methylsulfonylsulfanylmethane

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

Procedure: A solution of 1.115 g (5 mmol) of 9-nitroanthracene and 1.01 mL (5 mmol) of MMTS in 20 mL of anhydrous THF was treated with 1.375 g (5 mmol) of TASF dissolved in 3 mL of acetonitrile at -78° C. After addition of TASF had been completed, the reaction mixture was brought to -10° C. and stirred for 1 hr. Ten mL of water was then added, the mixture was warmed to room temperature, and the product was extracted into ether. The organic layer was washed with saturated sodium chloride solution, dried and concentrated. The melting point was 159° to 163° C. (dec). The product material was analyzed by ultraviolet absorption, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. was brought to -10° C. the product was extracted into ether The organic layer was washed with saturated sodium chloride solution dried concentrated The product material was analyzed by ultraviolet absorption

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

Procedure: (5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.120 g, 0.440 mmol) was dissolved in ethanol (5 mL) and 1.0 M potassium phosphate buffer (pH 7) (5.00 mL) and cooled in an ice bath (a ppt formed but it was ignored). S-methyl methanesulfonothioate (0.083 mL, 0.881 mmol) was added and the mixture stirred overnight with gradual (over 30 minutes) warming to room temperature. The reaction was diluted with dichloromethane and the organic layer was removed, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane and loaded onto a 500 micron ptlc plate and developed with 66% ethyl acetate in hexane. The band corresponding to the product was scraped, filtered using ethyl acetate, and concentrated to give (5-((2-methyl-2-(methyldisulfanyl)propylthio)methyl)-1,3-phenylene)dimethanol (0.091 g, 0.286 mmol, 64.9% yield). 1H NMR (400 Hz, CDCl3): δ 7.27 (s, 3H), 4.71 (s, 4H), 3.78 (s, 2H), 2.77 (s, 2H), 2.41 (s, 3H), 1.94 (br s, 2H), 1.38 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 139.0, 126.7, 124.2, 65.0, 51.8, 44.0, 38.2, 26.7, 25.3; MS (m/z), expected: 341.5. found 341.1 (M+Na). See FIG. 30. formed the organic layer was removed washed with water dried over anhydrous sodium sulfate concentrated in vacuo The residue was dissolved in dichloromethane filtered concentrated

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

Procedure: A solution of N-methylcysteine (Undhein, K., & Eidem, A., 23 Acta Chem. Scandinavica 3129-3133 (1970) (1.5 g, 11.1 mmol) in H2O (20 ml) was stirred at room temperature, under an atmosphere of argon, and treated with a solution of methyl methanethiol sulfonate (3.0 ml, 29.2 mmol) in ethanol (10 ml). The reaction mixture was stirred at this temperature for two hours and then diluted with H2O (100 ml) and washed with ether (4×40 ml). The aqueous layer was acidified to pH 2 and passed through an Amberlite IRA 93 (--OH form) column. The column was washed with water and the effluent was collected and evaporated to dryness under reduced pressure to give a white solid (1.2g, 60%), mp 194°-5° C. NMR (D2O, TMS ext. standard): δ2.2(3H, s), 2.5(3H, s), 3.2(2H,d), 3.7(1H,q). washed with ether (4×40 ml) The column was washed with water the effluent was collected evaporated to dryness under reduced pressure

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

Procedure: A solution of N-methylcysteine (Undhein, K., & Eidem, A., 23 Acta Chem. Scandinavica 3129-3133 (1970) (1.5 g, 11.1 mmol) in H2O (20 ml) was stirred at room temperature, under an atmosphere of argon, and treated with a solution of methyl methanethiol sulfonate (3.0 ml, 29.2 mmol) in ethanol (10 ml). The reaction mixture was stirred at this temperature for two hours and then diluted with H2O (100 ml) and washed with ether (4×40 ml). The aqueous layer was acidified to pH 2 and passed through an Amberlite IRA 93 (--OH form) column. The column was washed with water and the effluent was collected and evaporated to dryness under reduced pressure to give a white solid (1.2g, 60%), mp 194°-5° C. NMR (D2O, TMS ext. standard): δ2.2(3H, s), 2.5(3H, s), 3.2(2H,d), 3.7(1H,q). washed with ether (4×40 ml) The column was washed with water the effluent was collected evaporated to dryness under reduced pressure

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

Procedure: In 10 ml of a mixture of anhydrous tetrahydrofuran-hexamethylphosphoric acid triamide (7:3) was dissolved 1.00 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To the resulting solution was added 10 ml of a tetrahydrofuran solution of 1,1,1,3, 3,3-hexamethylsilazane lithium salt consisting of 1.17 g of 1,1,1,3,3,3-hexamethylsilazane and 6.6 millimoles of n-butyllithium at -78° C., and the resulting mixture was stirred for 40 minutes, after which 500 mg of methyl methanethiolsulfate was added at the same temperature and the mixture was stirred for 15 minutes. Subsequently, the temperature of the reaction mixture was elevated to room temperature. The reaction mixture was introduced into 80 ml of 2N hydrochloric acid with ice-cooling and the resulting mixture was extracted with two 40-ml portions of ethyl acetate. The extracts were combined and washed with water and saturated aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the oily product obtained was purified by a column chromatography (eluant: toluene:ethyl acetate=50:1) to obtain 480 mg (yield: 39.6%) of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one. the mixture was stirred for 15 minutes was elevated to room temperature cooling the resulting mixture was extracted with two 40-ml portions of ethyl acetate washed with water and saturated aqueous sodium chloride solution in this order dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure the oily product obtained was purified by a column chromatography (eluant: toluene:ethyl acetate=50:1)

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

Procedure: To a solution of p-aminobenzenethiol (125 mg, 1 mmol) in methanol (1 ml) was added MMTS (94 μl, 1 mmol) in a single portion. The reaction was stirred at RT under N2. After 2 hr, the solution was loaded onto an SCX column and eluted with methanol, followed by 1M ammonia in methanol. The basic eluents were concentrated in vacuo to a yellow oil. Chromatography (1:1 hexanes:CH2Cl2 with 1% isopropylamine) yielded 39a (140 mg, 82%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3): δ 7.28 (d, J=8.6 Hz, 2H); 6.54 (d, J=8.6 Hz, 2H); 3.60 (broad s, 2H); 2.34 (s, 3H). Treatment with HCl/ether gave 5 mg of the HCl salt. Biological testing was performed on the acid salt. 1H NMR (400 MHz, d6-DMSO): δ 7.46 (broad s, 2H); 7.05 (broad s, 2H); 2.47 (s, 3H); 2.43 (s, 3H). eluted with methanol The basic eluents were concentrated in vacuo to a yellow oil

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

Procedure: A 1 M ethylmagnesium bromide/THF solution (1.4 ml) was added under ice cooling to a solution of 0.31 g of 7-iodoimidazo[5,1-b]thiazole in 3 ml of dry THF in an argon atmosphere. The mixture was stirred at the same temperature for one hr. Methyl methanethiolsulfonate (0.15 ml) was added thereto. The mixture was stirred at room temperature for 12 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution. Ethyl acetate was added thereto. The mixture was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 0.15 g of 7-methylthioimidazo[5,1-b]thiazole. The mixture was stirred at room temperature for 12 hr The mixture was washed with a dilute aqueous sodium thiosulfate solution and saturated brine in that order The organic layer was dried over anhydrous magnesium sulfate The solvent was removed by distillation The residue was purified by column chromatography on silica gel (ethyl acetate)

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

Procedure: To a solution of 3-(4-bromophenyl)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product of Step A) (4.39 mg, 1.00 mmol) in tetrahydrofuran (10 mL) cooled below −75° C. was added a solution of n-butyllithium (2.5 M solution in hexanes) dropwise over three minutes, while maintaining the temperature at or below −72° C. Within one minute, S-methyl methanesulfonothioate (0.11=L, 1.2 mmol) was added dropwise. The reaction mixture was allowed to stir and warm slowly to ambient temperature, and then it was poured into 1 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate; and concentrated. The residue was subjected to chromatography on silica gel eluted with 10% ethyl acetate in hexanes. The isolated material was redissolved in dichloromethane (5 mL), treated with 3-chloroperoxybenzoic acid (˜77%, 0.39 g, 1.7 mmol) and allowed to stir at ambient temperature for 64 h. Additional 3-chloroperoxybenzoic acid (˜77%, 0.27 g, 1.2 mmol) was added, and the mixture was stirred for 4 h. To this mixture was added saturated aqueous sodium bisulfite solution, and then solid potassium carbonate was added carefully until gas evolution ceased. The phases were separated, and the organic phase was washed with 1 N aqueous sodium hydroxide solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and hexanes to obtain a solid which was collected on a glass frit. The solid was washed with a mixture of diether and hexanes, and dried to afford the title product (0.12 g), a compound of the present invention. while maintaining the temperature at or below −72° C the mixture was extracted with ethyl acetate The organic phase was washed with saturated aqueous sodium chloride solution dried over magnesium sulfate and concentrated eluted with 10% ethyl acetate in hexanes The isolated material was redissolved in dichloromethane (5 mL) to stir at ambient temperature for 64 h the mixture was stirred for 4 h The phases were separated the organic phase was washed with 1 N aqueous sodium hydroxide solution and with saturated aqueous sodium chloride solution dried over magnesium sulfate concentrated The residue was triturated with diethyl ether and hexanes to obtain a solid which was collected on a glass frit The solid was washed with a mixture of diether and hexanes dried

