4-bromo-3-fluoro-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:

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

Procedure: To 4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFA and acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate (3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. and heated for 24 h. It was then diluted to water, extracted with ethyl acetate. The product was obtained by flash column as a yellow solid (450 mg, 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3H) 7.40 (dd, J=9.0, 6.2 Hz, 1H) 7.54 (dd, J=9.0, 1.9 Hz, 1H). heated for 24 h extracted with ethyl acetate

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

Procedure: To 3-fluoro-2-methoxyaniline (2.8 g, 20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) in acetic acid (10 mL) dropwise. The reaction mixture was stirred at rt. for 30 min. Solid was filtered and washed with acetic acid to give the HBr salt. It was then dissolved in water, basified by addition of KOH, extracted with ethyl acetate. The organic layer was dried and concentrated to give a white solid (2.8 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3H) 6.42 (dd, J=8.6, 1.8 Hz, 1H) 7.01 (dd, J=8.6, 7.1 Hz, 1H). [M+H] calc'd for C7H7BrFNO, 222. found 222. Solid was filtered washed with acetic acid

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

Procedure: To a solution of 2-methoxy-3-fluoroaniline (2.18 g, 15.46 mmol) in AcOH (10 mL) was added a solution of bromine (1.98 g, 12.37 mmol) in AcOH (2 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and washed with acetic acid to give the title and a di-bromo-compound as the HBr salt. The solid (2.53 g) was dissolved in water, basified by addition of KOH, and extracted with EtOAc. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with 15% EtOAc in cyclohexanes to give the title compound as white solid (1.24 g, 36%). The resulting solid was filtered washed with acetic acid to give the title extracted with EtOAc The organic layer was dried with Na2SO4 concentrated in vacuo The residue was purified by Biotage silica gel column chromatography eluting with 15% EtOAc in cyclohexanes

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

Procedure: To a solution of 2-methoxy-3-fluoroaniline (Compound 147I, 7.70 g, 54.6 mmol) in AcOH (45.0 mL) was added a solution of bromine (6.98 g, 43.6 mmol) in AcOH (45.0 mL) dropwise. The reaction mixture was stirred at rt for 30 minutes. The resulting solid was filtered and washed with acetic acid to give the HBr salt of the desired product. The solid was dissolved in water (15 mL), basified by addition of KOH, and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a white solid. The crude material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→70:30) as eluent to yield the desired product as a white solid, 6.536 mg (54% yield). 1H NMR (CDCl3, 400 MHz): δ=3.93 (d, J=1.52 Hz, 3 H), 6.42 (dd, J=8.84, 1.77 Hz, 1 H), 7.01 (dd, J=8.72, 6.95 Hz, 1 H). MS (ES+): m/z 221.98 [MH+] (TOF, polar). The resulting solid was filtered washed with acetic acid

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

Procedure: To a solution of 2-methoxy-3-fluoroaniline (Compound 1471, 7.70 g, 54.6 mmol) in AcOH (45.0 mL) was added a solution of bromine (6.98 g, 43.6 mmol) in AcOH (45.0 mL) dropwise. The reaction mixture was stirred at rt for 30 minutes. The resulting solid was filtered and washed with acetic acid to give the HBr salt of the desired product. The solid was dissolved in water (15 mL), basified by addition of KOH, and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a white solid. The crude material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→70:30) as eluent to yield the desired product as a white solid, 6.536 mg (54% yield). 1H NMR (CDCl3, 400 MHz): δ=3.93 (d, J=1.52 Hz, 3H), 6.42 (dd, J=8.84, 1.77 Hz, 1H), 7.01 (dd, J=8.72, 6.95 Hz, 1H). MS (ES+): m/z 221.98 [MH+] (TOF, polar). The resulting solid was filtered washed with acetic acid

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

Procedure: To 4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFA and acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate (3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. and heated for 24 h. It was then diluted to water, extracted with ethyl acetate. The product was obtained by flash column as a yellow solid (450 mg, 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3 H) 7.40 (dd, J=9.0, 6.2 Hz, 1 H) 7.54 (dd, J=9.0, 1.9 Hz, 1 H). heated for 24 h extracted with ethyl acetate

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

Procedure: To 3-fluoro-2-methoxyaniline (2.8 g, 20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) in acetic acid (10 mL) dropwise. The reaction mixture was stirred at rt. for 30 min. Solid was filtered and washed with acetic acid to give the HBr salt. It was then dissolved in water, basified by addition of KOH, extracted with ethyl acetate. The organic layer was dried and concentrated to give a white solid (2.8 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3 H) 6.42 (dd, J=8.6, 1.8 Hz, 1 H) 7.01 (dd, J=8.6, 7.1 Hz, 1 H). [M+H] calc'd for C7H7BrFNO, 222; found 222. Solid was filtered washed with acetic acid

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

Procedure: To 4-bromo-3-fluoro-2-methoxyaniline (1 g, 4.5 mmol) in a mixture of TFA and acetic acid (10 mL/10 mL) was added sodium perborate tetrahydrate (3.2 g, 21 mmol). The reaction mixture was warmed up to 60° C. and heated for 24 h. It was then diluted to water, extracted with ethyl acetate. The product was obtained by flash column as a yellow solid (450 mg, 40%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.11 (s, 3H) 7.40 (dd, J=9.0, 6.2 Hz, 1H) 7.54 (dd, J=9.0, 1.9 Hz, 1H). heated for 24 h extracted with ethyl acetate

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

Procedure: To 3-fluoro-2-methoxyaniline (2.8 g, 20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) in acetic acid (10 mL) dropwise. The reaction mixture was stirred at rt. for 30 min. Solid was filtered and washed with acetic acid to give the HBr salt. It was then dissolved in water, basified by addition of KOH, extracted with ethyl acetate. The organic layer was dried and concentrated to give a white solid (2.8 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3H) 6.42 (dd, J=8.6, 1.8 Hz, 1H) 7.01 (dd, J=8.6, 7.1 Hz, 1H). [M+H] calc'd for C7H7BrFNO, 222. found 222. Solid was filtered washed with acetic acid