2-Bromo-4-methoxy-phenylamine

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

Procedure: 2-Bromo-4-methoxyaniline (1.2 g, 6 mmol; Desc. 7a) was dissolved in glacial acetic acid (10 ml) and heated to 75° C. To this solution was added triethylorthoformate (2.5 ml, 15 mmol) and heated at 75° C. for 1 hour. Sodium azide (1.16 g, 18 mmol) was added portionwise and reaction heated at 75° C. for a further 3 hours and stirred at ambient temperature for 24 hours. The reaction was diluted with water (100 ml) and product extracted into ethyl acetate (3×70 ml). The combined organics were washed with brine (100 ml), dried over magnesium sulphate and the solvent removed in vacuo. Medium pressure chromatography eluting with 40% ethyl acetate/hexane afforded the title compound as a white solid (1.5 g, 90%). 1H NMR (360 MHz, d6 -DMSO) δ 3.88 (3H, s), 7.20 (1H, dd, J 2.7 Hz, J 8.8 Hz), 7.51 (1H, d, J 2.7 Hz), 7.68 (1H, d, J 8.8 Hz), 9.83 (1H, s). heated at 75° C. for 1 hour reaction heated at 75° C. for a further 3 hours extracted into ethyl acetate (3×70 ml) The combined organics were washed with brine (100 ml) dried over magnesium sulphate the solvent removed in vacuo Medium pressure chromatography eluting with 40% ethyl acetate/hexane

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

Procedure: To a solution of p-anisidine (10 g, 0.08 mol) and sodium carbonate (17.2 g, 0.16 mol) in dichloromethane (400 ml) was added a solution of bromine (3.8 ml), 0.072 mol) in dichloromethane (200 ml) dropwise. The reaction was stirred at ambient temperature for 45 minutes, diluted with dichloromethane (200 ml) and washed with water (2×200 ml). The organic layer was dried over magnesium sulphate, and the solvent was removed in vacuo to yield a dark brown oil. Chromatography on silica eluting with a gradient of ethyl acetate in hexane (10%, 15% and 20%) afforded the title compound as a dark red oil (4 g, 25%), m/z (ES+) 202 (M30 +H, 100%). 1H NMR (250 MHz, CDCl3) δ 3.73 (3H, s), 3.78 (2H, broad s), 6.72 (2H, t, J 1.2 Hz), 7.00 (1H, q, J 1.26 Hz). washed with water (2×200 ml) The organic layer was dried over magnesium sulphate the solvent was removed in vacuo to yield a dark brown oil

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

Procedure: A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol) in 125 mL anhydrous methanol was treated with dimethyl acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was heated at reflux under nitrogen for 8 hours. The reaction mixture was cooled, concentrated, and redissolved in hot methanol. Yellow crystals were obtained by filtration (6.93 g, 68%). A second crop of crystals was obtained from ethanol (0.942 g, 9%). The filtrates were combined and purified by flash chromatography on silica gel using 4:1 hexanes:ethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%. 1H NMR (300 MHz, DMSO, d6) δ 9.60 (s, 1H, NH), 7.26 (d, 1H, Jm=2.7 Hz, ArH3), 6.93 (dd, 1H, Jo=8.7, Jm=2.7 Hz, ArH5), 6.87 (d, 1H, Jo=8.7 Hz, ArH6), 5.34 (s, 1H, C═CH), 3.76 (s, 3H, OCH3), 3.68 (s, 3H, CHCO2CH3), 3.66 (s, 3H, CNCO2CH3); Mass Spec.: calc. for [C13H14BrNO5+H]+ Theor. m/z=344, 346; Obs. 344, 346. the solution was heated at reflux under nitrogen for 8 hours The reaction mixture was cooled concentrated redissolved in hot methanol Yellow crystals were obtained by filtration (6.93 g, 68%) purified by flash chromatography on silica gel using 4:1 hexanes ethyl acetate to afford an additional 1.63 g (16%) for a total yield of 93%