2-bromo-4-chloro-1-(2,2,2-trifluoroethoxy)benzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a stirred solution of 2-bromo-4-chlorophenol (3.38 g, 16.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (25 ml) under an atmosphere of nitrogen, was added cesium carbonate (8.0 g, 24.4 mmol). The mixture was cooled to 0° C. before addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.78 g, 16.3 mmol) drop-wise over 2 minutes. The reaction was allowed to warm to room temperature and stirred for 14 hours. To encourage complete reaction the reaction mixture was warmed to 120° C. for 3 hours. The reaction mixture was cooled to room temperature then water (50 ml) was added. The layers were separated and the aqueous was extracted with heptane (3×50 ml). All organic extracts were combined then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (4.20 g, 89%). Material was taken on without further purification. reaction the reaction mixture was warmed to 120° C. for 3 hours The reaction mixture was cooled to room temperature The layers were separated the aqueous was extracted with heptane (3×50 ml) All organic extracts were combined then dried over anhydrous Na2SO4 (s) filtered evaporated in vacuo

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

実験手順: To a stirred solution of 2-bromo-4-chlorophenol (3.38 g, 16.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (25 ml) under an atmosphere of nitrogen, was added cesium carbonate (8.0 g, 24.4 mmol). The mixture was cooled to 0° C. before addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.78 g, 16.3 mmol) drop-wise over 2 minutes. The reaction was allowed to warm to room temperature and stirred for 14 hours. To encourage complete reaction the reaction mixture was warmed to 120° C. for 3 hours. The reaction mixture was cooled to room temperature then water (50 ml) was added. The layers were separated and the aqueous was extracted with heptane (3×50 ml). All organic extracts were combined then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo to afford crude title compound as a yellow oil (4.20 g, 89%). Material was taken on without further purification. reaction the reaction mixture was warmed to 120° C. for 3 hours The reaction mixture was cooled to room temperature The layers were separated the aqueous was extracted with heptane (3×50 ml) All organic extracts were combined then dried over anhydrous Na2SO4 (s) filtered evaporated in vacuo

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

実験手順: To a stirred cold (0° C.) suspension of oil free NaH (0.12 mol, 4.8 g of 60% NaH in mineral oil) in anhydrous DMF (50 mL), a solution of 2-bromo-4-chlorophenol in DMF (50 mL) was added over 30 minutes under nitrogen. The resultant gray suspension of the sodium salt of 2-bromo-4-chlorophenol was treated with neat 2,2,2-trifluoroethylmethane sulfonate (21.4 g, 0.12 mol). The stirred mixture was heated at reflux temperature for 2-3 days. The mixture was cooled in an ice water bath and extracted with diethyl ether (2×100 mL). The combined ether extract was washed with 1N NaOH (3×100 mL), 1N HCl, brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to provide a golden-yellow oil (18.4 g) which was then distilled in vacuo to afford the title compound as a colorless oil (14.7 g): bp 100-103° C. @ 0.5 torr. The stirred mixture was heated at reflux temperature for 2-3 days The mixture was cooled in an ice water bath extracted with diethyl ether (2×100 mL) The combined ether extract was washed with 1N NaOH (3×100 mL), 1N HCl, brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 10.4 mmol) and tetrahydrofuran (60 ml), cooled to −70° C., was added a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 5.7 ml). After warming to 0° C., the mixture was stirred for 1 hour. After cooling to −70° C., the mixture was treated with trimethylborate (1.2 g, 11.4 mmol). After stirring at room temperature for 12 hours, the mixture was treated with hydrochloric acid (2 M, 20 ml). After stirring for 40 minutes, the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hexane (50 ml). Filtration and drying of the solid under reduced pressure gave 5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenylboronic acid (1.6 g, 61% yield). 1H NMR (acetone-d6) δ 4.86 (q, 2H, J=8.5 Hz, CH2), 7.12 (d, 2H, J=4.6 Hz, OH), 7.20 (d, 1H, J=8.8 Hz, Ar), 7.49 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.76 (d, 1H, J—2.7 Hz, Ar). After warming to 0° C. After cooling to −70° C. After stirring at room temperature for 12 hours After stirring for 40 minutes the mixture was extracted with ethyl acetate (2×50 ml) The combined extracts were dried over magnesium sulfate concentrated under reduced pressure The residue was triturated with hexane (50 ml) Filtration drying of the solid under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-4-chloro-phenol (2.0 g, 9.6 mmol), trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (3.8 g, 16.4 mmol), potassium carbonate (8.0 g, 59 mmol), and N,N-dimethylformaldehyde (80 ml) was heated to 100° C. for 72 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was treated with water (150 ml) and extracted with ethyl acetate (160 ml). The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4) to give 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 100% yield). 1H NMR (acetone-d6) δ 4.80 (q, 2H, J=8.4 Hz, CH2), 7.28 (d, 1H, J=8.9 Hz, Ar), 7.45 (dd, 1H, J=8.9 Hz, J=2.5 Hz, Ar), 7.69 (d, 1H, J—2.5 Hz, Ar). After cooling to room temperature the mixture was concentrated under reduced pressure The residue was treated with water (150 ml) extracted with ethyl acetate (160 ml) The organic extract was dried over magnesium sulfate concentrated under reduced pressure The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 10.4 mmol) and tetrahydrofuran (60 ml), cooled to −70° C., was added a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 5.7 ml). After warming to 0° C., the mixture was stirred for 1 hour. After cooling to −70° C., the mixture was treated with trimethylborate (1.2 g, 11.4 mmol). After stirring at room temperature for 12 hours, the mixture was treated with hydrochloric acid (2 M, 20 ml). After stirring for 40 minutes, the mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hexane (50 ml). Filtration and drying of the solid under reduced pressure gave 5-chloro-2-(2,2,2-trifluoro-ethoxy)-phenylboronic acid (1.6 g, 61% yield). 1H NMR (acetone-d6) δ 4.86 (q, 2H, J=8.5 Hz, CH2), 7.12 (d, 2H, J=4.6 Hz, OH), 7.20 (d, 1H, J=8.8 Hz, Ar), 7.49 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.76 (d, 1H, J—2.7 Hz, Ar). After warming to 0° C. After cooling to −70° C. After stirring at room temperature for 12 hours After stirring for 40 minutes the mixture was extracted with ethyl acetate (2×50 ml) The combined extracts were dried over magnesium sulfate concentrated under reduced pressure The residue was triturated with hexane (50 ml) Filtration drying of the solid under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-4-chloro-phenol (2.0 g, 9.6 mmol), trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (3.8 g, 16.4 mmol), potassium carbonate (8.0 g, 59 mmol), and N,N-dimethylformaldehyde (80 ml) was heated to 100° C. for 72 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was treated with water (150 ml) and extracted with ethyl acetate (160 ml). The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4) to give 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene (3.0 g, 100% yield). 1H NMR (acetone-d6) δ 4.80 (q, 2H, J=8.4 Hz, CH2), 7.28 (d, 1H, J=8.9 Hz, Ar), 7.45 (dd, 1H, J=8.9 Hz, J=2.5 Hz, Ar), 7.69 (d, 1H, J—2.5 Hz, Ar). After cooling to room temperature the mixture was concentrated under reduced pressure The residue was treated with water (150 ml) extracted with ethyl acetate (160 ml) The organic extract was dried over magnesium sulfate concentrated under reduced pressure The residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:4)