* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: The substrate b-ketoesters 10 a–n were either purchased or synthesized following published procedures. Some benzoylacetates were commercially available. Ethyl 3-oxo-3-phenyl propanoate (10a) was purchased. The reaction of benzoylacetates 10 b–n was prepared as described in previous reports. 25–27 A solution of a substituted acetophenone 8 a–n (0.05 mol) dissolved in toluene (50 mL) was added dropwise to a solution containing diethyl carbonate (9) (0.10 mol) and sodium hydride (0.15 mol 60percent dispersion in mineral oil). The mixture was stirred at room temperature, and then refluxed for 30 min. The mixture was poured into ice water,acidified with glacial acetic acid, and extracted with EtOAc (3x100 mL). The EtOAc extract was then dried over anhydrous MgSO4. After removal of the solvent in vacuo, the crude products were purified by silica gel column chromatography eluting with dichloromethane to afford benzoylacetates 10 b–n. All synthetic compounds were in agreement with 1H NMR, 13C NMR, IR and mass spectroscopic data.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5064 - 5075
[2] Heterocycles, 1979, vol. 13, p. 239 - 246
[3] Journal of Medicinal Chemistry, 1997, vol. 40, # 20, p. 3217 - 3227
[4] Patent: JP2005/82549, 2005, A, . Location in patent: Page/Page column 19-20
[5] Angewandte Chemie - International Edition, 2011, vol. 50, # 32, p. 7304 - 7307
[6] Organic and Biomolecular Chemistry, 2015, vol. 13, # 11, p. 3243 - 3254
[7] European Journal of Organic Chemistry, 2015, vol. 2015, # 17, p. 3656 - 3660
[8] Tetrahedron Letters, 2016, vol. 57, # 27-28, p. 3024 - 3028
2
[ 2033-24-1 ]
[ 64-17-5 ]
[ 3535-37-3 ]
[ 4687-37-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With pyridine In dichloromethane at -5 - 0℃; for 0.5 h; Stage #2: at -5 - 25℃; for 1.5 h;
[Reference Example 1] Ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropionate To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (14.4 g 10 mmol) in dichloromethane (30 mL), pyridine (0.81 mL, 10 mmol) was added at 0°C or less, and this was stirred at -5°C for 0.5 hours. Subsequently, 3,4-dimethoxybenzoylchloride (2.00 g 10 mmol) was added at 0°C or less, stirred at -5°C for 0.5 hours, 0°C for 0.5 hours, and 25°C for 0.5 hours, and then 1 M hydrochloric acid (30 mL) was added while cooling on ice. This was then extracted with dichloromethane. After drying over magnesium sulfate, dichloromethane was distilled off, this was redissolved in ethanol (30 mL), refluxed for 1.5 hours, stirred at room temperature for 10 hours. It was then stirred at 60°C for 14 hours, ethanol was distilled off, and this was purified by silica gel column chromatography (elude: hexane: tetrahydrofuran = 3:1) which resulted in a colorless oily material (2.27 g, 90percent yield).
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 9, p. 748 - 749
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 10, p. 2477 - 2486
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 183 - 190
[4] Journal of the Indian Chemical Society, 1931, vol. 8, p. 271,273
[5] Journal of Chemical Research - Part S, 1998, # 3, p. 136 - 137
4
[ 2859-78-1 ]
[ 6148-64-7 ]
[ 82102-37-2 ]
[ 4687-37-0 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 37, p. 9763 - 9766[2] Angew. Chem., 2013, vol. 125, # 37, p. 9945 - 9948
5
[ 141-97-9 ]
[ 3535-37-3 ]
[ 4687-37-0 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2005, vol. 53, # 24, p. 9566 - 9570
[2] Pharmaceutical Chemistry Journal, 1988, vol. 22, # 1, p. 26 - 30[3] Khimiko-Farmatsevticheskii Zhurnal, 1988, vol. 22, # 1, p. 35 - 39
6
[ 93-07-2 ]
[ 4687-37-0 ]
Reference：
[1] Synthetic Communications, 2007, vol. 37, # 10, p. 1665 - 1673
[2] Journal of Chemical Research - Part S, 1998, # 3, p. 136 - 137
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 10, p. 2477 - 2486
[4] Journal of the American Chemical Society, 1948, vol. 70, p. 60,62
7
[ 6148-64-7 ]
[ 93-07-2 ]
[ 4687-37-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3978 - 3984
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 60,62
[2] Farmaco, 2003, vol. 58, # 9, p. 795 - 808
12
[ 3535-37-3 ]
[ 4687-37-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 10, p. 2477 - 2486
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 183 - 190
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 9, p. 748 - 749
13
[ 4687-37-0 ]
[ 10535-17-8 ]
Reference：
[1] Journal of Organic Chemistry, 1962, vol. 27, p. 2111 - 2114
General procedure: The substrate b-ketoesters 10 a-n were either purchased or synthesized following published procedures. Some benzoylacetates were commercially available. Ethyl 3-oxo-3-phenyl propanoate (10a) was purchased. The reaction of benzoylacetates 10 b-n was prepared as described in previous reports. 25-27 A solution of a substituted acetophenone 8 a-n (0.05 mol) dissolved in toluene (50 mL) was added dropwise to a solution containing diethyl carbonate (9) (0.10 mol) and sodium hydride (0.15 mol 60% dispersion in mineral oil). The mixture was stirred at room temperature, and then refluxed for 30 min. The mixture was poured into ice water,acidified with glacial acetic acid, and extracted with EtOAc (3x100 mL). The EtOAc extract was then dried over anhydrous MgSO4. After removal of the solvent in vacuo, the crude products were purified by silica gel column chromatography eluting with dichloromethane to afford benzoylacetates 10 b-n. All synthetic compounds were in agreement with 1H NMR, 13C NMR, IR and mass spectroscopic data.
(S8). To a suspension of 2.5 eq of sodium hydride (60%) in anhydrous toluene was added 2.5 eq of diethyl carbonate, and the mixture was heated to reflux. Subsequently, a solution of 3,4-dimethoxyacetophenone in toluene was added dropwise, and the resulting mixture was refluxed for another 30 min until hydrogen generation ceased. After cooling, a mixture of acetic acid and water (1: 1) was added. Subsequently, 20 mL of ice water was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate, the organic layers were combined and washed several times with brine, dried over Na 2 SO 4, and concentrated under reduced pressure. The residue was dried to obtain S8 and used directly in the next step.
Diethylcarbonate (2.5 eq.) was added to a suspension of sodium hydride (60%, 2.5 eq.) in anhydrous toluene and the mixture was heated to reflux. A solution of 3,4- dimethoxyacetophenone in toluene was added dropwise and the resulting mixture was refluxed for further 30 min until the production of hydrogen ceased. After cooling, a mixture of acetic acid and water (1 : 1) was added. Ice water (20 mL) was added, the organic layer was separated and the water layer was extracted with ethyl acetate. The organic layer was combined and washed with brine several times, dried over Na2S04 and concentrated under reduced pressure. The residue was dried to yield compound (xii) which was used directly in the next step.
(S9). Add 10 mol% BiCl3 to the mixture of S8 and 6-aminopyridin-2-ol,The mixture was subsequently stirred at 120 C for 6-8 hours. After cooling, ethyl acetate was added, and the organic layer was concentrated under reduced pressure. The crude product was subsequently purified by column chromatography.
With bismuth(III) chloride; at 120℃; for 8h;
BiCh (10 mol%) was added to a mixture of compound (xii) and 6-aminopyridin- 2-ol and the mixture was stirred at 120C for 6-8 hours. After cooling, ethyl acetate was added and the organic layer was concentrated under reduced pressure. The crude product was then purified by column chromatography to give compound (xiii).
1,3-diethyl-6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In ethanol; di-isopropyl ether; water; ethyl acetate;
EXAMPLE 10 To a mixture of ethyl veratroylacetate (10 g) and <strong>[623-76-7]N,N'-diethylurea</strong> (5.06 g) were added conc. hydrochloric acid (1 drop) and ethanol (1 ml). The mixture was heated at 120 C. for 3.5 hours under reduced pressure. To the residue was added another conc. hydrochloric acid (2 drops) and the mixture was heated again at 120 C. for 4 hours under reduced pressure. To the reaction mixture was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of diisopropyl ether and ethyl acetate to give 1,3-diethyl-6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.20 g). mp: 104-107 C. IR (Nujol): 1690, 1650 cm-1 NMR (DMSO-d6, delta): 6.8-7.0 (3H, m), 5.63 (1H, s), 4.06 (2H, q, J=7 Hz), 3.93 (3H, s), 3.90 (3H, s), 3.78 (2H, q, J=7 Hz), 1.29 (3H, t, J=7 Hz), 1.15 (3H, t, J=7 Hz).
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