3-methyl-1-phenyl-3-trimethylsilyloxybutan-1-one

反应条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask is charged with 1 (120.0 g, 0.366 mol), 2 (120.0 g, 0.479 mol) and NiCl2(dppe) (1.93 g, 3.66 mmol). The flask is purged with nitrogen and charged with DME (240 mL). The resultant slurry is cooled to about −20° C. and treated with diethylzinc (30 wt. % solution in toluene, 477 mL, 1.097 mol) at a rate to keep the temperature of the reaction mixture between −15 to −5° C. The reaction mixture is then stirred at −5 to 0° C. for 2 hours, treated with 6N aqueous HCl (600 mL), and stirred for 15 minutes. The reaction mixture is treated with isopropyl acetate (120 mL), stirred at 25° C. for 30 minutes, cooled to 10° C., and held at 10° C. for 30 minutes. The resultant solids are collected by filtration, and washed with water, toluene, and heptane. The solid is then dried at 70° C. for 18 hours to provide 3 as a white solid. Yield: 98.3 g, 62.1%; 97.1 wt. % purity. Diastereomeric ratio: 98.9:1.1. Melting point: 150-152° C. LC-MS: 419.8/421.8 (100%, 95%); calculated exact mass: 419.1. The flask is purged with nitrogen charged with DME (240 mL) between −15 to −5° C stirred for 15 minutes stirred at 25° C. for 30 minutes cooled to 10° C. held at 10° C. for 30 minutes The resultant solids are collected by filtration washed with water, toluene, and heptane The solid is then dried at 70° C. for 18 hours

反应条件: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A flask is charged with THF (1 L), cooled to −50° C., and treated with lithium diisopropylamide (LDA) (1.05 L, 1.89 mol, 1.1 equiv, 1.8M in THF/heptane/ethylbenzene). The reactor contents are then treated with acetophenone (200 mL, 1.71 mol, 1.0 equiv) at a rate to maintain the batch at about −50° C. The reaction mixture is stirred at about −50° C. for 30 minutes then treated with acetone (151 mL, 2.06 mol, 1.2 equiv) at a rate to maintain the mixture at about −50° C. The reaction mixture is stirred at about −50° C. for 1 hour then treated with water (1 L) and heptane (500 mL). The reaction mixture is allowed to warm to 25° C., and the resultant organic phase is collected and washed with water (400 mL). The organic phase is concentrated to an oil and treated with a solution of imidazole (233.4 g, 3.43 mol, 2.0 equiv) and DMF (600 mL). The resultant solution is treated with chlorotrimethylsilane (217.6 mL, 1.71 mol, 1.0 equiv) at a rate to maintain the reaction mixture at no more than 35° C. The reaction mixture is stirred at 25° C. for 1 hour, and diluted with heptane (600 mL) and water (1 L). The resultant organic phase is collected, washed with water (3×500 mL), and concentrated. The resultant oil is then vacuum distilled at 1-3 mm Hg (product distills at 83-88° C.) to provide 2 as a yellow liquid. Yield: 160.3 g, 37%. to maintain the batch at about −50° C to maintain the mixture at about −50° C The reaction mixture is stirred at about −50° C. for 1 hour to warm to 25° C. the resultant organic phase is collected washed with water (400 mL) The organic phase is concentrated to an oil to maintain the reaction mixture at no more than 35° C The reaction mixture is stirred at 25° C. for 1 hour The resultant organic phase is collected washed with water (3×500 mL) concentrated vacuum distilled at 1-3 mm Hg (product distills at 83-88° C.)