tert-butyl-(2-fluorophenoxy)-dimethylsilane

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

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 mL round bottom flask was charged with tert-butyldimethylchlorosilane (73.9 g, 491 mmol) (available from Aldrich), DMF (220 mL), 2-fluorophenol (41.3 mL, 446 mmol) (available from Aldrich), and imidazole (75.9 g, 1115 mmol). The pale yellow solution was stirred for 1.5 hours at 25° C. and diluted with hexanes (1 L). The organic phase was washed with water (1×300 mL), saturated aqueous NaHCO3 (3×300 mL), water (3×300 mL) and brine (1×300 mL). The organic phase was then dried (MgSO4), and concentrated to afford 84.A (101 g, 100% yield) as a colorless liquid. The crude product was used without further purification. The organic phase was washed with water (1×300 mL), saturated aqueous NaHCO3 (3×300 mL), water (3×300 mL) and brine (1×300 mL) The organic phase was then dried (MgSO4) concentrated

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

Procedure: tert-Butyldimethylsilyl 2-fluorophenyl ether (2.73 g, 12 mmol), prepared from 2-fluorophenol by the method in Example 1, was treated with sec-butyllithium (11 mL of 1.1M solution in cyclohexane) and 4-formyl-N,N -diethylbenzamide, (2.46 g, 12 mmol) from Example 11, by the procedure described in Example 29. Chromatography on silica gel with 1% methanol in dichloromethane gave 1.77 g (34%) of 4-(5-(tert-butyidimethylsilyloxy)-2-fluoro-α-hydroxybenzyl)-N,N-diethylbenzamide as a yellow oil that crystallized on standing.

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

Procedure: tert-Butyldimethylsilyl 2-fluorophenyl ether (2.73 g, 12 mmol), prepared from 2-fluorophenol by the method in Example 1, was treated with sec-butyllithium (11 mL of 1.1M solution in cyclohexane) and 4-formyl-N,N -diethylbenzamide, (2.46 g, 12 mmol) from Example 11, by the procedure described in Example 29. Chromatography on silica gel with 1% methanol in dichloromethane gave 1.77 g (34%) of 4-(5-(tert-butyidimethylsilyloxy)-2-fluoro-α-hydroxybenzyl)-N,N-diethylbenzamide as a yellow oil that crystallized on standing.

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

Procedure: A 1 L round bottom flask was charged with 84.A (17.0 mL, 73.0 mmol) and THF (70 mL) and cooled to −78° C. under N2. To the cold solution was added sec-butyllithium (1.20 M/cyclohexane) (66.3 mL, 79.6 mmol) dropwise. The mixture was stirred for 30 minutes, and to it was added a solution of 84.B (9.31 mL, 66.3 mmol) in THF (70 mL) dropwise. The final mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl (70 mL) and diluted with EtOAc (100 mL). The organic phase was washed with water (100 mL), 1 N HCl (100 mL) and brine (100 mL). The organic phase was then dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (2% EtOAc/hexane) to afford 84.C (14.9 g, 73% yield) as a yellow oil. The cooling bath was removed the mixture was stirred for 30 minutes at ambient temperature The reaction was quenched with saturated aqueous NH4Cl (70 mL) diluted with EtOAc (100 mL) The organic phase was washed with water (100 mL), 1 N HCl (100 mL) and brine (100 mL) The organic phase was then dried (MgSO4) concentrated The residue was purified by silica gel flash chromatography (2% EtOAc/hexane)

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

Procedure: tert-Butyldimethylsilyl 2-fluorophenyl ether (2.73 g, 12 mmol), prepared from 2-fluorophenol by the method in Example 1, was treated with sec-butyllithium (11 mL of 1.1M solution in cyclohexane) and 4-formyl-N,N-diethylbenzamide, (2.46 g, 12 mmol) from Example 11, by the procedure described in Example 29. Chromatography on silica gel with 1% methanol in dichloromethane gave 1.77 g (34%) of 4-(5-(tert-butyldimethylsilyloxy)-2-fluoro-α-hydroxybenzyl)-N,N-diethylbenzamide as a yellow oil that crystallized on standing.

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

Procedure: Sec-BuLi (1.3M solution in cyclohexane, 75 mL, 98 mmol) was added slowly at −78° C. to a solution of Intermediate 31, 1-(tert-Butyldimethylsilyl)oxy-2-fluorobenzene (20.1 g, 89 mmol) and TMEDA (14.8 mL, 98 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (7.5 mL, 98 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 30 min. The organic layer was separated. Aqueous layer was extracted with EtOAc (200 mL). The organic layers was washed with sat. NaHCO3, brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (16.7 g, 74%, 66 mmol) as a yellow oil. 1H NMR data (dmso-d6): 10.21 (s, 1H, CHO), 7.39-7.45 (m, 1H, H—Ar), 7.32-7.38 (m, 1H, H—Ar), 7.22-7.28 (m, 1H, H—Ar), 0.97 (s, 9H, t-Bu), 0.20 (s, 6H, 2CH3). the mixture was stirred at the same temperature for 1.5 h the reaction mixture was stirred at RT for 30 min The organic layer was separated Aqueous layer was extracted with EtOAc (200 mL) The organic layers was washed with sat. NaHCO3, brine dried with Na2SO4 evaporated in vacuo