甲基5-氧代双环[2.2.2]辛烷值-2-羧酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%). was kept below 30° C. by cooling with a waterbath The reaction mixture was washed with DCM (2×500 mL) The combined organic layers were extracted with water (300 mL) subsequently extracted with DCM (4×300 mL) The combined organic layers were dried over sodium sulfate the solvent was removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (−3° C.) solution of lithiumdiisopropylamide (0.9 M in methylcyclohexane, 607 mL, 546 mmol, 1.05 eq) was added a solution of cyclohex-2-enone (52.6 g, 53 mL, 520 mmol, 1.0 eq) in diethyl ether (650 mL) over 90 min. During addition, the temperature was kept below −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl acrylate (46.8 mL, 520 mmol, 1.0 eq) in diethyl ether (450 mL) was added dropwise over 60 minutes. The temperature of the mixture was kept below 0° C. overnight. The mixture was poured out in saturated solution of ammonium chloride (1.0M) and stirred for 10 min. The sticky polymer was removed by filtration (P3). The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The title compound was isolated by distillation (0.001 mbar at 120-130° C.) and was isolated as a slightly yellow oil (39.8 g, 220 mmol, 42%). During addition was kept below −3° C was added dropwise over 60 minutes The sticky polymer was removed by filtration (P3) The organic layer was separated the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL) The combined organic layers were dried over sodium sulfate concentrated

反应条件: temp:-11.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled solution of diisopropylamine (7.72 mL, 54.62 mmol) in ether (40 mL) at −78° C. was added 2.5M n-butyllithium (21.8 mL) dropwise. The reaction mixture was allowed to warm to −11° C. A solution of cyclohex-2-en-1-one (5.04 mL, 52.01 mmol) in diethyl ether (60 mL) was added over 45 minutes. During the addition, the temperature was maintained between −11° C. and −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl prop-2-enoate (4.68 mL, 52.01 mmol) in THF (40 mL) was added dropwise over 60 minutes. The reaction mixture was stirred at this temperature for 1 h and stored in a freezer overnight. The reaction mixture was poured into saturated ammonium chloride solution (200 mL) and stirred for 15 minutes. A brown sticky polymer was formed and removed using tweezers. The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches, to afford the title compound (2.98 g, 31%) as the trans isomer as a clear colourless liquid. δH (500 MHz, CDCl3) 3.70 (s, 3H), 2.76 (ddt, J 10.6, 6.4, 1.8 Hz, 1H), 2.53-2.48 (m, 1H), 2.47-2.38 (m, 1H), 2.37-2.31 (m, 1H), 2.22 (ddt, J 14.2, 6.3, 2.5 Hz, 1H), 2.13 (ddd, J 19.1, 2.9, 1.8 Hz, 1H), 2.02 (ddd, J 14.3, 11.0, 3.5 Hz, 1H), 1.89-1.74 (m, 3H), 1.70-1.60 (m, 1H). During the addition the temperature was maintained between −11° C. and −3° C was added dropwise over 60 minutes stored in a freezer overnight stirred for 15 minutes A brown sticky polymer was formed removed The organic layer was separated the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL) The combined organic layers were dried over sodium sulfate concentrated The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%). was kept below 30° C. by cooling with a waterbath The reaction mixture was washed with DCM (2×500 mL) The combined organic layers were extracted with water (300 mL) subsequently extracted with DCM (4×300 mL) The combined organic layers were dried over sodium sulfate the solvent was removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%). was kept below 30° C. by cooling with a waterbath The reaction mixture was washed with DCM (2×500 mL) The combined organic layers were extracted with water (300 mL) subsequently extracted with DCM (4×300 mL) The combined organic layers were dried over sodium sulfate the solvent was removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (−3° C.) solution of lithiumdiisopropylamide (0.9 M in methylcyclohexane, 607 mL, 546 mmol, 1.05 eq) was added a solution of cyclohex-2-enone (52.6 g, 53 mL, 520 mmol, 1.0 eq) in diethyl ether (650 mL) over 90 min. During addition, the temperature was kept below −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl acrylate (46.8 mL, 520 mmol, 1.0 eq) in diethyl ether (450 mL) was added dropwise over 60 minutes. The temperature of the mixture was kept below 0° C. overnight. The mixture was poured out in saturated solution of ammonium chloride (1.0M) and stirred for 10 min. The sticky polymer was removed by filtration (P3). The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The title compound was isolated by distillation (0.001 mbar at 120-130° C.) and was isolated as a slightly yellow oil (39.8 g, 220 mmol, 42%). During addition was kept below −3° C was added dropwise over 60 minutes The sticky polymer was removed by filtration (P3) The organic layer was separated the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL) The combined organic layers were dried over sodium sulfate concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%). was kept below 30° C. by cooling with a waterbath The reaction mixture was washed with DCM (2×500 mL) The combined organic layers were extracted with water (300 mL) subsequently extracted with DCM (4×300 mL) The combined organic layers were dried over sodium sulfate the solvent was removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (−3° C.) solution of lithiumdiisopropylamide (0.9 M in methylcyclohexane, 607 mL, 546 mmol, 1.05 eq) was added a solution of cyclohex-2-enone (52.6 g, 53 mL, 520 mmol, 1.0 eq) in diethyl ether (650 mL) over 90 min. During addition, the temperature was kept below −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl acrylate (46.8 mL, 520 mmol, 1.0 eq) in diethyl ether (450 mL) was added dropwise over 60 minutes. The temperature of the mixture was kept below 0° C. overnight. The mixture was poured out in saturated solution of ammonium chloride (1.0M) and stirred for 10 min. The sticky polymer was removed by filtration (P3). The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The title compound was isolated by distillation (0.001 mbar at 120-130° C.) and was isolated as a slightly yellow oil (39.8 g, 220 mmol, 42%). During addition was kept below −3° C was added dropwise over 60 minutes The sticky polymer was removed by filtration (P3) The organic layer was separated the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL) The combined organic layers were dried over sodium sulfate concentrated

