4-bromo-1-chloro-2-iodobenzene

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

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

Procedure: Following the method described in Example 81, 4-bromo-1-chloro-2-iodo-benzene, isopropylmagnesium chloride and trimethylborate provided 5-bromo-2-chloro-phenylboronic acid (36% yield).

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of copper (II) chloride (1.62 g, 12.0 mmol) and tert-butyl nitrite (15.0 mmol) in acetonitrile (40 ml), heated at 60° C., was added a solution of 4-bromo-2-iodo-phenylamine (2.98 g, 10.0 mmol) in acetonitrile (10 ml) dropwise over 50 minutes. After stirring at 60° C. for 1 hour, the mixture was poured into 20% hydrochloric acid (200 ml) and extracted with ether (2×30 ml). The crude product was purified by flash chromatography on silica gel eluting with hexane to provide 4-bromo-1-chloro-2-iodo-benzene (2.4 g, 76% yield). extracted with ether (2×30 ml) The crude product was purified by flash chromatography on silica gel eluting with hexane

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

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

Procedure: Following the method described in Example 81, 4-bromo-1-chloro-2-iodo-benzene, isopropylmagnesium chloride and trimethylborate provided 5-bromo-2-chloro-phenylboronic acid (36% yield).

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of copper (II) chloride (1.62 g, 12.0 mmol) and tert-butyl nitrite (15.0 mmol) in acetonitrile (40 ml), heated at 60° C., was added a solution of 4-bromo-2-iodo-phenylamine (2.98 g, 10.0 mmol) in acetonitrile (10 ml) dropwise over 50 minutes. After stirring at 60° C. for 1 hour, the mixture was poured into 20% hydrochloric acid (200 ml) and extracted with ether (2×30 ml). The crude product was purified by flash chromatography on silica gel eluting with hexane to provide 4-bromo-1-chloro-2-iodo-benzene (2.4 g, 76% yield). extracted with ether (2×30 ml) The crude product was purified by flash chromatography on silica gel eluting with hexane

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-1-chloro-2-iodobenzene (10.35 g, 33 mmol) is dissolved in anhydrous tetrahydrofuran (60 ml) and the solution is cooled to −75° C. under an atmosphere of argon. Isopropylmagnesium chloride (17.1 ml, 34 mmol, 2M solution in tetrahydrofuran) is added dropwise over 30 minutes, maintaining the internal temperature below −70° C. by external cooling. Once the addition is complete, the reaction mixture is stirred at approximately −70° C. for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then cooled to −78° C. and trimethyl borate (7.3 ml, 65 mmol) is added dropwise. The mixture is stirred at −78° C. for 30 minutes and then the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. 2M Aqueous hydrochloric acid (30 ml) is added, and the crude product is extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with hexane gives 5-bromo-2-chlorophenylboronic acid (6.16 g) as an off-white solid. maintaining the internal temperature below −70° C. by external cooling Once the addition to warm to room temperature stirred for 1 hour The reaction mixture is then cooled to −78° C. The mixture is stirred at −78° C. for 30 minutes the cooling bath is removed the mixture is stirred at room temperature for 1.5 hours 2M Aqueous hydrochloric acid (30 ml) is added the crude product is extracted with ethyl acetate The organic phase is washed with water and brine dried over anhydrous magnesium sulfate filtered the filtrate evaporated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl nitrite (11.1 ml, 93.3 mmol) is added to a suspension of copper(II) chloride (10.04 g, 75 mmol) in acetonitrile (224 ml) and the mixture is heated with stirring to 60° C. A solution of 4-bromo-2-iodoaniline (18.54 g, 62 mmol) in acetonitrile (56 ml) is added dropwise over about an hour, and once the addition is complete the mixture is stirred at 60° C. for 2 hours. The mixture is cooled to room temperature, poured into 20% aqueous hydrochloric acid (1.3 liters) and extracted with diethyl ether (1.5 liters). The organic extract is separated and the aqueous re-extracted with ether (1 liter). The organic extracts are combined and dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 4-bromo-1-chloro-2-iodobenzene (8.62 g) as an oil. the mixture is heated once the addition is stirred at 60° C. for 2 hours The mixture is cooled to room temperature extracted with diethyl ether (1.5 liters) The organic extract is separated the aqueous re-extracted with ether (1 liter) dried over anhydrous magnesium sulfate filtered the filtrate evaporated in vacuo The residue is further purified by column chromatography on silica gel

