3,5-Dichloro-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:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,5-dichloro-2,4-difluorobenzenamine (9.9 g, 50.0 mmol) in HBr (200 mL) was added a solution of NaNO2 (3.45 g, 50.0 mmol) in H2O (80 mL) slowly under salt ice-bath, then the mixture was stirred for 2 h, and CuBr (7.15 g, 50.0 mmol) was added at 0° C. The mixture was stirred for additional 2 h, and then poured into water (100 mL), extracted with DCM, dried over NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography over silica gel eluted with PE to give compound 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.49 (t, J=7.2 Hz, 1H) ppm. The mixture was stirred for additional 2 h extracted with DCM dried over NaSO4 filtered concentrated under reduced pressure The resulting residue was purified by chromatography over silica gel eluted with PE

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 31.1 g of 3,5-dichloro-2,4-difluoroaniline (0.157 mol) was added to 100 ml of a solution of concentrated hydrochloric acid and water (1:1) at 70° C. The resulting mixture was stirred to be a slurry and cooled to 0-5° C. To the mixture was added 11.6 g of aqueous solution of sodium nitrite (0.165 mol) over 30 minutes. The resulting solution was added to a solution of CuCl (0.188 mol) and hydrochloric acid (100 ml). The reaction mixture was stirred for 2 hours and kept overnight. Fractions obtained by wet-distillation were extracted with toluene. The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, dried over sodium sulfate and evaporated. The residue was recrystallized from toluene to give 27.7 g of 2,4-difluoro-1,3,5-trichlorobenzene (0.127 mol) in 81.1% yield. The reaction mixture was stirred for 2 hours Fractions obtained by wet-distillation were extracted with toluene The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water dried over sodium sulfate evaporated The residue was recrystallized from toluene

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 31.1 g of 3,5-dichloro-2,4-difluoroaniline (0.157 mol) was added to 100 ml of a solution of concentrated hydrochloric acid and water (1:1) at 70° C. The resulting mixture was stirred to be a slurry and cooled to 0-5° C. To the mixture was added 11.6 g of aqueous solution of sodium nitrite (0.165 mol) over 30 minutes. The resulting solution was added to a solution of CuCl (0.188 mol) and hydrochloric acid (100 ml). The reaction mixture was stirred for 2 hours and kept overnight. Fractions obtained by wet-distillation were extracted with toluene. The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, dried over sodium sulfate and evaporated. The residue was recrystallized from toluene to give 27.7 g of 2,4-difluoro-1,3,5-trichlorobenzene (0.127 mol) in 81.1% yield. The reaction mixture was stirred for 2 hours Fractions obtained by wet-distillation were extracted with toluene The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water dried over sodium sulfate evaporated The residue was recrystallized from toluene

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

Procedure: To a solution of 3,5-dichloro-2,4-difluorobenzenamine (9.9 g, 50.0 mmol) in HBr (200 mL) was added a solution of NaNO2 (3.45 g, 50.0 mmol) in H2O (80 mL) slowly under salt ice-bath, then the mixture was stirred for 2 h, and CuBr (7.15 g, 50.0 mmol) was added at 0° C. The mixture was stirred for additional 2 h, and then poured into water (100 mL), extracted with DCM, dried over NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography over silica gel eluted with PE to give compound 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.49 (t, J=7.2 Hz, 1H) ppm. The mixture was stirred for additional 2 h extracted with DCM dried over NaSO4 filtered concentrated under reduced pressure The resulting residue was purified by chromatography over silica gel eluted with PE

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

Procedure: Three grams (0.016 mol) of 2,6-difluoro-benzoyl isocyanate were added to a solution of 2.95 gm (0.015 mol) of 2,4-difluoro-3,5-dichloroaniline in 50 ml of toluene. The solution thus obtained was stirred for 15 hours at room temperature. Thereafter, the product which precipitated during that time was removed by suction filtration and dried. The solution thus obtained Thereafter, the product which precipitated during that time was removed by suction filtration dried

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

Procedure: Hydrogen chloride was passed into a well-stirred solution of 39.6 gm (0.20 mol) of 2,4-difluoro-3,5-dichloroaniline in 400 ml of toluene until a precipitate no longer separated out. The heterogeneous mixture thus obtained was cooled to 5° to 10° C. At this temperature, 40 gm (0.4 mol) of phosgene were passed in, with stirring. The mixture was then heated slowly, with stirring, so that after about two hours a temperature of 100° to 105° C. was reached. Stirring was then continued for seven hours at this temperature. During this time, a clear solution was formed, and hydrogen chloride was liberated. Nitrogen was then passed into the mixture for one hour at the same temperature to drive off the excess phosgene. Thereafter the solvent was distilled off, in vacuo at the end. The crude product which remained was distilled in a water pump vacuum. no longer separated out The heterogeneous mixture thus obtained was cooled to 5° to 10° C The mixture was then heated slowly with stirring Stirring was then continued for seven hours at this temperature During this time, a clear solution was formed Nitrogen was then passed into the mixture for one hour at the same temperature Thereafter the solvent was distilled off, in vacuo at the end The crude product which remained was distilled in a water pump vacuum

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

Procedure: Three grams (0.016 mol) of 2,6-difluoro-benzoyl isocyanate were added to a solution of 2.95 gm (0.015 mol) of 2,4-difluoro-3,5-dichloroaniline in 50 ml of toluene. The solution thus obtained was stirred for 15 hours at room temperature. Thereafter, the product which precipitated during that time was removed by suction filtration and dried. The solution thus obtained Thereafter, the product which precipitated during that time was removed by suction filtration dried

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

Procedure: Hydrogen chloride was passed into a well-stirred solution of 39.6 gm (0.20 mol) of 2,4-difluoro-3,5-dichloroaniline in 400 ml of toluene until a precipitate no longer separated out. The heterogeneous mixture thus obtained was cooled to 5° to 10° C. At this temperature, 40 gm (0.4 mol) of phosgene were passed in, with stirring. The mixture was then heated slowly, with stirring, so that after about two hours a temperature of 100° to 105° C. was reached. Stirring was then continued for seven hours at this temperature. During this time, a clear solution was formed, and hydrogen chloride was liberated. Nitrogen was then passed into the mixture for one hour at the same temperature to drive off the excess phosgene. Thereafter the solvent was distilled off, in vacuo at the end. The crude product which remained was distilled in a water pump vacuum. no longer separated out The heterogeneous mixture thus obtained was cooled to 5° to 10° C The mixture was then heated slowly with stirring Stirring was then continued for seven hours at this temperature During this time, a clear solution was formed Nitrogen was then passed into the mixture for one hour at the same temperature Thereafter the solvent was distilled off, in vacuo at the end The crude product which remained was distilled in a water pump vacuum

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

Procedure: To a solution of 3,5-dichloro-2,4-difluorobenzenamine (9.9 g, 50.0 mmol) in HBr (200 mL) was added a solution of NaNO2 (3.45 g, 50.0 mmol) in H2O (80 mL) slowly under salt ice-bath, then the mixture was stirred for 2 h, and CuBr (7.15 g, 50.0 mmol) was added at 0° C. The mixture was stirred for additional 2 h, and then poured into water (100 mL), extracted with DCM, dried over NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography over silica gel eluted with PE to give compound 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.49 (t, J=7.2 Hz, 1H) ppm. The mixture was stirred for additional 2 h extracted with DCM dried over NaSO4 filtered concentrated under reduced pressure The resulting residue was purified by chromatography over silica gel eluted with PE

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 31.1 g of 3,5-dichloro-2,4-difluoroaniline (0.157 mol) was added to 100 ml of a solution of concentrated hydrochloric acid and water (1:1) at 70° C. The resulting mixture was stirred to be a slurry and cooled to 0-5° C. To the mixture was added 11.6 g of aqueous solution of sodium nitrite (0.165 mol) over 30 minutes. The resulting solution was added to a solution of CuCl (0.188 mol) and hydrochloric acid (100 ml). The reaction mixture was stirred for 2 hours and kept overnight. Fractions obtained by wet-distillation were extracted with toluene. The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, dried over sodium sulfate and evaporated. The residue was recrystallized from toluene to give 27.7 g of 2,4-difluoro-1,3,5-trichlorobenzene (0.127 mol) in 81.1% yield. The reaction mixture was stirred for 2 hours Fractions obtained by wet-distillation were extracted with toluene The extract was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water dried over sodium sulfate evaporated The residue was recrystallized from toluene