N-cyclobutylidene-2-methylpropane-2-sulfinamide

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added IDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added LDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added LDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added IDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added IDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

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

Procedure: 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)

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

Procedure: A mixture of titanium (IV) ethoxide (22.4 mL, 107 mmol) and cyclobutanone (5.37 mL, 71.0 mmoL) in tetrahydrofuran (120 mL) was stirred for 10 minutes. Tert-butanesulfinamide (7.17 g, 59.0 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulphate and concentrated to give N-cyclobutylidene-2-methylpropane-2-sulfinamide (9.51 g, 77%) as a pale yellow oil which was used directly without purification. the reaction mixture was stirred at room temperature for 18 hours The mixture was concentrated the residue dissolved in ethyl acetate The solution was washed with saturated aqueous sodium hydrogen carbonate dried over sodium sulphate concentrated

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

Procedure: Titanium (IV) ethoxide (3.03 g, 13.3 mmol) was added to a stirring solution of trimethylsilyl cyanide (7.12 mL, 53.1 mmol) and N-cyclobutylidene-2-methylpropane-2-sulfinamide (4.6 g, 27 mmol) in DCM (100 mL) at rt. The reaction was allowed to stir for 16 h. An additional 1.7 mL of TMS-CN was added followed by 1.5 g of TiOEt4. The reaction was allowed to stir at rt for an additional 16 h. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give N-(1-cyanocyclobutyl)-2-methylpropane-2-sulfinamide (4.5 g, 22 mmol, 85% yield) consistent by NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.82-2.67 (m, 2H), 2.62-2.34 (m, 2H), 2.26-2.02 (m, 2H), 1.26 (s, 9H). to stir at rt for an additional 16 h washed The organic phase was dried over Na2SO4 filtered concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-methylpropane-2-sulfinamide (4.32 g, 35.7 mmol) and titanium(IV) ethoxide (16.3 g, 71.3 mmol) were added sequentially to a solution of cyclobutanone (2.5 g, 35.7 mmol) in THF (102 ml) at 22° C. The mixture was stirred at 60° C. for 5 h. The reaction mixture poured over a stirring saturated aqueous sodium chloride solution (60 mL). Celite was added to the suspension and it was filtered through a pad of Celite, washing with ethyl acetate (300 mL). The filtrate was washed with brine and the organic layers were combined and dried with anhydrous sodium sulfate. The dried solution was filtered and the filtrate was concentrated, yielding an oil which was purified on silica gel (Biotage, 25 g column, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product N-cyclobutylidene-2-methylpropane-2-sulfinamide (4.6 g, 27 mmol, 74% yield) consistent by NMR. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.59-3.22 (m, 2H), 3.21-3.03 (m, 2H), 2.12 (t, J=8.2 Hz, 2H), 1.24 (s, 9H). Celite was added to the suspension and it was filtered through a pad of Celite washing with ethyl acetate (300 mL) The filtrate was washed with brine dried with anhydrous sodium sulfate The dried solution was filtered the filtrate was concentrated yielding an oil which was purified on silica gel (Biotage, 25 g column, EtOAc/hexanes gradient, fraction collection at λ=254 nm)

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added LDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)

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

Procedure: To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added IDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2. to warm to room temperature stirred over 2 h The mixture was quenched with aqueous ammonium chloride the mixture was extracted with ethyl acetate (3×200 mL) The combined organic fractions were washed with brine dried over sodium sulfate filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes)