bromomethylsulfanylmethylbenzene

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

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1 M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc:hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1 M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc: hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc: hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc: hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1 M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc:hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1 M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc: hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of the N-acylated product of Step 6 (36.9 g, 185 mmol) in anhydrous THF (70 mL) was added to a magnetically stirred, cooled (-78° C.) solution of LDA (lithium diisopropylamide) (prepared from 28.6 mL (20.6 g, 204 mmol) of diisopropylamine and 127.5 mL (1.6M in hexane, 204 mmol) of n-butyllithium) in anhydrous THF (240 mL). After stirring for 0.5 h at -78° C. the resultant lithium enolate was treated with benzyl bromomethyl sulfide (52.3 g, 241 mmol) for 2 h at -20° C. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL). Volatiles were removed in vacuo and the product was extracted into CH2Cl2 (3×). The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo to give 76.5 g of a yellow liquid. This crude material was roughly purified by flash chromatography on silica with EtOAc: hexane 1:99, 2:98, 5:95, 10:90 and 15:85 to give the title compound as a colorless liquid (48.9 g), which was used as such for the next step. The reaction was quenched by the addition of half-saturated aq NH4Cl (200 mL) Volatiles were removed in vacuo the product was extracted into CH2Cl2 (3×) The combined organic extracts were successively washed with 1M aqueous sodium bisulfate (2×), 1M aqueous KHCO3 (2×) and brine dried over MgSO4 concentrated in vacuo

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

Procedure: A solution of lithium diisopropylamide was prepared from 1.96 mL (1.42 g) of diisopropylamine and 7.6 mL of n-butyllithium (1.75M in hexane) in 14 mL of THF. The solution was cooled to -78° C. with stirring, combined with a solution of (4S, 5R)-3-(1-oxo-4-methylpentyl)-4-methyl-5-phenyl-2-oxazolidinone (3.50 g) in THF (14 mL) and stirred for 30 min at -78° C. To this mixture was added 2.1 mL (3.1 g) of benzyl bromomethyl sulfide. The reaction mixture was stirred for 2 h at -25° C. and for 2 h at 0° C. Aqueous NH4Cl solution was added to the mixture. The organic solvents were removed in vacuo and the residue was extracted twice with CH2Cl2. The combined organic extract was washed twice with 1M aqueous NaHSO4, then with saturated NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was subjected to flash chromatography on silica gel (hexane-EtOAc) to give 5.0 g (96% yield) of (4S, 5R)-3-[(2S)-1-oxo-2-((benzylthio)methyl)-4-methylpentyl]-4-methyl-5-phenyl-2-oxazolidinone as a clear oil. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ7.24-7.47 (m, 10H), 5.66 (d, J=7 Hz, 1H), 4.81 (p, J= 7 Hz, 1H), 4.31-4.36 (m, 1H), 3.80 (AB q, J=13 Hz, 2H), 2.72 (dd, J=9, 14 Hz, 1H), 2.52 (dd, J=5, 14 Hz, 1H), 1.35-1.71 (m, 3H), 0.89-0.95 (m, 9H); [α]25D -91° (c=2.60, CH2Cl2) stirred for 30 min at -78° C The reaction mixture was stirred for 2 h at -25° C. and for 2 h at 0° C The organic solvents were removed in vacuo the residue was extracted twice with CH2Cl2 The combined organic extract was washed twice with 1M aqueous NaHSO4 with saturated NaHCO3, brine, dried over Na2SO4 evaporated

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

Procedure: To a solution of lithium diisopropylamide [prepared using freshly distilled diisopropylamine (4.47 g., 44.4 mmol) and n-butyl lithium/hexane (18 mL, 45 mmol, 2.5M)] in dry tetrahydrofuran (35 mL) was added a solution of 4,4,4-trifluorobutyric acid (3.0 g., 21.0 mmol) in tetrahydrofuran (25 mL). After stirring at 0° C. for 1.5 hours, the solution was cooled to -78° C. and treated with a solution of benzyl bromomethyl thioether in tetrahydrofuran (10 mL). The solution was allowed to stir overnight as the temperature rose to ambient. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and extracted with 1N sodium hydroxide (50 mL) and water (2×20 mL). The combined basic extracts were acidified with concentrated hydrochloric acid (8 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with water and brine, combined, dried (MgSO4), and concentrated in vacuo to give 3.82 g. of an oil. Flash chromatography on 350 mL of silica gel and elution with ethyl acetate:hexanes:acetic acid, 50:100:1 gave 1.36 g. of the title A product, TLC Rf =0.38 (ethyl acetate:hexanes:acetic acid, 50:50:1). the solution was cooled to -78° C. to stir overnight as the temperature Volatiles were removed in vacuo the residue was dissolved in ethyl acetate extracted with 1N sodium hydroxide (50 mL) and water (2×20 mL) extracted with ethyl acetate (2×100 mL) The organic extracts were washed with water and brine dried (MgSO4) concentrated in vacuo to give 3.82 g Flash chromatography on 350 mL of silica gel and elution with ethyl acetate hexanes:acetic acid, 50:100:1 gave 1.36 g

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

Procedure: To a solution of lithium diisopropylamide [prepared using freshly distilled diisopropylamine (4.47 g., 44.4 mmol) and n-butyl lithium/hexane (18 mL, 45 mmol, 2.5M)]in dry tetrahydrofuran (35 mL) was added a solution of 4,4,4-trifluorobutyric acid (3.0 g., 21.0 mmol) in tetrahydrofuran (25 mL). After stirring at 0° C. for 1.5 hours, the solution was cooled to -78° C. and treated with a solution of benzyl bromomethyl thioether in tetrahydrofuran (10 mL). The solution was allowed to stir overnight as the temperature rose to ambient. Volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and extracted with 1N sodium hydroxide (50 mL) and water (2 x 20 mL). The combined basic extracts were acidified with concentrated hydrochloric acid (8 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with water and brine, combined, dried (MgSO4), and concentrated in vacuo to give 3.82 g. of an oil. Flash chromatography on 350 mL of silica gel and elution with ethyl acetate:hexanes: acetic acid, 50:100:1 gave 1.36 g. of the title A product, TLC Rf =0.38 (ethyl acetate:hexanes:acetic acid, 50:50:1). the solution was cooled to -78° C. to stir overnight as the temperature Volatiles were removed in vacuo the residue was dissolved in ethyl acetate extracted with 1N sodium hydroxide (50 mL) and water (2 x 20 mL) extracted with ethyl acetate (2×100 mL) The organic extracts were washed with water and brine dried (MgSO4) concentrated in vacuo to give 3.82 g Flash chromatography on 350 mL of silica gel and elution with ethyl acetate hexanes: acetic acid, 50:100:1 gave 1.36 g

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

Procedure: A solution of lithium diisopropylamide was prepared from 1.96 mL (1.42 g) of diisopropylamine and 7.6 mL of n-butyllithium (1.75M in hexane) in 14 mL of THF. The solution was cooled to -78° C. with stirring, combined with a solution of (4S, 5R)-3-(1-oxo-4-methylpentyl)-4-methyl-5-phenyl-2-oxazolidinone (3.50 g) in THF (14 mL) and stirred for 30 min at -78° C. To this mixture was added 2.1 mL (3.1 g) of benzyl bromomethyl sulfide. The reaction mixture was stirred for 2 h at -25° C. and for 2 h at 0° C. Aqueous NH4Cl solution was added to the mixture. The organic solvents were removed in vacuo and the residue was extracted twice with CH2Cl2. The combined organic extract was washed twice with 1M aqueous NaHSO4, then with saturated NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was subjected to flash chromatography on silica gel (hexane-EtOAc) to give 5.0 g (96% yield) of (4S, 5R)-3-[(2S)-1-oxo-2-((benzylthio)methyl)-4-methylpentyl]-4-methyl-5-phenyl-2-oxazolidinone as a clear oil. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ7.24-7.47 (m, 10H), 5.66 (d, J=7 Hz, 1H), 4.81 (p, J= 7 Hz, 1H), 4.31-4.36 (m, 1H), 3.80 (AB q, J=13 Hz, 2H), 2.72 (dd, J=9, 14 Hz, 1H), 2.52 (dd, J=5, 14 Hz, 1H), 1.35-1.71 (m, 3H), 0.89-0.95 (m, 9H); [α]25D -91° (c=2.60, CH2Cl2) stirred for 30 min at -78° C The reaction mixture was stirred for 2 h at -25° C. and for 2 h at 0° C The organic solvents were removed in vacuo the residue was extracted twice with CH2Cl2 The combined organic extract was washed twice with 1M aqueous NaHSO4 with saturated NaHCO3, brine, dried over Na2SO4 evaporated