反应条件: temp:-11.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled solution of diisopropylamine (7.72 mL, 54.62 mmol) in ether (40 mL) at −78° C. was added 2.5M n-butyllithium (21.8 mL) dropwise. The reaction mixture was allowed to warm to −11° C. A solution of cyclohex-2-en-1-one (5.04 mL, 52.01 mmol) in diethyl ether (60 mL) was added over 45 minutes. During the addition, the temperature was maintained between −11° C. and −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl prop-2-enoate (4.68 mL, 52.01 mmol) in THF (40 mL) was added dropwise over 60 minutes. The reaction mixture was stirred at this temperature for 1 h and stored in a freezer overnight. The reaction mixture was poured into saturated ammonium chloride solution (200 mL) and stirred for 15 minutes. A brown sticky polymer was formed and removed using tweezers. The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches, to afford the title compound (2.98 g, 31%) as the trans isomer as a clear colourless liquid. δH (500 MHz, CDCl3) 3.70 (s, 3H), 2.76 (ddt, J 10.6, 6.4, 1.8 Hz, 1H), 2.53-2.48 (m, 1H), 2.47-2.38 (m, 1H), 2.37-2.31 (m, 1H), 2.22 (ddt, J 14.2, 6.3, 2.5 Hz, 1H), 2.13 (ddd, J 19.1, 2.9, 1.8 Hz, 1H), 2.02 (ddd, J 14.3, 11.0, 3.5 Hz, 1H), 1.89-1.74 (m, 3H), 1.70-1.60 (m, 1H). During the addition the temperature was maintained between −11° C. and −3° C was added dropwise over 60 minutes stored in a freezer overnight stirred for 15 minutes A brown sticky polymer was formed removed The organic layer was separated the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL) The combined organic layers were dried over sodium sulfate concentrated The crude residue was purified by column chromatography (Biotage; 0-60% ethyl acetate in heptane) in 2 batches

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-Oxo-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (Preparation 73, 390 g, 2.14 mol, 1.0 eq) was taken up in a mixture of THF:MeOH:water (2:2:1, 2.0 L). A solution of lithiumhydroxide monohydrate (198 g, 4.71 mol, 2.2 eq) in water (1.0 L) was added dropwise while a dark green solution emerged. The temperature was kept below 30° C. by cooling with a waterbath. The reaction mixture was washed with DCM (2×500 mL). The combined organic layers were extracted with water (300 mL). The combined aqueous layers were brought to pH ˜1 with concentrated HCl solution and subsequently extracted with DCM (4×300 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure and stripped with toluene (2×). This furnished title compound as a brownish solid (314 g, 1.87 mol, 87%). was kept below 30° C. by cooling with a waterbath The reaction mixture was washed with DCM (2×500 mL) The combined organic layers were extracted with water (300 mL) subsequently extracted with DCM (4×300 mL) The combined organic layers were dried over sodium sulfate the solvent was removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (−3° C.) solution of lithiumdiisopropylamide (0.9 M in methylcyclohexane, 607 mL, 546 mmol, 1.05 eq) was added a solution of cyclohex-2-enone (52.6 g, 53 mL, 520 mmol, 1.0 eq) in diethyl ether (650 mL) over 90 min. During addition, the temperature was kept below −3° C. The mixture was stirred for an additional 25 minutes before a solution of methyl acrylate (46.8 mL, 520 mmol, 1.0 eq) in diethyl ether (450 mL) was added dropwise over 60 minutes. The temperature of the mixture was kept below 0° C. overnight. The mixture was poured out in saturated solution of ammonium chloride (1.0M) and stirred for 10 min. The sticky polymer was removed by filtration (P3). The organic layer was separated and the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The title compound was isolated by distillation (0.001 mbar at 120-130° C.) and was isolated as a slightly yellow oil (39.8 g, 220 mmol, 42%). During addition was kept below −3° C was added dropwise over 60 minutes The sticky polymer was removed by filtration (P3) The organic layer was separated the aqueous layer was extracted with tert-butyl methyl ether (2×300 mL) The combined organic layers were dried over sodium sulfate concentrated