2-methyl-2-methylsulfonylpropanenitrile

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

Procedure: To a solution of methylsulfonylacetonitrile (25 g) and methyl iodide (27.4 mL) in N,N-dimethylformamide (300 mL) was added sodium hydride (20 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (18 g, yield 58%) as colorless crystals. the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure

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

Procedure: To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile (1.654 g, 11.24 mmol) in THF (14 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (4.49 mL, 11.24 mmol) dropwise via syringe. After 30 minutes at −78° C., a 0° C. solution of (R,Z)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (1.9 g, 5.62 mmol) in THF (14.00 mL), which had been pretreated with boron trifluoride diethyl etherate (0.693 mL, 5.62 mmol) at 0° C. for 15 minutes, was added dropwise via cannula. The reaction was stirred for 2 hours at −78° C., and then quenched with saturated aqueous ammonium chloride at −78° C. and diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered, concentrated, and purified by silica-gel chromatography, eluting with 25% ethyl acetate in hexanes followed by 40% ethyl acetate hexane to provide the title compound. The product was isolated as a 2:1 mixture of diastereomers. LC/MS (ESI+) m/z=485, 487 (M+H; 2 bromine isotopes). was added dropwise via cannula quenched with saturated aqueous ammonium chloride at −78° C. diluted with water and ethyl acetate The layers were separated the aqueous layer was extracted with EtOAc The combined organic extracts were washed with water and saturated aqueous sodium chloride dried over sodium sulfate The solution was filtered concentrated purified by silica-gel chromatography eluting with 25% ethyl acetate in hexanes

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

Procedure: To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile (1.654 g, 11.24 mmol) in THF (14 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (4.49 mL, 11.24 mmol) dropwise via syringe. After 30 minutes at −78° C., a 0° C. solution of (R,Z)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (1.9 g, 5.62 mmol) in THF (14.00 mL), which had been pretreated with boron trifluoride diethyl etherate (0.693 mL, 5.62 mmol) at 0° C. for 15 minutes, was added dropwise via cannula. The reaction was stirred for 2 hours at −78° C., and then quenched with saturated aqueous ammonium chloride at −78° C. and diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered, concentrated, and purified by silica-gel chromatography, eluting with 25% ethyl acetate in hexanes followed by 40% ethyl acetate hexane to provide the title compound. The product was isolated as a 2:1 mixture of diastereomers. LC/MS (ESI+) m/z=485, 487 (M+H; 2 bromine isotopes). was added dropwise via cannula quenched with saturated aqueous ammonium chloride at −78° C. diluted with water and ethyl acetate The layers were separated the aqueous layer was extracted with EtOAc The combined organic extracts were washed with water and saturated aqueous sodium chloride dried over sodium sulfate The solution was filtered concentrated purified by silica-gel chromatography eluting with 25% ethyl acetate in hexanes

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

Procedure: A 100 ml RBF was charged with 2-methyl-2-(methylsulfonyl)propanenitrile (1.028 g, 6.99 mmol) and THF (15 ml). The solution was cooled to −78° C. (dry ice-acetone bath) and to it a butyllithium solution, 1.6 m in hexane (4.66 ml, 6.99 mmol) was added dropwise. The mixture was stirred for 20 min at −78° C. In the separate 50 ml flask solution of N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.00 g, 3.49 mmol) in toluene (10 ml) was cooled to −78° C. (dry ice acetone bath) and trimethylaluminum (2M in heptane) (1.921 ml, 3.84 mmol) was added. The mixture was stirred for 5 min, then transferred via syringe to the solution of the metallated sulfone (dropwise addition at −78° C.). The mixture was stirred for 1 hr at −78° C. The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 and the flask was removed from the bath, stirred for 40 min and diluted with 5 ml EtOAc. After filtering through pad of celite organic fractions were separated, concentrated and purified by FC on 12 g RediSep Gold column using 10-80% EtOAc in heptane to give desired N-(1-((2-cyanopropan-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (0.902 g, 2.081 mmol, 59.6% yield). was added The mixture was stirred for 5 min (dropwise addition at −78° C.) The mixture was stirred for 1 hr at −78° C The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 the flask was removed from the bath stirred for 40 min diluted with 5 ml EtOAc After filtering through pad of celite organic fractions were separated concentrated purified by FC on 12 g RediSep Gold column

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

Procedure: A 100 ml RBF was charged with 2-methyl-2-(methylsulfonyl)propanenitrile (1.028 g, 6.99 mmol) and THF (15 ml). The solution was cooled to −78° C. (dry ice-acetone bath) and to it a butyllithium solution, 1.6 m in hexane (4.66 ml, 6.99 mmol) was added dropwise. The mixture was stirred for 20 min at −78° C. In the separate 50 ml flask solution of N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.00 g, 3.49 mmol) in toluene (10 ml) was cooled to −78° C. (dry ice acetone bath) and trimethylaluminum (2M in heptane) (1.921 ml, 3.84 mmol) was added. The mixture was stirred for 5 min, then transferred via syringe to the solution of the metallated sulfone (dropwise addition at −78° C.). The mixture was stirred for 1 hr at −78° C. The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 and the flask was removed from the bath, stirred for 40 min and diluted with 5 ml EtOAc. After filtering through pad of celite organic fractions were separated, concentrated and purified by FC on 12 g RediSep Gold column using 10-80% EtOAc in heptane to give desired N-(1-((2-cyanopropan-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (0.902 g, 2.081 mmol, 59.6% yield). was added The mixture was stirred for 5 min (dropwise addition at −78° C.) The mixture was stirred for 1 hr at −78° C The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 the flask was removed from the bath stirred for 40 min diluted with 5 ml EtOAc After filtering through pad of celite organic fractions were separated concentrated purified by FC on 12 g RediSep Gold column

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

Procedure: To a solution of 2-(methylsulfonyl)acetonitrile (60 g, 504 mmol) in DMF (252 mL) at 0° C. was added potassium carbonate (209 g, 1511 mmol) portion-wise, followed by iodomethane (136 mL, 1511 mmol). After 15 minutes, the ice bath was removed and the reaction was stirred at RT for 48 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with ethyl acetate and ether. The combined filtrates were concentrated and partitioned between ether and water. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the titled intermediate (58 g, 78% yield) as an off-white solid. the ice bath was removed The reaction mixture was filtered through a Celite pad the filter cake was rinsed with ethyl acetate and ether The combined filtrates were concentrated partitioned between ether and water The organic portion was dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of methylsulfonylacetonitrile (25 g) and methyl iodide (27.4 mL) in N,N-dimethylformamide (300 mL) was added sodium hydride (20 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (18 g, yield 58%) as colorless crystals. the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure

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

Procedure: To a solution of 2-methyl-2-(methylsulfonyl)propanenitrile (1.654 g, 11.24 mmol) in THF (14 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (4.49 mL, 11.24 mmol) dropwise via syringe. After 30 minutes at −78° C., a 0° C. solution of (R,Z)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (1.9 g, 5.62 mmol) in THF (14.00 mL), which had been pretreated with boron trifluoride diethyl etherate (0.693 mL, 5.62 mmol) at 0° C. for 15 minutes, was added dropwise via cannula. The reaction was stirred for 2 hours at −78° C., and then quenched with saturated aqueous ammonium chloride at −78° C. and diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered, concentrated, and purified by silica-gel chromatography, eluting with 25% ethyl acetate in hexanes followed by 40% ethyl acetate hexane to provide the title compound. The product was isolated as a 2:1 mixture of diastereomers. LC/MS (ESI+) m/z=485, 487 (M+H; 2 bromine isotopes). was added dropwise via cannula quenched with saturated aqueous ammonium chloride at −78° C. diluted with water and ethyl acetate The layers were separated the aqueous layer was extracted with EtOAc The combined organic extracts were washed with water and saturated aqueous sodium chloride dried over sodium sulfate The solution was filtered concentrated purified by silica-gel chromatography eluting with 25% ethyl acetate in hexanes

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

Procedure: A 100 ml RBF was charged with 2-methyl-2-(methylsulfonyl)propanenitrile (1.028 g, 6.99 mmol) and THF (15 ml). The solution was cooled to −78° C. (dry ice-acetone bath) and to it a butyllithium solution, 1.6 m in hexane (4.66 ml, 6.99 mmol) was added dropwise. The mixture was stirred for 20 min at −78° C. In the separate 50 ml flask solution of N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.00 g, 3.49 mmol) in toluene (10 ml) was cooled to −78° C. (dry ice acetone bath) and trimethylaluminum (2M in heptane) (1.921 ml, 3.84 mmol) was added. The mixture was stirred for 5 min, then transferred via syringe to the solution of the metallated sulfone (dropwise addition at −78° C.). The mixture was stirred for 1 hr at −78° C. The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 and the flask was removed from the bath, stirred for 40 min and diluted with 5 ml EtOAc. After filtering through pad of celite organic fractions were separated, concentrated and purified by FC on 12 g RediSep Gold column using 10-80% EtOAc in heptane to give desired N-(1-((2-cyanopropan-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (0.902 g, 2.081 mmol, 59.6% yield). was added The mixture was stirred for 5 min (dropwise addition at −78° C.) The mixture was stirred for 1 hr at −78° C The reaction mixture was quenched by addition of 1 ml saturated aqueous solution of Na2SO4 the flask was removed from the bath stirred for 40 min diluted with 5 ml EtOAc After filtering through pad of celite organic fractions were separated concentrated purified by FC on 12 g RediSep Gold column

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

Procedure: To a solution of 2-(methylsulfonyl)acetonitrile (60 g, 504 mmol) in DMF (252 mL) at 0° C. was added potassium carbonate (209 g, 1511 mmol) portion-wise, followed by iodomethane (136 mL, 1511 mmol). After 15 minutes, the ice bath was removed and the reaction was stirred at RT for 48 hours. The reaction mixture was filtered through a Celite pad, and the filter cake was rinsed with ethyl acetate and ether. The combined filtrates were concentrated and partitioned between ether and water. The organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the titled intermediate (58 g, 78% yield) as an off-white solid. the ice bath was removed The reaction mixture was filtered through a Celite pad the filter cake was rinsed with ethyl acetate and ether The combined filtrates were concentrated partitioned between ether and water The organic portion was dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of methylsulfonylacetonitrile (25 g) and methyl iodide (27.4 mL) in N,N-dimethylformamide (300 mL) was added sodium hydride (20 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (18 g, yield 58%) as colorless crystals. the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure