1-bromo-2-ethenyl-4-fluorobenzene

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: To a mixture of 1-bromo-4-fluoro-2-vinylbenzene (0.32 g, 1.592 mmol) in tetrahydrofuran (5 mL) at −78° C. was added BuLi (0.764 mL, 1.910 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.185 mL, 2.388 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then warmed to rt and stirred at rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 4-fluoro-2-vinylbenzaldehyde (0.2 g) as an oil, which was used in the next step without purification. A mixture of 4-fluoro-2-vinylbenzaldehyde (200 mg, 1.332 mmol) and NaBH4 (50.4 mg, 1.332 mmol) in MeOH (2 mL) was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOac/hexane to obtain (4-fluoro-2-vinylphenyl)methanol (150 mg, 0.986 mmol, 74.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=8.3, 5.9 Hz, 1H), 7.25 (dd, J=10.0, 2.7 Hz, 1H), 7.09-7.02 (m, 1H), 7.02-6.95 (m, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.44 (d, J=11.0 Hz, 1H), 4.75 (d, J=4.9 Hz, 2H). The reaction mixture was stirred at −78° C. for 30 min stirred at rt for 3 h It was then quenched with NH4Cl extracted with ether The organic layer was dried over MgSO4 filtered concentrated

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

Procedure: A mixture of methyltriphenylphosphonium iodide (1.195 g, 2.96 mmol) in tetrahydrofuran (25 mL) was added BuLi (1.182 mL, 2.96 mmol) at 0° C. and stirred at 0° C. for 0.5 h. It was then added 2-bromo-5-fluorobenzaldehyde (0.5 g, 2.463 mmol) and stirred at rt for 16 h. The reaction was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 5% EtOAc/hexane to obtain 1-bromo-4-fluoro-2-vinylbenzene (320 mg, 1.592 mmol, 64.6% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 1H), 7.33-7.23 (m, 1H), 7.09-6.96 (m, 1H), 6.89 (td, J=8.3, 3.1 Hz, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H). extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to obtain an oil, which was then purified by biotage eluting with 5% EtOAc/hexane

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

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

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.0 g 1-Bromo-4-fluoro-2-vinyl-benzene and 1.87 g copper (I) cyanide were dissolved in 16 ml dimethylformamide and heated under microwave irradiation at 200° C. for 25 minutes. The cooled reaction mixture was poured into 200 ml 1 M HCl and extracted five times with portions of 60 ml ethyl acetate. The combined organic layers were washed with 100 ml 1 N HCl, dried over MgSO4, then the solvent was removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=6:1 to obtain 1.77 g 4-Fluoro-2-vinyl-benzonitrile as a solid. The cooled reaction mixture extracted five times with portions of 60 ml ethyl acetate The combined organic layers were washed with 100 ml 1 N HCl dried over MgSO4 the solvent was removed in vacuo the resulting residue purified on silica gel with the eluent heptane=>n-heptane

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

Procedure: 21.12 g Methyltriphenylphosphonium bromide were suspended in 150 ml tetrahydrofuran and cooled in an ice bath. 21.68 ml n-butyl lithium (2.5 M in n-heptane) were added dropwise and the reaction mixture stirred at 0° C. for thirty minutes. Then 10.0 g commercially available 2-bromo-5-fluorobenzaldehyde were added slowly so that the reaction temperature did not exceed +5° C. After completion of the addition the cooling bath was removed and the reaction mixture stirred at room temperature for one hour. The reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 120 ml brine. The organic phase was dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=9:1 to obtain 7.9 g 1-Bromo-4-fluoro-2-vinyl-benzene as an oil. cooled in an ice bath did not exceed +5° C After completion of the addition the cooling bath was removed the reaction mixture stirred at room temperature for one hour The reaction mixture was diluted by addition of 300 ml ethyl acetate washed three times with portions of 120 ml brine The organic phase was dried over MgSO4 the solvent removed in vacuo the resulting residue purified on silica gel with the eluent heptane=>n-heptane

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

Procedure: To a mixture of 1-bromo-4-fluoro-2-vinylbenzene (0.32 g, 1.592 mmol) in tetrahydrofuran (5 mL) at −78° C. was added BuLi (0.764 mL, 1.910 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.185 mL, 2.388 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then warmed to rt and stirred at rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 4-fluoro-2-vinylbenzaldehyde (0.2 g) as an oil, which was used in the next step without purification. A mixture of 4-fluoro-2-vinylbenzaldehyde (200 mg, 1.332 mmol) and NaBH4 (50.4 mg, 1.332 mmol) in MeOH (2 mL) was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOac/hexane to obtain (4-fluoro-2-vinylphenyl)methanol (150 mg, 0.986 mmol, 74.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=8.3, 5.9 Hz, 1H), 7.25 (dd, J=10.0, 2.7 Hz, 1H), 7.09-7.02 (m, 1H), 7.02-6.95 (m, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.44 (d, J=11.0 Hz, 1H), 4.75 (d, J=4.9 Hz, 2H). The reaction mixture was stirred at −78° C. for 30 min stirred at rt for 3 h It was then quenched with NH4Cl extracted with ether The organic layer was dried over MgSO4 filtered concentrated

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

Procedure: A mixture of methyltriphenylphosphonium iodide (1.195 g, 2.96 mmol) in tetrahydrofuran (25 mL) was added BuLi (1.182 mL, 2.96 mmol) at 0° C. and stirred at 0° C. for 0.5 h. It was then added 2-bromo-5-fluorobenzaldehyde (0.5 g, 2.463 mmol) and stirred at rt for 16 h. The reaction was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 5% EtOAc/hexane to obtain 1-bromo-4-fluoro-2-vinylbenzene (320 mg, 1.592 mmol, 64.6% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 1H), 7.33-7.23 (m, 1H), 7.09-6.96 (m, 1H), 6.89 (td, J=8.3, 3.1 Hz, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H). extracted with EtOAc The organic layer was dried over MgSO4 filtered concentrated to obtain an oil, which was then purified by biotage eluting with 5% EtOAc/hexane

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

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