92% |
With diphenic acid In neat (no solvent) at 40℃; for 1.3h; Green chemistry; |
2.4.1 Condition A (under thermal conditions)
General procedure: All starting materials were purchased from Aldrich and were used without any further purification. In a typical experiment, a mixture of aldehyde (0.5mmol), ethyl acetoacetate (0.5mmol), urea (0.5mmol), diphenic acid (0.02g) were taken in a round-bottom flask (100mL) and SiO2/CuCl2 (0.05g) was added to it and stirred at 40°C in solvent-free conditions for appropriate time (Table 3). To this reaction mixture, 25-30ml of ethylacetate was added and heated on a water bath. This reaction mixture was filtered while hot under vacuum using a sintered glass crucible. Washings of hot water were given to remove the water soluble diphenic acid and impurities. To the resultant, anhydrous sodium sulphate was added and kept for an overnight. Then, resultant was filtered to remove hydrated sodium sulphate and the filterate was concentrated to get the crude product. The product thus obtained was purified through crystallization using ethylacetate. The reaction was monitored through TLC in 15% ethyl acetate and petroleum ether. The structures of the products were confirmed by IR, 1H NMR, 13C NMR and mass spectral data and comparison with authentic samples available commercially or prepared according to the literature methods. |
90% |
With L-tyrosine In neat (no solvent) at 20℃; for 0.25h; Milling; Green chemistry; |
|
88% |
With SILPOC at 60℃; for 1.5h; |
General Procedure for the Synthesis of 3,4-Dihydropyrimidinones
General procedure: First, 2 mmol of aldehyde, 2mmol of ethyl acetoacetate, and 2 mmol of urea were stirred for 5 min at 60 C, and then the catalyst (0.1 g) was added, and stirring was continued at 60 C using a magnetic stirrer (Scheme 6) for an appropriate time (Table 4). After completion of the reaction (monitored by TLC), the product was extracted with ethyl acetate and filtered off using a vacuum pump. The product was obtained after removal of the solvent under reduced pressure and finally crystallized from ethanol. |
87% |
With sulfuric acid immobilized on activated charcoal In hexane; acetonitrile for 0.25h; Reflux; |
|
82% |
With titanium(IV) oxide at 70℃; for 1h; |
|
80% |
With indium(III) bromide In ethanol for 7h; Heating; |
|
77% |
With N-benzyl-N,N,N-triethylammonium chloride at 100℃; for 0.5h; |
|
74% |
With zinc(II) chloride In tetrahydrofuran at 70℃; for 12h; |
The Biginelli synthesis of 4-substituted 3,4-dihydropyrimidin-2(1H)-ones 12a-n
General procedure: (General method). Amixture of urea 15 (0.180 g, 3.0 mmol), the correspondingcarbaldehyde 13 (2.0 mmol), alkyl acetoacetate 14(2.0 mmol), and ZnCl2 (0.027 g, 0.2 mmol) in THF (3 ml)was stirred at 70°C for 12 h. After completion of thereaction, as indicated by TLC, the reaction mixture waspoured onto crushed ice and stirred for 5-10 min. The solidseparated was filtered under vacuum, washed with ice-coldwater (20 ml), dried in vacuum, purified by columnchromatography (n-hexane-EtOAc, 4:1) on silica gel, andthen recrystallized from EtOH.(±)-Ethyl 6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (12a).18 Yield 273 mg (74%), white solid,mp 241-242°C. 1H NMR spectrum (CDCl3), δ, ppm(J, Hz): 1.19 (3H, t, J = 7.0, OCH2CH3); 2.15 (3H, s, CH3);3.86 (2H, s, CH2); 4.03 (2H, q, J = 7.0, OCH2CH3); 6.95(1H, br. s, NH); 8.87 (1H, br. s, NH). 13C NMR spectrum(CDCl3), δ, ppm: 14.2; 17.4; 43.2; 59.0; 94.5; 148.5; 152.8;165.5. |
73% |
With [MeC(OH)2]ClO4 In neat (no solvent) at 90℃; for 1h; |
|
72% |
With copper(II) nitrate trihydrate at 80 - 90℃; |
4.1. General Procedure for the Synthesis of 2-oxo-1,2,3,4-tetrahydropyrimidines 1-25
General procedure: 2-Oxo-1,2,3,4-tetrahydropyrimidine derivatives 1-25were synthesized by reacting urea (3 mmole), ethyl acetoacetate(4.5 mmole), and a variety of substituted benzaldehydes (3 mmole) in the presence of copper nitrate trihydrate (10%mmole) as catalyst in solvent free conditions at 80-90°C.Heating and stirring were continued until everything solidified. On solidification of reaction mixture, heating was suspended,and distilled water was added to the flask. Stirring was continued for 10 minutes. The resulting precipitates were filtered, washed with hexanes, and dried to obtain compounds 1-25 in high yields. Crystallization from ethanol afforded pure products. The structures of synthetic compounds were elucidated by 1H-NMR, EI, HREI mass spectroscopy,and elemental analysis. To the best of our knowledge,out of twenty-five synthesized compounds, only compound12 was new, while remaining compounds were reportedpreviously [48]. |
70% |
With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate; copper dichloride at 80℃; for 2h; Sealed tube; Schlenk technique; |
|
66% |
With zinc trifluoromethanesulfonate In ethanol at 85℃; for 7h; |
|
61% |
With psychotria douarrei suppprted on montmorillonite K10 In neat (no solvent) at 80℃; for 12h; Sealed tube; Green chemistry; |
|
61% |
With nickel In ethanol for 12h; Reflux; |
|
53% |
With acetic acid In ethanol Reflux; |
1.3 General procedure for the synthesis of 4j-4m
General procedure: Synthesis of 4j-4m was achieved by refluxing the mixture of ethylaceto acetate (7 mM), appropriate aldehyde (5 mM) and urea (12 mM) in ethanol, with catalytic amount of acetic acid. The reaction was monitored by TLC. After completion of the reaction (12 - 18 hr) the reaction mixture is cooled to room temperature and poured in to crushed ice. The precipitated solid was filtered and washed with cold water; re-crystallization from ethanol provided the pure product. |
21% |
With sodium dodecyl sulfate In water at 60℃; for 6h; |
|
|
With hydrogenchloride; aluminum (III) chloride In methanol for 4h; Reflux; |
|
|
With ammonium chloride at 100℃; for 3h; |
|