Dichloromethane → MK-0674

Participants

Reaction Conditions

Reaction Steps

The boronate ester of step 3 of example 1 (20 g, 40 mmoles) and the aryl bromide of step 2 of example 1 (11.4 g, 48 mmoles) were dissolved in dimethylformamide (400 mL) followed by an aqueous solution of sodium bicarbonate (60 mL, 120 mmoles). Nitrogen was then bubbled through a pipette for 15 minutes. [1,1-Bis(diphenylphosphine)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (PdCl2dppf.CH2Cl2, 2.4 g, 3 mmoles) was added and the reaction mixture immersed in an oil bath at 80° C. for 16 hours under a nitrogen atmosphere. Most of the dimethylformamide was removed under the rotovap at low pressure (45° C., approx 1-5 mm Hg). The residue was dissolved in ethyl acetate (400 mL) and filtered onto a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was taken-up in approx 10 mL of dichloromethane and separated by flash chromatography. The most pure fractions were swished in hexanes (100 mL) at 0° C. overnight three times and flashed again (90% hexanes; 10% ethyl acetate to 45 hexanes; 55% ethyl acetate). After evaporation of the volatiles under reduced pressure, the solid was stirred in hexanes for 2 days. The product still contained 4% of pinacol so the batch was divided in two. Fraction A was dissolved in a minimum of isopropyl alcohol with gentle warming. Hexanes were added until the solution was a bit cloudy and let cool down. White crystals appeared and the reaction was further cooled to 0° C. for 15 minutes. The solids were collected by filtration to obtain the product not contaminated with pinacol. Fraction B was stirred in 20% diethyl ether; 1% ethyl acetate; 79% hexanes (100 mL) for 3 hours at room temperature. The solids were collected by filtration was contaminated with only approximately 1% pinacol by 1H NMR. The enantiomeric excess was verified chiral AD-RH using 32% acetonitrile; 68% water; 0.1% formic acid; isocratic (24 min for enantiomer and 27 minutes for desired molecule). (MH)+ ESI=528.0.

Provenance & Evidence