1-methylpyrrolidin-3-one

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

Procedure: 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrolidine oxalate, compound 8, and (E) 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrrolidine oxalate, compound 9, starting form 1-methyl-pyrrolidin-3-one (J. Amer. Chem. Soc., 55, 1933, 1233-1241) and 3-methyl-5-trimethylsilylmethyl-isoxazole.

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

Procedure: This compound was prepared according to a procedure similar to that described in Procedure B. Into a solution of Ethynyl-triisopropyl-silane (1.1 g, 6 mmol) in tetrahydrofuran (10 mL) was dropped in n-BuLi (2.4 mL, 6 mmol) at −78° C. The solution was stirred for 0.5 h. Then 1-Methyl-pyrrolidin-3-one (0.5 g, 5 mmol) was added. The solution was allowed to warm up to room temperature and stirred for 3 h. Then the reaction mixture was added in 50 mL EtOAc and washed with water three times. The solvent was removed under vacuum to afford 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (0.55 g, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 5.53 (s, 1H), 2.74-2.63 (m, 2H), 2.46-2.44 (m, 1H), 2.23 (s, 3H), 2.13-1.96 (m, 2H), 1.07-0.97 (m, 21H). A solution of 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (1.0 g, 3.6 mmol) in tetrahydrofuran (10 mL) was treated with Tetrabutyl-ammonium fluoride (0.94 g, 3.6 mmol). The solution was stirred overnight at room temperature. Then the reaction mixture was purified by column (eluent: CH2Cl2: MeOH=10:1) to afford 3-Ethynyl-1-methyl-pyrrolidin-3-ol (0.26 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 1H), 3.31 (s, 1H), 2.74-2.56 (m, 3H), 2.49-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.91 (m, 2H). This compound was prepared stirred for 3 h washed with water three times The solvent was removed under vacuum

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

Procedure: 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrolidine oxalate, compound 8, and (E) 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrrolidine oxalate, compound 9, starting form 1-methyl-pyrrolidin-3-one (J. Amer. Chem. Soc., 55, 1933, 1233-1241) and 3-methyl-5-trimethylsilylmethyl-isoxazole.

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

Procedure: 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrolidine oxalate, compound 8, and (E) 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrrolidine oxalate, compound 9, starting form 1-methyl-pyrrolidin-3-one (J. Amer. Chem. Soc., 55, 1933, 1233-1241) and 3-methyl-5-trimethylsilylmethyl-isoxazole.

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

Procedure: A solution of 2-mercaptopyrimidine-4,6-diol (25 g, 173.61 mmol, 1.00 equiv.), sodium hydroxide (15.8 g, 395.00 mmol, 2.27 equiv.), 1-methylpyrrolidin-3-one (50 mL), and 1-iodopropane (30.6 g, 180.00 mmol, 1.05 equiv.) dissolved in water (60 mL) was stirred at ambient temperature for about 48 hours. The pH value of the solution was adjusted to 2-3 by adding hydrochloric acid. The solids were then collected by filtration to give the product as an off-white solid (35 g; (crude)). 1H NMR (300 MHz, DMSO-d6) δ: 11.78 (b, 1H), 10.30 (b, 1H), 5.13 (s, 1H), 3.07 (t, J=7.2 Hz, 2H), 1.58-1.70 (m, 2H), 0.96 (t, J=7.2 Hz, 2H). The solids were then collected by filtration

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

Procedure: A solution of 2-mercaptopyrimidine-4,6-diol (25 g, 173.61 mmol, 1.00 equiv.), sodium hydroxide (15.8 g, 395.00 mmol, 2.27 equiv.), 1-methylpyrrolidin-3-one (50 mL), and 1-iodopropane (30.6 g, 180.00 mmol, 1.05 equiv.) dissolved in water (60 mL) was stirred at ambient temperature for about 48 hours. The pH value of the solution was adjusted to 2-3 by adding hydrochloric acid. The solids were then collected by filtration to give the product as an off-white solid (35 g; (crude)). 1H NMR (300 MHz, DMSO-d6) δ: 11.78 (b, 1H), 10.30 (b, 1H), 5.13 (s, 1H), 3.07 (t, J=7.2 Hz, 2H), 1.58-1.70 (m, 2H), 0.96 (t, J=7.2 Hz, 2H). The solids were then collected by filtration

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

Procedure: The above nitro compound was hydrogenated under hydrogen atomosphere in EtOH for 1 hour and filtered through Celite. To the solution was added NaBHCN (1.3 eq) and 1-methyl-3-pyrrolidinone (1 eq), the reaction was stirred at RT overnight and evaporated in vacuo and further purified by flash chromatography on silica gel afforded title compound. Mass: (M+1), 480. filtered through Celite evaporated in vacuo further purified by flash chromatography on silica gel

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

Procedure: This compound was prepared according to a procedure similar to that described in Procedure B. Into a solution of Ethynyl-triisopropyl-silane (1.1 g, 6 mmol) in tetrahydrofuran (10 mL) was dropped in n-BuLi (2.4 mL, 6 mmol) at −78° C. The solution was stirred for 0.5 h. Then 1-Methyl-pyrrolidin-3-one (0.5 g, 5 mmol) was added. The solution was allowed to warm up to room temperature and stirred for 3 h. Then the reaction mixture was added in 50 mL EtOAc and washed with water three times. The solvent was removed under vacuum to afford 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (0.55 g, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 5.53 (s, 1H), 2.74-2.63 (m, 2H), 2.46-2.44 (m, 1H), 2.23 (s, 3H), 2.13-1.96 (m, 2H), 1.07-0.97 (m, 21H). A solution of 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (1.0 g, 3.6 mmol) in tetrahydrofuran (10 mL) was treated with Tetrabutyl-ammonium fluoride (0.94 g, 3.6 mmol). The solution was stirred overnight at room temperature. Then the reaction mixture was purified by column (eluent: CH2Cl2: MeOH=10:1) to afford 3-Ethynyl-1-methyl-pyrrolidin-3-ol (0.26 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 1H), 3.31 (s, 1H), 2.74-2.56 (m, 3H), 2.49-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.91 (m, 2H). This compound was prepared stirred for 3 h washed with water three times The solvent was removed under vacuum

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

Procedure: 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrolidine oxalate, compound 8, and (E) 3-(3-methyl-5-isoxazolyl)methylene-1-methylpyrrolidine oxalate, compound 9, starting form 1-methyl-pyrrolidin-3-one (J. Amer. Chem. Soc., 55, 1933, 1233-1241) and 3-methyl-5-trimethylsilylmethyl-isoxazole.