tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.14 mL (15.3 mmol) of N,N-diisopropylamine in 50 mL of tetrahydrofuran at −78° C. was added 7.96 mL (15.6 mmol, 2.5M in hexane) of n-butyl lithium and the mixture was stirred at −78° C. for 10 min. The reaction was warmed to 0° C. and stirred at 0° C. for 15 min. The mixture was cooled down to −78° C. again, and a solution 2.50 g (11.7 mmol) of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (Step C) in 5 mL of tetrahydrofuran was added to the mixture slowly. The mixture was stirred at −78° C. for 1 h. Then 1.77 mL (14.9 mmol) of trans-cinnamaldehyde in 5 mL of tetrahydrofuran (pre-cooled to −78° C.) was added to the reaction mixture and the reaction was stirred at −78° C. for 5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with three portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound. LC/MS 368 (M+23). The reaction was warmed to 0° C. stirred at 0° C. for 15 min The mixture was cooled down to −78° C. again The mixture was stirred at −78° C. for 1 h the reaction was stirred at −78° C. for 5 h The reaction was quenched with saturated aqueous sodium bicarbonate solution extracted with three portions of ether The combined organic layers were washed with brine dried over magnesium sulfate concentrated Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of oxalyl chloride (4.06 mL, 46.5 mmol) in 50 mL of dichloromethane was cooled to −78° C. and 4.95 mL (69.8 mmol) of dimethyl sulfoxide was added slowly and the mixture was stirred at −78° C. for 10 min. Then a solution of 5.00 g (23.3 mmol) of tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (Step B) in 5 mL of dichloromethane was added dropwise to above mixture. The mixture was stirred at −78° C. for 20 min, then 40.5 mL (232 mmol) of N,N-diisopropylethylamine was added to the mixture. The reaction was warmed to ambient temperature and continued to stir at ambient temperature for 1 h. The mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with three potions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the title compound. LC/MS 214 (M+1). The mixture was stirred at −78° C. for 20 min The reaction was warmed to ambient temperature to stir at ambient temperature for 1 h The mixture was partitioned between dichloromethane and water The aqueous phase was extracted with three potions of dichloromethane The combined organic layers were washed with brine dried over magnesium sulfate concentrated Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.14 mL (15.3 mmol) of N,N-diisopropylamine in 50 mL of tetrahydrofuran at −78° C. was added 7.96 mL (15.6 mmol, 2.5M in hexane) of n-butyl lithium and the mixture was stirred at −78° C. for 10 min. The reaction was warmed to 0° C. and stirred at 0° C. for 15 min. The mixture was cooled down to −78° C. again, and a solution 2.50 g (11.7 mmol) of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (Step C) in 5 mL of tetrahydrofuran was added to the mixture slowly. The mixture was stirred at −78° C. for 1 h. Then 1.77 mL (14.9 mmol) of trans-cinnamaldehyde in 5 mL of tetrahydrofuran (pre-cooled to −78° C.) was added to the reaction mixture and the reaction was stirred at −78° C. for 5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with three portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound. LC/MS 368 (M+23). The reaction was warmed to 0° C. stirred at 0° C. for 15 min The mixture was cooled down to −78° C. again The mixture was stirred at −78° C. for 1 h the reaction was stirred at −78° C. for 5 h The reaction was quenched with saturated aqueous sodium bicarbonate solution extracted with three portions of ether The combined organic layers were washed with brine dried over magnesium sulfate concentrated Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of oxalyl chloride (4.06 mL, 46.5 mmol) in 50 mL of dichloromethane was cooled to −78° C. and 4.95 mL (69.8 mmol) of dimethyl sulfoxide was added slowly and the mixture was stirred at −78° C. for 10 min. Then a solution of 5.00 g (23.3 mmol) of tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (Step B) in 5 mL of dichloromethane was added dropwise to above mixture. The mixture was stirred at −78° C. for 20 min, then 40.5 mL (232 mmol) of N,N-diisopropylethylamine was added to the mixture. The reaction was warmed to ambient temperature and continued to stir at ambient temperature for 1 h. The mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with three potions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the title compound. LC/MS 214 (M+1). The mixture was stirred at −78° C. for 20 min The reaction was warmed to ambient temperature to stir at ambient temperature for 1 h The mixture was partitioned between dichloromethane and water The aqueous phase was extracted with three potions of dichloromethane The combined organic layers were washed with brine dried over magnesium sulfate concentrated Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.14 mL (15.3 mmol) of N,N-diisopropylamine in 50 mL of tetrahydrofuran at −78° C. was added 7.96 mL (15.6 mmol, 2.5M in hexane) of n-butyl lithium and the mixture was stirred at −78° C. for 10 min. The reaction was warmed to 0° C. and stirred at 0° C. for 15 min. The mixture was cooled down to −78° C. again, and a solution 2.50 g (11.7 mmol) of tert-butyl 2-methyl-3-oxopiperidine-1-carboxylate (Step C) in 5 mL of tetrahydrofuran was added to the mixture slowly. The mixture was stirred at −78° C. for 1 h. Then 1.77 mL (14.9 mmol) of trans-cinnamaldehyde in 5 mL of tetrahydrofuran (pre-cooled to −78° C.) was added to the reaction mixture and the reaction was stirred at −78° C. for 5 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with three portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound. LC/MS 368 (M+23). The reaction was warmed to 0° C. stirred at 0° C. for 15 min The mixture was cooled down to −78° C. again The mixture was stirred at −78° C. for 1 h the reaction was stirred at −78° C. for 5 h The reaction was quenched with saturated aqueous sodium bicarbonate solution extracted with three portions of ether The combined organic layers were washed with brine dried over magnesium sulfate concentrated Purification by flash chromatography on a Biotage® system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the tide compound

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of oxalyl chloride (4.06 mL, 46.5 mmol) in 50 mL of dichloromethane was cooled to −78° C. and 4.95 mL (69.8 mmol) of dimethyl sulfoxide was added slowly and the mixture was stirred at −78° C. for 10 min. Then a solution of 5.00 g (23.3 mmol) of tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (Step B) in 5 mL of dichloromethane was added dropwise to above mixture. The mixture was stirred at −78° C. for 20 min, then 40.5 mL (232 mmol) of N,N-diisopropylethylamine was added to the mixture. The reaction was warmed to ambient temperature and continued to stir at ambient temperature for 1 h. The mixture was partitioned between dichloromethane and water. The aqueous phase was extracted with three potions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane) gave the title compound. LC/MS 214 (M+1). The mixture was stirred at −78° C. for 20 min The reaction was warmed to ambient temperature to stir at ambient temperature for 1 h The mixture was partitioned between dichloromethane and water The aqueous phase was extracted with three potions of dichloromethane The combined organic layers were washed with brine dried over magnesium sulfate concentrated Purification by flash chromatography on a Biotage®D system (silica gel, eluting with 10% ethyl acetate/hexane to 30% ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir: