2-(4-bromophenyl)-1-morpholin-4-ylethanone

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

Procedure: To a solution of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (153 mg, 0.581 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was added N,N-dimethylformiminium chloride (160 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then treated with 2N aqueous potassium carbonate (1.44 mL, 2.90 mmol) and 2-(4-bromophenyl)-1-(morpholin-4-yl)ethanone (165 mg, 0.58 mmol). The reaction was degassed with nitrogen, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.068 mmol). The reaction mixture was stirred at 90° C. for 30 minutes, cooled to room temperature, and poured into water (15 mL). The product was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried and concentrated in vacuo to give the title compound (249 mg, >100% yield) as a red solid, which was used in the next step without further purification. The reaction was degassed with nitrogen The reaction mixture was stirred at 90° C. for 30 minutes cooled to room temperature The product was extracted with ethyl acetate (3×20 mL) the combined organic phases were dried concentrated in vacuo

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

Procedure: To a solution of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (153 mg, 0.581 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was added N,N-dimethylformiminium chloride (160 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then treated with 2 N aqueous potassium carbonate (1.44 mL, 2.90 mmol) and 2-(4-bromophenyl)-1-(morpholin-4-yl)ethanone (165 mg, 0.58 mmol). The reaction was degassed with nitrogen, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.068 mmol). The reaction mixture was stirred at 90° C. for 30 minutes, cooled to room temperature, and poured into water (15 mL). The product was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried and concentrated in vacuo to give the title compound (249 mg, >100% yield) as a red solid, which was used in the next step without further purification. The reaction was degassed with nitrogen The reaction mixture was stirred at 90° C. for 30 minutes cooled to room temperature The product was extracted with ethyl acetate (3×20 mL) the combined organic phases were dried concentrated in vacuo

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

Procedure: To a solution of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (153 mg, 0.581 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was added N,N-dimethylformiminium chloride (160 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then treated with 2 N aqueous potassium carbonate (1.44 mL, 2.90 mmol) and 2-(4-bromophenyl)-1-(morpholin-4-yl)ethanone (165 mg, 0.58 mmol). The reaction was degassed with nitrogen, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.068 mmol). The reaction mixture was stirred at 90° C. for 30 minutes, cooled to room temperature, and poured into water (15 mL). The product was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried and concentrated in vacuo to give the title compound (249 mg, >100% yield) as a red solid, which was used in the next step without further purification. The reaction was degassed with nitrogen The reaction mixture was stirred at 90° C. for 30 minutes cooled to room temperature The product was extracted with ethyl acetate (3×20 mL) the combined organic phases were dried concentrated in vacuo

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of lithium aluminum hydride (3.35 g, 88.16 mmol, 2.00 equiv) in tetrahydrofuran (100 mL) maintained under nitrogen at −30° C. was added a solution of 2-(4-bromophenyl)-1-morpholinoethanone (12.5 g, 44.17 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) dropwise with stirring. The reaction mixture was stirred at −30° C. for 30 min and then at room temperature for 2 h. The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water. The solid was removed by filtration. The filtrate was extracted with 1×150 mL of ethyl acetate. The organic layer was collected then washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 11.5 g (97%) of 4-(4-bromophenethyl)morpholine as a white solid. LC-MS: (ES, m/z): 311 [M+CH3CN+H]+, 270 [M+H]+, 130, 102. The reaction mixture was stirred at −30° C. for 30 min The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water The solid was removed by filtration The filtrate was extracted with 1×150 mL of ethyl acetate The organic layer was collected then washed with 2×30 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: To a solution of morpholine (16 g, 183.91 mmol, 1.98 equiv) in dichloromethane (50 mL) at 0-5° C. was added a solution of 2-(4-bromophenyl)acetyl chloride (21.5 g, 92.67 mmol, 1.00 equiv) in dichloromethane (20 mL) dropwise with stirring. The reaction mixture was stirred for another hour at 0˜5° C. The reaction mixture was warmed to room temperature and diluted with 30 mL of dichloromethane. The mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 19.5 g (74%) of 2-(4-bromophenyl)-1-morpholinoethanone as a white solid. LC-MS: (ES, m/z): 284 [M+H]+. The reaction mixture was stirred for another hour at 0˜5° C The mixture was washed with 3×50 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: To a solution of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (153 mg, 0.581 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was added N,N-dimethylformiminium chloride (160 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then treated with 2N aqueous potassium carbonate (1.44 mL, 2.90 mmol) and 2-(4-bromophenyl)-1-(morpholin-4-yl)ethanone (165 mg, 0.58 mmol). The reaction was degassed with nitrogen, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.068 mmol). The reaction mixture was stirred at 90° C. for 30 minutes, cooled to room temperature, and poured into water (15 mL). The product was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried and concentrated in vacuo to give the title compound (249 mg, >100% yield) as a red solid, which was used in the next step without further purification. The reaction was degassed with nitrogen The reaction mixture was stirred at 90° C. for 30 minutes cooled to room temperature The product was extracted with ethyl acetate (3×20 mL) the combined organic phases were dried concentrated in vacuo

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

Procedure: The compound shown on the left above, 2-(4-bromo-phenyl)-1-morpholin-4-yl-ethanone, is obtained by reaction of the corresponding acid chloride (A), (4-bromo-phenyl)-acetyl chloride, with morpholine and Et3N in DCM at rt. The product is obtained in high yield. The intermediate acid chloride (A) is obtained by reaction of (4-bromo-phenyl)-acetic acid (B) and oxalyl chloride (C) in DCM at rt and using DMF as reaction initiator. The intermediate (A) is obtained in good yield.

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of lithium aluminum hydride (3.35 g, 88.16 mmol, 2.00 equiv) in tetrahydrofuran (100 mL) maintained under nitrogen at −30° C. was added a solution of 2-(4-bromophenyl)-1-morpholinoethanone (12.5 g, 44.17 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) dropwise with stirring. The reaction mixture was stirred at −30° C. for 30 min and then at room temperature for 2 h. The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water. The solid was removed by filtration. The filtrate was extracted with 1×150 mL of ethyl acetate. The organic layer was collected then washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 11.5 g (97%) of 4-(4-bromophenethyl)morpholine as a white solid. LC-MS: (ES, m/z): 311 [M+CH3CN+H]+, 270 [M+H]+, 130, 102. The reaction mixture was stirred at −30° C. for 30 min The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water The solid was removed by filtration The filtrate was extracted with 1×150 mL of ethyl acetate The organic layer was collected then washed with 2×30 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: To a solution of morpholine (16 g, 183.91 mmol, 1.98 equiv) in dichloromethane (50 mL) at 0-5° C. was added a solution of 2-(4-bromophenyl)acetyl chloride (21.5 g, 92.67 mmol, 1.00 equiv) in dichloromethane (20 mL) dropwise with stirring. The reaction mixture was stirred for another hour at 0˜5° C. The reaction mixture was warmed to room temperature and diluted with 30 mL of dichloromethane. The mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 19.5 g (74%) of 2-(4-bromophenyl)-1-morpholinoethanone as a white solid. LC-MS: (ES, m/z): 284 [M+H]+. The reaction mixture was stirred for another hour at 0˜5° C The mixture was washed with 3×50 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: To a solution of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (153 mg, 0.581 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was added N,N-dimethylformiminium chloride (160 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and then treated with 2 N aqueous potassium carbonate (1.44 mL, 2.90 mmol) and 2-(4-bromophenyl)-1-(morpholin-4-yl)ethanone (165 mg, 0.58 mmol). The reaction was degassed with nitrogen, and treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.068 mmol). The reaction mixture was stirred at 90° C. for 30 minutes, cooled to room temperature, and poured into water (15 mL). The product was extracted with ethyl acetate (3×20 mL), and the combined organic phases were dried and concentrated in vacuo to give the title compound (249 mg, >100% yield) as a red solid, which was used in the next step without further purification. The reaction was degassed with nitrogen The reaction mixture was stirred at 90° C. for 30 minutes cooled to room temperature The product was extracted with ethyl acetate (3×20 mL) the combined organic phases were dried concentrated in vacuo

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of lithium aluminum hydride (3.35 g, 88.16 mmol, 2.00 equiv) in tetrahydrofuran (100 mL) maintained under nitrogen at −30° C. was added a solution of 2-(4-bromophenyl)-1-morpholinoethanone (12.5 g, 44.17 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) dropwise with stirring. The reaction mixture was stirred at −30° C. for 30 min and then at room temperature for 2 h. The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water. The solid was removed by filtration. The filtrate was extracted with 1×150 mL of ethyl acetate. The organic layer was collected then washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 11.5 g (97%) of 4-(4-bromophenethyl)morpholine as a white solid. LC-MS: (ES, m/z): 311 [M+CH3CN+H]+, 270 [M+H]+, 130, 102. The reaction mixture was stirred at −30° C. for 30 min The reaction was then quenched sequentially by the addition of 3.5 mL of water, 10 mL of 15% aqueous sodium hydroxide solution and 3.5 mL of water The solid was removed by filtration The filtrate was extracted with 1×150 mL of ethyl acetate The organic layer was collected then washed with 2×30 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: To a solution of morpholine (16 g, 183.91 mmol, 1.98 equiv) in dichloromethane (50 mL) at 0-5° C. was added a solution of 2-(4-bromophenyl)acetyl chloride (21.5 g, 92.67 mmol, 1.00 equiv) in dichloromethane (20 mL) dropwise with stirring. The reaction mixture was stirred for another hour at 0˜5° C. The reaction mixture was warmed to room temperature and diluted with 30 mL of dichloromethane. The mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 19.5 g (74%) of 2-(4-bromophenyl)-1-morpholinoethanone as a white solid. LC-MS: (ES, m/z): 284 [M+H]+. The reaction mixture was stirred for another hour at 0˜5° C The mixture was washed with 3×50 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum