ones Catalyzed by Chlorosulfonic Acid

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3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives have attracted much synthetic interest due to their wide range of therapeutical and ...
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E-Journal of Chemistry Vol. 2, No. 4, pp 228-230, September 2005

One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones Catalyzed by Chlorosulfonic Acid JIN TONG-SHOU *, ZHAO YING, LIU LI-BIN and LI TONG-SHUANG College of Chemistry and Environmental Science, Hebei University, Hebei Province, Baoding 071002, P. R. China

Received 22 July 2005; Accepted 28 August 2005

Abstract: An efficient synthesis of 3,4-dihydropyrimidin-2-ones (DHPMs) from the

aldehydes, β-ketoesters and urea in ethanol using chlorosulfonic acid as the catalyst is described. Compared with the classical Biginelli reaction conditions, this method has the advantage of excellent yields and short reaction time.

Key words: 3,4-dihydropyrimidin-2(1H)-ones; chlorosulfonic acid; synthesis

Introduction 3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives have attracted much synthetic interest due to their wide range of therapeutical and pharmacological properties, as calcium channel blockers, anti-hypertensive agents, anti-tumor, anti-bacterial, α-1a-antagonists and anti-inflammatory behaviors1-4. Recently many improved procedures for the preparation of DHPMs have been reported 5-13. However, encouraged by the surge of catalytic processes and driven by economic factors, we focused our attention on the development of other alternative reagents that are inexpensive, work under mild and catalytic conditions together resulting in higher yields. Guided by these points, we would like to report a general and practical approach for the Biginelli cyclocondensation reaction using ClSO3H as catalyst (Scheme 1). The use of ClSO3H as a catalyst in the synthesis of pyrimidinones has not been reported yet.

229

JIN TONG-SHOU et.al., Ar O

O Ar

H

+

O

Me

O OR

+

H2N

Cl SO3H NH2

ROOC

NH

C2H5OH reflux N H

H3 C

1

2

3

O

4

Scheme 1 Synthesis of 3,4-dihydropyrimidin-2(1H)-ones using ClSO3H as catalyst

Experimental

Materials and Measurements All liquid reagents were distilled before use. IR spectra were recorded on Bio-Rad FTS-40 spectrometer (KBr). 1H NMR spectra were measured on Bruker AVANCE 400 (400 MHz) spectrometer using TMS as internal standard and DMSO as solvent.

Procedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using ClSO3H as catalyst A mixture of the aromatic aldehyde 1 (1 mmol), β-ketoestersand 2 (1 mmol) and urea 3 (1.5 mmol) and ClSO3H (0.2 mmol) in ethanol (5 mL) were heated at refluxing temperature for 2.5-5.5 hours. The reaction was continued until the aldehyde disappeared, as indicated by TLC. After cooling, the reaction mixture was poured onto crushed ice (80 g) and stirred for several minutes. The solid was filtered, washed with cold water (2×5 mL) and 40% EtOH (3×5 mL). After drying and recrystallization from the hot ethanol, pure products 4 were obtained. Selected spectral data of some products are given below: Compound 4i: 1H NMR (400MHz, DMSO-d6): δH 9.33 (s, 1H, NH), 7.77 (s, 1H, NH), 7.31-7.57 (m, 3H, ArH), 5.59 (d, J=2.8 Hz, 1H, CH), 3.90 (q, J=7.2 Hz, 2H, OCH2), 2.29 (s, 3H, CH3), 1.00 (t, J=7.2 Hz, 3H, CH3). IR (KBr) ν: 3219, 3104, 1699, 1641 cm-1. Compound 4l: 1H NMR (400MHz, DMSO-d6) δH 9.28 (s, 1H, NH), 7.80 (s, 1H, NH), 7.19-7.38 (m, 4H, ArH), 5.16 (s, 1H, CH), 3.55 (s, 3H, OCH3), 2.27 (s, 3H, CH3); IR (KBr) ν: 3224, 3098, 1704, 1651 cm-1. Compound 4o: 1H NMR (400MHz, DMSO-d6) δH: 9.19 (s, 1H, NH), 7.69 (s, 1H, NH), 6.68~6.86 (m, 3H, ArH), 5.99 (s, 2H, CH2), 5.07(s, 1H, CH), 3.56 (s, 3H, OCH3), 2.25 (s, 3H, CH3); IR (KBr) ν: 3234, 2961, 1700, 1648 cm-1. Compound 4p: 1HNMR (400MHz, DMSO-d6): δH 9.39 (s, 1H, NH), 8.20 (d, J = 8.4 Hz, 2H, ArH), 7.93 (s, 1H, NH), 7.50 (d, J = 8.4 Hz, 2H, ArH), 5.28 (s, 1H, CH), 3.53 (s, 3H, OCH3), 2.27 (s, 3H, CH3). IR (KBr) ν: 3233, 3113, 1703, 1643 cm-1.

