3-bromo-4-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:

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

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

Procedure: A mixture 2-bromo-4-nitroanisole (15 g, 64.6 mmol) and iron powder (27.3 g, 0.49M) in water (100 ml) and glacial acetic acid (25 ml) was stirred at reflux for 2h. The mixture was allowed to cool to ambient temperature and filtered through a pad of Hyflo™ (washed with 25% acetic acid/water). The filtrate was extracted with ethyl acetate (2×250 ml) and the organic layer was dried over sodium sulphate. Removal of the solvent in vacuo left an oil which was chromatographed on silica in 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%). MS (ES+) 202 (M+1). at reflux for 2h filtered through a pad of Hyflo™ (washed with 25% acetic acid/water) The filtrate was extracted with ethyl acetate (2×250 ml) the organic layer was dried over sodium sulphate Removal of the solvent in vacuo left an oil which was chromatographed on silica in 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%)

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

Procedure: A solution of sodium nitrite (3.16 g, 45.8 mmol) in water (30 ml) was added dropwise over 30 minutes to a stirred, cooled (-5° C.) suspension of 4-amino-2-bromoanisole (Description 7a) (7.31 g, 36.2 mmol) in concentrated hydrochloric acid (50 ml), maintaining the temperature below 0° C. The mixture was stirred at ca. 0° C. for 30 minutes then added portionwise to a suspension of tin (II) chloride dihydrate (36.87 g, 163 mmol) in concentrated hydrochloric acid (50 ml) at -10° C. The resulting thick paste was stirred at -2° C. for 15 min., allowed to warm to room temperature over 20 minutes and stirred at room temperature for a further 20 min. The reaction mixture was recooled, basified with aqueous sodium hydroxide (10M) and extracted with ethyl acetate (2×250 ml). The ex-tracts were washed with brine (250 ml), combined, dried (MgSO4) and the solvent was evaporated under reduced pressure to give 3-bromo-4-methoxphenylhydrazine (7.27 g, 93%). 1H NMR (250 MHz, CDCl3) δ 3.84 (3H, s), 6.75 (1H, dd, J=8.8, 2.6 Hz), 6.83 (1H, d, J=8.8 Hz), and 7.11 (1H, d, J=2.6 Hz). cooled maintaining the temperature below 0° C The resulting thick paste was stirred at -2° C. for 15 min. to warm to room temperature over 20 minutes stirred at room temperature for a further 20 min extracted with ethyl acetate (2×250 ml) The ex-tracts were washed with brine (250 ml) dried (MgSO4) the solvent was evaporated under reduced pressure to give 3-bromo-4-methoxphenylhydrazine (7.27 g, 93%)

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

Procedure: A solution of sodium nitrite (3.16 g, 45.8 mmol) in water (30 ml) was added dropwise over 30 minutes to a stirred, cooled (-5° C.) suspension of 4-amino-2-bromoanisole (Description 7a) (7.31 g, 36.2 mmol) in concentrated hydrochloric acid (50 ml), maintaining the temperature below 0° C. The mixture was stirred at ca. 0° C. for 30 minutes then added portionwise to a suspension of tin (II) chloride dihydrate (36.87 g, 163 mmol) in concentrated hydrochloric acid (50 ml) at -10° C. The resulting thick paste was stirred at -2° C. for 15 min., allowed to warm to room temperature over 20 minutes and stirred at room temperature for a further 20 min. The reaction mixture was recooled, basified with aqueous sodium hydroxide (10M) and extracted with ethyl acetate (2×250 ml). The ex-tracts were washed with brine (250 ml), combined, dried (MgSO4) and the solvent was evaporated under reduced pressure to give 3-bromo-4-methoxphenylhydrazine (7.27 g, 93%). 1H NMR (250 MHz, CDCl3) δ 3.84 (3H, s), 6.75 (1H, dd, J=8.8, 2.6 Hz), 6.83 (1H, d, J=8.8 Hz), and 7.11 (1H, d, J=2.6 Hz). cooled maintaining the temperature below 0° C The resulting thick paste was stirred at -2° C. for 15 min. to warm to room temperature over 20 minutes stirred at room temperature for a further 20 min extracted with ethyl acetate (2×250 ml) The ex-tracts were washed with brine (250 ml) dried (MgSO4) the solvent was evaporated under reduced pressure to give 3-bromo-4-methoxphenylhydrazine (7.27 g, 93%)

