ISRN Organic ChemistryVolume 2012 (2012), Article ID 474626, 4 pagesdoi:10.5402/2012/474626

Research Article

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 and Mohammad Sadegh Moaddeli

Department of Chemistry, Firoozabad Branch, Islamic Azad University, P.O. Box 74715-117, Firoozabad, Fars, Iran

Received 3 August 2012; Accepted 8 October 2012

Academic Editors: D.-M. Du and G. K. Patra

Copyright © 2012 Zahed Karimi-Jaberi and Mohammad Sadegh Moaddeli. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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, -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

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]

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-CarboxylateIR(KBr):3240, 3110, 1725, 1700, 1645; ¹H NMR (DMSO-): 1.12 (t Hz, 3H), 2.28 (s, 3H), 4.03 (q,  Hz, 2H), 5.17 (d,  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-CarboxylateIR(KBr):3230, 3120, 1730, 1710, 1650; ¹H NMR (DMSO-): 1.11 (t,  Hz, 3H), 2.29 (s, 3H), 4.00 (q,  Hz, 2H), 5.29 (d,  Hz, 1H), 7.51 (d,  Hz, 2 H), 7.91 (br s, 1H), 8.23 (d,  Hz, 2H), 9.37 (br s, 1H).

Ethyl-6-Methyl-4-(4-Methoxyphenyl)-3,4-Dihydropyrimidin-2(1H)-One-5-CarboxylateIR (KBr): 3390, 3243, 3106, 2958, 1706, 1651,1278, 1088. ¹H NMR (DMSO-): 1.01–1.20 (t, 3H,  Hz, CH₂CH₃), 2.30 (s, 3H, CH₃), 3.80 (s, 3H, OCH₃), 3.90–4.20 (q, 2H,  Hz, CH₂CH₃), 5.60 (s, 1H, C4-H), 6.80–6.90 (d,2H,  Hz, ArH), 7.15–7.25 (d, 2H,  Hz, ArH), 7.65 (bs, 1H, NH), 9.17 (bs, 1H, NH).

6-Methyl-4-Phenyl-3, 4-Dihydropyrimidin-2(1H)-Thione-5-CarboxylateIR (KBr): 3412, 3312, 3174, 3096, 2967, 1667, 1610, 1575. ¹H NMR (DMSO-): 1.02–1.18 (t, 3H,  Hz, CH₂CH₃), 2.32 (s, 3H, CH₃), 4.02–4.21 (q, 2H,  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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