2-bromo-2,2-difluoro-N,N-dimethylacetamide

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL) dried over Na2SO4 The crude product was obtained after evaporation of all volatiles Purification by chromatography on silica

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

Procedure: To a solution of ethyl bromodifluoroacetate (370 g, 1.82 mol) in 1000 mL of THF was added a solution of Me2NH in THF (2.0 M, 1000 mL, 2.0 mol). A slightly exothermic reaction occurred. The solution was stirred at room temperature overnight. The solvent was then carefully removed by distillation and the residue purified by rectification. The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield). A slightly exothermic reaction The solvent was then carefully removed by distillation the residue purified by rectification The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromo-5-fluoro-phenol (4.0 g, 20.7 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (4.4 g, 21.6 mmol) and K2CO3 (3.2 g, 23.2 mmol) in 20 mL of DMAC was heated to 100° C. for 120 min. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL), water and brine and dried over MgSO4. The product (5.7 g, >96% purity by NMR, 17.6 mmol, 85% yield) was obtained as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL), water and brine dried over MgSO4 The product (5.7 g, >96% purity by NMR, 17.6 mmol, 85% yield) was obtained as a yellow oil

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL) dried over Na2SO4 The crude product was obtained after evaporation of all volatiles Purification by chromatography on silica

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluoro-phenol (9.8 g, 87.4 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (18.3 g, 89.6 mmol) and K2CO3 (13.3 g, 96.2 mmol) in 75 g of dimethylacetamide (DMAC) was heated to 100° C. for 1 h and then heated to 120° C. for 2 h. The reaction mixture was then cooled to room temperature and poured on 250 mL of H2O and 50 mL of toluene. The aqueous phase was extracted with 25 g of toluene. The combined organic layers were extracted with 5% NaOH (20 g) and H2O (2×20 g) and dried over Na2SO4. The product (18.5 g, >98% purity by quant. HPLC, 77.8 mmol, 89% yield) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid. The material could be used in subsequent steps without further purification or purified by fractionated distillation. heated to 120° C. for 2 h The reaction mixture was then cooled to room temperature The aqueous phase was extracted with 25 g of toluene The combined organic layers were extracted with 5% NaOH (20 g) and H2O (2×20 g) dried over Na2SO4 The product (18.5 g, >98% purity by quant. HPLC, 77.8 mmol, 89% yield) was obtained after removal of all volatiles under reduced pressure as a slightly yellow liquid The material could be used in subsequent steps without further purification purified by fractionated distillation

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

Procedure: To a solution of ethyl bromodifluoroacetate (370 g, 1.82 mol) in 1000 mL of THF was added a solution of Me2NH in THF (2.0 M, 1000 mL, 2.0 mol). A slightly exothermic reaction occurred. The solution was stirred at room temperature overnight. The solvent was then carefully removed by distillation and the residue purified by rectification. The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield). A slightly exothermic reaction The solvent was then carefully removed by distillation the residue purified by rectification The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL) dried over Na2SO4 The crude product was obtained after evaporation of all volatiles Purification by chromatography on silica

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethylacetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL) dried over Na2SO4 The crude product was obtained after evaporation of all volatiles Purification by chromatography on silica

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethylacetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL) dried over Na2SO4 The crude product was obtained after evaporation of all volatiles Purification by chromatography on silica

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing. extracted with TBME (2×50 mL) The combined organic layers were washed with 10% NaOH (50 mL) dried over Na2SO4 The crude product was obtained after evaporation of all volatiles Purification by chromatography on silica

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

Procedure: To a solution of ethyl bromodifluoroacetate (370 g, 1.82 mol) in 1000 mL of THF was added a solution of Me2NH in THF (2.0 M, 1000 mL, 2.0 mol). A slightly exothermic reaction occurred. The solution was stirred at room temperature overnight. The solvent was then carefully removed by distillation and the residue purified by rectification. The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield). A slightly exothermic reaction The solvent was then carefully removed by distillation the residue purified by rectification The product was obtained as a colorless liquid (343 g, >99% pure by GC, 1.7 mol, 93% yield)