4-bromo-1-iodo-2-methoxybenzene

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

実験手順: The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-bromo-1-iodo-2-methoxy-benzene in analogy to Example 1a): MS (ISP): 490.0 (M+H)+ and 390.0 ((M-Boc)+H)+ (100%).

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-1-iodo-2-methoxybenzene (1100 mg, 3.5 mmol), diethylmalonate (1240 mg, 7.70 mmol), cesium carbonate (1830 mg, 5.60 mmol), 2-picolinic acid (62 mg, 0.39 mmol), copper (I) iodide (34 mg, 0.18 mmol), and dioxane (7 ml) was stirred at 55° C. for 2 days. A very heavy slurry formed, LCMS indicates that the starting iodoarene is about 70% consumed. The mixture was cooled to room temperature and diluted with 30 mL of water and extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate, and concentrated to obtain the title compound which was about 60% pure by LCMS and was used for the next step without purification. GCMS (ES+) 344 (M+). A very heavy slurry formed consumed The mixture was cooled to room temperature diluted with 30 mL of water extracted with ethyl acetate The extract was washed with water, brine dried over magnesium sulfate concentrated

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

実験手順: To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone (0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was added n-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and filtered, and concentrated under reduced pressure yielding 680 mg of crude oil. Purification by column chromatography (0-10% ethyl acetate/heptanes) afforded the title compound (133 mg, 25% yield) as a clear, colorless oil. MS (ES+) 226.9 (M−H2O+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.20 (d, 1H), 7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H). The reaction mixture was quenched with saturated aqueous ammonium chloride warmed to room temperature extracted with ethyl acetate (2×) The combined organic layers were dried over magnesium sulfate filtered concentrated under reduced pressure yielding 680 mg of crude oil Purification by column chromatography (0-10% ethyl acetate/heptanes)

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-1-iodo-2-methoxybenzene (1100 mg, 3.5 mmol), diethylmalonate (1240 mg, 7.70 mmol), cesium carbonate (1830 mg, 5.60 mmol), 2-picolinic acid (62 mg, 0.39 mmol), copper (I) iodide (34 mg, 0.18 mmol), and dioxane (7 ml) was stirred at 55° C. for 2 days. A very heavy slurry formed, LCMS indicates that the starting iodoarene is about 70% consumed. The mixture was cooled to room temperature and diluted with 30 mL of water and extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate, and concentrated to obtain the title compound which was about 60% pure by LCMS and was used for the next step without purification. GCMS (ES+) 344 (M+). A very heavy slurry formed consumed The mixture was cooled to room temperature diluted with 30 mL of water extracted with ethyl acetate The extract was washed with water, brine dried over magnesium sulfate concentrated

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

実験手順: To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone (0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was added n-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and filtered, and concentrated under reduced pressure yielding 680 mg of crude oil. Purification by column chromatography (0-10% ethyl acetate/heptanes) afforded the title compound (133 mg, 25% yield) as a clear, colorless oil. MS (ES+) 226.9 (M−H2O+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.20 (d, 1H), 7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H). The reaction mixture was quenched with saturated aqueous ammonium chloride warmed to room temperature extracted with ethyl acetate (2×) The combined organic layers were dried over magnesium sulfate filtered concentrated under reduced pressure yielding 680 mg of crude oil Purification by column chromatography (0-10% ethyl acetate/heptanes)

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

実験手順: The product from Example 6a (0.2 g, 0.467 mmol), 4-bromo-1-iodo-2-methoxybenzene (0.16 g, 0.514 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.014 g, 0.047 mmol) and potassium phosphate tribasic (0.347 g, 1.634 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred at ambient temperature for 20 minutes and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), treated with 3-mercaptopropyl functionalized silica gel for twenty minutes, filtered, and concentrated. Purification by chromatography (silica gel, 10-80% ethyl acetate in heptanes) afforded the title compound (0.2 g, 88%) sparged with argon for 15 minutes Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes transferred by syringe into the reaction vessel under argon partitioned between ethyl acetate and water The organic layer was washed with saturated aqueous sodium chloride dried (Na2SO4) treated with 3-mercaptopropyl functionalized silica gel for twenty minutes filtered concentrated Purification by chromatography (silica gel, 10-80% ethyl acetate in heptanes)

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

実験手順: The product from Example 6a (0.2 g, 0.467 mmol), 4-bromo-1-iodo-2-methoxybenzene (0.16 g, 0.514 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.013 g, 0.014 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.014 g, 0.047 mmol) and potassium phosphate tribasic (0.347 g, 1.634 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred at ambient temperature for 20 minutes and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), treated with 3-mercaptopropyl functionalized silica gel for twenty minutes, filtered, and concentrated. Purification by chromatography (silica gel, 10-80% ethyl acetate in heptanes) afforded the title compound (0.2 g, 88%) sparged with argon for 15 minutes Meanwhile a solution of 4:1 dioxane/water (7.5 mL) was sparged with nitrogen for 15 minutes transferred by syringe into the reaction vessel under argon partitioned between ethyl acetate and water The organic layer was washed with saturated aqueous sodium chloride dried (Na2SO4) treated with 3-mercaptopropyl functionalized silica gel for twenty minutes filtered concentrated Purification by chromatography (silica gel, 10-80% ethyl acetate in heptanes)

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

実験手順: The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-bromo-1-iodo-2-methoxy-benzene in analogy to Example 1a): MS (ISP): 490.0 (M+H)+ and 390.0 ((M-Boc)+H)+ (100%).

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-1-iodo-2-methoxybenzene (1100 mg, 3.5 mmol), diethylmalonate (1240 mg, 7.70 mmol), cesium carbonate (1830 mg, 5.60 mmol), 2-picolinic acid (62 mg, 0.39 mmol), copper (I) iodide (34 mg, 0.18 mmol), and dioxane (7 ml) was stirred at 55° C. for 2 days. A very heavy slurry formed, LCMS indicates that the starting iodoarene is about 70% consumed. The mixture was cooled to room temperature and diluted with 30 mL of water and extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate, and concentrated to obtain the title compound which was about 60% pure by LCMS and was used for the next step without purification. GCMS (ES+) 344 (M+). A very heavy slurry formed consumed The mixture was cooled to room temperature diluted with 30 mL of water extracted with ethyl acetate The extract was washed with water, brine dried over magnesium sulfate concentrated

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-1-iodo-2-methoxybenzene (1100 mg, 3.5 mmol), diethylmalonate (1240 mg, 7.70 mmol), cesium carbonate (1830 mg, 5.60 mmol), 2-picolinic acid (62 mg, 0.39 mmol), copper (I) iodide (34 mg, 0.18 mmol), and dioxane (7 ml) was stirred at 55° C. for 2 days. A very heavy slurry formed, LCMS indicates that the starting iodoarene is about 70% consumed. The mixture was cooled to room temperature and diluted with 30 mL of water and extracted with ethyl acetate. The extract was washed with water, brine, dried over magnesium sulfate, and concentrated to obtain the title compound which was about 60% pure by LCMS and was used for the next step without purification. GCMS (ES+) 344 (M+). A very heavy slurry formed consumed The mixture was cooled to room temperature diluted with 30 mL of water extracted with ethyl acetate The extract was washed with water, brine dried over magnesium sulfate concentrated

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

実験手順: To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone (0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was added n-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and filtered, and concentrated under reduced pressure yielding 680 mg of crude oil. Purification by column chromatography (0-10% ethyl acetate/heptanes) afforded the title compound (133 mg, 25% yield) as a clear, colorless oil. MS (ES+) 226.9 (M−H2O+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.20 (d, 1H), 7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H). The reaction mixture was quenched with saturated aqueous ammonium chloride warmed to room temperature extracted with ethyl acetate (2×) The combined organic layers were dried over magnesium sulfate filtered concentrated under reduced pressure yielding 680 mg of crude oil Purification by column chromatography (0-10% ethyl acetate/heptanes)

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

実験手順: To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone (0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was added n-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. The reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate and filtered, and concentrated under reduced pressure yielding 680 mg of crude oil. Purification by column chromatography (0-10% ethyl acetate/heptanes) afforded the title compound (133 mg, 25% yield) as a clear, colorless oil. MS (ES+) 226.9 (M−H2O+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.20 (d, 1H), 7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H). The reaction mixture was quenched with saturated aqueous ammonium chloride warmed to room temperature extracted with ethyl acetate (2×) The combined organic layers were dried over magnesium sulfate filtered concentrated under reduced pressure yielding 680 mg of crude oil Purification by column chromatography (0-10% ethyl acetate/heptanes)