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Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at 0 - 20℃; for 4 h; Stage #2: at 20℃; for 16 h;
A solution of M-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL) at 00C under nitrogen. The reaction mixture was stirred for 4 h at room temperature and cooled to 00C. Ethylene oxide (8.30 mL, 166 mmol) was added drop wise and the reaction mixture was allowed to warm to room temperature over 16 h. Saturated aqueous ammonium chloride was added, the resulting layers were separated, and the aqueous layer was extracted with diethyl ether (2 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-1850C) gave 10.1 g (80.3 mmol, 72percent) of Preparation IA as a light yellow oil.
80.3 mmol, 72%
With n-butyllithium In tetrahydrofuran
The starting compound, 2f(1), was made by the following procedure: A solution of n-BuLi (83 mL, 133.0 mmol, 1.2 eq, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10 mL, 110.8 mmol, 1 eq) in THF (85 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred for 4 h at room temperature then cooled to 0° C. Ethylene oxide (8.3 mL, 166.3 mmol, 1.5 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. After quenching with saturated aqueous NH4Cl, the resulting layers were separated and the aqueous layer was extracted with Et2O (2*). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-185° C.) gave 10.13 g (80.3 mmol, 72percent) of 5-methyl-2-furanethanol (2f(2)) as a light yellow oil:
80.3 mmol, 72%
With n-butyllithium In tetrahydrofuran
A. 5-Methyl-2-furanethanol (21A) A solution of n-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred for 4 h at room temperature then cooled to 0° C. Ethylene oxide (8.30 mL, 166 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. After quenching with saturated aqueous NH4Cl, the resulting layers were separated and the aqueous layer was extracted with Et2O (2*250 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-185° C.) gave 10.1 g (80.3 mmol, 72percent) of compound 21A as a light yellow oil.
A solution of M-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL) at 00C under nitrogen. The reaction mixture was stirred for 4 h at room temperature and cooled to 00C. Ethylene oxide (8.30 mL, 166 mmol) was added drop wise and the reaction mixture was allowed to warm to room temperature over 16 h. Saturated aqueous ammonium chloride was added, the resulting layers were separated, and the aqueous layer was extracted with diethyl ether (2 x 250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-1850C) gave 10.1 g (80.3 mmol, 72%) of Preparation IA as a light yellow oil.
10.13 g (80.3 mmol, 72%)
With n-butyllithium; In tetrahydrofuran;
The starting compound, 2f(1), was made by the following procedure: A solution of n-BuLi (83 mL, 133.0 mmol, 1.2 eq, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10 mL, 110.8 mmol, 1 eq) in THF (85 mL) at 0 C. under inert atmosphere. The reaction mixture was stirred for 4 h at room temperature then cooled to 0 C. Ethylene oxide (8.3 mL, 166.3 mmol, 1.5 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. After quenching with saturated aqueous NH4Cl, the resulting layers were separated and the aqueous layer was extracted with Et2O (2*). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-185 C.) gave 10.13 g (80.3 mmol, 72%) of 5-methyl-2-furanethanol (2f(2)) as a light yellow oil:
10.1 g (80.3 mmol, 72%)
With n-butyllithium; In tetrahydrofuran;
A. 5-Methyl-2-furanethanol (21A) A solution of n-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL) at 0 C. under inert atmosphere. The reaction mixture was stirred for 4 h at room temperature then cooled to 0 C. Ethylene oxide (8.30 mL, 166 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. After quenching with saturated aqueous NH4Cl, the resulting layers were separated and the aqueous layer was extracted with Et2O (2*250 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-185 C.) gave 10.1 g (80.3 mmol, 72%) of compound 21A as a light yellow oil.
