2-[1-(苯基甲基)哌啶-4-基]乙酸甲酯

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diisopropylamine (3.50 mL, 24.9 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in pentane, 9.8 mL, 24.5 mmol) was added to the mixture dropwise, and the reaction stirred at −78° C. for 15 min. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (5.50 g, 22.2 mmol) in THF (8 mL) was then added to the mixture dropwise over 20 minutes. The reaction was stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (3.70 g, 24.5 mmol) in THF (5 mL) was then added to the mixture dropwise over 15 minutes. The reaction was stirred at −78° C. for 30 minutes and quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was warmed to room temperature, extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. Mass spec.: 399.3 (MH)+. The reaction was stirred at −78° C. for 45 minutes The reaction was stirred at −78° C. for 30 minutes quenched by the addition of saturated aqueous ammonium chloride The resulting mixture was warmed to room temperature extracted with ethyl acetate (2×) The combined organics were dried (magnesium sulfate) filtered concentrated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60% in mineral oil, 10.55 g, 264 mmol) was washed with hexanes then suspended in N,N-dimethylformamide (200 mL). Mixture was cooled to 0° C. Trimethyl phosphonoacetate (38.0 mL, 249 mmol) was added to the mixture dropwise. The reaction was stirred at 0° C. for 30 minutes. 1-Benzyl-4-piperidone (40.0 mL, 220 mmol) was added to the reaction mixture dropwise. The reaction was warmed to ambient temperature and held with stirring for 1 h. The reaction mixture was diluted with diethyl ether (500 mL), washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in methanol (220 mL). Platinum(IV) oxide (600 mg, 2.64 mmol) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 40 psi of hydrogen gas, and shaken at room temperature for 5 h. The reaction mixture was removed from the apparatus, filtered through celite, and concentrated. The residue was passed through a short column of silica gel eluting with ethyl acetate. Fractions were concentrated in vacuo. The title compound was obtained as amber oil in 90% yield. 1H NMR (300 MHz, CDCl3): δ 7.31-7.16 (m, 5H), 3.62 (s, 3H), 3.45 (s, 2H), 2.83 (d, J=11.71, 2H), 2.20 (d, J-6.95, 2H), 2.00-1.88 (m, 1H), 1.82-1.69 (m, 1H), 1.69-1.59 (m, 2H), 1.38-1.25 (m, 2H). Mass spec.: 249.3 (MH)+. The reaction was warmed to ambient temperature with stirring for 1 h washed with water (2×) The organic layer was dried (magnesium sulfate) filtered concentrated in vacuo The residue was dissolved in methanol (220 mL) shaken at room temperature for 5 h The reaction mixture was removed from the apparatus filtered through celite concentrated Fractions were concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diisopropylamine (24.87 mmoles; 3.50 mL) was dissolved in tetrahydrofuran (30.00 mL). Mixture was cooled to −78° C. 2.5 M butyllithium in pentane (24.50 mmoles; 9.80 mL) was added to the mixture drop-wise. Reaction was stirred at −78° C. for 15 minutes. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (22.24 mmoles; 5.50 g) in 8 mL THF was then added to the mixture dropwise over 20 minutes. Reaction stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (24.48 mmoles; 3.70 g) in 5 mL THF was then added to the mixture dropwise over 15 minutes. Reaction was stirred at −78° C. for 30 minutes. Reaction was quenched with saturated aqueous ammonium chloride. Mixture was warmed to room temperature. Extracted from the mixture 2× EtOAc. Combined organics were dried (magnesium sulfate), filtered, then concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. MS m/e (M+H)+=399.3. Reaction Reaction stirred at −78° C. for 45 minutes Reaction was stirred at −78° C. for 30 minutes Reaction was quenched with saturated aqueous ammonium chloride Mixture was warmed to room temperature Extracted from the mixture 2× EtOAc Combined organics were dried (magnesium sulfate) filtered concentrated

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Diisopropylamine (3.50 mL, 24.9 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in pentane, 9.8 mL, 24.5 mmol) was added to the mixture dropwise, and the reaction stirred at −78° C. for 15 min. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (5.50 g, 22.2 mmol) in THF (8 mL) was then added to the mixture dropwise over 20 minutes. The reaction was stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (3.70 g, 24.5 mmol) in THF (5 mL) was then added to the mixture dropwise over 15 minutes. The reaction was stirred at −78° C. for 30 minutes and quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was warmed to room temperature, extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. Mass spec.: 399.3 (MH)+. The reaction was stirred at −78° C. for 45 minutes The reaction was stirred at −78° C. for 30 minutes quenched by the addition of saturated aqueous ammonium chloride The resulting mixture was warmed to room temperature extracted with ethyl acetate (2×) The combined organics were dried (magnesium sulfate) filtered concentrated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydride (60% in mineral oil, 10.55 g, 264 mmol) was washed with hexanes then suspended in N,N-dimethylformamide (200 mL). Mixture was cooled to 0° C. Trimethyl phosphonoacetate (38.0 mL, 249 mmol) was added to the mixture dropwise. The reaction was stirred at 0° C. for 30 minutes. 1-Benzyl-4-piperidone (40.0 mL, 220 mmol) was added to the reaction mixture dropwise. The reaction was warmed to ambient temperature and held with stirring for 1 h. The reaction mixture was diluted with diethyl ether (500 mL), washed with water (2×), then brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in methanol (220 mL). Platinum(IV) oxide (600 mg, 2.64 mmol) was added to the mixture. The reaction vessel was placed on a Parr apparatus, charged with 40 psi of hydrogen gas, and shaken at room temperature for 5 h. The reaction mixture was removed from the apparatus, filtered through celite, and concentrated. The residue was passed through a short column of silica gel eluting with ethyl acetate. Fractions were concentrated in vacuo. The title compound was obtained as amber oil in 90% yield. 1H NMR (300 MHz, CDCl3): δ 7.31-7.16 (m, 5H), 3.62 (s, 3H), 3.45 (s, 2H), 2.83 (d, J=11.71, 2H), 2.20 (d, J-6.95, 2H), 2.00-1.88 (m, 1H), 1.82-1.69 (m, 1H), 1.69-1.59 (m, 2H), 1.38-1.25 (m, 2H). Mass spec.: 249.3 (MH)+. The reaction was warmed to ambient temperature with stirring for 1 h washed with water (2×) The organic layer was dried (magnesium sulfate) filtered concentrated in vacuo The residue was dissolved in methanol (220 mL) shaken at room temperature for 5 h The reaction mixture was removed from the apparatus filtered through celite concentrated Fractions were concentrated in vacuo