(E)-4-methoxybut-3-en-2-one

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (E)-4-methoxy-but-3-en-2-one (20 mmol) and ethyl difluoroacetate (24 mmol) is added dropwise to a mixture of potassium tert-butoxide (26 mmol) and diethyl ether (50 ml) under nitrogen atmosphere at −15° C. over 30 min. The mixture is allowed to warm up to room temperature slowly over 3 h. After cooling to 0° C., acetic acid (26 mmol) and H2O (10 ml) are successively added dropwise to the reaction mixture. The organic layer is separated, washed with sat. aq. NaHCO3, dried over MgSO4, and evaporated in vacuo. The residue is dissolved in i-propanol (30 ml). To the solution, conc. HCl (2 ml) is added and the mixture is refluxed for 3 h. After cooling, the reaction mixture is neutralised with sat. aq. NaHCO3 and extracted with CH2Cl2. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is dissolved in i-propanol (20 ml). To the solution, 28% aq. NH3 (50 mmol) is added and the mixture is refluxed for 20 h. After cooling, the reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 2-difluoromethyl-pyridin-4-ol in 32% yield. After cooling to 0° C. The organic layer is separated washed with sat. aq. NaHCO3 dried over MgSO4 evaporated in vacuo The residue is dissolved in i-propanol (30 ml) To the solution, conc. HCl (2 ml) is added the mixture is refluxed for 3 h After cooling extracted with CH2Cl2 The organic layer is dried over MgSO4 evaporated in vacuo The residue is dissolved in i-propanol (20 ml) the mixture is refluxed for 20 h After cooling extracted with AcOEt The organic layer is dried over MgSO4 evaporated in vacuo The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (E)-4-methoxy-but-3-en-2-one (20 mmol) and ethyl difluoroacetate (24 mmol) is added dropwise to a mixture of potassium tert-butoxide (26 mmol) and diethyl ether (50 ml) under nitrogen atmosphere at −15° C. over 30 min. The mixture is allowed to warm up to room temperature slowly over 3 h. After cooling to 0° C., acetic acid (26 mmol) and H2O (10 ml) are successively added dropwise to the reaction mixture. The organic layer is separated, washed with sat. aq. NaHCO3, dried over MgSO4, and evaporated in vacuo. The residue is dissolved in i-propanol (30 ml). To the solution, conc. HCl (2 ml) is added and the mixture is refluxed for 3 h. After cooling, the reaction mixture is neutralised with sat. aq. NaHCO3 and extracted with CH2Cl2. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is dissolved in i-propanol (20 ml). To the solution, 28% aq. NH3 (50 mmol) is added and the mixture is refluxed for 20 h. After cooling, the reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 2-difluoromethyl-pyridin-4-ol in 32% yield. After cooling to 0° C. The organic layer is separated washed with sat. aq. NaHCO3 dried over MgSO4 evaporated in vacuo The residue is dissolved in i-propanol (30 ml) To the solution, conc. HCl (2 ml) is added the mixture is refluxed for 3 h After cooling extracted with CH2Cl2 The organic layer is dried over MgSO4 evaporated in vacuo The residue is dissolved in i-propanol (20 ml) the mixture is refluxed for 20 h After cooling extracted with AcOEt The organic layer is dried over MgSO4 evaporated in vacuo The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (10 g, 64.1 mmol) in CHCl3 (100 mL) cooled to 0° C. was added oxalyl chloride (7.29 mL, 83 mmol) dropwise. The mixture was stirred at 70° C. for 4 h. Then the mixture was concentrated. To a mixture of (E)-4-methoxybut-3-en-2-one (12.83 g, 128 mmol) in THF (100 mL) cooled to −78° C. was added LiHMDS (128 mL, 128 mmol) dropwise under N2. The mixture was stirred at −78° C. for 1 h. Then to the mixture was added a solution of 3,3,3-trifluoro-2,2-dimethylpropanoyl chloride in THF (100 mL) at −78° C. The whole mixture was allowed to warm to rt over 2 h and quenched by NH4Cl (saturated aqueous, 30 mL). THF was removed under vacuum. To the mixture was added H2O (80 mL) and then extracted with EA (100 mL×3). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=2:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.5) were combined to yield an off-white oil of (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one (1 g, 3.36 mmol, 5.2% yield): 1H NMR (400 MHz, CDCl3): δ 15.90 (s, 1H), 7.65 (d, J=12.4 Hz, 1H), 5.63 (s, 1H), 5.33 (d, J=12.4 Hz, 1H), 3.74 (s, 3H), 1.38 (s, 6H). ES-LCMS m/z 239.1 (M+H). Then the mixture was concentrated cooled to −78° C. The mixture was stirred at −78° C. for 1 h to warm to rt over 2 h quenched by NH4Cl (saturated aqueous, 30 mL) THF was removed under vacuum To the mixture was added H2O (80 mL) extracted with EA (100 mL×3) The organic layer was washed with brine (80 mL) dried over Na2SO4 filtered concentrated The crude material was purified by silica column chromatography (PE/EA=2:1)

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 7.92 ml, 69.9 mmol) and tert-butylmercaptan (5.54 ml, 48.9 mmol) in carbon tetrachloride (70 ml) was added, under ice cooling, trifluoroacetic acid (7.54 ml, 97.9 mmol), followed by heating, under reflux, on an oil bath at 95° C. for 4 hours. After ice cooling, ethyl ether was added 5 thereto, followed by washing with water (twice), an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous magnesium sulfate, the resultant product was concentrated under a reduced pressure and the residue was treated with the column chromatography (420 g, n-hexane:ethyl acetate=1:0-6:1) to thereby obtain the titled compound in the form of a pale yellow oil. by heating by washing with water (twice), an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine After drying with anhydrous magnesium sulfate the resultant product was concentrated under a reduced pressure the residue was treated with the column chromatography (420 g, n-hexane:ethyl acetate=1:0-6:1)

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 7.92 ml, 69.9 mmol) and tert-butylmercaptan (5.54 ml, 48.9 mmol) in carbon tetrachloride (70 ml) was added, under ice cooling, trifluoroacetic acid (7.54 ml, 97.9 mmol), followed by heating, under reflux, on an oil bath at 95° C. for 4 hours. After ice cooling, ethyl ether was added 5 thereto, followed by washing with water (twice), an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine. After drying with anhydrous magnesium sulfate, the resultant product was concentrated under a reduced pressure and the residue was treated with the column chromatography (420 g, n-hexane:ethyl acetate=1:0-6:1) to thereby obtain the titled compound in the form of a pale yellow oil. by heating by washing with water (twice), an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine After drying with anhydrous magnesium sulfate the resultant product was concentrated under a reduced pressure the residue was treated with the column chromatography (420 g, n-hexane:ethyl acetate=1:0-6:1)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (E)-4-methoxy-3-buten-2-one (purity: 90%, 15.0 ml, 0.13 mol) and 2-naphthalenethiol (21.16 g, 0.13 mol) in benzene (180 ml) was added p-toluene sulfonic acid-monohydrate (75 mg, 0.4 mmol), followed by heating, while stirring, on an oil bath at 50° C. for 70 minutes. After ice cooling, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extracting with ethyl acetate four times. The ethyl acetate layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine twice and then dried with anhydrous magnesium sulfate. After concentrating under a reduced pressure, the residue was treated with the column chromatography (670 g, n-hexane:methylene chloride:ethyl acetate=1:0:0-1:3:0-2:0:1), followed by recrystallizing from n-hexane-ethyl ether to thereby obtain the titled compound as a light brown crystalline. by heating by extracting with ethyl acetate four times The ethyl acetate layer was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine twice dried with anhydrous magnesium sulfate After concentrating under a reduced pressure the residue was treated with the column chromatography (670 g, n-hexane:methylene chloride:ethyl acetate=1:0:0-1:3:0-2:0:1) by recrystallizing from n-hexane-ethyl ether

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (E)-4-methoxy-3-buten-2-one (purity 90%, 5.66 ml, 49.9 mmol) and thiophenol (5.13 ml, 49.9 mmol) in benzene (60 ml) was added p-toluene 25 sulfonic acid-monohydrate (30 mg, 0.16 mmol), followed by heating while stirring on an oil bath at 55° C. for 30 minutes. After ice cooling, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extracting with cyclohexane 3 times. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution twice and with saturated brine, followed by drying with anhydrous magnesium sulfate. After concentrating under a reduced pressure, the residue was treated with the column chromatography (190 g, n-hexane:ethyl acetate=10:1). After evaporated under a reduced pressure, the titled compound was recrystallized from n-hexane-n-nonane to obtain as a colorless crystalline. by heating by extracting with cyclohexane 3 times The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution twice by drying with anhydrous magnesium sulfate After concentrating under a reduced pressure the residue was treated with the column chromatography (190 g, n-hexane:ethyl acetate=10:1) After evaporated under a reduced pressure the titled compound was recrystallized from n-hexane-n-nonane to obtain as a colorless crystalline

