2,2,2-trifluoro-1-piperidin-1-ylethanone

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-1,2-methylenedioxybenzene (4.02 g, 0.020 mole) was dissolved in dry diethylether (100 ml) and cooled to -30° C. under a dry argon atmosphere. At -30° C. to -40° C. n-butyllithium (12 ml, 0.002 mole; 1.85 molar solution in n-hexane) were added with stirring over 15 minutes. After 50 minutes at -30° C. the mixture was cooled to -50° C. and the solution of N-trifluoroacetyl piperidine (3.62 g, 0.020 mole) in dry ether (20 ml) was added over 5 minutes. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes, and to room temperature over another 30 minutes. Saturated aqueous ammonium chloride (25 ml) was added with vigorous stirring. The layers were separated and the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo to give trifluoromethyl (3,4-methylenedioxyphenyl)-methanone (2.2 g), (50.4%) b.p. 60° C./0.2 mm Hg. After 50 minutes at -30° C. the mixture was cooled to -50° C. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes to room temperature over another 30 minutes The layers were separated the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) dried over anhydrous sodium sulfate After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-1,2-methylenedioxybenzene (4.02 g, 0.020 mole) was dissolved in dry diethylether (100 ml) and cooled to -30° C. under a dry argon atmosphere. At -30° C. to -40° C. n-butyllithium (12 ml, 0.002 mole; 1.85 molar solution in n-hexane) were added with stirring over 15 minutes. After 50 minutes at -30° C. the mixture was cooled to -50° C. and the solution of N-trifluoroacetyl piperidine (3.62 g, 0.020 mole) in dry ether (20 ml) was added over 5 minutes. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes, and to room temperature over another 30 minutes. Saturated aqueous ammonium chloride (25 ml) was added with vigorous stirring. The layers were separated and the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo to give trifluoromethyl (3,4-methylenedioxyphenyl)-methanone (2.2 g), (50.4%) b.p. 60° C./0.2 mm Hg. After 50 minutes at -30° C. the mixture was cooled to -50° C. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes to room temperature over another 30 minutes The layers were separated the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) dried over anhydrous sodium sulfate After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of Intermediate 12A (460 mg, 1.446 mmol) in tetrahydrofuran (5 mL) at 0° C. was added isopropylmagnesium chloride (0.795 mL, 1.591 mmol) quickly. After 30 min, additional 0.25 eq of iPrMgCl was added and after 30 min, the mixture was cooled to −78° C. 2,2,2-Trifluoro-1-(piperidin-1-yl)ethanone (288 mg, 1.591 mmol) was added quickly and the reaction was warmed to rt and stirred for 3 h. The reaction was quenched with sat'd aq NH4Cl and diluted with EtOAc. The organic layer was washed with sat'd aq NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes) to give the desired product (265 mg, 64%) as clear oil. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.07-2.20 (m, 2H), 1.98-2.05 (m, 2H), 1.55-1.65 (m, 2H). the reaction was warmed to rt The reaction was quenched with sat'd aq NH4Cl diluted with EtOAc The organic layer was washed with sat'd aq NH4Cl dried over MgSO4 filtered concentrated in vacuo The crude product was purified by silica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes)

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-1,2-methylenedioxybenzene (4.02 g, 0.020 mole) was dissolved in dry diethylether (100 ml) and cooled to -30° C. under a dry argon atmosphere. At -30° C. to -40° C. n-butyllithium (12 ml, 0.002 mole; 1.85 molar solution in n-hexane) were added with stirring over 15 minutes. After 50 minutes at -30° C. the mixture was cooled to -50° C. and the solution of N-trifluoroacetyl piperidine (3.62 g, 0.020 mole) in dry ether (20 ml) was added over 5 minutes. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes, and to room temperature over another 30 minutes. Saturated aqueous ammonium chloride (25 ml) was added with vigorous stirring. The layers were separated and the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) and dried over anhydrous sodium sulfate. After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo to give trifluoromethyl (3,4-methylenedioxyphenyl)-methanone (2.2 g), (50.4%) b.p. 60° C./0.2 mm Hg. After 50 minutes at -30° C. the mixture was cooled to -50° C. After 45 minutes at -50° C. the reaction mixture was warmed up to -40° C. for 30 minutes to room temperature over another 30 minutes The layers were separated the organic top layer washed with 10% aqueous ammonium chloride (3× 50 ml) dried over anhydrous sodium sulfate After filtration and removal of the ether under reduced pressure the residual liquid was distilled in vacuo