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An efficient ultrasonic-assisted synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives
⁎Corresponding author. Tel.: +98 391 3202430; fax: +98 391 3202429. adarehkordi@yahoo.com (Ali Darehkordi) darehkordi@mail.vru.ac.ir (Ali Darehkordi)
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This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Dihydropyrimidinone derivatives were used as key intermediates for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives with use of diethyl and dimethyl acetylene dicarboxylate by two methods: (a) in methanol as a solvent under ultrasonic irradiation at ambient temperature (b) in methanol as a solvent at ambient temperature (conventional magnetic stirring).
Abstract
Dihydropyrimidinone derivatives were prepared by tri-component reaction of ethyl aceto acetate, aldehydes and thiourea in the presence of modified montmorillonite nanostructure as a catalyst and used as key intermediates for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyri midine-6-carboxylate derivatives with use of diethyl and dimethyl acetylene dicarboxylate by two methods: (a) in methanol as a solvent under ultrasonic irradiation at ambient temperature (b) in methanol as a solvent at ambient temperature (conventional magnetic stirring). Ultrasound-assisted synthesis provides excellent yields in short reaction times (15–25 min) at room temperature.
Keywords
Thiazolo pyrimidine
Dihydropyrimidinone thiazine
DMAD
DEAD
Montmorillonite
Ultrasonic irradiation
1 Introduction
Dihydropyrimidinone derivatives have attracted considerable interest in recent years because of therapeutic and pharmacological properties nowadays. For example, they can serve as the integral backbones of several calcium channel blockers (Rovnyak et al., 1995; Aswal et al., 1990), antihypertensive agents (Atwal et al., 1991; Grover et al., 1995) and α-1a-antagonists (Kappe, 2000a,b). In addition, several marine alkaloids containing the dihydropyrimidinone-5-carboxylate motifs also show interesting biological activities (Overman et al., 1995). Substituted 3, 4-dihydropyrimidines a and 3, 4-dihydro-1, 3-oxazines b are regarded as promising synthons in the design of new bioactive compounds (Scheme 1). For instance, structural scaffold a is represented by poly functional 3,4-dihydropyrimidines known as Biginelli compounds (Kappe, 1993, 2000a,b) which include a number of antiviral, anti-bacterial, anti-hypertensive, and anti-inflammatory agents (Kappe, 2000a,b).
Many pyrimidine derivatives have been reported to possess useful medicinal and biological activities (Barton and Ollis, 1974; Brown et al., 1984; Sasaki et al., 1980; Griengl et al., 1987). In the last few years, various pyrimidinone and pyrimidinone derivatives substituted either at C-5 or at C-6 positions have emerged in the field of chemotherapy (Scheme 2) (Parlato et al., 2004). Recently, the pyrimidinone derivatives 2-methylthio-6-[(2-alkylamino) ethyl]-4(3H)-pyrimidinones have been shown to posses activity against positive strand (vesicular stomatitis virus) RNA virus (Scheme 2) (Botta et al., 1999).
A series of 1-(biphenylmethylamidoalkyl) pyrimidinones have also been designed as nano molar inhibitors of recombinant lipoprotein-associated phospholipase A2 with high potency in whole human plasma. Also, thienopyrimidine derivatives have been reported to possess useful molluscidal, larvacidal activities against Biomphalaria alexandrina and Schistosoma mansoni, snails.
Although the Claisen rearrangement is an excellent method for C–C bond formation and has been successfully employed for the synthesis of a number of furo [3, 2-d] pyrimidines, pyrano [3, 2-d] pyrimidines and dihydrofuro [2, 3-d] pyrimidine derivatives (Kawahara et al., 1985; Majumdar and Das, 1997), there are hardly many reports in the pyrimidinone series. Previously synthesis and characterization of pyrimidinone-peptoid hybrid molecules that modulate Hsp70 activity in vitro and that, in some cases, prevent cancer cell proliferation have been reported (Wright et al., 2008; Fewell et al., 2004, 2001; Rodina et al., 2007). Recently we have reported synthesis a series of thiazoline compounds from reaction of thiosemicarbazone derivatives of aldehydes and ketoses with alkyl acetylenic esters (Darehkordi et al., 2007).
The sonochemistry is a unique method in chemical reactions, because of cavitations, a physical process that creates, enlarges, and implodes gaseous and vaporous cavities in an irradiated liquid. Cavitations induce very high local temperatures and pressures inside the bubbles (cavities), leading to turbulent flow of the liquid and enhanced mass transfer (Ranjbar-karimi et al., 2010).
Ultrasound irradiation has been considered as a clean and useful protocol in organic synthesis in the last three decades (Xue and Li, 2008; Wang et al., 2008; Li et al., 2010), and compared with traditional methods, the procedure is more convenient. A large number of organic reactions can be carried out in higher yield, shorter reaction time or milder conditions under ultrasonic irradiation (Deshmukh et al., 2001; Rajagopal et al., 2002; Bravo et al., 2006).
The aim of this study was the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives from reaction of dihydropyrimidinone derivatives with dimethyl and diethyl acetylenedicarboxylate using both ultrasonic irradiation method and a more conventional magnetic stirring method.
2 Results and discussion
The preparation of thiazoline compounds was developed in the over years. In continuing our work in the synthesis of five membered S, N-heterocyclic thiazoline (Darehkordi et al., 2007), we wish to report other heterocyclic compounds from pyrimidinone derivatives. In our earlier studies, we have reported reaction of thiosemicarbazone derivatives with DAMAD and DEAD at ambient temperature. Herein, we have reacted DMAD and DEAD with different dihydropyrimidine-2-(1H)-ones using both ultrasonic irradiation method and a conventional method.
Initially, we started the condensation of DMAD (0.001 mol) with ethyl 4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (0.001 mol) in dichloromethane at room temperature for 12 h. This led to poor yield (30%) of ethyl-5-(4-methoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro- 2H-thiazolo[3,2-a]pyrimidine-6-carboxylate(6c). To enhance the yield of the reaction, temperature was increased to 60 °C but no appreciable increment was observed in the product yield. Choice of solvent is also very crucial factor for condensation reaction. We also considered the solvent effect for this reaction. The reaction was tested in a variety of solvents such as H2O, EtOAC, H2O-EtOAC and EtOH, but none of the above solvents were found to be more effective than methanol (Table 1). Since water exhibits a unique reactivity and selectivity different from conventional organic solvents, the reaction was also carried out in water. Nevertheless, the reaction, at 60 °C, did not give the desired product and the starting material was recovered, whereas after a prolonged reaction (12 h) at 100 °C, only trace of the desired products was identified by TLC. It was identified that methanol and ethanol, especially methanol were a choice for the reaction and the desired product was obtained in methanol at 30 °C in excellent yield (Tables 1 and 3).
| Solvent | Temperature (°C) | Time (h) | Yield (%) |
|---|---|---|---|
| Dichloromethane | 30 | 12 | 30 |
| Dichloromethane | Reflux | 10 | 45 |
| Dichloromethane | Reflux | 12 | 50 |
| Ethyl acetate + H2O | 30 | 12 | 35 |
| Ethyl acetate | 30 | 12 | 30 |
| H2O | 60 | 12 | Trace |
| Ethanol | 30 | 8 | 70 |
| Methanol | 30 | 1 | 70 |
| Methanol | 30 | 2 | 94 |
| Entry | Product | λmax (nm) |
|---|---|---|
| 1 | 6a | 282.53, 377.20 |
| 2 | 6b | 309.66, 402.02 |
| 3 | 6c | 278.32, 376.62 |
| 4 | 6d | 274.45, 380.66 |
| 5 | 6e | 287.73, 378.35 |
| 6 | 6f | 310.82, 395.67 |
| 7 | 6g | 284.84, 376.6 |
| 8 | 6h | 286.58, 384.70 |
| 9 | 6i | 298.70, 386.43 |
| Entry | R | Acetylenic ester | Product | M.P (°C) | Time (min) | Yield | ||
|---|---|---|---|---|---|---|---|---|
| US | R.T | US | R.T | |||||
| 1 |
|
|
 6a |
154–155 | 25 | 120 | 95 | 92 |
| 2 |
|
|
 6b |
167–169 | 23 | 120 | 97 | 95 |
| 3 |
|
|
 6c |
131–132 | 24 | 125 | 96 | 94 |
| 4 |
|
|
 6d |
170–173 | 25 | 128 | 95 | 93 |
| 5 |
|
|
 6e |
196–197 | 22 | 123 | 94 | 93 |
| 6 |
|
|
 6f |
172–173 | 20 | 130 | 97 | 95 |
| 7 |
|
|
 6g |
158–160 | 24 | 122 | 96 | 95 |
| 8 |
|
|
 6h |
168–169 | 27 | 128 | 93 | 90 |
| 9 |
|
|
 6i |
168–170 | 26 | 120 | 95 | 93 |
In this pursuit we first examined the reaction of pyrimidinone derivative 4a with dimethyl acetylenedicarboxylate in ethanol at ambient temperature. This led to excellent yield (92%) of ethyl-5-(4-methoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro- 2H-thiazolo[3,2-a]pyrimidine-6-carboxylate 6c at 120 min. First of all, we studied the conventional magnetic stirring for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives. In general, the desire products were isolated in excellent yields without purification (Scheme 5 Table 3).![Suggested mechanism for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives.](/content/184/2019/12/8/img/10.1016_j.arabjc.2015.01.010-fig4.png)
![Synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3,2-a]pyrimidine-6-carboxylate derivatives.](/content/184/2019/12/8/img/10.1016_j.arabjc.2015.01.010-fig6.png)
To improve our studies, and in order to decrease the reaction times and increase the yield, the synthesis of the same compounds 6a–6i was carried out using ultrasound irradiation, at room temperature. In the first, we examined the reaction of pyrimidinone derivative 4a with dimethyl acetylenedicarboxylate promoted by ultrasound in ethanol to give the corresponding 5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate 6a in excellent yield (95%) only in 25 min (Table 3, entry 1). Therefore all of the compounds 6a–6i were synthesized using ultrasound irradiation, at room temperature, shorter reaction times and excellent yields. The ultrasonic method was simpler and the products were isolated without further purification (Scheme 6 Table 3).![Synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo[3, 2-a]pyrimidine-6-carboxylate derivatives under ultrasonic irradiation.](/content/184/2019/12/8/img/10.1016_j.arabjc.2015.01.010-fig7.png)
As therein revealed, using conventional magnetic stirring, the resulting product was obtained with 92% yield after 120 min (Table 3, entry 1); however, under ultrasonic irradiation, with the power 360 W, irradiation frequency 47 kHz and the reaction temperature 27–30 °C, the excellent products yield (95%) was obtained after only 20 min (Table 3, entry 1). To establish the generality of the ultrasonic-assisted reaction, a series of dihydropyrimidinone derivatives were employed in this reaction, and the results are listed in Table 3.
The reaction is mainly condensation which fallowed by cyclization. Initially the sulfur atom from dihydropyrimidinone attacks to the carbon triplet bond of acetylenic ester compound which is the prone to nucleophilic attack. Then cyclization proceeds on to the esoteric (CO2R) function to give products 6 and 7 in excellent yield (Scheme 5). A plausible mechanism has been proposed for the reactions of pyrimidinone derivatives with DMAD and DEAD to yield ethyl-5-(aryl)-2-(2-alkoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H thiazolo [3,2a] py- rimidine-6-carboxylate derivatives as shown in Scheme 3.
Compounds 6a–6i are yellow or orange solid. The UV–Visible absorption of these products demonstrates major absorption in wavelength ranges of 278.32–402.02 nm in DMSO solvent at room temperature as indicated in Table 2.
Table 3 shows the stricture and yield of the ethyl 5-(4-Alkylphenyl)-2-(2-Alkoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivative (6a–6i).
The structure of compound ethyl 5-(4-Alkylphenyl)-2-(2-Alkoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate was deduced from their 1H and 13C NMR, UV–Vis and elemental analysis.
3 Experimental section
3.1 Apparatus
A multiwave ultrasonic generator (Bandlin Sonopuls Gerate-Typ: UW 3200, Germany) equipped with a converter/transducer and titanium oscillator (horn), 12.5 mm in diameter, operating at 50 kHz with a maximum power output of 780 W, was used for the ultrasonic irradiation. The ultrasonic generator automatically adjusted the power level. Melting points were determined in open capillary tubes by an Electrothermal IA 9000 melting point apparatus. IR spectra (KBr) were obtained on a Matson-1000 FT-IR spectrometer. The proton and carbon-13 NMR spectra were recorded with a BRUKER DRX-500 AVANCE spectrometer at 500 and 125.7 MHz respectively with Me4Si as an internal standard (chemical shifts in δ, ppm). Element analyses (C, H, and N) were performed with a Heracus CHN-O-Rapid analyzer. UV–Vis spectra were recorded with a CARY 100 CONC spectrophotometer. Their results corresponded to the calculated values within experimental error. TLC was performed on silica gel PolyGram SIL G/UV 254 plates. The starting materials were purchased from Merck and used without further purification. All yields refer to isolated products. Pyrimidine derivatives were synthesized by following procedure:
A mixture of ethyl acetoacetate or acetyl acetone 2 (2 mmol), appropriate aldehyde 1 (2 mmol), thiourea 3 (3 mmol) and montmorillonite catalyst (0.6 g) was placed in a test tube and heated in a bathe oil under solvent free conditions, for 120 min (Scheme 4). After cooling the reaction mixture, ethanol was added to that and catalyst was removed by filtration. The filtrate was poured into the crushed ice water and the resulting precipitate recrystallized from hot ethanol to afford pure product. All of the compounds were characterized by MP, FT-IR, 13C and 1H NMR, UV–Vis spectrophotometer and elements analysis.
3.2 General procedure for synthesis of ethyl-5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (6a)
A solution of DMAD (0.001 mol, 0.140 g) or DEAD (0.001 mol, 0.172 g) in 3 ml methanol was added to a solution of pyrimidinones derivatives (0.001 mol, 0.346 g) in methanol (10 cc) in small portions. Mixture was stirred at ambient temperature for 2 h. The resulting yellow precipitate was filtered and washed with cold methanol or ethanol. The product was obtained without purification as yellow powder (Scheme 5).
3.3 General procedure for synthesis of ethyl-5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate under ultrasonic irradiation (6a)
A solution of DMAD (0.001 mol, 0.140 g) or DEAD (0.001 mol, 0.172 g) in 3 ml methanol was added to a solution of pyrimidinones derivatives (0.001 mol, 0.346 g) in methanol (4 cc) in small portions. This reaction mixture was sonicated at 45 kHz. After the completion of reaction as indicated by TLC, the reaction mixture was filtered. The resulting yellow precipitate was filtered and washed with cold methanol or ethanol. The product was obtained without purification as yellow powder (Scheme 6).
3.4 Commentary and spectra
3.4.1 Ethyl-5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (6a)
Yellow powder, m.p.: 150–155 °C, IR KBr (
, cm−1): 2978, 2959 (C—H, aliphatic), 3057 (C—H, aromatic), 1728, 1711 (C⚌O), 1617, 1489 (C⚌N, C⚌C). 1H NMR (DMSO-d6, 500 MHz); δ 1.09 (t, J = 7.0 H, 3H, CH3), 2.37 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.03 (q, J = 7.0 Hz, 2H, O—CH2), 5.97 (s, 1H, CH), 6.83 (s,1H, CH), 7.30 (d, J = 5 Hz, 2H, arom CH), 7.39 (d, J = 5 Hz, 2H, arom CH). 13C NMR (DMSO-d6, 125.77 MHz): δ = 13.71 (1C, CH3, CH3), 22.21 (1C, CH3, CH3), 52.73 (1C, CH, CH⚌N), 54.53 (1C, CH3, OCH3), 60.30 (1C, CH2, O—CH2), 117.48, 128.59, 129.60, 133.19, 138.29, 139.18, 150.34, 155.41, 162.71, 164.44, 165.66. Anal. Calcd for C19H17 N2O5SCl: C, 54.22; H, 4.07; N, 6.66. Found: C, 54.49; H, 4.23; N, 6.87%.
3.4.2 Ethyl-5-(4-cholorophenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6b)
Yellow powder, m.p.: 144–147 °C, IR KBr (
, cm−1): 2908, 2986 (C—H, aliphatic), 3070 (C—H, aromatic), 1729, 1708 (C⚌O), 1628, 1487 (C⚌N, C⚌C). 1H NMR (DMSO-d6, 500 MHZ): δ = 1.1 (t, J = 7.0 Hz, 3H, CH3), 1.25 (t, J = 7.0 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 4.05 (q, J = 7.0 Hz, 2H, OCH2), 4.23 (q, J = 7.0 Hz, 2H, OCH2), 5.99 (s, 1H, CH), 6.83 (s, 1H, CH), 7.32 (d, J = 7.0 Hz, arom CH) , 7.42(d, J = 7.0 Hz, arom CH). 13C NMR (DMSO-d6, 125.77 MHz): δ = 14.69 (1C, CH3), 14.80 (1C, CH3), 23.19 (1C, CH3), 55.47 (1C, O—CH2), 61.27 (1C, O—CH2), 62.71 (1C, O—CH2), 118.72, 129.57, 130.58, 134.13, 139.29, 140.03, 151.312, 156.46, 163.69, 165.41, 166.12. Anal. Calcd for C20H19N2O5SCl: C, 55.24; H, 4.40; N, 6.30%. Found; C, 55.36; H, 4.66; N, 6.42%.
