Sodium hydride → (2R,3S)-3-(4-Methoxyphenyl)oxirane Carboxylic Acid (1R,2S)-2-Phenylcyclohexyl Ester

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Reaction Steps

A 5.0-L three-necked flask equipped with a stirrer, a gas bubbler, a thermometer, an addition funnel and condenser was charged with 100 g (3.33 mole) of NaH (80% in mineral oil), and triturated with 3×500 mL=1.5 L of hexane. Each portion of hexane was decanted when the NaH had settled. Under an argon atmosphere, 1.5 L of tetrahydrofuran was added followed by a solution of 568 g (2.247 mole) of (-)-(1R,2S)-2-phenylcyclohexyl chloroacetate, 352 g (2.589 mole) of anisaldehyde and 250 mL of tetrahydrofuran over 0.5 hour via addition funnel. A vigorous evolution of H2 gas ensued along with an exotherm to about 55°. After the initial reaction subsided, the mixture was then stirred under argon at ambient temperature overnight. The mixture was heated at 55-60° for 1 hour and then quenched into 8.0 L of ice water. The pH was adjusted to 7 with 390 mL of 3N H2SO4 and the resulting mixture was extracted first with 4 L followed by 2×2 L for a total of 8.0 L of methylene chloride. The combined organic layers were dried (Na2SO4) and evaporated in vacuo to an oily, partially solid residue which on crystallization from 0.5 L of (9:1) hexanes-ethyl acetate afforded colorless needles. These crystals were collected by filtration, washed with 2×200 mL=400 mL of 9:1 hexanes-ethyl acetate followed by 2×500 mL=1.0 L of cold hexanes and finally dried in vacuo to afford 403 g (51%) of the title compound, m.p. 146-148° C., [α]D20 =-146°(c=1; CHC13).

Provenance & Evidence