fluoromethylsulfonylbenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione (1 g, 3.0 mmol) was added to a flame-dried round bottom flask with stir bar and dissolved in THF (30 mL). Next, ((fluoromethyl)sulfonyl)benzene (780 mg, 4.5 mmol) was added, and the mixture was cooled to −78° C. Lithium hexamethyldisilazide (1M in THF, 4.5 mL, 4.5 mmol) was added dropwise to the cooled solution, and the mixture was allowed to gradually warm to room temperature overnight. The reaction was quenched by addition of excess saturated brine, and then extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated and purified by silica gel chromatography (30-100% EtOAc in hexanes gradient) to afford 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one as a yellowish foam. To a scintillation vial containing a magnetic stir bar was added 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one (305 mg, 0.6 mmol), followed by DMF (6 mL), magnesium powder (150 mg, 6 mmol), and 3 mL of an acetic acid/sodium acetate (1:1) buffer solution (8 mol/L). The vial was sealed and allowed to stir at room temperature overnight. The mixture was diluted with water (100 mL), and then extracted with 5×25 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated, and purified by reversed-phase HPLC using 0.1% TFA in water/acetonitrile as a mobile phase to afford the title compound. LCMS: RT=0.67 min, >99% @ 254 nm, >99% @ 215 nm; m/z (M+1)+=370. 1HNMR (400 MHz, CDCl3, δ (ppm)): 7.53 (s, 1H), 7.47 (s, 1H), 7.3 (dt, J=7.8, 1.1 Hz, 1H), 7.2-7.1 (m, 2H), 7.1-7.0 (m, 2H), 6.9 (d, J=7.9 Hz, 1H), 5.0 (d, J=15.8 Hz, 1H), 4.9 (d, J=15.8 Hz, 1H), 4.8 (quartet, J=3.6 Hz, 1H), 4.6 (quartet, J=9.1, 4.0 Hz, 1H), 3.9 (s, 3H), HRMS calculated for C20H18N3O2F2 (M+H)+ m/z: 370.1367, measured: 370.1366. to gradually warm to room temperature overnight The reaction was quenched by addition of excess saturated brine extracted with 3×50 mL ethyl acetate dried over magnesium sulfate evaporated purified by silica gel chromatography (30-100% EtOAc in hexanes gradient)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione (1 g, 3.0 mmol) was added to a flame-dried round bottom flask with stir bar and dissolved in THF (30 mL). Next, ((fluoromethyl)sulfonyl)benzene (780 mg, 4.5 mmol) was added, and the mixture was cooled to −78° C. Lithium hexamethyldisilazide (1M in THF, 4.5 mL, 4.5 mmol) was added dropwise to the cooled solution, and the mixture was allowed to gradually warm to room temperature overnight. The reaction was quenched by addition of excess saturated brine, and then extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated and purified by silica gel chromatography (30-100% EtOAc in hexanes gradient) to afford 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one as a yellowish foam. To a scintillation vial containing a magnetic stir bar was added 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one (305 mg, 0.6 mmol), followed by DMF (6 mL), magnesium powder (150 mg, 6 mmol), and 3 mL of an acetic acid/sodium acetate (1:1) buffer solution (8 mol/L). The vial was sealed and allowed to stir at room temperature overnight. The mixture was diluted with water (100 mL), and then extracted with 5×25 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated, and purified by reversed-phase HPLC using 0.1% TFA in water/acetonitrile as a mobile phase to afford the title compound. LCMS: RT=0.67 min, >99% @ 254 nm, >99% @ 215 nm; m/z (M+1)+=370. 1HNMR (400 MHz, CDCl3, δ (ppm)): 7.53 (s, 1H), 7.47 (s, 1H), 7.3 (dt, J=7.8, 1.1 Hz, 1H), 7.2-7.1 (m, 2H), 7.1-7.0 (m, 2H), 6.9 (d, J=7.9 Hz, 1H), 5.0 (d, J=15.8 Hz, 1H), 4.9 (d, J=15.8 Hz, 1H), 4.8 (quartet, J=3.6 Hz, 1H), 4.6 (quartet, J=9.1, 4.0 Hz, 1H), 3.9 (s, 3H), HRMS calculated for C20H18N3O2F2 (M+H)+ m/z: 370.1367, measured: 370.1366. to gradually warm to room temperature overnight The reaction was quenched by addition of excess saturated brine extracted with 3×50 mL ethyl acetate dried over magnesium sulfate evaporated purified by silica gel chromatography (30-100% EtOAc in hexanes gradient)

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under a nitrogen atmosphere, 25.0 grams (0.14 mole) of distilled fluoromethyl phenyl sulfone (prepared by the method of J. R McCarthy et al., Org. Syn. 1993, 72, 209), 24.8 grams (0.14 mole) of diethyl chlorophosphate, and 300 mL of anhydrous tetrahydrofuran are placed in a reaction vessel. The stirring mixture is cooled to about -70° C., and a solution of 310 mL (0.31 mole) of lithium bis(trimethylsilyl)amide (commercially available-1M in tetrahydrofuran) is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred at about -70° C. for one hour. After this time a solution of 19.7 grams (0.10 mole) of 3-(4-chlorophenyl)-3-methylbutyraldehyde in 65 mL of tetrahydrofuran is added via a syringe. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about two hours. The reaction mixture is then poured into an ice-cold mixture of 250 mL of ethyl acetate, 250 mL of saturated aqueous ammonium chloride, and 30 mL of concentrated hydrochloric acid. The organic layer is separated, and the aqueous o layer is extracted with ethyl acetate. The extract and the organic layer are combined, washed with 100 mL of saturated aqueous sodium chloride, and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 1-fluoro-1-phenylsulfonyl-3-methyl-3-(4-chlorophenyl)-1-butene. Upon completion of addition Upon completion of addition to warm to ambient temperature where it is stirred for about two hours The organic layer is separated the aqueous o layer is extracted with ethyl acetate The extract washed with 100 mL of saturated aqueous sodium chloride dried with magnesium sulfate The mixture is filtered the filtrate is concentrated under reduced pressure to a residue concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under a nitrogen atmosphere, 25.0 grams (0.14 mole) of distilled fluoromethyl phenyl sulfone (prepared by the method of J. R McCarthy et al., Org. Syn. 1993, 72, 209), 24.8 grams (0.14 mole) of diethyl chlorophosphate, and 300 mL of anhydrous tetrahydrofuran are placed in a reaction vessel. The stirring mixture is cooled to about -70° C., and a solution of 310 mL (0.31 mole) of lithium bis(trimethylsilyl)amide (commercially available-1M in tetrahydrofuran) is added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture is stirred at about -70° C. for one hour. After this time a solution of 19.7 grams (0.10 mole) of 3-(4-chlorophenyl)-3-methylbutyraldehyde in 65 mL of tetrahydrofuran is added via a syringe. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about two hours. The reaction mixture is then poured into an ice-cold mixture of 250 mL of ethyl acetate, 250 mL of saturated aqueous ammonium chloride, and 30 mL of concentrated hydrochloric acid. The organic layer is separated, and the aqueous o layer is extracted with ethyl acetate. The extract and the organic layer are combined, washed with 100 mL of saturated aqueous sodium chloride, and dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 1-fluoro-1-phenylsulfonyl-3-methyl-3-(4-chlorophenyl)-1-butene. Upon completion of addition Upon completion of addition to warm to ambient temperature where it is stirred for about two hours The organic layer is separated the aqueous o layer is extracted with ethyl acetate The extract washed with 100 mL of saturated aqueous sodium chloride dried with magnesium sulfate The mixture is filtered the filtrate is concentrated under reduced pressure to a residue concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of ((fluoromethyl)sulfonyl)benzene (5.0 g, 28.7 mmol) in tetrahydrofuran (100 mL) at −78° C. under argon was added n-butyl lithium (18.0 mL, 28.7 mmol) and the reaction mixture was stirred for 40 minutes at this temperature. N-cyclobutylidene-2-methylpropane-2-sulfinamide (3.23 g, 18.7 mmol) was added to the mixture at −78° C. and the reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water and extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford a brown oil. The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate, 3:2 to 2:3) to give N-(1-(fluoro(phenylsulfonyl)methyl)cyclobutyl)-2-methylpropane-2-sulfinamide (3.00 g, 33%) as a yellow oil. stirred overnight The reaction mixture was quenched by the addition of water extracted 3 times with dichloromethane The combined organic layers were washed with brine dried over sodium sulfate concentrated to afford a brown oil The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate, 3:2 to 2:3)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisopropyl amine (0.27 ml, 1.88 mmol) was added to THF (5 mL) and this solution was cooled to 0° C. n-butyllithium (1.06 mL, 1.70 mmol, 1.6M in hexanes) was added and the reaction was held at 0° C. for 15 min and cooled to −78° C. To solution this was added (fluoromethylsulfonyl)benzene (327 mg, 1.88 mmol) in THF (5 mL) and the reaction was stirred at −78° C. for 20 min. A solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07 (400 mg, 1.62 mmol) in THF (5 mL) was added. The reaction was stirred at −78° C. for 1.5 h, at which time LC/MS analysis indicated complete reaction. The reaction was quenched at −78° C. by addition of sat′ d NH4Cl solution (10 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. was added The reaction was stirred at −78° C. for 1.5 h, at which time LC/MS analysis reaction The reaction was quenched at −78° C. by addition extracted with EtOAc (2×20 mL) The combined organics were washed with water and brine The organic layer was dried (MgSO4) filtered concentrated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of fluoromethyl phenyl sulfone (0.50 g, 2.9 mmol) and phosphorochloridic acid, diethyl ester (0.415 mL, 2.87 mmol) in tetrahydrofuran (6 mL, 70 mmol) was added 1.000 M of lithium hexamethyldisilazide in tetrahydrofuran (6.2 mL, 6.2 mmol) dropwise at −78° C. After the mixture was stirred at −78° C. for 1 h, a solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.378 g, 2.21 mmol) in tetrahydrofuran (1.3 mL, 16 mmol) was added. The reaction was allowed to warm to ambient temperature and stirred for 2 h at rt. The reaction was poured into an ice-cold mixture of EtOAc and sat. ammonium chloride. The organic layer was separated and the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the desired product (560 mg, 77.5%). LCMS calculated for C15H18FNO4SNa(M+Na)+: m/z=350.1. Found (M+Na) 350.3. to warm to ambient temperature stirred for 2 h at rt The organic layer was separated the aq. layer was extracted with EtOAc The combined organic layers were washed with brine dried over sodium sulfate The solvent was removed under reduced pressure the resulting residue was purified on silica gel eluting with 0 to 50% EtOAc in hexane