oxetane-3-carbaldehyde

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

Procedure: In a round-bottomed flask, oxetane-3-carbaldehyde (452 mg, 3.15 mmol) was dissolved in dichloromethane (18 ml) and (S)-2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) and anhydrous copper (II) sulfate (1.11 g, 6.93 mmol) were added. The reaction mixture was stirred at room temperature for 48 h then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 173 mg (29%) of (S)-2-methyl-propane-2-sulfinic acid 1-oxetan-3-yl-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.28 (d, J=4.9 Hz, 1H), 4.74-5.00 (m, 4H), 4.00-4.19 (m, 1H), 1.23 (s, 9H). then filtered through a glass microfiber filter rinsing with dichloromethane The filtrate was concentrated the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc)

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

Procedure: In a round-bottomed flask, oxetane-3-carbaldehyde (452 mg, 3.15 mmol) was dissolved in dichloromethane (18 ml) and (S)-2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) and anhydrous copper (II) sulfate (1.11 g, 6.93 mmol) were added. The reaction mixture was stirred at room temperature for 48 h then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 173 mg (29%) of (S)-2-methyl-propane-2-sulfinic acid 1-oxetan-3-yl-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.28 (d, J=4.9 Hz, 1H), 4.74-5.00 (m, 4H), 4.00-4.19 (m, 1H), 1.23 (s, 9H). then filtered through a glass microfiber filter rinsing with dichloromethane The filtrate was concentrated the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc)

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

Procedure: In a round-bottomed flask, oxetane-3-carbaldehyde (452 mg, 3.15 mmol) was dissolved in dichloromethane (18 ml) and (S)-2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) and anhydrous copper (II) sulfate (1.11 g, 6.93 mmol) were added. The reaction mixture was stirred at room temperature for 48 h then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 173 mg (29%) of (S)-2-methyl-propane-2-sulfinic acid 1-oxetan-3-yl-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.28 (d, J=4.9 Hz, 1H), 4.74-5.00 (m, 4H), 4.00-4.19 (m, 1H), 1.23 (s, 9H). then filtered through a glass microfiber filter rinsing with dichloromethane The filtrate was concentrated the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc)

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

Procedure: To a slurry of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (74.mg, 0.16 mmol) in ethanol (3 mL) was added 3-methy)oxetane-3-carbaldehyde (78.54 mg, 0.78 mmol) and then piperidine (0.02 mL, 0.16 mmol) and the mixture heated to 80° C. with stirring. After 3 h, the mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and the filtered. Solvents were removed to afford an oil which was purified by column chromatography (gradient from neat methylene chloride to 95-5 methylene chloride:MeOH). The pure fractions were concentrated, then taken up in acetonitrile/water, frozen and lyophilized to afford 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile as a colorless solid weighing 14 mg. the mixture was cooled partitioned between ethyl acetate and water The organic phase was washed with brine dried over sodium sulfate Solvents were removed to afford an oil which was purified by column chromatography (gradient from neat methylene chloride to 95-5 methylene chloride:MeOH) The pure fractions were concentrated frozen

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

Procedure: In a round-bottomed flask, oxetane-3-carbaldehyde (452 mg, 3.15 mmol) was dissolved in dichloromethane (18 ml) and (S)-2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) and anhydrous copper (II) sulfate (1.11 g, 6.93 mmol) were added. The reaction mixture was stirred at room temperature for 48 h then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 173 mg (29%) of (S)-2-methyl-propane-2-sulfinic acid 1-oxetan-3-yl-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.28 (d, J=4.9 Hz, 1H), 4.74-5.00 (m, 4H), 4.00-4.19 (m, 1H), 1.23 (s, 9H). then filtered through a glass microfiber filter rinsing with dichloromethane The filtrate was concentrated the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc)