4-bromo-2-methoxyaniline

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

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

Procedure: 2-Methoxyaniline (o-anisidine) (15 g, 0.122 mol) was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (50 g, 0.122 mol) by dissolving the aniline in 250 ml of methylene chloride, chilling the solution to -10°, and slowly adding and brominating agent, keeping the temperature below -5°. The reaction was allowed to warm at room temperature, and then washed with 2N sodium hydroxide (2×75 ml), then washed with water (2×25 ml), dried over magnesium sulfate, and evaporated to dryness. The product was purified on a silica gel column, eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether). Anal. Calcd for C7H8BrNO: C, 41.61; H, 3.99; Br, 39.55; N, 6.93. Found: C, 41.59; H, 3.99; Br, 39.49; N, 6.92. chilling the solution to -10° slowly adding the temperature below -5° washed with 2N sodium hydroxide (2×75 ml) washed with water (2×25 ml) dried over magnesium sulfate evaporated to dryness The product was purified on a silica gel column eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether)

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

Procedure: 2-Methoxyaniline (o-anisidine) (15 g, 0.122 mol) was brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (50 g, 0.122 mol) by dissolving the aniline in 250 ml of methylene chloride, chilling the solution to -10°, and slowly adding and brominating agent, keeping the temperature below -5°. The reaction was allowed to warm at room temperature, and then washed with 2N sodium hydroxide (2×75 ml), then washed with water (2×25 ml), dried over magnesium sulfate, and evaporated to dryness. The product was purified on a silica gel column, eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether). Anal. Calcd for C7H8BrNO: C, 41.61; H, 3.99; Br, 39.55; N, 6.93. Found: C, 41.59; H, 3.99; Br, 39.49; N, 6.92. chilling the solution to -10° slowly adding the temperature below -5° washed with 2N sodium hydroxide (2×75 ml) washed with water (2×25 ml) dried over magnesium sulfate evaporated to dryness The product was purified on a silica gel column eluted with methylene chloride giving 23.68 g (96%) of the title compound, mp 56.5°-58° (petroleum ether)

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

Procedure: Hydroxylamine hydrochloride (6.67 g, 96 mmol) in water (15 mL) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol (6.96 g, 36 mmol) and sodium sulfate (38.3 g, 270 mmol) in water (45 mL) and 2N HCl (30 mL). The mixture was stirred at 60° C. for 20 min. 4-Bromo-2-methoxybenzenamine (6.06 g, 30 mol) in 2N HCl (30 mL) was added, and the mixture was heated to 90° C. for 2 h. The mixture was cooled to room temperature. The solid was collected by filtration, washed with water, and air dried to afford the title compound (5.55 g, crude, 68% yield). This material was used in the next step without further purification. MS (ESI) m/e [M+1]+ 273, 275. the mixture was heated to 90° C. for 2 h The mixture was cooled to room temperature The solid was collected by filtration washed with water, and air dried

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

Procedure: Hydroxylamine hydrochloride (6.67 g, 96 mmol) in water (15 mL) was added to a suspension of 2,2,2-trichloro-1-ethoxyethanol (6.96 g, 36 mmol) and sodium sulfate (38.3 g, 270 mmol) in water (45 mL) and 2N HCl (30 mL). The mixture was stirred at 60° C. for 20 min. 4-Bromo-2-methoxybenzenamine (6.06 g, 30 mol) in 2N HCl (30 mL) was added, and the mixture was heated to 90° C. for 2 h. The mixture was cooled to room temperature. The solid was collected by filtration, washed with water, and air dried to afford the title compound (5.55 g, crude, 68% yield). This material was used in the next step without further purification. MS (ESI) m/e [M+1]+ 273, 275. the mixture was heated to 90° C. for 2 h The mixture was cooled to room temperature The solid was collected by filtration washed with water, and air dried

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

Procedure: 4-Amino-3-methoxy-3′-nitro-biphenyl was prepared from 4-bromo-2-methoxyaniline (Synth. Commun. 23(6), 855-9(1993)) and 3-nitrophenyl boronic acid according to the procedure of Example 5. White solid: mp 167-168° C.; 1H-NMR (CDCl3) δ 8.39 (t, 1H, J=1.97 Hz), 8.13-8.09 (m, 1H), 7.88-7.84 (m, 1H), 7.55 (t, 1H, J=8.0 Hz), 7.09 (dd, 1H, J=7.98, 1.94 Hz), 7.04 (d, 1H, J=1.89 Hz), 6.80 (d, 1H, J=8.04 Hz), 4.0 (s, 5H).

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

Procedure: To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL DMF was added diethylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(diethylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) the fractions were concentrated the solution was concentrated

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

Procedure: To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) the fractions were concentrated the solution was concentrated

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

Procedure: To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) the fractions were concentrated the solution was concentrated

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

Procedure: To a solution of 4-bromo-2-methoxyaniline (0.100 g, 0.495 mmol) in 2 mL DMF was added dipropylphosphine oxide (0.0730 g, 0.544 mmol), palladium acetate (5.6 mg, 0.025 mmol), XANTPHOS (17.2 mg, 0.030 mmol), and potassium phosphate (0.116 g, 0.544 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) and the fractions were concentrated. The residue was acidified with 2.5 M HCl in ethanol and the solution was concentrated to provide 4-(dipropylphosphoryl)-2-methoxyaniline as the hydrochloride salt (0.132 g, 91% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-12% 7N ammonia in methanol:dichloromethane) the fractions were concentrated the solution was concentrated

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

Procedure: A solution of 4-bromo-2-methoxyaniline (8.096 g, 40.04 mmol) in dichloromethane (100 mL) was treated with triethylamine (6.06 g, 60.06 mmol), then hydrocinnamoyl chloride (7.08 g, 42.04 mmol). The reaction mixture was stirred for 48 h under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added. The precipitate was filtered, and the filtrate was evaporated to a solid under reduced pressure. The solid was dissolved in ethyl acetate, and washed with 5 N hydrochloric acid solution, 5 N sodium hydroxide solution, water and brine. The crude material (two spots by thin layer chromatography) was triturated with methanol. The un-dissolved solid was filtered to give 6 g (50%) of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.17 (s, 1H), 7.92-7.90 (m, 1H), 7.30-7.24 (m, 4H), 7.20-7.18 (m, 2H), 7.09-7.07 (m, 1H), 3.83 (s, 3H), 2.90-2.86 (m, 2H), 2.72-2.69 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.491 min (97%). The solvent was removed under reduced pressure, and ethyl acetate was added The precipitate was filtered the filtrate was evaporated to a solid under reduced pressure The solid was dissolved in ethyl acetate washed with 5 N hydrochloric acid solution, 5 N sodium hydroxide solution, water and brine The crude material (two spots by thin layer chromatography) was triturated with methanol The un-dissolved solid was filtered

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

Procedure: A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at −5° C. Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature. Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned. The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89%) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89%). the addition of the brominating agent the dry ice/acetone bath was removed Sodium hydroxide solution (1N) was added to the reaction mixture the layers were partitioned The organic layer was washed with 1 N sodium hydroxide solution (1 L) washed with water (750 mL) dried over magnesium sulfate filtered evaporated under reduced pressure