tert-butyl N-(3-bromo-2,6-difluorophenyl)carbamate

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

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

Procedure: To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS (m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H). The volatiles were removed in vacuo The aqueous mixture was extracted with EtOAc Organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane)

Conditions: temp:111.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask containing 3-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) under nitrogen with a condenser was added toluene (35 mL) and t-BuOH (35 mL). To this solution was added DIEA (4.4 ml, 25.3 mmol) and DPPA (5.7 mL, 26.4 mmol). The reaction mixture was heated to 111° C. in an oil bath for 48 hours. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane) afforded 3.49 g (54%) of tert-butyl 3-bromo-2,6-difluorophenylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.54 (m, 9H) 7.17 (m, 1H) 7.63 (ddd, J=8.9, 7.9, 5.9 Hz, 1H). to cool to room temperature the volatiles were removed in vacuo extracted with EtOAc The organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane)

Conditions: temp:111.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask containing 3-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) under nitrogen with a condenser was added toluene (35 mL) and t-BuOH (35 mL). To this solution was added DIEA (4.4 ml, 25.3 mmol) and DPPA (5.7 mL, 26.4 mmol). The reaction mixture was heated to 111° C. in an oil bath for 48 hours. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane) afforded 3.49 g (54%) of tert-butyl 3-bromo-2,6-difluorophenylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.54 (m, 9H) 7.17 (m, 1H) 7.63 (ddd, J=8.9, 7.9, 5.9 Hz, 1H). to cool to room temperature the volatiles were removed in vacuo extracted with EtOAc The organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane)

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

Procedure: To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS(m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H). The volatiles were removed in vacuo The aqueous mixture was extracted with EtOAc Organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane)

Conditions: temp:111.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask containing 3-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) under nitrogen with a condenser was added toluene (35 mL) and t-BuOH (35 mL). To this solution was added DIEA (4.4 ml, 25.3 mmol) and DPPA (5.7 mL, 26.4 mmol). The reaction mixture was heated to 111° C. in an oil bath for 48 hours. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane) afforded 3.49 g (54%) of tert-butyl 3-bromo-2,6-difluorophenylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.54 (m, 9H) 7.17 (m, 1H) 7.63 (ddd, J=8.9, 7.9, 5.9 Hz, 1H). to cool to room temperature the volatiles were removed in vacuo extracted with EtOAc The organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane)

Conditions: temp:111.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask containing 3-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) under nitrogen with a condenser was added toluene (35 mL) and t-BuOH (35 mL). To this solution was added DIEA (4.4 ml, 25.3 mmol) and DPPA (5.7 mL, 26.4 mmol). The reaction mixture was heated to 111° C. in an oil bath for 48 hours. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane) afforded 3.49 g (54%) of tert-butyl 3-bromo-2,6-difluorophenylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.54 (m, 9H) 7.17 (m, 1H) 7.63 (ddd, J=8.9, 7.9, 5.9 Hz, 1H). to cool to room temperature the volatiles were removed in vacuo extracted with EtOAc The organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane)

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

Procedure: To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS (m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H). The volatiles were removed in vacuo The aqueous mixture was extracted with EtOAc Organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane)

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

Procedure: To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS (m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H). The volatiles were removed in vacuo The aqueous mixture was extracted with EtOAc Organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane)

Conditions: temp:111.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a round bottom flask containing 3-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) under nitrogen with a condenser was added toluene (35 mL) and t-BuOH (35 mL). To this solution was added DIEA (4.4 ml, 25.3 mmol) and DPPA (5.7 mL, 26.4 mmol). The reaction mixture was heated to 111° C. in an oil bath for 48 hours. The reaction was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane) afforded 3.49 g (54%) of tert-butyl 3-bromo-2,6-difluorophenylcarbamate: 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.54 (m, 9H) 7.17 (m, 1H) 7.63 (ddd, J=8.9, 7.9, 5.9 Hz, 1H). to cool to room temperature the volatiles were removed in vacuo extracted with EtOAc The organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-100% EtOAc in heptane)

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

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

Procedure: To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS (m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H). The volatiles were removed in vacuo The aqueous mixture was extracted with EtOAc Organic phase was washed with water, brine dried (Na2SO4) filtered concentrated onto silica Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane)