tert-butyl-(3-iodopropoxy)-dimethylsilane

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 solution of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester (199 grams, 0.42 mole) in dry N,N-dimethylformamide (2.5 L) at room temperature was added potassium hexamethyldisilazide (100 grams, 0.50 mole) and, after 3 hours, tert-butyl-(3-iodopropoxy)dimethylsilane (150 grams, 0.50 mole). The resulting mixture was stirred at room temperature for 16 hours. Additional tert-butyl-3-iodopropoxy)-dimethylsilane (20 grams, 0.067 mole) was then added. Stirring at room temperature was continued for a further 3.5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed with water and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford crude 1-{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester as an amber oil (279.6 grams). Stirring at room temperature was continued for a further 3.5 hours The mixture was quenched by addition of saturated ammonium chloride solution The N,N-dimethylformamide was removed by evaporation under vacuum washed with water and brine After drying over magnesium sulfate the diethyl ether was evaporated

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

Procedure: Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (0.84 g, 3.16 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (2.56 mL, 1.3 M in hexane, 3.33 mmol). After 30 minutes, add 3-(t-butyldimethylsilyloxy)propyl iodide (1.0 g, 3.33 mmol). After the addition is complete, warm to ambient temperature. After 2 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound. After the addition warm to ambient temperature After 2 hours extract three times with ethyl acetate Dry the combined organic layers over Na2SO4 filter concentrate in vacuo to obtain a residue

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

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

Procedure: To a solution of 5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (700 mg, 2.3 mmol, 1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (1.58 mL, 1.6 M in heptane, 2.54 mmol, 1.1 equiv). The resulting solution was stirred at −78° C. for 30 minutes, after which it was added a solution of tert-Butyl-(3-iodo-propoxy)-dimethyl-silane (693 mg, 2.3 mmol, 1.0 equiv) in THF (1.0 mL). The solution was stirred at −78° C. for 30 minutes and 2 hours at room temperature after which it was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was combined, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 30% to give product 480 mg (yield 44%). The solution was stirred at −78° C. for 30 minutes and 2 hours at room temperature after which it was quenched by addition of sat. aq. NH4Cl solution The mixture was extracted with EtOAc dried over MgSO4 concentrated The residue was purified by silica gel column chromatography, EtOAc/heptane 30%

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

Procedure: To a solution of 5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (700 mg, 2.3 mmol, 1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (1.58 mL, 1.6 M in heptane, 2.54 mmol, 1.1 equiv). The resulting solution was stirred at −78° C. for 30 minutes, after which it was added a solution of tert-Butyl-(3-iodo-propoxy)-dimethyl-silane (693 mg, 2.3 mmol, 1.0 equiv) in THF (1.0 mL). The solution was stirred at −78° C. for 30 minutes and 2 hours at room temperature after which it was quenched by addition of sat. aq. NH4Cl solution. The mixture was extracted with EtOAc. The organic layer was combined, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography, EtOAc/heptane 30% to give product 480 mg (yield 44%). The solution was stirred at −78° C. for 30 minutes and 2 hours at room temperature after which it was quenched by addition of sat. aq. NH4Cl solution The mixture was extracted with EtOAc dried over MgSO4 concentrated The residue was purified by silica gel column chromatography, EtOAc/heptane 30%

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

Procedure: To a lithium diisopropylamide (LDA) solution [prepared from diisopropylamine (3.82 mL, 27 mmol) and nBuLi (7.26 mL of a 2.5 M solution in hexanes, 18 mmol) in tetrahydrofuran (THF, 12 mL) at 0° C.] at −78° C. was added 3-ethoxy-2-cyclohexen-1-one (2.64 mL, 18 mmol) in THF (6 mL), dropwise, over 40 min. After stirring for an additional 30 min at −78° C., hexamethyl phosphoramide (HMPA, 3.16 mL, 18 mmol) was added followed by the dropwise addition of 3-iodo-1-tert-butyldimethylsiloxypropane (5.45 g, 18 mmol) in THF (8 mL). The resultant mixture was allowed to warm to rt, stirred for 6 h and then quenched by the addition of water (10 mL). The reaction mixture was then partitioned between dichloromethane (DCM, 100 mL) and sat. NH4Cl (40 mL). The aqueous phase was extracted with DCM (3×50 mL), the organic phases combined and washed with brine (50 mL), dried over anhydrous MgSO4 and reduced to dryness. The resultant syrup was purified by flash column chromatography (hexanes/EtOAc 8/2) to yield 2 as a pale yellow oil (2.92 g, 51.2%). Rf 0.21 (hexanes/EtOAc 8/2); 1H NMR (300 MHz, CDCl3) δ 5.26 (1H, s), 3.83 (2H, q, J=7.0 Hz), 3.59 (1H, t, J=6.5 Hz), 3.58 (H, t, J=6.5 Hz), 2.38 (2H, t, J=6.2 Hz), 2.20-1.99 (2H, m), 1.85-1.35 (5H, in), 1.31 (3H, t, J=7.0 Hz), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 201.6, 176.7, 102.3, 64.2, 63.4, 45.0, 30.5, 28.0, 26.4, 26.0 (x2), 18.4, 14.2, −5.2. to warm to rt stirred for 6 h quenched by the addition of water (10 mL) The reaction mixture was then partitioned between dichloromethane (DCM, 100 mL) and sat. NH4Cl (40 mL) The aqueous phase was extracted with DCM (3×50 mL) washed with brine (50 mL) dried over anhydrous MgSO4 The resultant syrup was purified by flash column chromatography (hexanes/EtOAc 8/2)

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

Procedure: To a solution of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester (199 grams, 0.42 mole) in dry N,N-dimethylformamide (2.5 L) at room temperature was added potassium hexamethyldisilazide (100 grams, 0.50 mole) and, after 3 hours, tert-butyl-(3-iodopropoxy)dimethylsilane (150 grams, 0.50 mole). The resulting mixture was stirred at room temperature for 16 hours. Additional tert-butyl-3-iodopropoxy)-dimethylsilane (20 grams, 0.067 mole) was then added. Stirring at room temperature was continued for a further 3.5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed with water and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford crude 1-{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester as an amber oil (279.6 grams). Stirring at room temperature was continued for a further 3.5 hours The mixture was quenched by addition of saturated ammonium chloride solution The N,N-dimethylformamide was removed by evaporation under vacuum washed with water and brine After drying over magnesium sulfate the diethyl ether was evaporated

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

Procedure: To a solution of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester (199 grams, 0.42 mole) in dry N,N-dimethylformamide (2.5 L) at room temperature was added potassium hexamethyldisilazide (100 grams, 0.50 mole) and, after 3 hours, tert-butyl-(3-iodopropoxy)dimethylsilane (150 grams, 0.50 mole). The resulting mixture was stirred at room temperature for 16 hours. Additional tert-butyl-3-iodopropoxy)-dimethylsilane (20 grams, 0.067 mole) was then added. Stirring at room temperature was continued for a further 3.5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed with water and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford crude 1-{[3-(tert-butyl-dimethylsilanyloxy)-propyl]-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester as an amber oil (279.6 grams). Stirring at room temperature was continued for a further 3.5 hours The mixture was quenched by addition of saturated ammonium chloride solution The N,N-dimethylformamide was removed by evaporation under vacuum washed with water and brine After drying over magnesium sulfate the diethyl ether was evaporated