Results and Discussion This is a novel, one-pot combination that not only preserves the simplicity of Biginelli’s one-pot reaction but also consistently produces 82-94% yields of the dihydropyrimidin-2(1H)-ones. All the products were confirmed by melting points and spectral data. The results are shown in the Table 1. It can be seen from Table 1 that ethyl acetoacetate and methyl acetoacetate gave good yields. We have tested a variety of reaction conditions with p-chlorobenzaldehyde using ClSO3H as a catalyst. First, the influence of the amount of the catalyst on the reaction yield was studied. It was found that the presence of 0.2mmol of ClSO3H as a reaction mediator per mmol of reactions provided higher yields, higher amount of ClSO3H did not improved the result to a great extent. The effects of solvent on the reaction were also examined using p-chlorophenaldehyde, ethyl acetoacetate and urea as the reactants, which other conditions are the same as that of Table1. It seems that ethanol is a much better solvent (yield 92%) than all others tested (such as methyl cyanide, tetrahydrofuran, dichloromethane and water). The best results were achieved by carrying out the reaction under the optimized conditions; with a 1:1:1.5 ratios of aldehyde 1, β-ketoester 2, and urea 3 in a one-pot condensation employing refluxing ethanol as solvent in the presence of 0.2 equiv. ClSO3H.

One-Pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones

230

Table 1 Synthesis of 3,4-dihydropyrimidin-2(1H)-ones using ClSO3H as catalyst Entry

Ar

R

C6H5 C2H5 a 2-ClC6H4 C2H5 b 3-ClC6H4 C2H5 c 4-ClC H C2H5 d 6 4 4-H3COC6H4 C2H5 e 3,4-(OCH2O)C6H3 C2H5 f 4-O2NC6H4 C2H5 g 3-O2NC6H4 C2H5 h 2,4-Cl2C6H3 C2H5 i C6H5 CH3 j 2-ClC6H4 CH3 k 3-ClC6H4 CH3 l 4-ClC6H4 CH3 m 4-H3COC6H4 CH3 n 3,4-(OCH2O)C6H3 CH3 o 4-O2NC6H4 CH3 p 3-O2NC6H4 CH3 q 2,4-Cl2C6H3 CH3 r a Isolated yield based on aromatic aldehydes.

Time h 3 5.5 4 4 2.5 4 3 3 4.5 4 5.5 4 4 2.5 4 3 3 4.5

Yielda % 86 91 85 92 87 82 84 88 86 90 84 85 94 83 85 92 84 87

M. P. oC Found 204-206 217-219 192-193 212-215 201-203 184-186 205-207 226-228 247-249 210-212 225-227 256-258 205-207 193-194 245-247 239-241 280-282 256-258

Reported 202-20414 215-2185 192-1935 213-21514 201-20214 187-18814 207-208.514 226-227.514 249-2515 209-2126 224-2255 204-2076 192-1946 239-2416 278-2795 254-2555

Conclusions In conclusion, the use of ClSO3H as a catalyst provides an efficient and much improved modification of Biginelli reaction. The yields of the one-pot Biginelli reatcion increased to 82-94% while the reaction time shortened to 2.5-5.5 hours. This improved modification of Biginelli reaction is a simple, timesaving and high yielding process.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14

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