N-methoxy-N-methyl-3-oxocyclobutane-1-carboxamide

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

実験手順: Benzylamine (751 mg, 7.02 mmol), N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (423 mg, 2.70 mmol), and sodium cyanoborohydride (237 mg, 3.78 mmol) were dissolved in 25 mL of anhydrous methanol. The pH of the solution was brought to 5 by addition of acetic acid, and the reaction was stirred for 24 hours at room temperature. The pH of the solution then was brought to 8 by addition of 1 M aqueous sodium bicarbonate. The solvents were removed under reduced pressure. The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL). The organic layer was washed with water and brine and dried, purified using flash column chromatography with hexanes/ethyl acetate (2:1) as an eluant to give 3-(benzylamino)-N-methoxy-N-methylcyclobutanecarboxamide (498 mg, 2.00 mmol, 75% yield) as an oil. The solvents were removed under reduced pressure The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL) The organic layer was washed with water and brine dried purified

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

実験手順: A mixture of 3-oxo-cyclobutanecarboxylic acid (2.28 g, 20.0 mmol), O,N-dimethyl-hydroxylamine hydrochloride (1.94 g, 20.0 mmol), 1-hydroxybenzotriazole (2.99 g, 22.0 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.22 g, 22.0 mmol) and triethylamine (4.04 g, 40.0 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hours. The mixture was diluted with water (30 mL), and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by silica chromatography to provide N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (2.68 g, 17.0 mmol, yield: 85%). extracted with dichloromethane (2×30 mL) The combined organic extracts were washed with water (20 mL) and brine (20 mL) dried over sodium sulfate The filtrate was evaporated in vacuo the residue was purified by silica chromatography

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

実験手順: N-Methoxy-N-methyl-3-oxocyclobutanecarboxamide (1 g, 0.006 mol) was dissolved in methanol (8 mL, 0.2 mol). To the mixture, sodium borohydride (0.2 g, 0.006 mol) was added. The reaction was stirred at rt for 1 h. To the reaction mixture was added 1N aq. HCl to adjust the pH to 2. The mixture was concentrated, then extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude product (1.4 g) as light yellow oil. LCMS calculated for C7H14NO3(M+H)+: 160.0. Found: 160.3. The mixture was concentrated extracted with EtOAc The combined organic layers were dried over MgSO4 concentrated

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

実験手順: To a mixture of N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.054 mol), and 3-oxocyclobutanecarboxylic acid (4.0 g, 0.035 mol) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 0.052 mol), 1-hydroxybenzotriazole (7.1 g, 0.052 mol) followed by triethylamine (34 mL, 0.24 mol) at 0° C. The mixture was stirred at rt over night, then quenched with water. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex) to give the desired product (4.3 g, 78%) as light yellow oil. LCMS calculated for C7H12NO3(M+H)+: 158.1. Found: 158.3. quenched with water The mixture was extracted with EtOAc The organic layers were dried over MgSO4 concentrated purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex)

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

実験手順: N-Methoxy-N-methyl-3-oxocyclobutanecarboxamide (1 g, 0.006 mol) was dissolved in methanol (8 mL, 0.2 mol). To the mixture, sodium borohydride (0.2 g, 0.006 mol) was added. The reaction was stirred at rt for 1 h. To the reaction mixture was added 1N aq. HCl to adjust the pH to 2. The mixture was concentrated, then extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude product (1.4 g) as light yellow oil. LCMS calculated for C7H14NO3(M+H)+: 160.0; Found: 160.3. The mixture was concentrated extracted with EtOAc The combined organic layers were dried over MgSO4 concentrated

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

実験手順: To a mixture of N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.054 mol), and 3-oxocyclobutanecarboxylic acid (4.0 g, 0.035 mol) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 0.052 mol), 1-hydroxybenzotriazole (7.1 g, 0.052 mol) followed by triethylamine (34 mL, 0.24 mol) at 0° C. The mixture was stirred at rt over night, then quenched with water. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex) to give the desired product (4.3 g, 78%) as light yellow oil. LCMS calculated for C7H12NO3(M+H)+: 158.1; Found: 158.3. quenched with water The mixture was extracted with EtOAc The organic layers were dried over MgSO4 concentrated purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex)

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

実験手順: Benzylamine (751 mg, 7.02 mmol), N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (423 mg, 2.70 mmol), and sodium cyanoborohydride (237 mg, 3.78 mmol) were dissolved in 25 mL of anhydrous methanol. The pH of the solution was brought to 5 by addition of acetic acid, and the reaction was stirred for 24 hours at room temperature. The pH of the solution then was brought to 8 by addition of 1 M aqueous sodium bicarbonate. The solvents were removed under reduced pressure. The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL). The organic layer was washed with water and brine and dried, purified using flash column chromatography with hexanes/ethyl acetate (2:1) as an eluant to give 3-(benzylamino)-N-methoxy-N-methylcyclobutanecarboxamide (498 mg, 2.00 mmol, 75% yield) as an oil. The solvents were removed under reduced pressure The crude product was partitioned between ethyl acetate (80 mL) and water (25 mL) The organic layer was washed with water and brine dried purified

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

実験手順: A mixture of 3-oxo-cyclobutanecarboxylic acid (2.28 g, 20.0 mmol), O,N-dimethyl-hydroxylamine hydrochloride (1.94 g, 20.0 mmol), 1-hydroxybenzotriazole (2.99 g, 22.0 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.22 g, 22.0 mmol) and triethylamine (4.04 g, 40.0 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hours. The mixture was diluted with water (30 mL), and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by silica chromatography to provide N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (2.68 g, 17.0 mmol, yield: 85%). extracted with dichloromethane (2×30 mL) The combined organic extracts were washed with water (20 mL) and brine (20 mL) dried over sodium sulfate The filtrate was evaporated in vacuo the residue was purified by silica chromatography