methyl 2-bromo-4,5-difluorobenzoate

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

Procedure: A mixture of methyl 2-bromo-4,5-difluorobenzoate (0.5 g, 1.992 mmol), allyltributylstannane (0.679 mL, 2.191 mmol), lithium chloride (0.169 g, 3.98 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.070 g, 0.100 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution for 5 times, then dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4,5-difluorobenzoate (330 mg, 1.555 mmol, 78% yield) as an oil. 1H NMR (400 MHz, CDCl3) 7.78 (dd, J=11.1, 8.2 Hz, 1H), 7.11 (dd, J=11.1, 7.7 Hz, 1H), 5.98 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.16-5.02 (m, 2H), 3.91 (s, 3H), 3.76 (d, J=6.6 Hz, 2H). It was then degassed for 2 min filled with N2 it was quenched with NH4Cl extracted with EtOAc The organic layer was washed with KF solution for 5 times dried over MgSO4 filtered concentrated to obtain an oil, which was then purified by biotage eluting with 10% EtOAc/hexane

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

Procedure: To a mixture of 2-bromo-4,5-difluorobenzoic acid (1 g, 4.22 mmol) in dichloromethane (10 mL) and MeOH (1 mL) was added trimethylsilyl)diazomethane (2.110 mL, 4.22 mmol) and the reaction was stirred at rt for 1 h. It was then concentrated to obtain methyl 2-bromo-4,5-difluorobenzoate (1 g, 3.98 mmol, 94% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=10.5, 8.3 Hz, 1H), 7.57-7.49 (m, 1H), 3.96 (s, 3H). It was then concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromo-4,5-difluoro-benzoic acid methyl ester (1.45 g, 5.78 mmol) in toluene (42 mL) was cooled at −78° C. under nitrogen. Diisobutylaluminum hydride (1 M in toluene) (7.51 mL, 7.51 mmol) was added drop-wise over 20 minutes. The reaction mixture was stirred at −78° C. for another hour, and then allowed to warm to room temperature overnight. The reaction mixture was then cooled to 0° C. and quenched with ethyl acetate, followed by addition of saturated Rochelle's salt solution. The biphasic slurry was then allowed to warm to room temperature and stirred for 2 hours. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to afford crude (2-bromo-4,5-difluoro-phenyl)-methanol (1.55 g, 90%), which was used in the next step without further purification. to warm to room temperature overnight The reaction mixture was then cooled to 0° C. quenched with ethyl acetate followed by addition of saturated Rochelle's salt solution to warm to room temperature stirred for 2 hours The organic layer was collected dried over sodium sulfate filtered concentrated

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

Procedure: To a solution of 2-bromo-4,5-difluoro-benzoic acid (5 g, 21.10 mmol) in methanol (100 mL) was added concentrated sulfuric acid (0.21 mL, 2.11 mmol) at 0° C. The reaction mixture was then heated at 80° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered, and concentrated to afford the crude product 2-bromo-4,5-difluoro-benzoic acid methyl ester (1.48 g, 28%) as a clear oil, which was used in the next step without further purification. After cooling to room temperature extracted with ethyl acetate The organic layer was washed with saturated sodium bicarbonate brine, dried over sodium sulfate filtered concentrated

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

Procedure: A mixture of methyl 2-bromo-4,5-difluorobenzoate (0.5 g, 1.992 mmol), allyltributylstannane (0.679 mL, 2.191 mmol), lithium chloride (0.169 g, 3.98 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.070 g, 0.100 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution for 5 times, then dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4,5-difluorobenzoate (330 mg, 1.555 mmol, 78% yield) as an oil. 1H NMR (400 MHz, CDCl3) 7.78 (dd, J=11.1, 8.2 Hz, 1H), 7.11 (dd, J=11.1, 7.7 Hz, 1H), 5.98 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.16-5.02 (m, 2H), 3.91 (s, 3H), 3.76 (d, J=6.6 Hz, 2H). It was then degassed for 2 min filled with N2 it was quenched with NH4Cl extracted with EtOAc The organic layer was washed with KF solution for 5 times dried over MgSO4 filtered concentrated to obtain an oil, which was then purified by biotage eluting with 10% EtOAc/hexane

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

Procedure: To a mixture of 2-bromo-4,5-difluorobenzoic acid (1 g, 4.22 mmol) in dichloromethane (10 mL) and MeOH (1 mL) was added trimethylsilyl)diazomethane (2.110 mL, 4.22 mmol) and the reaction was stirred at rt for 1 h. It was then concentrated to obtain methyl 2-bromo-4,5-difluorobenzoate (1 g, 3.98 mmol, 94% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=10.5, 8.3 Hz, 1H), 7.57-7.49 (m, 1H), 3.96 (s, 3H). It was then concentrated