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-1-chloro-2-iodobenzene (10.35 g, 33 mmol) is dissolved in anhydrous tetrahydrofuran (60 ml) and the solution is cooled to −75° C. under an atmosphere of argon. Isopropylmagnesium chloride (17.1 ml, 34 mmol, 2M solution in tetrahydrofuran) is added dropwise over 30 minutes, maintaining the internal temperature below −70° C. by external cooling. Once the addition is complete, the reaction mixture is stirred at approximately −70° C. for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then cooled to −78° C. and trimethyl borate (7.3 ml, 65 mmol) is added dropwise. The mixture is stirred at −78° C. for 30 minutes and then the cooling bath is removed and the mixture stirred at room temperature for 1.5 hours. 2M Aqueous hydrochloric acid (30 ml) is added, and the crude product is then extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with hexane gives 5-bromo-2-chlorophenylboronic acid (6.16 g) as an off-white solid. maintaining the internal temperature below −70° C. by external cooling Once the addition to warm to room temperature stirred for 1 hour The reaction mixture is then cooled to −78° C. The mixture is stirred at −78° C. for 30 minutes the cooling bath is removed the mixture stirred at room temperature for 1.5 hours 2M Aqueous hydrochloric acid (30 ml) is added the crude product is then extracted with ethyl acetate The organic phase is washed with water and brine dried over anhydrous magnesium sulfate filtered the filtrate evaporated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl nitrite (3 ml, 25 mmol) is added to a suspension of copper(II) chloride (2.71 g, 20 mmol) in acetonitrile (60 ml) and the mixture is heated with stirring to 60° C. A solution of 4-bromo-2-iodoaniline (5 g, 17 mmol) in acetonitrile (15 ml) is added dropwise, and once the addition is complete the mixture is stirred at 60° C. for 2.5 hours. The mixture is cooled to room temperature, poured into 20% aqueous hydrochloric acid and extracted with diethyl ether. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 4-bromo-1-chloro-2-iodobenzene (4.32 g) as an oil. the mixture is heated once the addition is stirred at 60° C. for 2.5 hours The mixture is cooled to room temperature extracted with diethyl ether The organic extract is dried over anhydrous magnesium sulfate filtered the filtrate evaporated in vacuo The residue is further purified by column chromatography on silica gel

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

Procedure: The compound was prepared according to Liu et al. J. Org. Chem. 2005, 70, 10135. 4-(1H-Imidazol-4-yl)-benzonitrile (75 mg, 0.44 mmol; prepared from 4-(2-bromo-acetyl)-benzonitrile using the method of Lynch et al. J. Am. Chem. Soc. 1994, 116, 11030), 4-bromo-1-chloro-2-iodobenzene (169 mg, 0.532 mmol), Cs2CO3 (577 mg, 1.77 mmol), CuI (3 mg, 0.013 mmol), 8-hydroxyquinoline (2 mg, 0.013 mmol), and DMF/H2O (2 mL; 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150° C. for 30 min. The contents were then filtered and concentrated to dryness affording intermediate 5-bromo-2-chlorophenyl)-1H-imidazol-4-yl]-benzonitrile (68 mg, 43%). The compound was prepared fitted with magnetic stir bar irradiation at 150° C. for 30 min The contents were then filtered concentrated to dryness affording intermediate 5-bromo-2-chlorophenyl)-1H-imidazol-4-yl]-benzonitrile (68 mg, 43%)

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-1-chloro-2-iodobenzene (10.35 g, 33 mmol) is dissolved in anhydrous tetrahydrofuran (60 ml) and the solution is cooled to −75° C. under an atmosphere of argon. Isopropylmagnesium chloride (17.1 ml, 34 mmol, 2M solution in tetrahydrofuran) is added dropwise over 30 minutes, maintaining the internal temperature below −70° C. by external cooling. Once the addition is complete, the reaction mixture is stirred at approximately −70° C. for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is then cooled to −78° C. and trimethyl borate (7.3 ml, 65 mmol) is added dropwise. The mixture is stirred at −78° C. for 30 minutes and then the cooling bath is removed and the mixture stirred at room temperature for 1.5 hours. 2M Aqueous hydrochloric acid (30 ml) is added, and the crude product is then extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. Trituration with hexane gives 5-bromo-2-chlorophenylboronic acid (6.16 g) as an off-white solid. maintaining the internal temperature below −70° C. by external cooling Once the addition to warm to room temperature stirred for 1 hour The reaction mixture is then cooled to −78° C. The mixture is stirred at −78° C. for 30 minutes the cooling bath is removed the mixture stirred at room temperature for 1.5 hours 2M Aqueous hydrochloric acid (30 ml) is added the crude product is then extracted with ethyl acetate The organic phase is washed with water and brine dried over anhydrous magnesium sulfate filtered the filtrate evaporated in vacuo