N-methoxy-N,1-dimethylcyclopropane-1-carboxamide

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

Procedure: Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (2.00 g) in tetrahydrofuran (42 mL) was slowly added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 22 mL) at −45° C., and the mixture was stirred for 45 minutes. Then, a solution of N-methoxy-N,1-dimethylcyclopropane carboxamide (1.33 g) in tetrahydrofuran (4.2 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 45 minutes, and then stirred at room temperature for 3 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.77 g). 1H-NMR (CDCl3) δ ppm: 0.80-0.89 (2H, m), 1.35-1.44 (5H, m), 1.52 (9H, s), 3.55 (2H, s), 3.80 (3H, s), 6.57 (1H, dd, J=2.8, 8.3 Hz), 6.97 (1H, d, J=8.3 Hz), 7.46 (1H, br s), 7.90-8.28 (1H, br). the mixture was stirred at −45° C. for 45 minutes stirred at room temperature for 3 hours followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane)

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

Procedure: Under an argon atmosphere, to a solution of tert-butyl (5-methoxy-2-methylphenyl)carbamate (2.00 g) in tetrahydrofuran (42 mL) was slowly added dropwise sec-butyllithium (1.08 mol/L hexane-cyclohexane solution, 22 mL) at −45° C., and the mixture was stirred for 45 minutes. Then, a solution of N-methoxy-N,1-dimethylcyclopropane carboxamide (1.33 g) in tetrahydrofuran (4.2 mL) was added dropwise thereto, and the mixture was stirred at −45° C. for 45 minutes, and then stirred at room temperature for 3 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.77 g). 1H-NMR (CDCl3) δ ppm: 0.80-0.89 (2H, m), 1.35-1.44 (5H, m), 1.52 (9H, s), 3.55 (2H, s), 3.80 (3H, s), 6.57 (1H, dd, J=2.8, 8.3 Hz), 6.97 (1H, d, J=8.3 Hz), 7.46 (1H, br s), 7.90-8.28 (1H, br). the mixture was stirred at −45° C. for 45 minutes stirred at room temperature for 3 hours followed by extraction with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane)

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

Procedure: Under argon, 7.587 g (15.37 mmol) of 2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 ml of THF and cooled to −78° C. 7.65 ml (15.27 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 30 min. 2 g (13.97 mmol) of N-methoxy-N,1-dimethylcyclopropanecarboxamide [R. Shintani et al., Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of THF, were then slowly added dropwise to the reaction solution. The reaction mixture obtained was then slowly warmed to room temperature and stirred at this temperature overnight. 50 ml of an ice-cold saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% of theory) of the title compound. The reaction solution was then slowly warmed to −40° C. were then slowly added dropwise to the reaction solution The reaction mixture obtained was then slowly warmed to room temperature stirred at this temperature overnight After separation of the phases the aqueous phase was extracted three more times with ethyl acetate the combined organic phases were dried over magnesium sulphate filtered evaporated to dryness

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

Procedure: Under argon, 7.587 g (15.37 mmol) of 2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 ml of THF and cooled to −78° C. 7.65 ml (15.27 mmol) of a 2 M solution of isopropylmagnesium chloride in diethyl ether were then slowly added dropwise. The reaction solution was then slowly warmed to −40° C. and stirred at this temperature for 30 min. 2 g (13.97 mmol) of N-methoxy-N,1-dimethylcyclopropanecarboxamide [R. Shintani et al., Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of THF, were then slowly added dropwise to the reaction solution. The reaction mixture obtained was then slowly warmed to room temperature and stirred at this temperature overnight. 50 ml of an ice-cold saturated aqueous ammonium chloride solution were then added to the reaction mixture. After separation of the phases, the aqueous phase was extracted three more times with ethyl acetate, and the combined organic phases were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% of theory) of the title compound. The reaction solution was then slowly warmed to −40° C. were then slowly added dropwise to the reaction solution The reaction mixture obtained was then slowly warmed to room temperature stirred at this temperature overnight After separation of the phases the aqueous phase was extracted three more times with ethyl acetate the combined organic phases were dried over magnesium sulphate filtered evaporated to dryness

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

Procedure: A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (116 mg, 0.2 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to −78° C. and treated with nBuLi (2.13M in hexanes, 0.13 ml, 0.27 mmol) dropwise. The solution was stirred for 30 seconds and 1-methyl-cyclopropanecarboxylic acid methoxy-methyl-amide (88 mg, 0.61 mmol) was added in one portion. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NaHSO4 and then partitioned between EtOAc/brine. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow oil. The oil was purified by silica gel chromatography using 2-30% EtOAc in hexanes as eluant to provide 20 mg (19%) of (1-methyl-cyclopropyl)-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone. The reaction mixture was stirred at −78° C. for 30 minutes The reaction mixture was quenched with saturated aqueous NaHSO4 partitioned between EtOAc/brine The organic layers were collected dried over MgSO4 filtered concentrated giving a yellow oil The oil was purified by silica gel chromatography

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

Procedure: To a solution of N-methoxy-N,1-dimethylcyclopropanecarboxamide (C50) (18 g, 0.126 mol) in tetrahydrofuran (360 mL) was added a solution of allylmagnesium bromide (1.0 M in diethyl ether, 500 mL, 0.5 mol) drop-wise at −60° C. The mixture was stirred at −60° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (50 mL). The reaction was extracted with dichloromethane (2×500 mL), the organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried, and concentrated in vacuo to give the product as a yellow oil, which was used directly in the next step. was quenched with saturated aqueous ammonium chloride solution (50 mL) The reaction was extracted with dichloromethane (2×500 mL) the organic layers were washed with saturated aqueous sodium chloride solution (200 mL) dried concentrated in vacuo

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

Procedure: To a solution of 1-methylcyclopropanecarboxylic acid (C49) (30 g, 300 mmol) in dichloromethane (500 mL) was added 1,1′-carbonyldiimidazole (51 g, 315 mmol) portion-wise, not allowing the temperature to exceed 25° C. The mixture was stirred at room temperature for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (34.8 g, 357 mmol) was added in one portion and stirred at room temperature for 12 hours. The mixture was washed with water (2×200 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate and concentrated to give crude product as a colorless oil, which was directly used in the next step. Yield: 49 g, 342 mmol, 114%. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.20 (s, 3H), 1.34 (s, 3H), 1.01 (dd, J=6.4, 4.4 Hz, 2H), 0.53 (dd, J=6.4, 4.4 Hz, 2H). to exceed 25° C stirred at room temperature for 12 hours The mixture was washed with water (2×200 mL) and saturated aqueous sodium chloride solution (100 mL) dried over sodium sulfate concentrated to give crude product as a colorless oil, which