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. 2012 Oct 15;2012:474626. doi: 10.5402/2012/474626

Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Their Corresponding 2(1H)Thiones Using Trichloroacetic Acid as a Catalyst under Solvent-Free Conditions

Zahed Karimi-Jaberi 1,*, Mohammad Sadegh Moaddeli 1
PMCID: PMC3767353  PMID: 24052844

Abstract

Trichloroacetic acid was found to be a convenient catalyst for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and their corresponding 2(1H)-thiones through a one-pot three-component reaction of aldehydes, alkyl acetoacetate, and urea or thiourea at 70°C under solvent-free conditions.

1. Introduction

Biginelli reaction is a useful three-component reaction offering versatile protocol for the production of 3,4-dihydropyrimidin-2(1H)-ones which exhibit widespread biological applications such as antihypertensive, antiviral, antitumor, antibacterial, α-1a-antagonism, antioxidant, and anti-inflammatory actions [9, 10].

Although numerous catalysts have been developed in accelerating this reaction [1–8, 11–22], it is still desirable to develop this reaction using newer reagents with greater efficiency, simpler operational procedure, and milder reaction condition, and a higher yield of products coupled with potential bioactivity is important.

With the awareness of environmental issues and importance of this reaction and keeping our interest in the development of synthetic routes to heterocyclic compounds [23–27], herein, we report a heterogeneous, solid trichloroacetic acid, as an alternative, cheap, and efficient catalyst for the Biginelli reaction (Scheme 1).

Scheme 1.

Scheme 1

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Trichloroacetic acid is a readily available and inexpensive solid reagent and it has been used by our group for the synthesis of dihydropyrano[2,3-c]pyrazoles [23] and tetrahydrobenzo[a]xanthen-11-ones and dibenzo[a,j]xanthenes [24].

2. Results and Discussion

The catalytic activity of trichloroacetic acid was first investigated using three-component reaction of benzaldehyde, ethyl acetoacetate, and urea as a model reaction. After carrying out the reaction at different conditions, the best results have been obtained with 20 mol% trichloroacetic acid at 70°C after 4 min with 85% yield under solvent-free conditions. In the absence of trichloroacetic acid, only 20% yield of the product was obtained even after heating at 70°C for 12 h with recovery of starting material.

The reaction was also examined in solvents such as EtOH, H2O, CHCl3, and toluene. In the presence of solvents, reaction was sluggish and the formation of by-products was observed. The reaction temperature was also optimized, below 70°C the reaction proceeded slow giving a relatively low yield and no improvement was observed above 70°C.

Having established the reaction conditions, various 3,4-dihydropyrimidin-2(1H)-ones were synthesized in excellent yields through the reaction of different aldehydes, alkyl acetoacetate, and urea. The results are summarized in Table 1, which clearly indicates the generality and scope of the reaction with respect to various aromatic, heteroaromatic, unsaturated, and aliphatic aldehydes. It is noteworthy that acid-sensitive aldehydes such as furfural and cinnamaldehyde that (Table 1) worked well gave the corresponding products. The reaction can also proceed with methyl acetoacetate (Table 1, entries 18–30). In all cases, dihydropyrimidinones were the sole products and no by-product was observed.

Table 1.

Trichloroacetic acid catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones or thiones under solvent-free conditions.

Entry R1 R2 X Time (min) Yield (%) mp (°C, obsd) mp (°C, lit) (ref.)
1 C6H5 OEt O 4 85 201–203 202–205 [1]
2 4-ClC6H4 OEt O 9 92 212–216 210–212 [1]
3 4-HOC6H4 OEt O 40 90 226–228 231–233 [2]
4 3-O2NC6H4 OEt O 20 93 225–228 227-228 [1]
5 4-O2NC6H4 OEt O 5 85 206–209 207–209 [1]
6 C6H5CH=CH OEt O 3 90 225–227 223–226 [1]
7 4-MeOC6H4 OEt O 20 95 200–202 202–204 [1]
8 2,4-(Cl)2C6H3 OEt O 4 91 247–249 246–248 [3]
9 4-MeC6H4 OEt O 5 90 213–215 214–216 [1]
10 2-MeOC6H4 OEt O 2 94 262-263 260 [4]
11 2,6-(Cl)2C6H3 OEt O 3 96 226–228 226 [5]
12 2-ClC6H4 OEt O 9 85 221–223 221–223 [2]
13 4-BrC6H4 OEt O 11 90 212–214 215 [6]
14 CH3 OEt O 3 92 188–190 194-195 [7]
15 CH3CH2CH OEt O 50 88 163–165 164–166 [7]
16 3-MeC6H4 OEt O 8 93 219–222 224–226 [2]
17 2-Furyl OEt O 19 86 202–205 202–204 [5]
18 C6H5 OMe O 5 94 208–211 210–213 [1]
19 4-MeOC6H4 OMe O 9 85 192–195 193–196 [3]
20 4-ClC6H4 OMe O 8 92 204–206 203–205 [1]
21 4-O2NC6H4 OMe O 3 95 235–237 235-236 [5]
22 2-ClC6H4 OMe O 6 84 180–182 181–183 [1]
23 3-O2NC6H4 OMe O 12 90 271–274 273–275 [2]
24 4-MeC6H4 OMe O 14 93 206–209 210–213 [3]
25 4-HOC6H4 OMe O 7 87 235–237 231–233 [2]
26 2-MeOC6H4 OMe O 2 95 284–286 285–287 [2]
27 3-MeC6H4 OMe O 4 96 214–217 216–218 [2]
28 3-ClC6H4 OMe O 9 92 208–211 209-210 [2]
29 2,4-(Cl)2C6H3 OMe O 3 94 252–255 252-253 [3]
30 2-Furyl OMe O 11 88 216–218 214–216 [8]
31 C6H5 OEt S 25 90 210–212 210–212 [1]
32 4-ClC6H4 OEt S 18 86 181–183 184-185 [3]
33 4-MeOC6H4 OEt S 20 85 136–138 137–139 [3]
34 3-O2NC6H4 OEt S 15 87 205–208 205-206 [8]
35 C6H5 OMe S 13 92 220–222 221-222 [3]
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The reaction of aldehydes with alkyl acetoacetate and thiourea under similar reaction conditions also provided the corresponding 3,4-dihydropyrimidin-2(1H)-thiones in high yields (Table 1, entries 31–35), which are also of interest with respect to their biological activities [21].

3. Conclusion

In conclusion, a novel approach to explore the use of trichloroacetic acid for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones and their corresponding 2(1H)thione has been described through the Biginelli reaction at 70°C under solvent-free conditions. This method offers several advantages including high yields, short reaction times, solvent-free condition, a simple work-up procedure without using any chromatographic methods, and it also has the ability to tolerate a wide variety of substitutions in all three components.

4. Experimental

All chemicals were commercially available and used without further purification. Melting points were recorded on an electrothermal type 9100 melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu spectrophotometer as KBr disks. The NMR spectra were recorded on a Bruker 250 MHz spectrometer.

4.1. General Procedure for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones/Thiones

A mixture of aldehyde (1 mmol), alkyl acetoacetate (1 mmol), urea/thiourea (1 mmol), and trichloroacetic acid (0.032 g, 20 mol%) was stirred at 70°C for the appropriate time indicated in Table 1. The progress of reactions was monitored by TLC (ethyl acetate/n-hexane). After completion of the reaction, a solid was obtained. It was allowed to cool to room temperature, and ethanol (5 mL) was added, and the catalyst was recovered by filtration. The filtrate was concentrated and allowed to crystallize the desired product.

4.2. Selected Characterization Data

Ethyl-6-Methyl-2-Oxo-4-Phenyl-1,2,3,4-Tetrahydropyrimidine-5-Carboxylate —

IR(KBr):3240, 3110, 1725, 1700, 1645; 1H NMR (DMSO-d6): δ 1.12 (t, J = 7.5 Hz, 3H), 2.28 (s, 3H), 4.03 (q, J = 7.5 Hz, 2H), 5.17 (d, J = 3.0 Hz, 1H), 7.22–7.41 (m, 5H), 7.78 (br s, 1H), 9.22 (br s, 1H).

Ethyl-6-Methyl-4-(4-Nitrophenyl)-2-Oxo-1,2,3,4-Tetrahydropyrimidine-5-Carboxylate —

IR(KBr):3230, 3120, 1730, 1710, 1650; 1H NMR (DMSO-d6): δ 1.11 (t, J = 7.5 Hz, 3H), 2.29 (s, 3H), 4.00 (q, J = 7.5 Hz, 2H), 5.29 (d, J = 3.0 Hz, 1H), 7.51 (d, J = 10 Hz, 2 H), 7.91 (br s, 1H), 8.23 (d, J = 10.0 Hz, 2H), 9.37 (br s, 1H).

Ethyl-6-Methyl-4-(4-Methoxyphenyl)-3,4-Dihydropyrimidin-2(1H)-One-5-Carboxylate —

IR (KBr): 3390, 3243, 3106, 2958, 1706, 1651,1278, 1088. 1H NMR (DMSO-d6): δ 1.01–1.20 (t, 3H, J = 7 Hz, CH2CH3), 2.30 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.90–4.20 (q, 2H, J = 7 Hz, CH2CH3), 5.60 (s, 1H, C4-H), 6.80–6.90 (d,2H, J = 7.2 Hz, ArH), 7.15–7.25 (d, 2H, J = 7.2 Hz, ArH), 7.65 (bs, 1H, NH), 9.17 (bs, 1H, NH).

6-Methyl-4-Phenyl-3, 4-Dihydropyrimidin-2(1H)-Thione-5-Carboxylate —

IR (KBr): 3412, 3312, 3174, 3096, 2967, 1667, 1610, 1575. 1H NMR (DMSO-d6): δ 1.02–1.18 (t, 3H, J = 7.1 Hz, CH2CH3), 2.32 (s, 3H, CH3), 4.02–4.21 (q, 2H, J = 7.1 Hz,CH2CH3), 5.50 (s, 1H, C4-H), 7.15–7.35 (m, 5H, ArH), 8.90 (bs, 1H, NH), 9.95 (bs, 1H, NH).

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