(3aα,4α,7α,7aα)-4-[1,3,3a,4,7,7a-Hexahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With phosphoric acid; In dichloromethane;
A. (3aalpha,4beta,7beta,7aalpha)- and (3aalpha,4alpha,7alpha,7aalpha)-4-[1,3,3a,4,7,7a-Hexahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl]-2-(trifluoromethyl)benzonitrile (25Ai and 25Aii, Respectively) A solution of compound 21A (252 mg, 2.00 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile (798 mg, 3.00 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel eluding with 65% EtOAc/hexanes gave 217 mg of pure compound 25Ai, 73 mg of pure compound 25Aii and 310 mg of a mixture of both compound 25Ai and 25Aii. All three fractions were isolated as white solids with a total isolated yield of 600 mg (1.53 mmol, 76.5%). Compound 25Ai: HPLC: 90% at 2.56 min (retention time) (YMC S5 ODS column 4.6*50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). Compound 25Aii: HPLC: 90% at 2.56 min (retention time) (YMC S5 ODS column 4.6*50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
(3aα,4β,7β,7aα)-4-[2-[[(1,1-Dimethylethyl)dimethylsilyl]-oxy]ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isobenzofuran-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid;palladium-carbon; In 1,1-dichloroethane; ethanol; N,N-dimethyl-formamide; SiO2;
The starting material, 2h(1), was made by the following procedure. To a solution of <strong>[35942-94-0]5-methyl-2-furanethanol</strong> 2f(2) (2.00 g, 15.9 mmol) in DMF (50 mL) was added imidazole (1.62 g, 23.9 mmol), followed by tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol). After 2 h at 25 C., the reaction was poured into diethyl ether (300 mL) and washed with water (1*100 mL), 1N HCl (1*100 mL), water (1*100 mL), brine (1*50 mL) and dried over anhydrous MgSO4. Crude 2-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-5-methylfuran (2h(2)) was analyzed by LCMS and NMR and determined to be pure enough to be carried on directly to the next step. HPLC: 100% at 4.347 min (retention time) (YMC S5 ODS column 4.6*50 mm eluding with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm): 2h(2) (4.0 g, 18.9 mmol) and maleic anhydride (1.42 g, 14.51 mmol) were dissolved in dichloroethane (10 mL) and stirred at 25 C. for 60 hours. The volatiles were then removed in vacuo and the resulting orange oil was dissolved in absolute ethanol (50 mL) and Pd/C (10% Pd, 1.00 g) was added. Hydrogen was then introduced via a balloon. After 3 h, the reaction was filtered through celite rinsing with EtOAc and concentrated in vacuo. The crude anhydride was purified by rapid flash chromatography in SiO2 eluding with acetone/chloroform (0-2-4% acetone) to give 1.30 g of (3aalpha,4beta,7beta,7aalpha)-4-[2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isobenzofuran-1,3(2H)-dione (2h(3)) as a clear oil, in addition to 3.00 g of the starting 2-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-5-methylfuran.
A. 5-Methyl-2-furanethanol 4-methylbenzenesulfonate (24A) 4-Methylbenzenesulfonyl chloride (907 mg, 4.76 mmol) was added to a solution of compound 21A (500 mg, 3.96 mmol) in 6 mL of dry pyridine. The reaction was stirred at room temperature for 4 h and then quenched with ice. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous sodium bicarbonate and water, dried and concentrated under reduced pressure to give 900 mg (81%) of compound 24A as a yellow oil.
A. 2-Methyl-5-[2-[4-(trifluoromethyl)phenoxy]ethyl]furan (232A) To a solution of triphenylphosphine (1.56 g, 5.95 mmol) in THF (40 mL) was added DBAD (1.37 g, 5.95 mmol). After 10 min, 4-trifluoromethylphenol (0.964 g, 5.95 mmol) was added. After 10 additional minutes, compound 21A (0.500 g, 3.97 mmol) was added. After 14 h at 25 C., the reaction was concentrated in vacuo and purified by flash chromatography on silica eluding with chloroform to give 0.713 g (44%) of compound 232A as a clear oil.
2-[4-[2-(5-Methyl-2-furanyl)ethoxy]phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
270 mg (1.04 mmol, 52%)
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; dichloromethane;
A. 2-[4-[2-(5-Methyl-2-furanyl)ethoxy]phenyl]acetamide (26A) Triphenylphosphine (681 mg, 2.60 mmol) was added to a solution of compound 21A (252 mg, 2.00 mmol) and 4-acetamidophenol (302 mg, 2.00 mmol) in CH2Cl2 (4 mL). THF (5 mL) was added to make the reaction mixture homogeneous and the mixture was then cooled to 0 C. DEAD (0.41 mL, 2.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification by flash chromatography on silica gel eluding with 60% EtOAc/hexanes followed by reverse phase preparative HPLC gave 270 mg (1.04 mmol, 52%) of compound 26A as a light brown solid. MS (ESI): m/z 260.09 [M+H]+.
B. 2-(2-Bromoethyl)-5-methylfuran (21B) Ph3Br2 (3.68 g, 8.72 mmol) was added to a solution of compound 21A (1.00 g, 7.93 mmol) in DMF (8 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to H2O and extracted with EtOAc (3*). The combined organic layers were washed with H2O (2*), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluding with 10% EtOAc/hexanes gave 0.507 g (2.68 mmol, 34%) of compound 21B.
With 1H-imidazole; In N,N-dimethyl-formamide; at 25℃; for 2h;
To a solution of Preparation IA (2.00 g, 15.9 mmol) in DMF (50 mL) were added successively imidazole (1.62 g, 23.9 mmol) and tert-butyldimethylsilyl chloride (2.63 g, 17.5 mmol). After 2 h of stirring at 25C, the reaction mixture was poured into diethyl ether (300 mL) and washed with water (1 x 100 mL), aq. 1 N HCl (1 x 100 mL), water (1 x 100 mL), brine (1 x 50 mL) and dried over anhydrous MgSO4. Preparation IB (3.85 g, 100%) was analyzed by LCMS and NMR. HPLC: 4.35 min (RT) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
To a solution of alcohol1 (500 mg, 4.12 mmol) in dry DCM was added NEt3 (0.75 mL, 5.36 mmol) at 0 oC under an argon atmosphere and stirred for 5 min. MsCl (0.38 mL, 4.94 mmol) was then added and allowed to warm to RT. Upon the completion as judged by TLC, it was quenched with H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were dried over with Na2SO4 and concentrated in vacuo. The residue was used directly without further purification
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