4-BROMO-3-METHOXYANILINE

White to brown crystalline powder

To a solution of 1-bromo-2-methoxy-4-nitrobenzene (23 g, 99.6 mmol) in THF (200 mL) was added ammonium chloride (64 g, 1.2 mol) and zinc dust (78.1 g, 1.2 mol) and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth (Celite®) bed and the filtrate was concentrated under reduced pressure. The residue was partitionedbetween water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 4-bromo-3-methoxyaniline (17.4 g, 87percent yield) as a yellow solid: ‘F1NMR(DMSO-d6. 400 MI-Iz) ö 7.1 (d, 1H), 6.31 (s, 1H), 6.1 (d. IH), 5.27 (bs, 2H), 3, 72 (s, 3H) ppm.To a mixture of 16f(358 mg, 1.61 mmol) and Zn powder (697 mg, 10.66 mmol) inMeOH (16 mL) was added AcOH (4.8 mL). The whole wasstirred at r.t. for 4.5 h and then extracted with AcOEt threetimes. The organic layer was combined, washed with waterand brine, dried and concentrated. Column chromatography(n-hexane : AcOEt=3 : 1 to 2 : 1) of the residue gave the titlecompound (205 mg, 1.01 mmol, 63percent) as a yellow paste.To a 0 °C mixture of 3-methoxyaniline (3.00 g, 24.4 mmol) in anhydrous acetonitrile (24mL) was added a solution of NBS (4.34 g, 24.4 mmol) in anhydrous acetonitrile (24 mL).The solution was allowed to reach ambient temperature and stirred for 20 hours. The reactionmixture was quenched with H2O (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated aq. NaCl solution (50 mL), dried overanhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified bysilica-gel column chromatography (n-pentan/EtOAc 7/3, Rf = 0.33). This gave 1.89 g (9.36mmol, 39 percent) of 4-bromo-3-methoxyaniline as a pale solid, mp 94 - 96 °C (lit. [2] 93 - 94°C);m-Anisidine (5.00 g, 40.6 mmol) was dissolved in chloroform (40 mL) and the solution was chilled to 5 °C. N-Bromosuccinimide (7.23 g, 40.6 mmol) was added portionwise to the chilled solution over a 1 h period and the mixture was then stirred for another 4 h in an ice bath at 5-10 °C. The reaction mixture was allowed to warm at room temperature and stirring was continued overnight. The mixture was washed with sodium hydroxide (2 M, 50 mL), followed by water (60 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to afford a dark brown viscous liquid. The crude material was chromatographed (silica gel, dichloromethane/hexane 2:1) to afford a mixture of 2-bromo-5-methoxyaniline and 2, 4-dibromo-5-methoxyaniline as the first major band eluted. Subsequently, another major band was eluted to afford 4-bromo-3-methoxyaniline (860 mg, 10percent) as peach coloured crystals: mp 97-98 °C (lit.