5-bromo-2-methoxyaniline

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

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

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

Procedure: A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder (113.7 g) in ethanol (1.51) was heated to reflux and treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for a further 3 hours the reaction mixture was cooled to room temperature then filtered through hyflosupercel. The filtrate was evaporated and the residue was treated with saturated sodium bicarbonate solution (21) then filtered. The solid was washed with water then recrystallised from cyclohexane to give the title compound (61.98 g) as a pale brown solid, m.p. 93-93° C. was heated to reflux After refluxing for a further 3 hours the reaction mixture then filtered through hyflosupercel The filtrate was evaporated the residue was treated with saturated sodium bicarbonate solution (21) then filtered The solid was washed with water then recrystallised from cyclohexane

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

Procedure: A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder (113.7 g) in ethanol (1.51) was heated to reflux and treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for a further 3 hours the reaction mixture was cooled to room temperature then filtered through hyflosupercel. The filtrate was evaporated and the residue was treated with saturated sodium bicarbonate solution (21 ) then filtered. The solid was washed with water then recrystallised from cyclohexane to give the title compound (61.98 g) as a pale brown solid, m.p. 93-93° C. was heated to reflux After refluxing for a further 3 hours the reaction mixture then filtered through hyflosupercel The filtrate was evaporated the residue was treated with saturated sodium bicarbonate solution (21 ) then filtered The solid was washed with water then recrystallised from cyclohexane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100° C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100° C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 m, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443. The mixture was cooled to ambient temperature the mixture was extracted with ethyl acetate (3×25 ml) The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) The organic solution was dried over magnesium sulfate filtered the filtrate evaporated under reduced pressure to give a residue Purification of the material by flash chromatography on silica gel

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100° C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100° C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 m, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443. The mixture was cooled to ambient temperature the mixture was extracted with ethyl acetate (3×25 ml) The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) The organic solution was dried over magnesium sulfate filtered the filtrate evaporated under reduced pressure to give a residue Purification of the material by flash chromatography on silica gel

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

Procedure: A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20° C. After this time the theoretical amount of hydrogen had been absorbed (2.5 l), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+). After this time the theoretical amount of hydrogen had been absorbed (2.5 l) so the catalyst was filtered off the solvent evaporated

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

Procedure: A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20° C. After this time the theoretical amount of hydrogen had been absorbed (2.5 1), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+). After this time the theoretical amount of hydrogen had been absorbed (2.5 1) so the catalyst was filtered off the solvent evaporated

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

Procedure: To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 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 (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.365 g, 85% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

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

Procedure: To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 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 (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.365 g, 85% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

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

Procedure: To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 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 (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.365 g, 85% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)

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

Procedure: To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 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 (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.365 g, 85% yield). The mixture was purged with nitrogen The reaction mixture was concentrated purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane)