2-[tert-butyl(dimethyl)silyl]oxy-N-methoxy-N-methylacetamide

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

実験手順: To a suspension of magnesium turnings (2.10 g, 85.7 mmol) in anhydrous THY (120 mL), was added slowly at RT 1-bromo-3-fluorobenzene (10.0 g, 57.2 mmol) and 1,2-dibromoethane (0.10 mL). After stirring for 40 min under argon, the mixture was cooled to −78° C., and 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (9.3 g, 40 mmol) was added. The resulting mixture was warmed to 0° C. and stirred for 2 h. The reaction was quenched with saturated NH4Cl (5.0 mL), and the insoluble material was filtered. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1) to afford 10.3 g (93%) of 2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethanone (58a) as oil. LCMS (ESI) m/z: 268.0[M+H]+. The resulting mixture was warmed to 0° C. stirred for 2 h The reaction was quenched with saturated NH4Cl (5.0 mL) the insoluble material was filtered The filtrate was dried (Na2SO4) filtered concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1)

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

実験手順: 0.5M (3-Chloro-4-fluorophenyl)magnesium bromide in THF (27.4 mL, 13.7 mmol) was added dropwise to 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (2.00 g, 8.57 mmol) in THF (20 mL) cooled in ice. The mixture became turbid after about half of the Grignard reagent was added. This was stirred in an ice bath for 2 hours, quenched with saturated aqueous NH4Cl, and concentrated to remove the THF. The aqueous residue was extracted with 2 portions DCM. The combined DCM layers were dried over MgSO4, filtered, and evaporated to yield a crude product (3.62 g) as an oil. This was taken up in hexane and purified on a silica gel plug with hexane until product started eluting, then 15:1 hexane/EtOAc. Product-containing fractions yielded 2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28 g, 7.53 mmol, 87.9% yield) as an oil. cooled in ice was added quenched with saturated aqueous NH4Cl concentrated to remove the THF The aqueous residue was extracted with 2 portions DCM The combined DCM layers were dried over MgSO4 filtered evaporated to yield a crude product (3.62 g) as an oil purified on a silica gel plug with hexane until product started eluting

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

実験手順: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O -dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to 1/3 volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil. cooled in ice The reaction mixture was quenched with aqueous NH4Cl concentrated to 1/3 volume The residue was diluted with water extracted with EtOAc The EtOAc was washed with brine dried over MgSO4 filtered evaporated

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

実験手順: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O -dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to 1/3 volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil. cooled in ice The reaction mixture was quenched with aqueous NH4Cl concentrated to 1/3 volume The residue was diluted with water extracted with EtOAc The EtOAc was washed with brine dried over MgSO4 filtered evaporated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62). the reaction was extracted with DCM The organic layer was separated dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62). the reaction was extracted with DCM The organic layer was separated dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62). the reaction was extracted with DCM The organic layer was separated dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane

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

実験手順: To a solution of ethyl 2-(tert-butyldimethylsilyloxy)acetate (59, 20.0 g, 91.59 mmol), N,O-dimethylhydroxylamine hydrochloride (18.76 g, 192.3 mmol) and THF (800 mL) cooled to 0° C. was added dropwise via addition funnel isopropylmagnesium chloride (183.2 mL, 366.4 mmol) and the reaction was stirred for 3 h. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 20% EtOAc/hexane to afford 15.12 g (70.7%) of 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (60). The reaction was quenched with saturated NH4Cl extracted with EtOAc The organic layer was dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 20% EtOAc/hexane

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

実験手順: 0.5M (3-Chloro-4-fluorophenyl)magnesium bromide in THF (27.4 mL, 13.7 mmol) was added dropwise to 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (2.00 g, 8.57 mmol) in THF (20 mL) cooled in ice. The mixture became turbid after about half of the Grignard reagent was added. This was stirred in an ice bath for 2 hours, quenched with saturated aqueous NH4Cl, and concentrated to remove the THF. The aqueous residue was extracted with 2 portions DCM. The combined DCM layers were dried over MgSO4, filtered, and evaporated to yield a crude product (3.62 g) as an oil. This was taken up in hexane and purified on a silica gel plug with hexane until product started eluting, then 15:1 hexane/EtOAc. Product-containing fractions yielded 2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28 g, 7.53 mmol, 87.9% yield) as an oil. cooled in ice was added quenched with saturated aqueous NH4Cl concentrated to remove the THF The aqueous residue was extracted with 2 portions DCM The combined DCM layers were dried over MgSO4 filtered evaporated to yield a crude product (3.62 g) as an oil purified on a silica gel plug with hexane until product started eluting

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

実験手順: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O-dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to ⅓ volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil. cooled in ice The reaction mixture was quenched with aqueous NH4Cl concentrated The residue was diluted with water extracted with EtOAc The EtOAc was washed with brine dried over MgSO4 filtered evaporated

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

実験手順: To a suspension of magnesium turnings (2.10 g, 85.7 mmol) in anhydrous THY (120 mL), was added slowly at RT 1-bromo-3-fluorobenzene (10.0 g, 57.2 mmol) and 1,2-dibromoethane (0.10 mL). After stirring for 40 min under argon, the mixture was cooled to −78° C., and 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (9.3 g, 40 mmol) was added. The resulting mixture was warmed to 0° C. and stirred for 2 h. The reaction was quenched with saturated NH4Cl (5.0 mL), and the insoluble material was filtered. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1) to afford 10.3 g (93%) of 2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethanone (58a) as oil. LCMS (ESI) m/z: 268.0[M+H]+. The resulting mixture was warmed to 0° C. stirred for 2 h The reaction was quenched with saturated NH4Cl (5.0 mL) the insoluble material was filtered The filtrate was dried (Na2SO4) filtered concentrated in vacuo The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1)