KAl(SO4)2·12H2O supported on silica gel as a novel heterogeneous system catalyzed biginelli reaction

Applied Catalysis A: General 300 (2006) 85–88 www.elsevier.com/locate/apcata

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KAl(SO4)2
12H2O supported on silica gel as a novel heterogeneous system catalyzed biginelli reaction One-pot synthesis of di-hydropyrimidinones under solvent-free conditions Javad Azizian *, Ali A. Mohammadi, Ali R. Karimi, Mohammad R. Mohammadizadeh Department of Chemistry, Faculty of Sciences, Shahid Beheshty University, P.O. Box 19395-1775, Tehran, Iran Received 13 June 2005; received in revised form 28 October 2005; accepted 3 November 2005 Available online 5 December 2005

Abstract 3,4-Dihydropyrimidin-2(1H)-ones derivatives were synthesized in moderate to high yields in one-pot three component reaction from the corresponding aldehydes, ketones or 1,3-dicarbonyl compounds and urea, in the presence of catalytic amount of KAl(SO4)2
12H2O (Alum) supported on silica gel (Alum-SiO2) as a non-toxic, reusable, inexpensive and easily available reagent, under solvent-free conditions at 80 8C. Compared to the classical Biginelli reaction, this new method consistently has the advantage of good yields. # 2005 Elsevier B.V. All rights reserved. Keywords: KAl(SO4)2
12H2O-SiO2 (Alum-SiO2); Biginelli reaction; Solvent-free conditions; Di-hydropyrimidinones; 1,3-Dicarbonyl; Aldehydes; Ketone; Urea

1. Introduction The Biginelli reaction was first reported more than a century ago and recently reviewed [1], and involves the synthesis of 3,4dihydropyrimidin-2(1H)-ones (DHPMs) of type 4 by a very simple one-pot condensation reaction of ethylacetoacetate 1a, benzaldehyde 2a and urea 3 in ethanol. However, this one-pot, one-step protocol often provides only low to moderate yields of the desired target molecules 4, in particular when substituted aromatic or aliphatic aldehydes are employed (Scheme 1). 3,4-Dihydropyrimidin-2(1H)-ones 4 have been reported to possess diverse biological activities such as antibacterial, antihypertensive, antiviral, antitumor effects and integral backbones of several calcium channel blockers [2]. Moreover, several alkaloids containing the dihydropyrimidine core unit have been isolated from marine sources, which also exhibit interesting biological properties [3]. Most notably among these are the batzelladine alkaloids, which were found to be potent

* Corresponding author. Tel.: +98 21 29902895; fax: +98 21 22401765. E-mail address: [email protected] (J. Azizian). 0926-860X/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.apcata.2005.11.001

HIV gp-120-CD4 inhibitors [4]. Thus, syntheses of these heterocyclic compounds are of much current importance. Several improved procedures for the preparation of DHPMs have been reported, either by modification of the classical onepot Biginelli approach itself [5]. Recently, several other methods indicate the use of lanthanide compounds [6], Lewis acids such as BF3
OEt2, FeCl3, Yb(OTf)3, ZrCl4, BiCl3, Mn(OAc)3, LiClO4, Cu(OTf)2 [7], HCl [8], polyphosphate ester (PPE) [9] and NH4Cl [10] can overcome the drawback of the classical Biginelli reaction. 2. Results and discussions In connection with our ongoing work on multi-component condensations (MCCs) [11] and in view of our interest in the KAl(SO4)2
12H2O catalyzed reactions [12], we now wish to report a facile and rapid one-pot three component procedure preparation of DHPMs derivatives with KAl(SO4)2
12H2OSiO2 as a non-toxic, reusable, inexpensive and easily available reagent, under solvent-free conditions at 80 8C. The results of optimization experiments for the threecomponent Biginelli condensation involving acetoacetate 1a,

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J. Azizian et al. / Applied Catalysis A: General 300 (2006) 85–88

Scheme 1.