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

Procedure: To a solution of 3-(4-bromophenyl)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product of Step A) (4.39 mg, 1.00 mmol) in tetrahydrofuran (10 mL) cooled below −75° C. was added a solution of n-butyllithium (2.5 M solution in hexanes) dropwise over three minutes, while maintaining the temperature at or below −72° C. Within one minute, S-methyl methanesulfonothioate (0.11=L, 1.2 mmol) was added dropwise. The reaction mixture was allowed to stir and warm slowly to ambient temperature, and then it was poured into 1 N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate; and concentrated. The residue was subjected to chromatography on silica gel eluted with 10% ethyl acetate in hexanes. The isolated material was redissolved in dichloromethane (5 mL), treated with 3-chloroperoxybenzoic acid (˜77%, 0.39 g, 1.7 mmol) and allowed to stir at ambient temperature for 64 h. Additional 3-chloroperoxybenzoic acid (˜77%, 0.27 g, 1.2 mmol) was added, and the mixture was stirred for 4 h. To this mixture was added saturated aqueous sodium bisulfite solution, and then solid potassium carbonate was added carefully until gas evolution ceased. The phases were separated, and the organic phase was washed with 1 N aqueous sodium hydroxide solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and hexanes to obtain a solid which was collected on a glass frit. The solid was washed with a mixture of diether and hexanes, and dried to afford the title product (0.12 g), a compound of the present invention. while maintaining the temperature at or below −72° C the mixture was extracted with ethyl acetate The organic phase was washed with saturated aqueous sodium chloride solution dried over magnesium sulfate and concentrated eluted with 10% ethyl acetate in hexanes The isolated material was redissolved in dichloromethane (5 mL) to stir at ambient temperature for 64 h the mixture was stirred for 4 h The phases were separated the organic phase was washed with 1 N aqueous sodium hydroxide solution and with saturated aqueous sodium chloride solution dried over magnesium sulfate concentrated The residue was triturated with diethyl ether and hexanes to obtain a solid which was collected on a glass frit The solid was washed with a mixture of diether and hexanes dried

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

Procedure: A solution of 1.115 g (5 mmol) of 9-nitroanthracene and 1.01 mL (5 mmol) of MMTS in 20 mL of anhydrous THF was treated with 1.375 g (5 mmol) of TASF dissolved in 3 mL of acetonitrile at -78° C. After addition of TASF had been completed, the reaction mixture was brought to -10° C. and stirred for 1 hr. Ten mL of water was then added, the mixture was warmed to room temperature, and the product was extracted into ether. The organic layer was washed with saturated sodium chloride solution, dried and concentrated. The melting point was 159° to 163° C. (dec). The product material was analyzed by ultraviolet absorption, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. was brought to -10° C. the product was extracted into ether The organic layer was washed with saturated sodium chloride solution dried concentrated The product material was analyzed by ultraviolet absorption

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

Procedure: Methanethiosulfonic acid S-methyl ester (0.02 ml, 0.22 mmol) was dissolved in an EtOH (0.46 mL) and saturated NaCO3/H2O (pH 8) solution (0.8 mL) under argon at 0° C. A solution of 2,2,2-trifluoro-1-(4-mercapto-phenyl)-ethanol (5) (22 mg, 0.11 mmol) dissolved in THF (1.5 mL) under argon was added dropwise. After 10 minutes, the reaction temperature was raised to room temperature. After 36 hours, the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL). The combined organic phases were dried over Na2SO4 and under reduced pressure. Flash chromatography on silica gel using 0-30% acetone/hexane gave Compound 15 as a yellow oil (23 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 4H), 5.02 (q, J=6.7 Hz, 1H), 2.45 (s, 3H); 19F NMR (376 Hz, CDCl3) δ −78.79 (d); 13C NMR (100 MHz, CH3OD): δ 137.6, 134.2, 128.8, 126.4, 124.6 (q, JCF=281.7 Hz), 71 (q, JCF=31.5 Hz), 21.5. was added dropwise After 36 hours the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL) The combined organic phases were dried over Na2SO4 and under reduced pressure

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

Procedure: Methanethiosulfonic acid S-methyl ester (0.02 ml, 0.22 mmol) was dissolved in an EtOH (0.46 mL) and saturated NaCO3/H2O (pH 8) solution (0.8 mL) under argon at 0° C. A solution of 2,2,2-trifluoro-1-(4-mercapto-phenyl)-ethanol (5) (22 mg, 0.11 mmol) dissolved in THF (1.5 mL) under argon was added dropwise. After 10 minutes, the reaction temperature was raised to room temperature. After 36 hours, the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL). The combined organic phases were dried over Na2SO4 and under reduced pressure. Flash chromatography on silica gel using 0-30% acetone/hexane gave Compound 15 as a yellow oil (23 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 4H), 5.02 (q, J=6.7 Hz, 1H), 2.45 (s, 3H); 19F NMR (376 Hz, CDCl3) δ −78.79 (d); 13C NMR (100 MHz, CH3OD): δ 137.6, 134.2, 128.8, 126.4, 124.6 (q, JCF=281.7 Hz), 71 (q, JCF=31.5 Hz), 21.5. was added dropwise After 36 hours the reaction was extracted with ethyl acetate (3×30 mL) and H2O (30 mL) The combined organic phases were dried over Na2SO4 and under reduced pressure