) cr Temperature (oC) us Entry Solvent ip t loadinga te mmol) were refluxed in the presence of DBSA with various solvents (5 ml) and also heated at 80 oC under solvent-free conditions Isolated yields Ac ce p b Page 30 of 35 32 Table DBSA - catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thionesa Entry R1 R X Product Time Yield (h) (%)b Mp (oC) Found O 4a 3.0 94 200 – 202 202 – OEt O 4b 2.5 81 205 – 207 206 – OEt O 4c 2.5 93 176 – 178 174 – OEt O 4d 2.5 84 212 – 214 213 – OEt O 4e 2.5 88 183 – 185 182 – OEt O 4f 2.5 93 195 – 198 196 – OEt O 4g 3.0 86 202 – 204 203 – OEt O 4h 2.5 90 224 – 226 226 – OEt O 4i 3.0 89 202 – 204 205 – 4j 3.0 87 155 – 157 157 – O 4k 3.0 88 155 – 157 156 – OMe O 4l 3.0 89 212 – 214 210 – OMe O 4m 3.0 86 191 – 194 190 – OMe O 4n 2.5 94 205 – 206 204 – OMe O 4o 2.5 90 240 – 242 241 – OEt S 4p 3.0 88 208 – 210 210 – OEt S 4q 3.0 85 155 – 157 154 – OEt S 4r 3.0 85 215 – 217 214 – OMe OMe OMe OMe S S S S 4s 4t 4u 4v 3.0 2.5 2.5 2.5 87 89 81 94 220 – 222 184 – 186 194 – 196 208 – 210 – – – – OEt cr us an M d O te OEt ip t OEt Ac ce p Reported C6H5 203 [22] 2-NO2-C6H4 208 [13] 4-F-C6H4 176 [13] 2-Cl-C6H4 216 [18] 3-Br-C6H4 184 [16] 4-OH-C6H4 197 [25] 4-OCH3-C6H4 204 [22] 3- NO2-C6H4 228 [22] 2-Furfuryl 206 [20] 10 n-C3H7 158 [24] 11 n-C4H9 158 [27] 12 C6H5 213 [18] 13 4-OCH3-C6H4 192 [18] 14 4- Cl-C6H4 206 [18] 15 4- OH-C6H4 242 [16] 16 C6H5 211 [25] 17 4-OCH3-C6H4 156 [13] 18 2-Thienyl 216 [27] 19 C6H5 20 4- Cl-C6H4 21 2- NO2-C6H4 22 4-F-C6H4 Page 31 of 35 33 a ip t Reaction 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 b Isolated yield Table Comparison of catalytic activity of DBSA with other catalysts reported in the Conditions Time (h) 6.0 CH3CN/Reflux 10.0 an us Acetic acid/100 oC 79 84 94 EtOH/Reflux 8.0 81 Solvent-free/100 oC 10.0 70 EtOH/Reflux 6.0 91 CH3CN/75-80 oC 6.0 91 Solvent-free/100 oC 48.0 77 H2O/100 oC 5.0 80 EtOH/Reflux 3.0 68 EtOH/Reflux 3.5 64 Solvent-free/100 oC 0.5 91 Solvent-free/80 oC 3.0 94 M 4.0 te Ac ce p Yield (%) EtOH/Reflux d Entry Catalyst Ref Copper(II) Sulfamate [16] Zeolite-supported HPA [21] Nafion-H [25] p-Sulfonic acid calixarenes [15] Triphenyl phosphine [17] Silica sulfuric acid [24] Bioglycerol based carbon [14] Montmorillonite KSF [19] Cellulose sulfuric acid [12] 10 Quartz [20] 11 Granite [20] 12 RuCl3 [23] 13 DBSA work cr literature for the synthesis of 3,4-dihydropyrimidinones Present Page 32 of 35 34 Table DBSA - catalyzed synthesis of various substituted 4-aryl-3,4-dihydro-1Hindeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2- a Yield (%)b Time (h) 2.5 O 6b 2.5 O 6c O 6d 3.0 88 S 6e 3.0 89 S 6f 2.5 92 6g 3.5 88 6h 3.5 87 6i 3.0 90 S 6j 3.0 91 S 6k 3.5 88 S 6l 3.5 87 2.5 an te S d S us 6a M Product O S Ac ce p C6H5 208 – 210 3-NO2-C6H4 216 – 218 4-Cl-C6H4 196 – 198 2-Cl-C6H4 184 – 186 C6H5 212 – 214 4-NO2-C6H4 220 – 222 4-CH3-C6H4 200 – 202 2-Cl-C6H4 190 – 192 3-NO2-C6H4 198 – 200 10 3-Br-C6H4 204 – 206 11 4-OCH3-C6H4 226 – 228 12 2-CH3-C6H4 202 – 204 X cr Entry R1 Mp (oC) ip t d]pyrimidine-5-onesa 91 90 92 Reaction conditions: substituted benzaldehydes (1 mmol), 2H-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 b Isolated yield Page 33 of 35 36 OH O ip t O S O O DBSA (5 mol%) CH2(CH2)10CH3 RO + R1-CHO + H2N NH2 us R = CH3, C2H5 H3C Solvent-free, 80 oC O NH X = O, S N H X 4a-v an H3C RO cr X R Ac ce p te d M Scheme – DBSA - catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones O R -CHO + O S O O NH2 + O OH H2N X X = O, S R1 DBSA (5 mol%) CH2(CH2)10CH3 Solvent-free, 80 oC NH N H X 6a-l Page 34 of 35 37 Scheme – DBSA - catalyzed synthesis of various substituted 4-aryl-3,4-dihydro-1Hindeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro- M an us cr ip t indeno[1,2-d]pyrimidine-5-ones 94% 94 d 96 Recyclability of DBSA te 92% 90 Ac ce p Yield (%) 92 90% 88% 88 86 Number of Runs 251658240 Figure 1: Recycling of catalyst DBSA for the synthesis of 3,4-dihydropyrimidin-2(1H)one Page 35 of 35 ... NH -1) , 9 .18 (s, 1H, NH -3) ppm; 13 C NMR ( 12 5 MHz, DMSO -d6 ) δ: 17 .4, 46 .8, 1 04. 9, 1 24 . 6, 12 5 .6, 12 6 .3, 12 7 .9, 12 8 .5, 12 9 .5, 1 34 .5, Page 18 of 35 19 13 5 .7, 13 6 .2, 1 42 .3, 14 4 .3, 1 83. 3, 18 9 .4 ppm;... δ: 17 .1, 46 .2, 10 5 .3, 1 24 . 4, 12 5 .4, ip t (s, 1H, NH -3) ppm; 12 6 .3, 12 7 .7, 12 8 .5, 12 9 .4, 1 34 .5, 13 5 .5, 13 6 .5, 14 1 .9, 14 4 .4, 1 83. 4, 18 9 .3 ppm; cr MS(ESI): m/z 30 7 (M+H)+; Anal Calcd for C18H14N2OS:... [25 ] 4- OCH3-C6H4 2 04 [22 ] 3- NO2-C6H4 22 8 [22 ] 2- Furfuryl 20 6 [20 ] 10 n-C3H7 15 8 [ 24 ] 11 n-C4H9 15 8 [27 ] 12 C6H5 2 13 [18 ] 13 4- OCH3-C6H4 1 92 [18 ] 14 4- Cl-C6H4 20 6 [18 ] 15 4- OH-C6H4 24 2 [16 ] 16