3.4.3 Ethyl-5-(4-methoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6c)
Yellow powder, m.p.: 129–132 °C, IR KBr (
, cm−1): 2981 (C—H, aliphatic), 3064 (C—H, aromatic), 1720, 1711 (C⚌O), 1611, 1464 (C⚌N, C⚌C). 1H NMR (DMSO-d6, 500 MHz): δ = 1.1 (t, J = 7.0 Hz, 3H, CH3), 2.38 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.78 (s, 3H, OCH3) , 4.03 (q, J = 7.0 Hz, 2H, O—CH2) , 5.95 (s, 1H, HC—N), 6.88 (s, 1H, CH⚌C), 6.90 (d, J = 8.6 Hz, arom CH), 7.2 (d, J = 8.6 Hz, arom CH). 13C NMR (DMSO-d6, 125.77 MHz): δ = 14.72 (1C, CH3), 23.07 (1C, CH3), 53.71 (1C, CH3), 55.43 (1C, O—CH3), 55.96 (1C, CH), 61.18 (1C, CH2), 118.27, 129.88, 132.45, 140.30, 150.67, 156.14, 160.18, 163.69, 165.59, 166.69. Anal. Calcd for C20H20N2O6S: C, 57.68; H, 4.84; N, 6.73. Found; C, 57.98; H, 5.01; N, 6.79%.
3.4.4 Ethyl-5-(4-methoxyphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6d)
Yellow powder, m.p.: 167–173 °C, IR KBr (
, cm−1): 2958 (C—H, aliphatic), 3066 (C—H, aromatic), 1728, 1703 (C⚌O), 1612, 1463 (C⚌N, C⚌C). 1H NMR (DMSO-d6, 500 MHz): δ = 1.12 (t, J = 7.1 Hz, 3H, CH3), 1.25 (t, J = 7.1 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.04 (q, J = 7.1 Hz, 2H, O—CH2), 4.25 (q, J = 7.1 Hz, 2H, O—CH2), 5.95 (s, 1H, CH, HC—N), 6.82 (s, 1H, CH), 6.90 (2H, arom CH), 7.20 (2H, arom CH). Anal. Calcd for C21H22 N2O6S: C, 58.59; H, 5.15; N, 6.51. Found; C, 58.77; H, 5.36; N, 6.67%.
3.4.5 Ethyl-5-(4-methylphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6e)
Yellow powder, m.p.: 192–197 °C, IR KBr (
, cm−1): 2981, 2957 (C—H, aliphatic), 3058 (C—H, aromatic), 1719, 1712 (C⚌O), 1615, 1437 (C⚌N, C⚌C); 13C NMR (DMSO-d6, 125.77 MHz): δ = 14.71 (1C, CH3), 21.55 (1C, CH3), 23.08 (1C, OCH3), 53.70 (1C, OCH3), 55.75 (1C, CH), 61.20 (1C, O—CH2), 118.31, 128.37, 130.11, 137.54, 139.01 , 150.73, 156.25, 163.65, 165.58, 166.67. Anal. Calcd for C20H20N2O5S: C, 59.99; H, 5.03; N, 7.00. Found; C, 60.29; H, 5.26 N, 7.14%.
3.4.6 Ethyl-5-(4-methylphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6f)
Yellow powder, m.p.: 169–174 °C, IR KBr (
, cm−1): 2985, 2969 (C—H, aliphatic), 3067 (C—H, aromatic), 1727, 1708 (C⚌O), 1621, 1445 (C⚌N, C⚌C); 1H NMR (DMSO-d6, 500 MHz): δ = 1.14 (t, J = 7.0 Hz, 3H, CH3) , 1.25 (t, J = 7.0 Hz, 3H, CH3) , 2.25 (s, 3H, CH3) , 2.38 (s, 3H, CH3) , 4.04 (q, J = 7.1 Hz, 2H, O—CH2), , 4.21 (q, J = 7.1 Hz, 2H, O—CH2), 5.96 (s, 1H, HC—N), 6.81 (s, 1H, CH⚌C), 7.13–7.17 (4H, arom CH). 13C NMR (DMSO-d6, 125.77 MHz): δ = 14.71 (1C, CH3), 14.80 (1C, CH3), 21.55 (1C, CH3), 23.07(1C, CH3), 55.74 (1C, CH), 61.19 (1C, O—CH2), 62.68 (1C, O—CH2), 118.59, 128.36, 130.11, 137.55, 138.99, 140.11, 150.74, 156.29, 163.66, 165.57, 166.11. Anal. Calcd for C21H22N2O5S: C, 60.85; H, 5.35; N, 6.76. Found; C, 61.13; H, 5.72; N, 6.80%.
3.4.7 Ethyl-5-(3,4-dimethoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6g)
yellow powder, m.p.: 156–160 °C, IR KBr (
, cm−1): 2908, 2986 (C—H, aliphatic), 3070 (C—H, aromatic), 1729, 1708 (C⚌O), 1628, 1487 (C⚌N, C⚌C); 1H NMR (DMSO-d6, 500 MHz): δ = 1.14 (t, J = 7.0 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 3.72 (s, 6H, OCH3), 3.78 (s, 3H, OCH3), 4.06 (q, J = 7.1 Hz , 2H, O—CH2), 5.95 (s, 1H, HC—N), 6.76 (d, J = 8.4 Hz, 1H, CH), 6.83 (d, 2H, arom CH), 6.90 (d, J = 8.4 Hz, 1H, arom CH) 13C NMR (DMSO-d6, 125.77 MHz): δ = 14.77 (1C, CH3), 23.03 (1C, CH3), 53.71 (1C, CH3), 55.72 (1C, CH3), 56.32 (1C, CH3), 56.39 (1C, CH3), 61.17 (1C, O—CH2), 112.45, 112.71, 118.28, 120.59, 132.85, 140.32, 149.24, 149.90, 150.60, 156.14, 163.74, 165.63, 166.67. Anal. Calcd for C21H22N2O7S: C, 56.49; H, 4.97; N, 6.27. Found; C, 56.67; H, 5.07; N, 6.13%.
3.4.8 Ethyl-5-(3,4-dimethoxyphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6h)
Yellow powder, mp.: 165–169 °C, IR KBr (
, cm−1): 2984, 2936 (C—H, aliphatic), 3058 (C—H, aromatic), 1717, 1711 (C⚌O), 1622, 1464 (C⚌N, C⚌C); 1H-NMR (DMSO-d6, 500 MHz): δ = 1.14 (t, J = 7.1 Hz, 3H, CH3), 1.25 (t, J = 7.0 Hz, 3H, CH3), 2.39 (s, 3H, OCH3), 3.72 (s, 6H, OCH3), 4.06 (q, J = 7.1 Hz, 2H, O—CH2), 4.20 (q, J = 7.0 Hz, 2H, O—CH2), 5.95 (s, 1H, HC—N), 6.70 (1H, arom CH), 6.83 (s, 2H, arom CH), 6.90 (1H, arom CH). Anal. Calcd for C22H24N2O7S: C, 57.38; H, 5.24; N, 6.08. Found; C, 57.64; H, 5.36; N, 6.12%.
3.4.9 Ethyl-5-(4-phenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6i)
Yellow powder, m.p.: 165–17 0 °C, IR KBr (
, cm−1): 2987, 2949 (C—, aliphatic), 3062 (C—H, aromatic), 1722, 1708 (C⚌O), 1617, 1464 (C⚌N, C⚌C); 1H NMR (DMSO-d6, 500 MHz): δ = 1.11 (t, J = 7.0 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.04 (q, J = 7.0 Hz, 2H, O—CH2), 5.99 (s, 1H, HC-N), 6.85 (s, 1H, CH), 7.27–7.37(m, 5H, Arom CH). 13C NMR (DMSO-d6, 125.77 MHz): δ = 14.68 (1C, CH3), 23.11 (1C, CH3), 53.70 (1C, CH3), 56.04 (1C, CH), 61.20 (1C, O—CH2), 118.39, 128.47, 129.53, 129.58, 140.19, 140.43, 150.88, 156.35, 163.04, 166.66, 167.14. Anal. Calcd for C19H18 N2O5S: C, 59.06; H, 4.70; N, 7.25. Found; C, 59.40; H, 4.86; N, 7.55%.
4 Conclusion
In conclusion, we have developed two different simple synthetic methods to prepare ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives, conventional magnetic stirring and ultrasonic irradiation. Both of the methods led to excellent yield. Ultrasonic irradiation displays dramatically reduced reaction time compared to conventional magnetic stirring method, and also affords the desired products in high yields and purity.
Acknowledgment
We gratefully acknowledge the financial support, for this Project, of Vali-e-Asr University of Rafsanjan, Faculty Research Grant.
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