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.
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,
Although numerous catalysts have been developed in accelerating this reaction [
With the awareness of environmental issues and importance of this reaction and keeping our interest in the development of synthetic routes to heterocyclic compounds [
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 [
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
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 [ |
2 | 4-ClC6H4 | OEt | O | 9 | 92 | 212–216 | 210–212 [ |
3 | 4-HOC6H4 | OEt | O | 40 | 90 | 226–228 | 231–233 [ |
4 | 3-O2NC6H4 | OEt | O | 20 | 93 | 225–228 | 227-228 [ |
5 | 4-O2NC6H4 | OEt | O | 5 | 85 | 206–209 | 207–209 [ |
6 | C6H5CH=CH | OEt | O | 3 | 90 | 225–227 | 223–226 [ |
7 | 4-MeOC6H4 | OEt | O | 20 | 95 | 200–202 | 202–204 [ |
8 | 2,4-(Cl)2C6H3 | OEt | O | 4 | 91 | 247–249 | 246–248 [ |
9 | 4-MeC6H4 | OEt | O | 5 | 90 | 213–215 | 214–216 [ |
10 | 2-MeOC6H4 | OEt | O | 2 | 94 | 262-263 | 260 [ |
11 | 2,6-(Cl)2C6H3 | OEt | O | 3 | 96 | 226–228 | 226 [ |
12 | 2-ClC6H4 | OEt | O | 9 | 85 | 221–223 | 221–223 [ |
13 | 4-BrC6H4 | OEt | O | 11 | 90 | 212–214 | 215 [ |
14 | CH3 | OEt | O | 3 | 92 | 188–190 | 194-195 [ |
15 | CH3CH2CH | OEt | O | 50 | 88 | 163–165 | 164–166 [ |
16 | 3-MeC6H4 | OEt | O | 8 | 93 | 219–222 | 224–226 [ |
17 | 2-Furyl | OEt | O | 19 | 86 | 202–205 | 202–204 [ |
18 | C6H5 | OMe | O | 5 | 94 | 208–211 | 210–213 [ |
19 | 4-MeOC6H4 | OMe | O | 9 | 85 | 192–195 | 193–196 [ |
20 | 4-ClC6H4 | OMe | O | 8 | 92 | 204–206 | 203–205 [ |
21 | 4-O2NC6H4 | OMe | O | 3 | 95 | 235–237 | 235-236 [ |
22 | 2-ClC6H4 | OMe | O | 6 | 84 | 180–182 | 181–183 [ |
23 | 3-O2NC6H4 | OMe | O | 12 | 90 | 271–274 | 273–275 [ |
24 | 4-MeC6H4 | OMe | O | 14 | 93 | 206–209 | 210–213 [ |
25 | 4-HOC6H4 | OMe | O | 7 | 87 | 235–237 | 231–233 [ |
26 | 2-MeOC6H4 | OMe | O | 2 | 95 | 284–286 | 285–287 [ |
27 | 3-MeC6H4 | OMe | O | 4 | 96 | 214–217 | 216–218 [ |
28 | 3-ClC6H4 | OMe | O | 9 | 92 | 208–211 | 209-210 [ |
29 | 2,4-(Cl)2C6H3 | OMe | O | 3 | 94 | 252–255 | 252-253 [ |
30 | 2-Furyl | OMe | O | 11 | 88 | 216–218 | 214–216 [ |
31 | C6H5 | OEt | S | 25 | 90 | 210–212 | 210–212 [ |
32 | 4-ClC6H4 | OEt | S | 18 | 86 | 181–183 | 184-185 [ |
33 | 4-MeOC6H4 | OEt | S | 20 | 85 | 136–138 | 137–139 [ |
34 | 3-O2NC6H4 | OEt | S | 15 | 87 | 205–208 | 205-206 [ |
35 | C6H5 | OMe | S | 13 | 92 | 220–222 | 221-222 [ |
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
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.
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.
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
IR(KBr):3240, 3110, 1725, 1700, 1645; 1H NMR (DMSO-
IR(KBr):3230, 3120, 1730, 1710, 1650; 1H NMR (DMSO-
IR (KBr): 3390, 3243, 3106, 2958, 1706, 1651,1278, 1088. 1H NMR (DMSO-
IR (KBr): 3412, 3312, 3174, 3096, 2967, 1667, 1610, 1575. 1H NMR (DMSO-