2-(4-aminophenyl)-N-tert-butylbenzenesulfonamide

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: A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the title compound. 1H NMR (CDCl3) δ: 8.14 (d, 1H) ; 7.53 (t, 1H) ; 7.43 (t, 1H); 7.33 (d, 2H); 7.27 (d, 1H); 6.76 (d, 2H); 3.7 (br s, 1H); 0.99 (s, 9H). After cooling The two phases were separated the organic phase was washed with water dried with MgSO4 concentrated in vacuo The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane

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

Procedure: A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the title compound. 1H NMR (CDCl3) δ: 8.14 (d, 1H) ; 7.53 (t, 1H) ; 7.43 (t, 1H); 7.33 (d, 2H); 7.27 (d, 1H); 6.76 (d, 2H); 3.7 (br s, 1H); 0.99 (s, 9H). After cooling The two phases were separated the organic phase was washed with water dried with MgSO4 concentrated in vacuo The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 250 mL three-necked round bottom flask fitted with a condenser and a Dean-Stark trap, a mixture of pyridoxal hydrochloride (330 mg, 1.62 mmol), 4′-amino-biphenyl-2-sulfonic acid tert-butylamide (494 mg, 1.62 mmol), p-toluenesulfonic acid monohydrate (68 mg, 0.36 mmol) in toluene (150 mL) was heated at 100° C. under nitrogen atmosphere for 3 hours. The solvent was then evaporated and the crude product was dissolved in dichloromethane (70 mL), cooled down to 0° C. and then sodium borohydride (163 mg, 4.32 mmol) and methyl alcohol (15 mL) were added. The reaction mixture was stirred at room temperature overnight, after which the solvent was removed. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (9:1) as eluant to give 4′-[(3hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (7) (178 mg, 24% overall yield for two steps) as a colorless solid. In a 250 mL three-necked round bottom flask fitted with a condenser The solvent was then evaporated the crude product was dissolved in dichloromethane (70 mL) cooled down to 0° C. after which the solvent was removed The residue was diluted with saturated aqueous sodium bicarbonate extracted with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate filtered evaporated The crude product was purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (9:1) as eluant

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL three neck flask fitted with a condenser and Dean-Stark apparatus was added 4′-amino-biphenyl-2-sulfonic acid tert-butylamide (1.22 g, 4.0 mmol), p-toluenesulfonic acid monohydrate (152 mg, 0.8 mmol), 2,2,8-trimethyl-4H-[1,3]dioxino [4,5-c]pyridine-5-carbaldehyde (995 mg, 4.8 mmol) and toluene (120 ml). The reaction mixture was stirred at 120° C. under nitrogen atmosphere for 7 hours before concentrating to dryness. The resulting solid was then dissolved in acetic acid (20 mL), cooled to 0° C., followed by a slow addition of sodium borohydride (529 mg, 14 mmol). After the addition of sodium borohydride, dichloromethane (30 mL) was then added to the reaction mixture and stirring was continued at room temperature for an additional 3 hours. Sodium hydroxide (5 N) was added to neutralize the solution, and the reaction mixture was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated. The crude mixture was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:1) as eluant, to give 4′-[(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (1) (0.457 g, 24% yield) as a colorless solid. before concentrating to dryness The resulting solid was then dissolved in acetic acid (20 mL) cooled to 0° C. was then added to the reaction mixture stirring was continued at room temperature for an additional 3 hours the reaction mixture was extracted with ethyl acetate dried over MgSO4 filtered evaporated The crude mixture was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:1) as eluant

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL three neck flask fitted with a condenser and Dean-Stark apparatus was added 4′-amino-biphenyl-2-sulfonic acid tert-butylamide (1.22 g, 4.0 mmol), p-toluenesulfonic acid monohydrate (152 mg, 0.8 mmol), 2,2,8-trimethyl-4H-[1,3]dioxino [4,5-c]pyridine-5-carbaldehyde (995 mg, 4.8 mmol) and toluene (120 ml). The reaction mixture was stirred at 120° C. under nitrogen atmosphere for 7 hours before concentrating to dryness. The resulting solid was then dissolved in acetic acid (20 mL), cooled to 0° C., followed by a slow addition of sodium borohydride (529 mg, 14 mmol). After the addition of sodium borohydride, dichloromethane (30 mL) was then added to the reaction mixture and stirring was continued at room temperature for an additional 3 hours. Sodium hydroxide (5 N) was added to neutralize the solution, and the reaction mixture was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated. The crude mixture was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:1) as eluant, to give 4′-[(2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (1) (0.457 g, 24% yield) as a colorless solid. before concentrating to dryness The resulting solid was then dissolved in acetic acid (20 mL) cooled to 0° C. was then added to the reaction mixture stirring was continued at room temperature for an additional 3 hours the reaction mixture was extracted with ethyl acetate dried over MgSO4 filtered evaporated The crude mixture was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:1) as eluant

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

Procedure: A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the aniline. 1H NMR (CDCl3): δ8.14 (d, 1H); 7.53 (t, 1H); 7.43 (t, 1H); 7.33 (d, 2H); 7.27 (d, 1H); 6.76 (d, 2H); 3.7 (br s, 1H); 0.99 (s, 9H). After cooling The two phases were separated the organic phase was washed with water dried with MgSO4 concentrated in vacuo The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane

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

Procedure: A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the aniline. 1H NMR (CDCl3): δ8.14 (d, 1H); 7.53 (t, 1H); 7.43 (t, 1H); 7.33 (d, 2H); 7.27 (d, 1H); 6.76 (d, 2H); 3.7 (br s, 1H); 0.99 (s, 9H). After cooling The two phases were separated the organic phase was washed with water dried with MgSO4 concentrated in vacuo The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane

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

Procedure: To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (60 mg, 0.197 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.3 ml, 0.59 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl 2-(3-cyanophenyl)-1-cyclopentene-1-carboxylate (48 mg, 0.197 mmol) in lml anhydrous dichloromethane. Reaction was stirred at room temperature overnight. Reaction was quenched with 15 ml 1N HCl after which an additional 10 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate and concentrated to give N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3-cyanophenyl)cyclopent-1-enyl]carboxamide (80 mg, 80%) as a white powder which was sufficiently pure to be used without further purification. Reaction Reaction Reaction was quenched with 15 ml 1N HCl after which an additional 10 ml dichloromethane was added Organic was washed with 2×20 ml water dried over magnesium sulfate concentrated