2-(2-bromoethyl)-2-methyl-1,3-dioxolane

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A mixture of 75 g of 4-bromo-2-butanone, 40 g of ethylene glycol, 250 mg of p-toluenesulfonic acid acid and 500 ml of toluene is refluxed for about 4-6 hours under a Dean-Stark water trap. The mixture is cooled, poured into ethyl acetate and dilute potassium carbonate solution. The organic layer is separated, washed with water, dried over sodium sulfate, stripped of solvent and the residue is distilled under reduced pressure to give the title product. The mixture is cooled The organic layer is separated washed with water dried over sodium sulfate the residue is distilled under reduced pressure

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the product of Example 7a (9.75 g, 0.05 mole, 1.3 eq), dibromoethane (6.4 g, 0.03 mole, 0.8 eq), and 30 mL of dry THF was added over a 2.5 hr period to a slurry of 99.9% magnesium turnings (3.6 g, 0.15 mole, 3 eq) and 75 mL THF with vigorous stirring. The temperature was maintained at 24°-27° C. by external cooling. The resulting Grignard solution was then cooled to -78° C. until further use. In a separate flask, phenylacetylene (3.9 g, 0.038 mole, 1 eq) in 20 mL THF was cooled to -78° C., n-butyllithium (1.38 molar, 28 mL, 0.038 mole, 1 eq) was added via syringe, the solution stirred 30 min at -78° C., warmed to 0° C. for 30 min and cooled again to -78° C. In a separate flask, benzoquinone (4.2 g, 0.038 mole, 1 eq) in 20 mL of THF was cooled to -78° C., the phenylacetylide solution was added dropwise, resulting in a blue solution which was stirred 25 min at -78° C. DMPU (30 g, 0.23 mole, 6 eq) was added, the reaction warmed to -5° C., and the Grignard reagent solution added over about a 15 min period. The cooling bath was allowed to warm to RT and the reaction stirred overnight. The reaction mixture was quenched with 100 mL of saturated ammonium chloride solution, 100 mL of water added, the layers separated and the aqueous layer extracted with three 150 mL portions of ether. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The dried solution was evaporated in vacuo to give a brown oil, 9.21 g portion of which was purified by trituration with ether followed by flash chromatography on silica gel eluting with 3:1 hexane/EtOAc to 1:1 hexane/EtOAc to yield 2.4 g of the title compound. The temperature was maintained at 24°-27° C. by external cooling warmed to 0° C. for 30 min cooled again to -78° C resulting in a blue solution which was stirred 25 min at -78° C the reaction warmed to -5° C. to warm to RT the reaction stirred overnight The reaction mixture was quenched with 100 mL of saturated ammonium chloride solution, 100 mL of water added the layers separated the aqueous layer extracted with three 150 mL portions of ether The combined organic layers were washed with water, brine dried over anhydrous sodium sulfate The dried solution was evaporated in vacuo to give a brown oil, 9.21 g portion of which was purified by trituration with ether

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the product of Example 7a (9.75 g, 0.05 mole, 1.3 eq), dibromoethane (6.4 g, 0.03 mole, 0.8 eq), and 30 mL of dry THF was added over a 2.5 hr period to a slurry of 99.9% magnesium turnings (3.6 g, 0.15 mole, 3 eq) and 75 mL THF with vigorous stirring. The temperature was maintained at 24°-27° C. by external cooling. The resulting Grignard solution was then cooled to -78° C. until further use. In a separate flask, phenylacetylene (3.9 g, 0.038 mole, 1 eq) in 20 mL THF was cooled to -78° C., n-butyllithium (1.38 molar, 28 mL, 0.038 mole, 1 eq) was added via syringe, the solution stirred 30 min at -78° C., warmed to 0° C. for 30 min and cooled again to -78° C. In a separate flask, benzoquinone (4.2 g, 0.038 mole, 1 eq) in 20 mL of THF was cooled to -78° C., the phenylacetylide solution was added dropwise, resulting in a blue solution which was stirred 25 min at -78° C. DMPU (30 g, 0.23 mole, 6 eq) was added, the reaction warmed to -5° C., and the Grignard reagent solution added over about a 15 min period. The cooling bath was allowed to warm to RT and the reaction stirred overnight. The reaction mixture was quenched with 100 mL of saturated ammonium chloride solution, 100 mL of water added, the layers separated and the aqueous layer extracted with three 150 mL portions of ether. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The dried solution was evaporated in vacuo to give a brown oil, 9.21 g portion of which was purified by trituration with ether followed by flash chromatography on silica gel eluting with 3:1 hexane/EtOAc to 1:1 hexane/EtOAc to yield 2.4 g of the title compound. The temperature was maintained at 24°-27° C. by external cooling warmed to 0° C. for 30 min cooled again to -78° C resulting in a blue solution which was stirred 25 min at -78° C the reaction warmed to -5° C. to warm to RT the reaction stirred overnight The reaction mixture was quenched with 100 mL of saturated ammonium chloride solution, 100 mL of water added the layers separated the aqueous layer extracted with three 150 mL portions of ether The combined organic layers were washed with water, brine dried over anhydrous sodium sulfate The dried solution was evaporated in vacuo to give a brown oil, 9.21 g portion of which was purified by trituration with ether

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

実験手順: To a cold HBr saturated solution of ethylene glycol (210 mL) was added dropwise 118 mL of methyl vinyl ketone. The solution was allowed to warm to RT and the reaction mixture was extracted four times with pentane. The pentane layers were combined, washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated on a rotary evaporator to yield a yellow oil which was vacuum distilled to 67 g of a clear oil, bp 55°-60° C., which was the title compound. the reaction mixture was extracted four times with pentane washed with 5% sodium bicarbonate solution dried over anhydrous magnesium sulfate evaporated on a rotary evaporator to yield a yellow oil which distilled to 67 g of a clear oil, bp 55°-60° C., which

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A freshly prepared solution of lithium diisopropylamide, was generated by the addition of n-butyllithium (16.2 mL, 25.9 mmol, 1.6 M in hexane) to a solution of diisopropylamine (6.6 mL, 47.0 mmol) in tetrahydrofuran (20 mL) at −20° C., and allowed to warm to 0° C. and stir for 30 minutes. N-(2-methylpropylidene)-2-methyl-2-propanamine (3.0 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring at 0° C. for 2 hours, 2-bromoethyl-2-methyl-1,3-dioxolane (5.0 g, 25.9 mmol) in tetrahydrofuran (10 mL) was added over 15 minutes. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. After cooling in an ice bath, an aqueous solution of oxalic acid (100 mL, 10 wgt %) was added and reaction stirred for 1 hour. The layers were separated and the aqueous was extracted with ether (100 mL). The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:9) to afford the title compound (1.0 g, 23%) as a clear liquid; After stirring at 0° C. for 2 hours to warm to ambient temperature stirring was continued for 16 hours After cooling in an ice bath reaction stirred for 1 hour The layers were separated the aqueous was extracted with ether (100 mL) The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated in vacuo chromatographed (silica gel, ethyl acetate/hexane, 1:9)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A freshly prepared solution of lithium diisopropylamide, was generated by the addition of n-butyllithium (16.2 mL, 25.9 mmol, 1.6 M in hexane) to a solution of diisopropylamine (6.6 mL, 47.0 mmol) in tetrahydrofuran (20 mL) at −20° C., and allowed to warm to 0° C. and stir for 30 minutes. N-(2-methylpropylidene)-2-methyl-2-propanamine (3.0 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring at 0° C. for 2 hours, 2-bromoethyl-2-methyl-1,3-dioxolane (5.0 g, 25.9 mmol) in tetrahydrofuran (10 mL) was added over 15 minutes. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. After cooling in an ice bath, an aqueous solution of oxalic acid (100 mL, 10 wgt %) was added and reaction stirred for 1 hour. The layers were separated and the aqueous was extracted with ether (100 mL). The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:9) to afford the title compound (1.0 g, 23%) as a clear liquid; After stirring at 0° C. for 2 hours to warm to ambient temperature stirring was continued for 16 hours After cooling in an ice bath reaction stirred for 1 hour The layers were separated the aqueous was extracted with ether (100 mL) The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated in vacuo chromatographed (silica gel, ethyl acetate/hexane, 1:9)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A freshly prepared solution of lithium diisopropylamide, was generated by the addition of n-butyllithium (16.2 mL, 25.9 mmol, 1.6 M in hexane) to a solution of diisopropylamine (6.6 mL, 47.0 mmol) in tetrahydrofuran (20 mL) at −20° C., and allowed to warm to 0° C. and stir for 30 minutes. N-(2-methylpropylidene)-2-methyl-2-propanamine (3.0 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring at 0° C. for 2 hours, 2-bromoethyl-2-methyl-1,3-dioxolane (5.0 g, 25.9 mmol) in tetrahydrofuran (10 mL) was added over 15 minutes. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. After cooling in an ice bath, an aqueous solution of oxalic acid (100 mL, 10 wgt %) was added and reaction stirred for 1 hour. The layers were separated and the aqueous was extracted with ether (100 mL). The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:9) to afford the title compound (1.0 g, 23%) as a clear liquid; After stirring at 0° C. for 2 hours to warm to ambient temperature stirring was continued for 16 hours After cooling in an ice bath reaction stirred for 1 hour The layers were separated the aqueous was extracted with ether (100 mL) The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated in vacuo chromatographed (silica gel, ethyl acetate/hexane, 1:9)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A freshly prepared solution of lithium diisopropylamide, was generated by the addition of n-butyllithium (16.2 mL, 25.9 mmol, 1.6 M in hexane) to a solution of diisopropylamine (6.6 mL, 47.0 mmol) in tetrahydrofuran (20 mL) at −20° C., and allowed to warm to 0° C. and stir for 30 minutes. N-(2-methylpropylidene)-2-methyl-2-propanamine (3.0 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring at 0° C. for 2 hours, 2-bromoethyl-2-methyl-1,3-dioxolane (5.0 g, 25.9 mmol) in tetrahydrofuran (10 mL) was added over 15 minutes. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. After cooling in an ice bath, an aqueous solution of oxalic acid (100 mL, 10 wgt %) was added and reaction stirred for 1 hour. The layers were separated and the aqueous was extracted with ether (100 mL). The combined organic layers were washed with brine (50.mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:9) to afford the title compound (1.0 g, 23%) as a clear liquid; After stirring at 0° C. for 2 hours to warm to ambient temperature stirring was continued for 16 hours After cooling in an ice bath reaction stirred for 1 hour The layers were separated the aqueous was extracted with ether (100 mL) The combined organic layers were washed with brine (50.mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated in vacuo chromatographed (silica gel, ethyl acetate/hexane, 1:9)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A freshly prepared solution of lithium diisopropylamide, was generated by the addition of n-butyllithium (16.2 mL, 25.9 mmol, 1.6 M in hexane) to a solution of diisopropylamine (6.6 mL, 47.0 mmol) in tetrahydrofuran (20 mL) at −20° C., and allowed to warm to 0° C. and stir for 30 minutes. N-(2-methylpropylidene)-2-methyl-2-propanamine (3.0 g, 23.5 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring at 0° C. for 2 hours, 2-bromoethyl-2-methyl-1,3-dioxolane (5.0 g, 25.9 mmol) in tetrahydrofuran (10 mL) was added over 15 minutes. The reaction was allowed to warm to ambient temperature and stirring was continued for 16 hours. After cooling in an ice bath, an aqueous solution of oxalic acid (100 mL, 10 wgt %) was added and reaction stirred for 1 hour. The layers were separated and the aqueous was extracted with ether (100 mL). The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:9) to afford the title compound (1.0 g, 23%) as a clear liquid; After stirring at 0° C. for 2 hours to warm to ambient temperature stirring was continued for 16 hours After cooling in an ice bath reaction stirred for 1 hour The layers were separated the aqueous was extracted with ether (100 mL) The combined organic layers were washed with brine (50 mL), saturated sodium bicarbonate/water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated in vacuo chromatographed (silica gel, ethyl acetate/hexane, 1:9)

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

実験手順: A mixture of 75 g of 4-bromo-2-butanone, 40 g of ethylene glycol, 250 mg of p-toluenesulfonic acid acid and 500 ml of toluene is refluxed for about 4-6 hours under a Dean-Stark water trap. The mixture is cooled, poured into ethyl acetate and dilute potassium carbonate solution. The organic layer is separated, washed with water, dried over sodium sulfate, stripped of solvent and the residue is distilled under reduced pressure to give the title product. The mixture is cooled The organic layer is separated washed with water dried over sodium sulfate the residue is distilled under reduced pressure