N-(1,4-dioxaspiro[4.5]decan-8-ylidene)-2-methylpropane-2-sulfinamide

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: To diisopropyl amine (318 μL, 2.23 mmol) in tetrahydrofuran (3.7 mL) at 0° C. was added N-butyllithium (2.5 M in hexanes, 892 μL, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then the product of Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred for 2 h, and then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate:hexanes gradient, then 0:100 to 15:85 methanol:dichloromethane gradient) afforded 2-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as a brown solid. MS ESI: [M+H]+ m/z 596. was added dropwise over 5 minutes The mixture was stirred for 30 minutes at −78° C. was added dropwise The reaction mixture was stirred for 2 h quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (3×) the combined organic fractions were dried over sodium sulfate filtered concentrated Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate

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 (S)-(−)-2-methyl-2-propanesulfinamide (854 mg, 7 mmol) and 1,4-dioxaspiro[4,5]decan-8-one (1 g, 6.40 mmol) in tetrahydrofuran (13 mL) was added titanium(IV) ethoxide (5.11 mL, 16 mmol). The mixture was stirred for 4 h at room temperature, poured over stirring saturated aqueous sodium bicarbonate (10 mL) and acetonitrile (10 mL), and stirred for 20 minutes. Magnesium sulfate was added and the mixture was stirred for 20 minutes, filtered over celite and concentrated. The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient) to afford N-(1,4-dioxaspiro[4.5]dec-8-ylidene)-2-methylpropane-2-sulfinamide (466 mg, 1.8 mmol, 28% yield) as a white solid. MS ESI: [M+H]+ m/z 260. poured stirred for 20 minutes the mixture was stirred for 20 minutes filtered over celite and concentrated The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient)

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

実験手順: To diisopropyl amine (318 μL, 2.23 mmol) in tetrahydrofuran (3.7 mL) at 0° C. was added N-butyllithium (2.5 M in hexanes, 892 μL, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then the product of Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred for 21), and then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate:hexanes gradient, then 0:100 to 15:85 methanol:dichloromethane gradient) afforded 2-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as a brown solid. MS ESI: [M+H]+ m/z 596. was added dropwise over 5 minutes The mixture was stirred for 30 minutes at −78° C. was added dropwise The reaction mixture was stirred for 21), and then quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (3×) the combined organic fractions were dried over sodium sulfate filtered concentrated Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate

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

実験手順: To diisopropyl amine (318 μL, 2.23 mmol) in tetrahydrofuran (3.7 mL) at 0° C. was added N-butyllithium (2.5 M in hexanes, 892 μL, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then the product of Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred for 21), and then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate:hexanes gradient, then 0:100 to 15:85 methanol:dichloromethane gradient) afforded 2-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as a brown solid. MS ESI: [M+H]+ m/z 596. was added dropwise over 5 minutes The mixture was stirred for 30 minutes at −78° C. was added dropwise The reaction mixture was stirred for 21), and then quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (3×) the combined organic fractions were dried over sodium sulfate filtered concentrated Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate

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 (S)-(−)-2-methyl-2-propanesulfinamide (854 mg, 7 mmol) and 1,4-dioxaspiro[4,5]decan-8-one (1 g, 6.40 mmol) in tetrahydrofuran (13 mL) was added titanium(IV) ethoxide (5.11 mL, 16 mmol). The mixture was stirred for 4 h at room temperature, poured over stirring saturated aqueous sodium bicarbonate (10 mL) and acetonitrile (10 mL), and stirred for 20 minutes. Magnesium sulfate was added and the mixture was stirred for 20 minutes, filtered over celite and concentrated. The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient) to afford N-(1,4-dioxaspiro[4.5]dec-8-ylidene)-2-methylpropane-2-sulfinamide (466 mg, 1.8 mmol, 28% yield) as a white solid. MS ESI: [M+H]+ m/z 260. poured stirred for 20 minutes the mixture was stirred for 20 minutes filtered over celite and concentrated The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient)

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

実験手順: To diisopropyl amine (318 μL, 2.23 mmol) in tetrahydrofuran (3.7 mL) at 0° C. was added N-butyllithium (2.5 M in hexanes, 892 μL, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then the product of Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred for 2 h, and then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate:hexanes gradient, then 0:100 to 15:85 methanol:dichloromethane gradient) afforded 2-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as a brown solid. MS ESI: [M+H]+ m/z 596. was added dropwise over 5 minutes The mixture was stirred for 30 minutes at −78° C. was added dropwise The reaction mixture was stirred for 2 h quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (3×) the combined organic fractions were dried over sodium sulfate filtered concentrated Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate

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

実験手順: To diisopropyl amine (318 μL, 2.23 mmol) in tetrahydrofuran (3.7 mL) at 0° C. was added N-butyllithium (2.5 M in hexanes, 892 μL, 2.23 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. INTERMEDIATE 4 (250 mg, 0.74 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then the product of Step 1 (212 mg, 0.82 mmol) dissolved in tetrahydrofuran (1 mL) was added dropwise. The reaction mixture was stirred for 2 h, and then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate:hexanes gradient, then 0:100 to 15:85 methanol:dichloromethane gradient) afforded 2-methyl-N-{8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]dec-8-yl}propane-2-sulfinamide (318 mg, 0.40 mmol, 75% yield) as a brown solid. MS ESI: [M+H]+ m/z 596. was added dropwise over 5 minutes The mixture was stirred for 30 minutes at −78° C. was added dropwise The reaction mixture was stirred for 2 h quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (3×) the combined organic fractions were dried over sodium sulfate filtered concentrated Purification by column chromatography on silica gel (0:100 to 80:20 ethyl acetate

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 (S)-(−)-2-methyl-2-propanesulfinamide (854 mg, 7 mmol) and 1,4-dioxaspiro[4,5]decan-8-one (1 g, 6.40 mmol) in tetrahydrofuran (13 mL) was added titanium(IV) ethoxide (5.11 mL, 16 mmol). The mixture was stirred for 4 h at room temperature, poured over stirring saturated aqueous sodium bicarbonate (10 mL) and acetonitrile (10 mL), and stirred for 20 minutes. Magnesium sulfate was added and the mixture was stirred for 20 minutes, filtered over celite and concentrated. The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient) to afford N-(1,4-dioxaspiro[4.5]dec-8-ylidene)-2-methylpropane-2-sulfinamide (466 mg, 1.8 mmol, 28% yield) as a white solid. MS ESI: [M+H]+ m/z 260. poured stirred for 20 minutes the mixture was stirred for 20 minutes filtered over celite and concentrated The residue was purified by column chromatography on silica gel (10:90 to 70:30 ethyl acetate:hexanes gradient)

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

実験手順: An oven dried round-bottom flask was cooled to room temperature by flushing with N2(g) for 30 min. 1,4-Dioxa-spiro[4.5]decan-8-one (1.35 g, 8.66 mmol) (dissolved in 12 mL THF), 2-Methyl-propane-2-sulfinic acid amide (1.0 g, 8.25 mmol) (dissolved in THF), and titanium(IV) ethoxide (3.77 g, 16.50 mmol) were added. The reaction was stirred for 4 h at room temperature. To the mixture was added 15 mL saturated NaHCO3 followed by filtration and an EtOAc rinse. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure yielding 0.98 g of Compound 15. by flushing with N2(g) for 30 min followed by filtration an EtOAc rinse The organic layer was dried with MgSO4 filtered concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir: