(4-bromo-2,3-difluorophenyl)boronic acid

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromopyrimidine (2.0 g, 12.7 mmol), 4-bromo-2,3-difluorobenzeneboronic acid (1.0 g, 4.22 mmol), potassium carbonate (2.93 g, 21.1 mmol) in a mixture of toluene (30 ml)/ethanol (30 ml)/water (15 ml) were purged with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (488 mg, 0.42 mmol) was added and the mixture was stirred at 90° C. in a sealed-tube for overnight. The mixture was cooled to r.t. and was diluted with water and ethyl acetate. Layers were separated. The separated organic layer was dried (MgSO4), filtered and solvents were removed in vacuum. Column purification [Hexanes-Ethyl acetate, 2:1 (v/v)] gave bromide 3AC (0.97 g, 85%) as white solid. were purged with nitrogen for 15 min The mixture was cooled to r.t. Layers were separated The separated organic layer was dried (MgSO4) filtered solvents were removed in vacuum Column purification [Hexanes-Ethyl acetate, 2:1 (v/v)]

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

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

Procedure: The title compound was prepared using analogous conditions to those described in 5-(4-chloro-2-fluorophenyl)pyrazin-2-amine using (4-bromo-2,3-difluorophenyl)boronic acid and 5-bromopyrimidin-2-amine. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (4-bromo-2,3-difluorophenyl)boronic acid (400 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (588 mg, 3.38 mmol was suspended in EtOH (5.6 ml) and toluene (5.7 mL) The resulting mixture was treated with aqueous Na2CO3 (2.0 N, 4.2 mL, 8.45 mmol). The resulting mixture was then sparged with nitrogen through the mixture for 10 min, and then Pd(PPh3)4 (98 mg, 0.085 mmol) was added. The reaction vessel was sealed and heated at 80° Celsius for 17 hours. The reaction mixture was cooled to rt and then partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was dried over MgSO4 and concentrated to dryness. The residue was suspended in DCM and the solid isolated by filtration to afford the title compound (160 mg, 33%), which was used without further purification. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=1.2, 1H), 7.68-7.56 (m, 2H), 6.87 (s, 2H). The resulting mixture was then sparged with nitrogen through the mixture for 10 min The reaction vessel was sealed The reaction mixture was cooled to rt partitioned between saturated aqueous NH4Cl and EtOAc The organic layer was dried over MgSO4 concentrated to dryness the solid isolated by filtration

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a microwave vessel, methyl 4-iodo-2-methylnicotinate (1.00 g, 3.61 mmol) was taken in a mixture of 1,4-dioxane (18 mL) and water (2 mL) under inert atmosphere. (4-bromo-2,3-difluorophenyl)boronic acid (1.03 g, 4.33 mmol) and Na2CO3 (765 mg, 7.22 mmol) were added to the reaction mixture and degassed for 5 minutes. Pd(Ph3P)4 (83 mg, 0.072 mmol) was added to the reaction mixture and heated in microwave at 110° C. for 90 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient of ethyl acetate and petroleum ether) to afford methyl 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinate (540 mg, 1.58 mmol, 44% yield) as a yellow liquid. LC/MS (ESI) m/e 344.0 [(M+2H)+, calcd for C14H12BrF2NO2 344.1]; LC/MS retention time (method C): tR=2.48 min. degassed for 5 minutes extracted with ethyl acetate (200 mL) The organic phase was washed with brine (2×100 mL) dried over Na2SO4 concentrated under reduced pressure The residue was purified by silica gel chromatography (gradient of ethyl acetate and petroleum ether)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromopyrimidine (2.0 g, 12.7 mmol), 4-bromo-2,3-difluorobenzeneboronic acid (1.0 g, 4.22 mmol), potassium carbonate (2.93 g, 21.1 mmol) in a mixture of toluene (30 ml)/ethanol (30 ml)/water (15 ml) were purged with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium(0) (488 mg, 0.42 mmol) was added and the mixture was stirred at 90° C. in a sealed-tube for overnight. The mixture was cooled to r.t. and was diluted with water and ethyl acetate. Layers were separated. The separated organic layer was dried (MgSO4), filtered and solvents were removed in vacuum. Column purification [Hexanes-Ethyl acetate, 2:1 (v/v)] gave bromide 3AC (0.97 g, 85%) as white solid. were purged with nitrogen for 15 min The mixture was cooled to r.t. Layers were separated The separated organic layer was dried (MgSO4) filtered solvents were removed in vacuum Column purification [Hexanes-Ethyl acetate, 2:1 (v/v)]