2-bromo-1-fluoro-4-iodobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-1-fluoro-4-iodobenzene (13.23 g, 44 mmol) in anhydrous tetrahydrofuran (30 mL) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 24.18 mL, 48.4 mmol) at −20° C. After the addition, the reaction mixture was stirred at 0° C. for 3 hours, and was added to a solution of 3,4,5,6-tetrahydrophthalic anhydride (6.08 g, 40 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. Thionyl chloride (10.4 mL, 142 mol) was added dropwise to methanol (40 mL) at −10° C., and the solution was stirred at 0° C. for 30 minutes. To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol (15 mL). The reaction mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in methylene chloride (40 mL), and was treated with triethylamine (5.58 mL) at 0° C. for 1 hour. Water was added, and the mixture was washed with sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 341, 343 (M+H)+. After the addition The mixture was stirred for 2 hours then was stirred at room temperature for 30 minutes the mixture was filtered The filtrate was concentrated the solution was stirred at 0° C. for 30 minutes The reaction mixture was stirred at room temperature overnight was concentrated The residue was dissolved in methylene chloride (40 mL) was treated with triethylamine (5.58 mL) at 0° C. for 1 hour Water was added the mixture was washed with sodium bicarbonate, brine and water The organic phase was dried over magnesium sulfate filtered concentrated The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane)

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

Procedure: Add bis(triphenylphosphine)palladium (II) dichloride (93 mg, 0.13 mmol), copper (I) iodide (50 mg, 0.26 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (350 mg, 2.6 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (1.03 g, 3.4 mmol) in triethylamine (4.0 mL, 39.5 mmol). Stir at room temperature for 20 h then concentrate. Purify by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (750 mg, 93%). then concentrate Purify by silica gel chromatography eluting with 100:0 to 80:20 dichloromethane eluting with 75:25 to 60:40 hexanes

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

Procedure: Add bis(triphenylphosphine)palladium (II) dichloride (93 mg, 0.13 mmol), copper (I) iodide (50 mg, 0.26 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (350 mg, 2.6 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (1.03 g, 3.4 mmol) in triethylamine (4.0 mL, 39.5 mmol). Stir at room temperature for 20 h then concentrate. Purify by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (750 mg, 93%). then concentrate Purify by silica gel chromatography eluting with 100:0 to 80:20 dichloromethane eluting with 75:25 to 60:40 hexanes

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

Procedure: Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.11 mmol), copper (I) iodide (42 mg, 0.22 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (0.78 g, 2.6 mmol) in triethylamine (3.3 mL, 33 mmol). Stir at room temperature for 24 h then concentrate. Purify by silica gel chromatography, eluting with 75:25 dichloromethane:hexanes to 100:0 dichloromethane:hexanes to 95:5 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 95:5 to 90:10 hexanes:ethyl acetate, to give the title compound as a white solid (560 mg, 82%). then concentrate Purify by silica gel chromatography eluting with 75:25 dichloromethane eluting with 95:5 to 90:10 hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add at 0° C. a solution of sodium nitrite (2.0 g, 28.9 mmol) in water (15 mL) to a suspension of 3-bromo-4-fluorophenylamine (5.0 g, 26.3 mmol) in a 6 N aqueous solution of hydrochloric acid (25 mL) at 0° C. slowly over 10 min. Stir the mixture at 0° C. for 5 min. Add this solution to a solution of potassium iodide (4.37 g, 26.3 mmol) in water (125 mL) via syringe at 0° C. under nitrogen over 15 min. Stir at 0° C. for 30 min. Warm to room temperature. Extract with four times with dichloromethane (100 mL), dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 95:5 hexanes:ethyl acetate to give the title compound as a colorless oil (5.83 g, 74%). Stir at 0° C. for 30 min Warm to room temperature Extract with four times with dichloromethane (100 mL) dry (sodium sulfate) filter concentrate Purify by silica gel chromatography eluting with 100:0 to 95:5 hexanes

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-1-fluoro-4-iodobenzene (13.23 g, 44 mmol) in anhydrous tetrahydrofuran (30 mL) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 24.18 mL, 48.4 mmol) at −20° C. After the addition, the reaction mixture was stirred at 0° C. for 3 hours, and was added to a solution of 3,4,5,6-tetrahydrophthalic anhydride (6.08 g, 40 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. Thionyl chloride (10.4 mL, 142 mol) was added dropwise to methanol (40 mL) at −10° C., and the solution was stirred at 0° C. for 30 minutes. To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol (15 mL). The reaction mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in methylene chloride (40 mL), and was treated with triethylamine (5.58 mL) at 0° C. for 1 hour. Water was added, and the mixture was washed with sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 341, 343 (M+H)+. After the addition The mixture was stirred for 2 hours then was stirred at room temperature for 30 minutes the mixture was filtered The filtrate was concentrated the solution was stirred at 0° C. for 30 minutes The reaction mixture was stirred at room temperature overnight was concentrated The residue was dissolved in methylene chloride (40 mL) was treated with triethylamine (5.58 mL) at 0° C. for 1 hour Water was added the mixture was washed with sodium bicarbonate, brine and water The organic phase was dried over magnesium sulfate filtered concentrated The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-bromo-1-fluoro-4-iodobenzene (13.23 g, 44 mmol) in anhydrous tetrahydrofuran (30 mL) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 24.18 mL, 48.4 mmol) at −20° C. After the addition, the reaction mixture was stirred at 0° C. for 3 hours, and was added to a solution of 3,4,5,6-tetrahydrophthalic anhydride (6.08 g, 40 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. The mixture was stirred for 2 hours, and a saturated aqueous ammonium chloride solution was added to the reaction mixture, which then was stirred at room temperature for 30 minutes. Anhydrous magnesium sulfate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. Thionyl chloride (10.4 mL, 142 mol) was added dropwise to methanol (40 mL) at −10° C., and the solution was stirred at 0° C. for 30 minutes. To the thionyl chloride solution was then added the residue from the filtrate in anhydrous methanol (15 mL). The reaction mixture was stirred at room temperature overnight, and was concentrated. The residue was dissolved in methylene chloride (40 mL), and was treated with triethylamine (5.58 mL) at 0° C. for 1 hour. Water was added, and the mixture was washed with sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 341, 343 (M+H)+. After the addition The mixture was stirred for 2 hours then was stirred at room temperature for 30 minutes the mixture was filtered The filtrate was concentrated the solution was stirred at 0° C. for 30 minutes The reaction mixture was stirred at room temperature overnight was concentrated The residue was dissolved in methylene chloride (40 mL) was treated with triethylamine (5.58 mL) at 0° C. for 1 hour Water was added the mixture was washed with sodium bicarbonate, brine and water The organic phase was dried over magnesium sulfate filtered concentrated The residue was separated by flash chromatography (10-35% gradient ethyl acetate in hexane)

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

Procedure: Add bis(triphenylphosphine)palladium (II) dichloride (93 mg, 0.13 mmol), copper (I) iodide (50 mg, 0.26 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (350 mg, 2.6 mmol) to a solution of 2-bromo-1-fluoro-4-iodobenzene, (prepared as described in PREPARATION 43), (1.03 g, 3.4 mmol) in triethylamine (4.0 mL, 39.5 mmol). Stir at room temperature for 20 h then concentrate. Purify by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (750 mg, 93%). then concentrate Purify by silica gel chromatography eluting with 100:0 to 80:20 dichloromethane eluting with 75:25 to 60:40 hexanes