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

Authors: Zahed Karimi-Jaberi; Mohammad Sadegh Moaddeli
Journal: ISRN Organic Chemistry
 (2012)

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## 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.


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## Body

## 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 1Trichloroacetic 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 Table1, 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 (Table1, 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 Table1. 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).


## 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 Table1. 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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*Source: 474626-2012-11-14.xml*