3-Dimethylaminoacrolein

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the above reaction mixture of tert-butyl 3-carbamimidoyl-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (assumed 4.98 mmol) in methanol (5 mL) was added sodium methoxide (0.509 g, 9.42 mmol) and (E)-3-(dimethylamino)acrylaldehyde (0.560 g, 5.65 mmol), and the resulting solution was heated at 70° C. overnight. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The mixture was washed with water followed by saturated brine solution, and then dried over Na2SO4 and concentrated. The crude product was then purified by column chromatography (50% EtOAc in Hexane) to afford tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 200 mg (overall 12%). 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J=4.8 Hz, 2H), 7.24 (m, 1H), 4.63-4.48 (m, 2H), 4.23 (d, J=9.2 Hz, 2H), 1.47 (s, 9H), 1.29 (s, 9H). LCMS: (ES+) m/z observed=255.2 (M+H)+ of 2-methyl-N-(3-(pyrimidin-2-yl)azetidin-3-yl)propane-2-sulfinamide. The reaction mixture was then concentrated the residue dissolved in ethyl acetate The mixture was washed with water dried over Na2SO4 concentrated The crude product was then purified by column chromatography (50% EtOAc in Hexane)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the above reaction mixture of tert-butyl 3-carbamimidoyl-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (assumed 4.98 mmol) in methanol (5 mL) was added sodium methoxide (0.509 g, 9.42 mmol) and (E)-3-(dimethylamino)acrylaldehyde (0.560 g, 5.65 mmol), and the resulting solution was heated at 70° C. overnight. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The mixture was washed with water followed by saturated brine solution, and then dried over Na2SO4 and concentrated. The crude product was then purified by column chromatography (50% EtOAc in Hexane) to afford tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 200 mg (overall 12%). 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J=4.8 Hz, 2H), 7.24 (m, 1H), 4.63-4.48 (m, 2H), 4.23 (d, J=9.2 Hz, 2H), 1.47 (s, 9H), 1.29 (s, 9H). LCMS: (ES+) m/z observed=255.2 (M+H)+ of 2-methyl-N-(3-(pyrimidin-2-yl)azetidin-3-yl)propane-2-sulfinamide. The reaction mixture was then concentrated the residue dissolved in ethyl acetate The mixture was washed with water dried over Na2SO4 concentrated The crude product was then purified by column chromatography (50% EtOAc in Hexane)

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

実験手順: N-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05 mmol) was taken up in THF (10 ml) under nitrogen and cooled to <−70° C. n-Butyl lithium (4.05 ml, 10.12 mmol, 2.5M solution in hexanes) was added over 30 min keeping the temperature below −60° C. and then stirred at below −70° C. for 1 h. (2E)-3-(dimethylamino)-2-propenal (0.607 ml, 6.07 mmol) in THF (2 ml) was added over 30 min keeping the temperature below −60° C. The reaction was stirred at below −70° C. for 20 min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCl (5 ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2CO3 and extracted with EtOAc (4×25 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12% diethyl ether in cyclohexane for 2 CVs, then with 12%-63% diethyl ether in cyclohexane over 10 CVs then held at 63% for SCVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42 g). was added over 30 min the temperature below −60° C. was added over 30 min the temperature below −60° C was quenched with 5M HCl (5 ml) refluxed overnight was cooled to room temperature extracted with EtOAc (4×25 ml) The combined organics were dried with Na2SO4 filtered concentrated to yield a brown solid evaporated

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

実験手順: To a yellow solution of 3-(1,1-dimethylethylsulfinamido)oxetane-3-carboximidamide (crude from above, assumed 0.494 mmol) in MeOH (2 ml) in a 50 ml sealed tube was added (E)-3-(dimethylamino)acrylaldehyde (0.090 g, 0.912 mmol), and the reaction mixture stirred for 10 min. Sodium methoxide (0.43 ml, 1.824 mmol, 25 wt % in MeOH) was added to the mixture, which was then stirred at 65° C. for overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate (3×25 ml). The combined organic layers was washed with saturated brine solution, dried over Na2SO4, filtered and concentrated. The crude material was purified by pre-HPLC. Overall yield of two steps: (30 mg, 24%). was then stirred at 65° C. for overnight washed with water The aqueous layer was back extracted with ethyl acetate (3×25 ml) The combined organic layers was washed with saturated brine solution dried over Na2SO4 filtered concentrated The crude material was purified by pre-HPLC

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

実験手順: A mixture of (E)-3-(dimethylamino)acrylaldehyde (3.26 g, 32.9 mmol), the product from Step 1 (5.00 g, 25.3 mmol) and acetic acid (7.24 mL, 127 mmol) in DMF (40 mL) was heated to 120° C. for 48 h and cooled to room temperature. Ethyl acetate (400 mL) was added and the mixture washed with saturated NaHCO3 (40 mL), water (40 mL), brine (40 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 10-40% ethyl acetate in hexanes) to provide 8-chloro-5H-chromeno[2,3-b]pyridin-5-one (600 mg, 10%). MS (ES+) m/z: 232 (M+H). the mixture washed with saturated NaHCO3 (40 mL), water (40 mL), brine (40 mL) dried (MgSO4) concentrated The residue was purified by flash column chromatography (silica, 10-40% ethyl acetate in hexanes)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the above reaction mixture of tert-butyl 3-carbamimidoyl-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (assumed 4.98 mmol) in methanol (5 mL) was added sodium methoxide (0.509 g, 9.42 mmol) and (E)-3-(dimethylamino)acrylaldehyde (0.560 g, 5.65 mmol), and the resulting solution was heated at 70° C. overnight. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The mixture was washed with water followed by saturated brine solution, and then dried over Na2SO4 and concentrated. The crude product was then purified by column chromatography (50% EtOAc in Hexane) to afford tert-butyl 3-(1,1-dimethylethylsulfinamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate Yield: 200 mg (overall 12%). 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J=4.8 Hz, 2H), 7.24 (m, 1H), 4.63-4.48 (m, 2H), 4.23 (d, J=9.2 Hz, 2H), 1.47 (s, 9H), 1.29 (s, 9H). LCMS: (ES+) m/z observed=255.2 (M+H)+ of 2-methyl-N-(3-(pyrimidin-2-yl)azetidin-3-yl)propane-2-sulfinamide. The reaction mixture was then concentrated the residue dissolved in ethyl acetate The mixture was washed with water dried over Na2SO4 concentrated The crude product was then purified by column chromatography (50% EtOAc in Hexane)

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

実験手順: N-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05 mmol) was taken up in THF (10 ml) under nitrogen and cooled to <−70° C. n-Butyl lithium (4.05 ml, 10.12 mmol, 2.5M solution in hexanes) was added over 30 min keeping the temperature below −60° C. and then stirred at below −70° C. for 1 h. (2E)-3-(dimethylamino)-2-propenal (0.607 ml, 6.07 mmol) in THF (2 ml) was added over 30 min keeping the temperature below −60° C. The reaction was stirred at below −70° C. for 20 min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCl (5 ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2CO3 and extracted with EtOAc (4×25 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12% diethyl ether in cyclohexane for 2 CVs, then with 12%-63% diethyl ether in cyclohexane over 10 CVs then held at 63% for SCVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42 g). was added over 30 min the temperature below −60° C. was added over 30 min the temperature below −60° C was quenched with 5M HCl (5 ml) refluxed overnight was cooled to room temperature extracted with EtOAc (4×25 ml) The combined organics were dried with Na2SO4 filtered concentrated to yield a brown solid evaporated