6-bromo-2-fluoro-3-methoxybenzaldehyde

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: A solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (2.0 g, 8.6 mmol) in dichloromethane (43 mL) under a nitrogen balloon was cooled to −78° C. in an acetone dry ice bath. Boron tribromide (1 M in dichloromethane, 9.5 mL) was added dropwise under nitrogen atmosphere. The reaction was stirred at room temperature overnight. The flask was then put on an ice water bath and the excess boron tribromide was quenched with ice chips. Water was added and the solution was extracted with dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 86%). The flask was then put on an ice water bath the excess boron tribromide was quenched with ice chips Water was added the solution was extracted with dichloromethane The aqueous layer was extracted twice with dichloromethane washed with brine dried over anhydrous sodium sulfate filtered The solvent was removed under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (11 mL) in anhydrous THF (50 mL) was cooled to 0° C. and was added 1.6 M n-butyl lithium/hexanes (47 mL) dropwise under nitrogen atmosphere. The mixture was stirred for 10 min at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A solution of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous THF (50 mL) was added dropwise. The mixture was then allowed to stir for 30 min at −78° C. DMF (7.5 mL) was added dropwise at −78° C. The reaction was stirred for 1 h at room temperature. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected by filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58%). was then cooled to −78° C. with an acetone dry ice bath to stir for 30 min at −78° C The reaction was stirred for 1 h at room temperature Half of the solvent from the solution was removed under reduced pressure the solution was extracted The organic layer was washed with brine dried over anhydrous sodium sulfate filtered The solvent was removed under reduced pressure The residue was crystallized by washing with hexanes The solid was collected by filtration dried under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (11 mL) in anhydrous THF (50 mL) was cooled to 0° C. and was added 1.6 M n-butyl lithium/hexanes (47 mL) dropwise under nitrogen atmosphere. The mixture was stirred for 10 min at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A solution of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous THF (50 mL) was added dropwise. The mixture was then allowed to stir for 30 min at −78° C. DMF (7.5 mL) was added dropwise at −78° C. The reaction was stirred for 1 h at room temperature. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected by filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58%). was then cooled to −78° C. with an acetone dry ice bath to stir for 30 min at −78° C The reaction was stirred for 1 h at room temperature Half of the solvent from the solution was removed under reduced pressure the solution was extracted The organic layer was washed with brine dried over anhydrous sodium sulfate filtered The solvent was removed under reduced pressure The residue was crystallized by washing with hexanes The solid was collected by filtration dried under reduced pressure

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

Procedure: To a stirred solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (13 g, 56 mmol) in nPrOH (200 mL) were added potassium vinyltrifluoroborate (7.9 g, 59 mmol), PdCl2(dppf) (0.91 g, 1.1 mmol), and TEA (7.8 mL, 56 mmol). The reaction mixture was purged with N2 for 10 min, heated to reflux for 3 h, cooled to room temperature, treated with water, and concentrated. The residue was extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.53 (s, 1H); 7.43 (dd, 1H); 7.31 (d, 1H); 7.16 (t, 1H); 5.60 (d, 1H); 5.36 (d, 1H); 3.95 (s, 3H). The reaction mixture was purged with N2 for 10 min heated to reflux for 3 h treated with water concentrated The residue was extracted with EtOAc (×3) The combined organics were washed with brine dried (Na2SO4) concentrated purified by flash chromatography

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

Procedure: To a stirred solution of LDA (62 mmol) in THF (100 mL) was added 4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowly at −78° C. The reaction mixture was left to stir at −78° C. for 2 h, treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at −78° C. for 1 h, and allowed to warm to room temperature as the bath did. The reaction mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04 (t, 1H); 3.92 (s, 3H). The reaction mixture was left left to stir at −78° C. for 1 h to warm to room temperature as the bath extracted with EtOAc (×3) The combined organics were washed with brine dried (Na2SO4) concentrated purified by flash chromatography

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

Procedure: To a stirred solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (13 g, 56 mmol) in nPrOH (200 mL) were added potassium vinyltrifluoroborate (7.9 g, 59 mmol), PdCl2(dppf) (0.91 g, 1.1 mmol), and TEA (7.8 mL, 56 mmol). The reaction mixture was purged with N2 for 10 min, heated to reflux for 3 h, cooled to room temperature, treated with water, and concentrated. The residue was extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.53 (s, 1H); 7.43 (dd, 1H); 7.31 (d, 1H); 7.16 (t, 1H); 5.60 (d, 1H); 5.36 (d, 1H); 3.95 (s, 3H). The reaction mixture was purged with N2 for 10 min heated to reflux for 3 h treated with water concentrated The residue was extracted with EtOAc (×3) The combined organics were washed with brine dried (Na2SO4) concentrated purified by flash chromatography

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

Procedure: To a stirred solution of LDA (62 mmol) in THF (100 mL) was added 4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowly at −78° C. The reaction mixture was left to stir at −78° C. for 2 h, treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at −78° C. for 1 h, and allowed to warm to room temperature as the bath did. The reaction mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04 (t, 1H); 3.92 (s, 3H). The reaction mixture was left left to stir at −78° C. for 1 h to warm to room temperature as the bath extracted with EtOAc (×3) The combined organics were washed with brine dried (Na2SO4) concentrated purified by flash chromatography

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

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

Procedure: A solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (2.0 g, 8.6 mmol) in dichloromethane (43 mL) under a nitrogen balloon was cooled to −78° C. in an acetone dry ice bath. Boron tribromide (1 M in dichloromethane, 9.5 mL) was added dropwise under nitrogen atmosphere. The reaction was stirred at room temperature overnight. The flask was then put on an ice water bath and the excess boron tribromide was quenched with ice chips. Water was added and the solution was extracted with dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 86%). The flask was then put on an ice water bath the excess boron tribromide was quenched with ice chips Water was added the solution was extracted with dichloromethane The aqueous layer was extracted twice with dichloromethane washed with brine dried over anhydrous sodium sulfate filtered The solvent was removed under reduced pressure

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

Procedure: A solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (2.0 g, 8.6 mmol) in dichloromethane (43 mL) under a nitrogen balloon was cooled to −78° C. in an acetone dry ice bath. Boron tribromide (1 M in dichloromethane, 9.5 mL) was added dropwise under nitrogen atmosphere. The reaction was stirred at room temperature overnight. The flask was then put on an ice water bath and the excess boron tribromide was quenched with ice chips. Water was added and the solution was extracted with dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 86%). The flask was then put on an ice water bath the excess boron tribromide was quenched with ice chips Water was added the solution was extracted with dichloromethane The aqueous layer was extracted twice with dichloromethane washed with brine dried over anhydrous sodium sulfate filtered The solvent was removed under reduced pressure