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of KOtBu (729 mg, 6.49 mmol) in diethyl ether (10 mL) at 5° C. were added methyl 2,2,2-trifluoroacetate (767 mg, 5.99 mmol) and (E)-4-methoxybut-3-en-2-one (500 mg, 4.99 mmol). The reaction mixture was stirred at rt for 3 h, and quenched with water and then extracted with ether. Combined organic portions were dried over Na2SO4, filtered and concentrated. The residue was dissolved in isopropanol (150 mL) and 35% solution of hydrochloric acid (0.5 mL) and refluxed for 45 min. Then the solution was concentrated to remove alcohol and fractionated at reduced pressure to get the title product as yellow oil. quenched with water extracted with ether Combined organic portions were dried over Na2SO4 filtered concentrated The residue was dissolved in isopropanol (150 mL) 35% solution of hydrochloric acid (0.5 mL) and refluxed for 45 min Then the solution was concentrated to remove alcohol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (E)-4-methoxy-but-3-en-2-one (20 mmol) and ethyl difluoroacetate (24 mmol) is added dropwise to a mixture of potassium tert-butoxide (26 mmol) and diethyl ether (50 ml) under nitrogen atmosphere at −15° C. over 30 min. The mixture is allowed to warm up to room temperature slowly over 3 h. After cooling to 0° C., acetic acid (26 mmol) and H2O (10 ml) are successively added dropwise to the reaction mixture. The organic layer is separated, washed with sat. aq. NaHCO3, dried over MgSO4, and evaporated in vacuo. The residue is dissolved in i-propanol (30 ml). To the solution, conc. HCl (2 ml) is added and the mixture is refluxed for 3 h. After cooling, the reaction mixture is neutralised with sat. aq. NaHCO3 and extracted with CH2Cl2. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is dissolved in i-propanol (20 ml). To the solution, 28% aq. NH3 (50 mmol) is added and the mixture is refluxed for 20 h. After cooling, the reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 2-difluoromethyl-pyridin-4-ol in 32% yield. After cooling to 0° C. The organic layer is separated washed with sat. aq. NaHCO3 dried over MgSO4 evaporated in vacuo The residue is dissolved in i-propanol (30 ml) To the solution, conc. HCl (2 ml) is added the mixture is refluxed for 3 h After cooling extracted with CH2Cl2 The organic layer is dried over MgSO4 evaporated in vacuo The residue is dissolved in i-propanol (20 ml) the mixture is refluxed for 20 h After cooling extracted with AcOEt The organic layer is dried over MgSO4 evaporated in vacuo The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of sodium ethoxide in EtOH (prepared from sodium (0.5 g, 21.75 mmol) dissolved in EtOH (40 mL)) is added ethyl 3-oxo-3-(phenylamino)propanoate (4 g, 19.30 mmol) and trans-4-methoxy-3-buten-2-one (2 g, 19.98 mmol). After the reaction is stirred at reflux overnight, the mixture is concentrated. The residue is partitioned between H2O (50 mL) and EtOAc (50 mL). The aqueous layer is acidified with concentrated HCl to a pH 3˜4 and then it is extracted with EtOAc. The organic extracts are dried and concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (25:1) to give the product (1.20 g, 27% yield). MS (m/z): 230.0 (M+H). at reflux overnight the mixture is concentrated The residue is partitioned between H2O (50 mL) and EtOAc (50 mL) it is extracted with EtOAc The organic extracts are dried concentrated The residue is purified by silica gel column chromatography eluting with DCM:MeOH (25:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of sodium ethoxide in EtOH (prepared from sodium (0.5 g, 21.75 mmol) dissolved in EtOH (40 mL)) is added ethyl 3-oxo-3-(phenylamino)propanoate (4 g, 19.30 mmol) and trans-4-methoxy-3-buten-2-one (2 g, 19.98 mmol). After the reaction is stirred at reflux overnight, the mixture is concentrated. The residue is partitioned between H2O (50 mL) and EtOAc (50 mL). The aqueous layer is acidified with concentrated HCl to a pH 3˜4 and then it is extracted with EtOAc. The organic extracts are dried and concentrated. The residue is purified by silica gel column chromatography eluting with DCM:MeOH (25:1) to give the product (1.20 g, 27% yield). MS (m/z): 230.0 (M+H). at reflux overnight the mixture is concentrated The residue is partitioned between H2O (50 mL) and EtOAc (50 mL) it is extracted with EtOAc The organic extracts are dried concentrated The residue is purified by silica gel column chromatography eluting with DCM:MeOH (25:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3-(4-fluorophenylamino)-3-oxopropanoate(10.1 g, 48 mmol) in EtOH (100 mL) is added trans-4-methoxy-3-buten-2-one (5.7 g, 57 mmol) and CH3ONa (3.1 g, 57 mmol). The mixture is heated at reflux overnight and then concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAC (from 5:1 to 2:1) to give the product (2.1 g, 16% yield). MS (m/z): 276.1 (M+H). The mixture is heated at reflux overnight concentrated The residue is purified by silica gel column chromatography eluting with PE