(5R)-5-propan-2-ylmorpholin-3-one

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

Procedure: To ice-cold tetrahydrofuran (8.0 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (R)-5-isopropylmorpholin-3-one (1.7 g, 12.0 mmol) in tetrahydrofuran (8 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added water (1.0 mL), then a 15% solution of sodium hydroxide (1.0 mL), and then water (1.0 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with ethyl acetate (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (R)-3-isopropylmorpholine (1.4 g, 93%) as a light yellow oil. 1H NMR consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solid with ethyl acetate (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To ice-cold tetrahydrofuran (8.0 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (R)-5-isopropylmorpholin-3-one (1.7 g, 12.0 mmol) in tetrahydrofuran (8 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added water (1.0 mL), then a 15% solution of sodium hydroxide (1.0 mL), and then water (1.0 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with ethyl acetate (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (R)-3-isopropylmorpholine (1.4 g, 93%) as a light yellow oil. 1H NMR consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solid with ethyl acetate (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of sodium hydride (60% in oil, 1.6 g, 40.0 mmol) in toluene (52 mL) was added dropwise a solution of (R)-2-amino-3-methylbutan-1-ol (1.8 g, 17.0 mmol) in toluene (38 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (8 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 40.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol) to give (R)-5-isopropylmorpholin-3-one (1.7 g, 68%) as a light yellow solid. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol)

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

Procedure: To an ice cold, stirred suspension of sodium hydride (60% in oil, 1.6 g, 40.0 mmol) in toluene (52 mL) was added dropwise a solution of (R)-2-amino-3-methylbutan-1-ol (1.8 g, 17.0 mmol) in toluene (38 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (8 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 40.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol) to give (R)-5-isopropylmorpholin-3-one (1.7 g, 68%) as a light yellow solid. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol)

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

Procedure: To ice-cold tetrahydrofuran (8.0 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (R)-5-isopropylmorpholin-3-one (1.7 g, 12.0 mmol) in tetrahydrofuran (8 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added water (1.0 mL), then a 15% solution of sodium hydroxide (1.0 mL), and then water (1.0 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with ethyl acetate (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (R)-3-isopropylmorpholine (1.4 g, 93%) as a light yellow oil. 1H NMR consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solid with ethyl acetate (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of sodium hydride (60% in oil, 1.6 g, 40.0 mmol) in toluene (52 mL) was added dropwise a solution of (R)-2-amino-3-methylbutan-1-ol (1.8 g, 17.0 mmol) in toluene (38 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (8 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 40.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol) to give (R)-5-isopropylmorpholin-3-one (1.7 g, 68%) as a light yellow solid. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (6.24 g, 60% wt in mineral oil, 156 mmol, 2.3 equiv) was charged into a 1 L RB flask, followed by addition of 100 mL of toluene. The suspension was stirred in an ice bath. (2R)-2-Amino-3-methyl-1-butanol (7.0 g, 67.9 mmol) in 50 mL of toluene was added portion-wise. Addition took 10 minutes, followed with removal of the cooling bath. The mixture was stirred at ambient temperature for 15 minutes, and cooled in an ice bath. To the cooled mixture was added portion-wise a solution of chloroacetyl chloride (6.25 mL, 78 mmol, 1.15 equiv) in 50 mL of toluene. The mixture began to foam. When the addition neared completion, foaming subsided. The resulting mixture was heated under a reflux condenser to 90° C. (oil bath temp) for 20 hours. The mixture was cooled to room temperature, followed by addition of 22 g of NH4Cl and then water (50 mL). The phases were separated. The aqueous phase was extracted with EtOAc (2×150 mL). The combined organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in 30 mL of hexane. The solids formed were collected by filtration, washing with hexane (2×10 mL). Drying under vacuum at room temperature for 5 hours gave the title compound (6.53 g) as a cream-colored solid. LC-MS (ES) m/z=144 Addition followed with removal of the cooling bath The mixture was stirred at ambient temperature for 15 minutes cooled in an ice bath When the addition The mixture was cooled to room temperature The phases were separated The aqueous phase was extracted with EtOAc (2×150 mL) The combined organic was dried over Na2SO4 filtered concentrated in vacuo The residue was triturated in 30 mL of hexane The solids formed were collected by filtration washing with hexane (2×10 mL) Drying under vacuum at room temperature for 5 hours

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (6.24 g, 60% wt in mineral oil, 156 mmol, 2.3 equiv) was charged into a 1 L RB flask, followed by addition of 100 mL of toluene. The suspension was stirred in an ice bath. (2R)-2-Amino-3-methyl-1-butanol (7.0 g, 67.9 mmol) in 50 mL of toluene was added portion-wise. Addition took 10 minutes, followed with removal of the cooling bath. The mixture was stirred at ambient temperature for 15 minutes, and cooled in an ice bath. To the cooled mixture was added portion-wise a solution of chloroacetyl chloride (6.25 mL, 78 mmol, 1.15 equiv) in 50 mL of toluene. The mixture began to foam. When the addition neared completion, foaming subsided. The resulting mixture was heated under a reflux condenser to 90° C. (oil bath temp) for 20 hours. The mixture was cooled to room temperature, followed by addition of 22 g of NH4Cl and then water (50 mL). The phases were separated. The aqueous phase was extracted with EtOAc (2×150 mL). The combined organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in 30 mL of hexane. The solids formed were collected by filtration, washing with hexane (2×10 mL). Drying under vacuum at room temperature for 5 hours gave the title compound (6.53 g) as a cream-colored solid. LC-MS (ES) m/z=144 Addition followed with removal of the cooling bath The mixture was stirred at ambient temperature for 15 minutes cooled in an ice bath When the addition The mixture was cooled to room temperature The phases were separated The aqueous phase was extracted with EtOAc (2×150 mL) The combined organic was dried over Na2SO4 filtered concentrated in vacuo The residue was triturated in 30 mL of hexane The solids formed were collected by filtration washing with hexane (2×10 mL) Drying under vacuum at room temperature for 5 hours

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: NaH (6.24 g, 60% wt in mineral oil, 156 mmol, 2.3 equiv) was charged into a 1 L RB flask, followed by addition of 100 mL of toluene. The suspension was stirred in an ice bath. (2R)-2-Amino-3-methyl-1-butanol (7.0 g, 67.9 mmol) in 50 mL of toluene was added portion-wise. Addition took 10 minutes, followed with removal of the cooling bath. The mixture was stirred at ambient temperature for 15 minutes, and cooled in an ice bath. To the cooled mixture was added portion-wise a solution of chloroacetyl chloride (6.25 mL, 78 mmol, 1.15 equiv) in 50 mL of toluene. The mixture began to foam. When the addition neared completion, foaming subsided. The resulting mixture was heated under a reflux condenser to 90° C. (oil bath temp) for 20 hours. The mixture was cooled to room temperature, followed by addition of 22 g of NH4Cl and then water (50 mL). The phases were separated. The aqueous phase was extracted with EtOAc (2×150 mL). The combined organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in 30 mL of hexane. The solids formed were collected by filtration, washing with hexane (2×10 mL). Drying under vacuum at room temperature for 5 hours gave the title compound (6.53 g) as a cream-colored solid. LC-MS (ES) m/z=144 Addition followed with removal of the cooling bath The mixture was stirred at ambient temperature for 15 minutes cooled in an ice bath When the addition The mixture was cooled to room temperature The phases were separated The aqueous phase was extracted with EtOAc (2×150 mL) The combined organic was dried over Na2SO4 filtered concentrated in vacuo The residue was triturated in 30 mL of hexane The solids formed were collected by filtration washing with hexane (2×10 mL) Drying under vacuum at room temperature for 5 hours

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

Procedure: To ice-cold tetrahydrofuran (8.0 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 23.0 mL, 23.0 mmol). Once the addition was complete, a solution of (R)-5-isopropylmorpholin-3-one (1.7 g, 12.0 mmol) in tetrahydrofuran (8 mL) was added dropwise over 20 min. Once the addition was completed, the ice bath was removed and the reaction mixture stirred at reflux for 20 h. The reaction was cooled in an ice-bath and to this was slowly added water (1.0 mL), then a 15% solution of sodium hydroxide (1.0 mL), and then water (1.0 mL). The resulting mixture was stirred at room temperature for 1.5 h and then filtered washing the solid with ethyl acetate (50 mL). The filtrate was concentrated at room temperature under reduced pressure to provide (R)-3-isopropylmorpholine (1.4 g, 93%) as a light yellow oil. 1H NMR consistent. Once the addition Once the addition the ice bath was removed at reflux for 20 h The reaction was cooled in an ice-bath The resulting mixture was stirred at room temperature for 1.5 h filtered washing the solid with ethyl acetate (50 mL) The filtrate was concentrated at room temperature under reduced pressure

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

Procedure: To an ice cold, stirred suspension of sodium hydride (60% in oil, 1.6 g, 40.0 mmol) in toluene (52 mL) was added dropwise a solution of (R)-2-amino-3-methylbutan-1-ol (1.8 g, 17.0 mmol) in toluene (38 mL). After the addition was completed, the reaction mixture was warmed to room temperature and a solution of ethyl chloroacetate (2.3 g, 19.0 mmol) in toluene (8 mL) was added in a dropwise manner. The resulting mixture was then stirred at reflux for 20 h, cooled to room temperature, and solid ammonium chloride (2.1 g, 40.0 mmol) added to the reaction. The mixture was stirred for 20 min and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol) to give (R)-5-isopropylmorpholin-3-one (1.7 g, 68%) as a light yellow solid. After the addition at reflux for 20 h cooled to room temperature The mixture was stirred for 20 min concentrated under reduced pressure The crude material was purified by column chromatography (silica gel, 95:5 dichloromethane/methanol)