1-(2-bromo-5-fluorophenyl)ethanone

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 suspension of methyltriphenylphosphonium bromide (5.69 g, 15.91 mmol) in diethyl ether (80 mL) at room temperature was added n-BuLi (2.5 M in hexanes, 6.37 mL, 15.91 mmol) dropwise. The reaction immediately turned bright orange and the resulting solution was stirred for 35 min at room temperature after which time a solution of l-(2-bromo-5-fluorophenyl)ethanone (3.14 g, 14.47 mmol) in diethyl ether (20 mL) was added dropwise. The reaction lost the bright yellow color and became almost completely white with a significant amount of white precipitate, the reaction was stirred for 89 h after it was quenched by addition of water and extracted with diethyl ether (3×), the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-5% Diethyl Ether/Hexanes) to afford 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (dd, J=8.8, 5.3 Hz, 1H), 6.92 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (td, J=8.3, 3.1 Hz, 1H), 5.24 (t, J=1.7 Hz, 1H), 4.96 (s, 1H), 2.08 (d, J=1.4 Hz, 3H). The reaction immediately turned bright orange was added dropwise was quenched by addition of water extracted with diethyl ether (3×) the combined organic layers were dried over anhydrous MgSO4 filtered concentrated in vacuo The resulting crude material was purified by column chromatography (SiO2, 0-5% Diethyl Ether/Hexanes)

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

Procedure: To a suspension of methyltriphenylphosphonium bromide (5.69 g, 15.91 mmol) in diethyl ether (80 mL) at room temperature was added n-BuLi (2.5 M in hexanes, 6.37 mL, 15.91 mmol) dropwise. The reaction immediately turned bright orange and the resulting solution was stirred for 35 min at room temperature after which time a solution of l-(2-bromo-5-fluorophenyl)ethanone (3.14 g, 14.47 mmol) in diethyl ether (20 mL) was added dropwise. The reaction lost the bright yellow color and became almost completely white with a significant amount of white precipitate, the reaction was stirred for 89 h after it was quenched by addition of water and extracted with diethyl ether (3×), the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-5% Diethyl Ether/Hexanes) to afford 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (dd, J=8.8, 5.3 Hz, 1H), 6.92 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (td, J=8.3, 3.1 Hz, 1H), 5.24 (t, J=1.7 Hz, 1H), 4.96 (s, 1H), 2.08 (d, J=1.4 Hz, 3H). The reaction immediately turned bright orange was added dropwise was quenched by addition of water extracted with diethyl ether (3×) the combined organic layers were dried over anhydrous MgSO4 filtered concentrated in vacuo The resulting crude material was purified by column chromatography (SiO2, 0-5% Diethyl Ether/Hexanes)

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

Procedure: To a solution of 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide (1.54 g, 5.88 mmol) in THF (60 mL) at 0° C. was added McMgI (3.0 M in diethyl ether, 1.998 mL, 5.99 mmol) dropwise over 5 min, the reaction immediately turned bright yellow after a few drops and then after continued addition the reaction lost the yellow color and a significant amount of white precipitate crashed out. After 15 min the reaction was warmed to room temperature and stirred for 15 h after which an additional 3×0.5 equiv. McMgI (1.0 mL) was added every 3 h until after 23 h the reaction was quenched by addition of sat. aq. NH4Cl solution and extracted with diethy ether (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Hexanes) to afford 1-(2-bromo-5-fluorophenyl)ethanone (1.038 g, 4.78 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.57 (dd, J=8.8, 4.9 Hz, 1H), 7.18 (dd, J=8.4, 3.1 Hz, 1H), 7.07-6.99 (m, 1H), 2.63 (s, 3H). the reaction immediately turned bright yellow after a few drops addition the reaction McMgI (1.0 mL) was added every 3 h until after 23 h the reaction was quenched by addition of sat. aq. NH4Cl solution extracted with diethy ether (3×) The combined organic layers were dried over anhydrous MgSO4 filtered concentrated in vacuo the resulting crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Hexanes)

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

Procedure: Ethylene glycol (25.6 mL, 458 mmol) and p-toluenesulfonic acid (4.36 g, 22.9 g) were added to a solution of 1-(2-bromo-5-fluorophenyl)ethanone (10.5 g, 45.8 mmol) stirring in benzene (250 mL). The reaction mixture was equipped with a Dean Stark trap containing 4.0 angstrom molecular sieves and refluxed for 16 h. The reaction was transferred to a separatory funnel containing a 1:1 mixture of H2O and sat. NaHCO3 (aq) and extracted with EtOAc (3×100 mL). The combined organics were washed with H2O, brine, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography to give 2-(2-bromo-5-fluorophenyl)-2-methyl-1,3-dioxolane (7.20 g) in 58% yield. 1H NMR (CDCl3, 300 MHz) δ2.60 (s, 3 H) 4.02-4.20 (m, 4H), 6.85-6.90 (m, 1H), 7.29-7.33 (m, 1H), 7.48-7.56 (m, 1H). The reaction mixture was equipped with a Dean Stark trap containing 4.0 angstrom molecular sieves refluxed for 16 h The reaction was transferred to a separatory funnel containing extracted with EtOAc (3×100 mL) The combined organics were washed with H2O, brine dried over Na2SO4 concentrated The resulting oil was purified by column chromatography

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

Procedure: 2-Bromo-5-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 0.015 mol) was dissolved in THF (30 mL) and the solution was cooled to 0° C. under N2blanket. Methyl magnesium bromide (15.26 mL, 0.046 mol) was added dropwise over 30 min. The solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 0° C. and quenched with HCl/EtOH (9 mL, 4 M solution). The reaction mixture was transferred to a separatory funnel, diluted with H2O (30 mL), and extracted with Ethyl Acetate (2×40 mL). The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. The solution was concentrated to afford 1-(2-bromo-5-fluorophenyl)ethanone as a yellow oil in 93% yield . This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 500 MHz) δ2.61 (s, 3H), 7.00-7.04 (m, 1H) 7.15-7.18 (m, 1H), 7.53-7.59 (m, 1H). The solution was warmed to room temperature The solution was cooled to 0° C. quenched with HCl/EtOH (9 mL, 4 M solution) The reaction mixture was transferred to a separatory funnel diluted with H2O (30 mL) extracted with Ethyl Acetate (2×40 mL) The combined organic extracts were washed with H2O, brine dried over Na2SO4 The solution was concentrated

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

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

Procedure: Ethylene glycol (25.6 mL, 458 mmol) and p-toluenesulfonic acid (4.36 g, 22.9 g) were added to a solution of 1-(2-bromo-5-fluorophenyl)ethanone (10.5 g, 45.8 mmol) stirring in benzene (250 mL). The reaction mixture was equipped with a Dean Stark trap containing 4.0 angstrom molecular sieves and refluxed for 16 h. The reaction was transferred to a separatory funnel containing a 1:1 mixture of H2O and sat. NaHCO3 (aq) and extracted with EtOAc (3×100 mL). The combined organics were washed with H2O, brine, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography to give 2-(2-bromo-5-fluorophenyl)-2-methyl-1,3-dioxolane (7.20 g) in 58% yield. 1H NMR (CDCl3, 300 MHz) δ2.60 (s, 3 H) 4.02-4.20 (m, 4H), 6.85-6.90 (m, 1H), 7.29-7.33 (m, 1H), 7.48-7.56 (m, 1H). The reaction mixture was equipped with a Dean Stark trap containing 4.0 angstrom molecular sieves refluxed for 16 h The reaction was transferred to a separatory funnel containing extracted with EtOAc (3×100 mL) The combined organics were washed with H2O, brine dried over Na2SO4 concentrated The resulting oil was purified by column chromatography

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

Procedure: 2-Bromo-5-fluoro-N-methoxy-N-methylbenzamide (4.0 g, 0.015 mol) was dissolved in THF (30 mL) and the solution was cooled to 0° C. under N2blanket. Methyl magnesium bromide (15.26 mL, 0.046 mol) was added dropwise over 30 min. The solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 0° C. and quenched with HCl/EtOH (9 mL, 4 M solution). The reaction mixture was transferred to a separatory funnel, diluted with H2O (30 mL), and extracted with Ethyl Acetate (2×40 mL). The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. The solution was concentrated to afford 1-(2-bromo-5-fluorophenyl)ethanone as a yellow oil in 93% yield . This material was used in the subsequent step without further purification. 1H NMR (CDCl3, 500 MHz) δ2.61 (s, 3H), 7.00-7.04 (m, 1H) 7.15-7.18 (m, 1H), 7.53-7.59 (m, 1H). The solution was warmed to room temperature The solution was cooled to 0° C. quenched with HCl/EtOH (9 mL, 4 M solution) The reaction mixture was transferred to a separatory funnel diluted with H2O (30 mL) extracted with Ethyl Acetate (2×40 mL) The combined organic extracts were washed with H2O, brine dried over Na2SO4 The solution was concentrated

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

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

Procedure: To a solution of 2-([(4-methoxyphenyl)sulfonyl]{[2-(trimethylsilyl)ethoxy]methyl}amino) phenylboronic acid (3.31 g, 7.57 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.87 g, 0.76 mmol) in dimethoxyethane (30 niL) under argon was added 1-(2-bromo-5-fluorophenyl)ethanone (1.86 g, 8.57 mmol) in ethanol (1 mL). Aqueous sodium carbonate (2 M, 40 mL) was added and the reaction mixture was heated at 90° C. for 14 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and a saturated, aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate was evaporated in vacuo to yield the crude title compound as an oil. Purification by silica gel column chromatography by elution with hexane-ethyl acetate (5:1) gave the title compound as a pale yellow oil, which crystallized on standing (2.22 g, 4.19 mmol, 55 %), m.p. 94-95° C. The solvent was removed in vacuo the residue was partitioned between water and ethyl acetate The organic layer was washed with water After drying over anhydrous magnesium sulfate the organic phase was filtered the filtrate was evaporated in vacuo to yield the crude title compound as an oil Purification by silica gel column chromatography by elution with hexane-ethyl acetate (5:1)