5-ethyl-2-fluorophenol

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

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

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

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 5-ethyl-2-fluorophenol (10 g, 71.4 mmol) and imidazole (5.4 g, 78.5 mmol) in DMF (100 mL) was added t-butyldimethylsilylchloride (10.8 g, 71.4 mmol) and stirred 18 h. Diluted with EtOAc and washed with H2O (3×50 mL) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 12.2 g of intermediate 368.1. 1H NMR (400 MHz, CDCl3) δ ppm 0.15 (s, 6H) 0.97 (s, 9H) 1.16 (t, J=7.47 Hz, 3H) 2.52 (q, J=7.76 Hz, 2H) 6.63-6.72 (m, 2H) 6.90 (dd, J=10.77, 8.13 Hz, 1H). washed with H2O (3×50 mL) and brine dried (Na2SO4) concentrated The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient)

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

Procedure: To a solution of Intermediate 188.1 (5.42 g, 38.7 mmol) in 25 mL DMF at rt, were added imidazole (2.90 g, 42.5 mmol) and TBS-Cl (5.83 mmol). The mixture was stirred for 1.5 h, then was diluted with hexanes. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), then concentrated. Purification by flash chromatography (100% hexanes) afforded 7.50 g of Intermediate 188.2 as a colorless oil. The organic phase was washed with H2O (3×) and brine dried (Na2SO4) concentrated Purification by flash chromatography (100% hexanes)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-ethyl-4-fluorobenzene (5.0 g, 40.3 mmol) and PMDTA (8.5 mL, 40.7 mmol) in 20 mL THF at −40° C., was added BuLi (1.4 M in hexanes, 31.6 mL, 44.3 mmol). The tan suspension was stirred at −60° C. for 40 min, was recooled to −78° C., then B(OMe)3 (9.03 mL, 80.6 mmol). The mixture was stirred at −78° C. for 30 min, then was allowed to warm to rt. The reaction was quenched with 8 mL AcOH, then was cooled to 0° C. and treated with 9.8 mL 30% H2O2. The mixture was stirred for 30 min, then was quenched with aq. Na2SO3. The mixture was diluted with hexanes, washed with H2O (3×) and brine, dried (Na2SO4), filtered through 2″ silica gel (eluting with 20% EtOAc/hexanes), then concentrated to afford 5.42 g of Intermediate 188.1 as a pale yellow oil. was recooled to −78° C. The mixture was stirred at −78° C. for 30 min to warm to rt The reaction was quenched with 8 mL AcOH was cooled to 0° C. treated with 9.8 mL 30% H2O2 The mixture was stirred for 30 min was quenched with aq. Na2SO3 The mixture was diluted with hexanes washed with H2O (3×) and brine dried (Na2SO4) filtered through 2″ silica gel (eluting with 20% EtOAc/hexanes) concentrated

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

Procedure: After adding 9.16 g of imidazole and 19.4 g of t-butyldimethylchlorosilane to a solution of 16.4 g of 5-ethyl-2-fluorophenol in 40 ml of DMF, the reaction mixture was stirred at room temperature for 18 hours. After then adding 500 ml of diethyl ether and 500 ml of water to the reaction mixture, the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and then dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (25.38 g) as a colorless liquid (boiling point: 133-135° C., 20 mmHg). the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order dried over anhydrous magnesium sulfate the desiccating agent was filtered off the filtrate was concentrated under reduced pressure The residue was subjected to distillation

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

Procedure: A solution of 15.5 g of 4-ethylfluorobenzene and 14.6 g of N,N,N′N′-tetramethylethylenediamine in 500 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 126 ml of s-butyllithium (0.99M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 28 ml of trimethyl borate, the reaction mixture was warmed to room temperature and 14.4 ml of acetic acid was added. After stirring for 30 minutes, the reaction mixture was cooled to 0° C., and then 28.4 ml of 30% aqueous hydrogen peroxide was added and the mixture was stirred at room temperature for 18 hours. Next, 500 ml of saturated aqueous sodium sulfite was added to the reaction mixture and extraction was performed with 1 liter of diethyl ether. The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (16.35 g) as a colorless liquid (boiling point: 76-80° C., 17 mmHg). After stirring for 30 minutes the reaction mixture was cooled to 0° C. the mixture was stirred at room temperature for 18 hours The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order dried over anhydrous magnesium sulfate the desiccating agent was filtered the filtrate was concentrated under reduced pressure The residue was subjected to distillation

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

Procedure: After adding 9.16 g of imidazole and 19.4 g of t-butyldimethylchlorosilane to a solution of 16.4 g of 5-ethyl-2-fluorophenol in 40 ml of DMF, the reaction mixture was stirred at room temperature for 18 hours. After then adding 500 ml of diethyl ether and 500 ml of water to the reaction mixture, the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and then dried over anhydrous magnesium sulfate, the desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (25.38 g) as a colorless liquid (boiling point: 133-135° C., 20 mmHg). the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order dried over anhydrous magnesium sulfate the desiccating agent was filtered off the filtrate was concentrated under reduced pressure The residue was subjected to distillation

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

Procedure: A solution of 15.5 g of 4-ethylfluorobenzene and 14.6 g of N,N,N′N′-tetramethylethylenediamine in 500 ml of THF was cooled to −75° C. under a nitrogen atmosphere, and then 126 ml of s-butyllithium (0.99M, cyclohexane solution) was added and the mixture was stirred for 2 hours. After then adding 28 ml of trimethyl borate, the reaction mixture was warmed to room temperature and 14.4 ml of acetic acid was added. After stirring for 30 minutes, the reaction mixture was cooled to 0° C., and then 28.4 ml of 30% aqueous hydrogen peroxide was added and the mixture was stirred at room temperature for 18 hours. Next, 500 ml of saturated aqueous sodium sulfite was added to the reaction mixture and extraction was performed with 1 liter of diethyl ether. The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate, the desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to distillation to give the title compound (16.35 g) as a colorless liquid (boiling point: 76-80° C., 17 mmHg). After stirring for 30 minutes the reaction mixture was cooled to 0° C. the mixture was stirred at room temperature for 18 hours The organic layer was washed with 500 ml of water and 500 ml of saturated aqueous sodium chloride in that order dried over anhydrous magnesium sulfate the desiccating agent was filtered the filtrate was concentrated under reduced pressure The residue was subjected to distillation