One-Pot Synthesis of 3 , 4-Dihydropyrimidin-2 ( 1 H )-ones Catalyzed by Chlorosulfonic Acid

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.


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 behaviors [1][2][3][4] .Recently many improved procedures for the preparation of DHPMs have been reported [5][6][7][8][9][10][11][12][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 ClSO 3 H as catalyst (Scheme 1).The use of ClSO 3 H as a catalyst in the synthesis of pyrimidinones has not been reported yet.

Materials and Measurements
All liquid reagents were distilled before use.IR spectra were recorded on Bio-Rad FTS-40 spectrometer (KBr). 1 H 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 ClSO 3 H as catalyst
A mixture of the aromatic aldehyde 1 (1 mmol), β-ketoestersand 2 (1 mmol) and urea 3 (1.5 mmol) and ClSO 3 H (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:

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 ClSO 3 H 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 ClSO 3 H as a reaction mediator per mmol of reactions provided higher yields, higher amount of ClSO 3 H 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.ClSO 3 H.

Conclusions
In conclusion, the use of ClSO 3 H 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.