4-bromo-2-fluoro-5-methoxybenzaldehyde

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

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

Procedure: To a mixture of 2-bromo-4-fluoro-1-methoxybenzene (4.10 g) and titanium tetrachloride (4.4 mL), dichloromethyl methyl ether (3.5 mL) was added under ice cooling, and then the reaction mixture was stirred at 0° C. for 2.5 hours. To the reaction mixture was added chloroform, and the reaction mixture was poured into ice water, and then stirred at room temperature for 1 hour. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was added hexane and the produced solid was filtered to give the titled compound (1.61 g) as a white solid. was added under ice cooling stirred at room temperature for 1 hour The organic layer was separated dried over anhydrous sodium sulfate filtered the filtrate was concentrated under reduced pressure The obtained residue was added hexane the produced solid was filtered

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

Procedure: Bromine (15 mL, 0.3 mol) was added slowly to a solution of 2-fluoro-5-methoxy-benzaldehyde (23.1 g, 0.15 mol) in chloroform (500 mL) and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes to give 4-bromo-2-fluoro-methoxy-benzaldehyde (20.7 g, 60%). To a solution of 4-bromo-2-fluoro-5-methoxy-benzaldeyde (4.0 g, 17.3 mmol) in MeOH at 0° C. was added NaBH4 (0.65 g, 17.3 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taked up in ethyl ether washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product. (3.9 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3 H), 4.74 (d, J=6.02 Hz, 2 H), 6.82 (q, J=6.1 Hz, 1 H), 7.29 (d, J=10.58 Hz, 1 H). to warm to room temperature washed with water dried over MgSO4 filtered concentrated The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product

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

Procedure: Bromine (15 mL, 0.3 mol) was added slowly to a solution of 2-fluoro-5-methoxy-benzaldehyde (23.1 g, 0.15 mol) in chloroform (500 mL) and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes to give 4-bromo-2-fluoro-methoxy-benzaldehyde (20.7 g, 60%). To a solution of 4-bromo-2-fluoro-5-methoxy-benzaldeyde (4.0 g, 17.3 mmol) in MeOH at 0° C. was added NaBH4 (0.65 g, 17.3 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taked up in ethyl ether washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product. (3.9 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3 H), 4.74 (d, J=6.02 Hz, 2 H), 6.82 (q, J=6.1 Hz, 1 H), 7.29 (d, J=10.58 Hz, 1 H). to warm to room temperature washed with water dried over MgSO4 filtered concentrated The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product

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

Procedure: Bromine (15 ml, 300 mmol) was added slowly to a solution of 2-Fluoro-5-methoxy-benzaldehyde (23.12 g, 150 mmol) in chloroform (500 ml), and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes) to give the product. Yield: 20.7 g, 60%. 1H NMR (CDCl3) δ: 3.93 (s, 3H), 7.08–7.13 (m, 1H), 7.29 (d, J=12.4 Hz, 1H). extracted with chloroform (2×200 mL) The organics were washed with water (200 mL) and brine (200 mL) dried over MgSO4 filtered concentrated The residue was purified by flash column chromatography (2–16% EtOAc in hexanes) to give the product

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

Procedure: To a solution of 4-Bromo-2-fluoro-5-methoxy-benzaldehyde (4.03 g, 17.33 mmol) from step (1) below in Methanol at 0° C. was added NaBH4 (0.65 g, 17.33 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taken up in ethyl ether, washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product. Yield: 3.90 g, 99.0%. 1H NMR (CDCl3) δ: 3.90 (s, 3H), 4.74 (d, J=6.02 Hz, 2H), 6.82 (d, J=6.1 Hz, 1H), 7.29 (d, J=10.58 Hz, 1H). to warm to room temperature washed with water dried over MgSO4 filtered concentrated The residue was purified by flash chromatography (25–45% EtOAc in hexanes) to give the product

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

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

Procedure: Bromine (15 mL, 0.3 mol) was added slowly to a solution of 2-fluoro-5-methoxy-benzaldehyde (23.1 g, 0.15 mol) in chloroform (500 mL) and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2-16% EtOAc in hexanes to give 4-bromo-2-fluoro-methoxy-benzaldehyde (20.7 g, 60%). To a solution of 4-bromo-2-fluoro-5-methoxy-benzaldehyde (4.0 g, 17.3 mmol) in MeOH at 0° C. was added NaBH4 (0.65 g, 17.3 mmol). After the reaction mixture was stirred at 0° C. for 2 hours, it was allowed to warm to room temperature. The organic layer was taked up in ethyl ether washed with water and dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (25-45% EtOAc in hexanes) to give the product. (3.9 g, 99%). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3 H), 4.74 (d, J=6.02 Hz, 2 H), 6.82 (q, J=6.1 Hz, 1 H), 7.29 (d, J=10.58 Hz, 1 H). to warm to room temperature washed with water dried over MgSO4 filtered concentrated The residue was purified by flash chromatography (25-45% EtOAc in hexanes) to give the product

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

Procedure: 4-Bromo-2-fluoro-5-methoxy-benzaldehyde (100 mg, 0.43 mmol) is dissolved in CH2Cl2 and cooled to −78° C. and then BBr3 (2 mL, 1 M solution in CH2Cl2, 2 mmol) is added. The resulting mixture is allowed to stir at room temperature until no starting material is left. The reaction is quenched and the product is isolated after chromatography (60 mg, 57%). MS (ESI): 216.9 (M−1)−1. is left The reaction is quenched the product is isolated after chromatography (60 mg, 57%)

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

Procedure: 4-Bromo-2-fluoro-5-methoxy-benzaldehyde (100 mg, 0.43 mmol) is dissolved in CH2Cl2 and cooled to −78° C. and then BBr3 (2 mL, 1 M solution in CH2Cl2, 2 mmol) is added. The resulting mixture is allowed to stir at room temperature until no starting material is left. The reaction is quenched and the product is isolated after chromatography (60 mg, 57%). MS (ESI): 216.9 (M−1)−1. is left The reaction is quenched the product is isolated after chromatography (60 mg, 57%)

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

Procedure: 4-Bromo-2-fluoro-5-methoxy-benzaldehyde (100 mg, 0.43 mmol) is dissolved in CH2Cl2 and cooled to −78° C. and then BBr3 (2 mL, 1 M solution in CH2Cl2, 2 mmol) is added. The resulting mixture is allowed to stir at room temperature until no starting material is left. The reaction is quenched and the product is isolated after chromatography (60 mg, 57%). MS (ESI): 216.9 (M−1)−1. is left The reaction is quenched the product is isolated after chromatography (60 mg, 57%)

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

Procedure: To a N2 purged flask is added TiCl4 (0.44 mL) followed by 2-Bromo-4-fluoro-1-methoxy-benzene (400 mg, 1.95 mmol). The stirred mixture is cooled in an ice water bath and treated dropwise with 1,1-dichloromethyl methyl ether (0.35 mL, 1.95 mmol). After stirring for 90 minutes, the resulting slurry is treated with CH2Cl2 (200 mL) and reaction is allowed to warm up to room temperature. After passing through a column, the title compound is isolated (220 mg, 48%). MS (ESI): 232.9 (M+1)+1. The stirred mixture is cooled in an ice water bath