5-bromo-2,4-difluoroaniline

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: 5-bromo-2,4-difluoroaniline (500 mg, 2.40 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (INTERMEDIATE 16, 797 mg, 2.88 mmol), sodium carbonate (2.40 mL, aq., 2M, 2.88 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (196 mg, 0.24 mmol) and ethanol (15 ml) were heated in an 80° C. oil bath for 3 hours then allowed to cool to ambient overnight. Volatiles were removed under reduced pressure. The pot residue was worked up w/DCM/brine/Na2SO4/filtration/concentration to afford a dark oil. The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by a 0% to 40% EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=277.09; found=278.03 (M+1)+. to cool to ambient overnight Volatiles were removed under reduced pressure w/DCM/brine/Na2SO4/filtration/concentration to afford a dark oil The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge) The column was eluted by a 0% to 40% EtOAc/hexanes gradient mixture concentrated in vacuo

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

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

Procedure: 5-bromo-2,4-difluoroaniline (500 mg, 2.40 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (INTERMEDIATE 16, 797 mg, 2.88 mmol), sodium carbonate (2.40 mL, aq., 2M, 2.88 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (196 mg, 0.24 mmol) and ethanol (15 ml) were heated in an 80° C. oil bath for 3 hours then allowed to cool to ambient overnight. Volatiles were removed under reduced pressure. The pot residue was worked up w/DCM /brine/Na2SO4/filtration/concentration to afford a dark oil. The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge). The column was eluted by a 0% to 40% EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS (ESI) calc.=277.09; found=278.03 (M+1)+. to cool to ambient overnight Volatiles were removed under reduced pressure w/DCM /brine/Na2SO4/filtration/concentration to afford a dark oil The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge) The column was eluted by a 0% to 40% EtOAc/hexanes gradient mixture concentrated in vacuo

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

Procedure: To a solution of 5-bromo-2,4-difluoro aniline (1.0 g, 4.81 mmol) in acetone (25.0 mL) was added drop wise benzoyl isothiocyanate (0.71 mL, 5.29 mmol). The resulting reaction mixture was allowed to stir at room temperature for 30 min. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue was washed with hexane and ether to get the title compound (1.70 g, quantitative yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.02-7.06 (m, 1H), 7.56 (t, J=8.0 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 7.91 (d, J=7.60 Hz, 2H), 8.67 (t, J=7.60 Hz, 1H), 9.15 (br s, 1H) and 12.65 (br s, 1H). The resulting reaction mixture After the completion of the reaction (TLC monitoring) the solvent was evaporated the residue was washed with hexane and ether

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

Procedure: To a solution of 5-bromo-2,4-difluoro aniline (1.0 g, 4.81 mmol) in acetone (25.0 mL) was added drop wise benzoyl isothiocyanate (0.71 mL, 5.29 mmol). The resulting reaction mixture was allowed to stir at room temperature for 30 min. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue was washed with hexane and ether to get the title compound (1.70 g, quantitative yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 7.02-7.06 (m, 1H), 7.56 (t, J=8.0 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 7.91 (d, J=7.60 Hz, 2H), 8.67 (t, J=7.60 Hz, 1H), 9.15 (br s, 1H) and 12.65 (br s, 1H). The resulting reaction mixture After the completion of the reaction (TLC monitoring) the solvent was evaporated the residue was washed with hexane and ether

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

Procedure: 2,4-Difluoro-5-bromoaniline (208 mg, 1.04 mmol) was added to a solution of thiocarbonyldiimidazole (185 mg 1.04 mmol) in DMF (10 mL) and the mixture was stirred for 16 h. 2-Hydrazino-N-(4-morpholin-4-ylphenyl)-2 oxoacetamide (Intermediate 27, 211 mg, 0.8 mmol) was added and the mixture was stirred at 80° C. until a clear solution was obtained. EDAC (306 mg, 1.6 mmol) was added and stirring was continued for a further 1 h. The mixture was cooled then diluted with water (25 mL) and the resulting precipitate was filtered and dried to give the title compound the title compound (135 mg) as a solid; the mixture was stirred at 80° C. until a clear solution was obtained stirring was continued for a further 1 h The mixture was cooled the resulting precipitate was filtered dried

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

Procedure: To a solution of 5-bromo-2,4-difluoro-aniline (1.0 g, 4.81 mmol) in acetone (25.0 mL) was added drop wise benzoyl isothiocyanate (0.71 mL, 5.29 mmol) and the mixture stirred at RT for 30 min. The solvent was evaporated and the residue washed with hexane and Et2O to get i (1.70 g). 1H-NMR (400 MHz, CDCl3): δ 7.02-7.06 (m, 1H), 7.56 (t, J=8.0 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 7.91 (d, J=7.60 Hz, 2H), 8.67 (t, J=7.60 Hz, 1H), 9.15 (br s, 1H) and 12.65 (br s, 1H). The solvent was evaporated the residue washed with hexane and Et2O to get i (1.70 g)

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

Procedure: Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline and 2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at 0° C. was slowly added 1.6 mL (15.1 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3.3 g (11.8 mmol, 94%) of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide: ESMS m/e: 278.1 (M+H)+. at 0° C. concentrated in vacuo The residue was dissolved in EtOAc washed with H2O, saturated aqueous Na2CO3 and brine The organic layer was dried over MgSO4 concentrated in vacuo

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

Procedure: To a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (5.04 g, 21.3 mmol) in EtOH (100 mL), THF (50 mL), NH4Cl (sat) (25 mL) and H2O (25 mL) was added iron powder (5.0 g, 89.5 mmol). The mixture was refluxed for 2 h and filtered through celite. The filter pad was washed with EtOAc (3×50 mL). The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The organic layer was dried over MgSO4 and concentrated. Purification by flash chromatography (5–10% EtOAc/Hexane) provided 2.6 g (59%) of 5-bromo-2,4-difluoroaniline: ESMS m/e: 208.2 (M+H)+. The mixture was refluxed for 2 h filtered through celite The filter pad was washed with EtOAc (3×50 mL) The filtrate was concentrated the residue was partitioned between EtOAc and brine The organic layer was dried over MgSO4 concentrated Purification by flash chromatography (5–10% EtOAc/Hexane)