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

Procedure: Acetic anhydride (3.11 ml, 3.37 g, 33 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 3-bromo-4methoxyaniline (6.06 g, 30 mmol) in dichloromethane (60 ml). The mixture was stirred at room temperature for 90 minutes, methanol (10 ml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous hydrochloric acid (1M, 100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate (20 ml)/hexane (50 ml) and the solid was collected and dried in vacuo to give the title compound as a tan solid (6.41 g, 88%), 1H NMR (360 MHz, CDCl3) δ 7.68 (1H, d, J=2.5 Hz), 7.45 (1H, dd, J=8.8, 2.5 Hz), 7.36 (1H, br s), 6.84 (1H, d, J=8.8 Hz), 3.87 (3H, s), and 2.16 (3H, s). the mixture was stirred at room temperature for 30 minutes The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added the mixture was extracted with ethyl acetate (3×100 ml) The combined organic fractions were washed with aqueous hydrochloric acid (1M, 100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml) dried (MgSO4) evaporated under reduced pressure The residue was recrystallized from ethyl acetate (20 ml)/hexane (50 ml) the solid was collected dried in vacuo

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

Procedure: 4-Amino-2-bromoanisole (4.7 g) was suspended in triethylorthoformate (50 ml), trifluoroacetic acid (1.8 ml) was added, and the reaction was heated at reflux for 36 hrs. The triethylorthoformate was removed in vacuo to afford a brown oil, which was dissolved in acetic acid (25 ml), sodium azide (2.25 g) was added and the mixture was heated for 4 hrs. The solvent was removed in vacuo and the residue dispersed between ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with water, brine, dried (MgSO4) and the solvent removed. Purification on flash silica eluting with 100% dichloromethane→0.25%→0.5%→0.75% methanol in dichloromethane afforded the title compound (4 g) as a brown solid. 1H NMR (250 MHz, DMSO) δ 4.06 (3H, s), 7.48 (1H, d, J=8.9) 8.03 (1H, dd, J=8.9, 2.7), 8.31 (1H, d, J=2.5), 10.15 (1H, s). the reaction was heated at reflux for 36 hrs The triethylorthoformate was removed in vacuo to afford a brown oil, which the mixture was heated for 4 hrs The solvent was removed in vacuo the residue dispersed between ethyl acetate and saturated sodium hydrogen carbonate The organic layer was washed with water, brine dried (MgSO4) the solvent removed Purification on flash silica eluting with 100% dichloromethane→0.25%→0.5%→0.75% methanol in dichloromethane

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

Procedure: A mixture 2-bromo-4-nitroanisole (15 g, 64.6 mmol) and iron powder (27.3 g, 0.49 mol) in water (100 ml) and glacial acetic acid (25 ml) was stirred at reflux for 2 hours. The mixture was allowed to cool to ambient temperature and filtered through a pad of Hyflo™ (washed with 25% acetic acid/water). The filtrate was extracted with ethyl acetate (2×250 ml) and the organic layer was dried over sodium sulphate. Removal of the solvent in vacuo left an oil which was chromatographed on silica eluting with 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%). Mass Spec ES+ 202 M+1. at reflux for 2 hours filtered through a pad of Hyflo™ (washed with 25% acetic acid/water) The filtrate was extracted with ethyl acetate (2×250 ml) the organic layer was dried over sodium sulphate Removal of the solvent in vacuo left an oil which was chromatographed on silica eluting with 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%)

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

Procedure: A mixture 2-bromo-4-nitroanisole (15 g, 64.6 mmol) and iron powder (27.3 g, 0.49 mol) in water (100 ml) and glacial acetic acid (25 ml) was stirred at reflux for 2 hours. The mixture was allowed to cool to ambient temperature and filtered through a pad of Hyflo™ (washed with 25% acetic acid/water). The filtrate was extracted with ethyl acetate (2×250 ml) and the organic layer was dried over sodium sulphate. Removal of the solvent in vacuo left an oil which was chromatographed on silica eluting with 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%). Mass Spec ES+ 202 M+1. at reflux for 2 hours filtered through a pad of Hyflo™ (washed with 25% acetic acid/water) The filtrate was extracted with ethyl acetate (2×250 ml) the organic layer was dried over sodium sulphate Removal of the solvent in vacuo left an oil which was chromatographed on silica eluting with 40% ethyl acetate/hexane giving the title compound as a brown solid (10.32 g, 79%)

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

Procedure: To a mixture of 2-bromo-4-nitroanisole (5.0 g, 21.5 mmol, Lancaster), ethanol (25 mL) and water (25 mL), was added powdered iron (4.8 g, 86 mmol) and 12 N HCl (0.5 mL). The solution was heated at reflux for 20 minutes. 1N NaOH (10 mL) was added and the reaction mixture was filtered through a pad of celite while still hot, and then rinsed with ethanol (2×50 mL). The ethanol was removed under reduced pressure and the residue extracted with dichloromethane (2×100 mL). The organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography on silica gel (75 g) eluting with dichloromethane, to give 4-amino-2-bromoanisole as a light tan solid. The solution was heated at reflux for 20 minutes the reaction mixture was filtered through a pad of celite while still hot, and then rinsed with ethanol (2×50 mL) The ethanol was removed under reduced pressure the residue extracted with dichloromethane (2×100 mL) The organic extracts were dried (Na2SO4) concentrated The crude product was purified by flash chromatography on silica gel (75 g) eluting with dichloromethane