benzaldehyde 2a and urea 3 with KAl(SO4)2
12H2O supported on silica gel as catalysts are presented in Table 1. It is remarkable to note that the condensation proceeded with a low catalyst concentration [KAl(SO4)2
12H2O-SiO2 contains 25 mol% of KAl(SO4)2
12H2O (see Section 3)] at ambient conditions and gave 3,4-dihydropyrimidin-2(1H)-ones 4a in high yields. Promoted by this success, we extended this reaction of urea with a range of other 1,3-dicarbonyl compounds 1b–q or a-tetralon and aldehydes 2b–q (Scheme 2), under similar conditions, furnishing the respective 3,4-dihdropyrimidin2(1H)-ones 4b–q and 5a in good to excellent yields. The optimized results are summarized in Table 2. In summary, we have described a successful strategy, efficient and convenient green synthesis for the preparation of 3,4-dihdro pyrimidin-2(1H)-ones in valuing cyclocondensation reaction of 1,3-dicarbonyl compounds, aldehydes and urea using the inexpensive, non-toxic and easily available SiO2-KAl(SO4)2
12H2O catalyst. The method offers several advantages including high yield of products, recyclable of the catalyst and easy experimental work-up procedure, which makes it a useful process for the synthesis of 3,4-dihdropyrimidin-2(1H)-ones. 3. Experimental Melting points were measured on the Electrothermal 9100 apparatus and are uncorrected. IR spectra were measured on a Bomen FT-IR-MB 100 spectrometer. 1H and 13C NMR spectra were measured with a Bruker DRX-300 Avance spectrometer at Table 1 KAl(SO4)2
12H2O-SiO2 catalyzed condensation of benzaldehyde, ethyl acetoacetate and ureaa No.

Catalyst

Catalyst

Solvent

Yield of 2a (%) b

1

KAl(SO4)2
12H2O KAl(SO4)2
12H2O KAl(SO4)2
12H2O KAl(SO4)2
12H2O KAl(SO4)2
12H2O KAl(SO4)2
12H2O KAl(SO4)2
12H2O SiO2-KAl(SO4)2
12H2O SiO2-KAl(SO4)2
12H2O SiO2-KAl(SO4)2
12H2O SiO2-KAl(SO4)2
12H2O SiO2-KAl(SO4)2
12H2O SiO2-KAl(SO4)2
12H2O

100 mol% 10 mol% 4 mol% 3 mol% 4 mol% 4 mol% 4 mol% 1g 0.5 g 0.16 g 0.16 g 0.16 g 0.16 g

EtOH EtOH EtOH EtOH CH3CN H2O EtOH EtOH EtOH CH3CN H2O –

10 40 83 75 80 45 73 20 50 90 85 52 93

2

a Reaction conditions benzaldehyde (5 mmol), ethyl acetoacetate (5 mmol), urea (6 mmol), 80 8C. b Yields of pure isolated product based on benzaldehyde.

300 and 75 MHz using TMS as internal standard. Chemical shifts are reported (d) relative to TMS and coupling constant (J) is reported in hertz (Hz). Mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer. Elemental analysis for C, H and N were performed using a Heraus CHN rapid analyzer. 4. General procedure 4.1. Preparation of the supported catalyst To a suspension of 7.5 g of silica gel (Merck, Silica gel 0.063–200 mm) in 20 ml of water 2.5 g KAl(SO4)2
12H2O was added. The suspension stirred at room temperature for 6 h, then was water evaporated under reduced pressure for 20 min and the residue dried at 60 8C for 3 h. 4.2. General procedure for preparation of 3,4dihdropyrimidin-2(1H)-ones A mixture containing an appropriate b-ketoesters or 1,3diketones or a-tetralon (5 mmol), corresponding aldehydes (5 mmol), urea and SiO2-KAl(SO4)2
12H2O (0.16 g) was heated with stirring at 80 8C for the time period as indicated in Table 2. After completion of the reaction, as indicated by TLC, the reaction mixture was cooled to room temperature and filtered through a sinter funnel, then was washed with cold water and recystallized from ethanol to afford pure product. 4.3. Spectral data for new products 6-Methyl-5-propionyl-4-pyridin-3-yl-3,4-dihydro-1H-pyrimidin-2-one (4j): white powder, yield 82%, mp 217–218 8C, IR (KBr), (nmax, cm 1): 3340, 3220, 1680, 1639. 1H NMR (DMSO) dH: 1.06 (t, 3H, J = 7.08 Hz, CH3), 2.26 (s, 3H, CH3), 3.98 (q, 2H, J = 5.49 Hz, CH2), 5.19 (s, 1H, CH), 7.35 (m, 1H), 7.59 (d, 1H, J = 7.73 Hz, H2), 7.78 (s, 1H, NH), 8.44 (d, 2H, J = 4.82 Hz), 9.29 (s, 1H, NH). 13C NMR (DMSO) dC: 13.87,

Scheme 2.

J. Azizian et al. / Applied Catalysis A: General 300 (2006) 85–88

87

Table 2 SiO2-KAl(SO4)2
12H2O catalyzed synthesis of different dihydropyrimidinones under solvent less conditions Productsa

R

R1

R2

Time (h)

Yielda,b (%)

mp (8C)

Lit mp (8C)

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 5a

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Ph Ph –

OEt OEt OEt OEt OEt OEt OEt OEt OEt OEt OMe OMe OMe Me Me OEt Ph a-Tetralon

Ph 4-ClC6H4 4-NO2C6H4 4-MeOC6H4 3-ClC6H4 2-BrC6H4 4-FC6H4 n-C3H7 n-C4H9 Pyridin-3-aldehyde Ph 4-MeOC6H4 4-ClC6H4 Ph 4-MeOC6H4 Ph Ph Ph

4 4 4 4 4 4 4 6.5 6.5 6 4 4 4 6 6 6 6.5 6.5

92 93 89 91 93 97 90 73 62 82 91 92 91 77 90 83 70 70

203–204 212–213 207–209 200–202 192–194 205–207 183–185 156–157 155–157 217–218 208–210 190–192 202–204 231–234 167–168 156–158 243–244 286–288 dec.

202–204 212–214 206–208 198–200 193–195 206–208 185–186 154 [17] 154–156 – 207–210 192–194 203–205 232–235 168–170 155–157 – –[18]

[13] [14] [15] [15] [14] [16] [13] [10] [16] [13] [17] [10] [16] [17]

a

All products were characterized by 1H, 13C NMR, IR, MS and elemental analyses. Reaction conditions b-ketoesters or 1,3-diketones or a-tetralon (5 mmol), corresponding aldehydes (5 mmol), urea and SiO2-KAl (SO4)2
12H2O (0.16 g) was heated with stirring at 80 8C. b

17.64, 52.00, 59.13, 98.19, 123.61, 133.75, 139.65, 147.76, 148.41, 148.96, 151.70, 164.91. MS (m/z, %): 261 (M+, 100), 232 (35), 219 (35), 183 (50), 155 (30), 137 (25), 51 (25), 41 (35). Anal. Calcd. for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C, 59.67; H, 5.70; N, 15.97. 4-Phenyl-3,4,5,6-tetrahydro-1H-benzo[h]quinazolin-2-one (5a): white powder, yield 70%, mp 286–288 dec.8C, IR (KBr), (nmax, cm 1): 3225, 3085, 1681. 1H NMR (DMSO) dH: 1.74 (m, 1H), 2.11 (m, 1H), 2.56 (m, 1H), 2.68 (m, 1H), 4.92 (s, 1H, CH), 7.17 (m, 3H), 7.27 (m, 2H), 7.33 (m, 3H), 7.36 (s, 1H, NH), 7.57 (d, 1H, J = 7.34 Hz), 8.25 (s, 1H, NH). 13C NMR (DMSO) dC: 23.36, 27.45, 58.95, 107.88, 121.06, 126.14, 126.73, 127.26, 127.29, 127.41, 127.54, 128.40, 128.64, 135.24, 144.01, 153.15. MS (m/z, %): 276 (M+, 15), 275 (100), 232 (50), 119 (90), 181 (30), 154 (25), 128 (25), 115 (30), 77 (50), 51 (35), 39 (25). Anal. Calcd. for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.15; H, 5.74; N, 10.06. 5-Benzoyl-4,6-diphenyl-3,4-dihydro-1H-pyrimidin-2-one (4q): yellow powder, yield 70%, mp 243–244 8C, IR (KBr), (nmax, cm 1): 3360, 3175, 1675, 1632. 1H NMR (DMSO) dH: 5.36 (s, 1H, CH), 6.98–7.35 (m, 14H), 8.00 (s, 1H, NH), 8.10 (d, J = 8.5 Hz 1H), 9.42 (s, 1H, NH). 13C NMR (DMSO) dC: 55.39, 109.27, 126.32, 127.18, 127.24, 127.58, 128.30, 128.49, 129.45, 129.51, 130.47, 133.30, 139.43, 143.94, 147.99, 152.50, 194.67. MS (m/z, %): 354 (M+, 100), 277 (90), 249 (90), 206 (25), 178 (25), 105 (80), 77 (85), 51 (45), 39 (10). Anal. Calcd. for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 77.84; H, 5.06; N, 7.81.

Acknowledgment We gratefully acknowledge for financial support from the Research Council of Shahid Beheshti University.

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