Ethyl diazoacetate → (1S,2S)-2-(4-tert-Butoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester

Participants

Reaction Conditions

Reaction Steps

In a one liter three necked flask equipped with a magnetic stirrer bar, an alcohol thermometer, nitrogen inlet and addition inlet sealed with a suba seal, (R,R)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline) (417 mg, 1.42 mmol) and copper(I) trifluoromethanesulfonate benzene complex (714 mg, 1.42 mmol) are dissolved in degassed tert-butyl methyl ether (120 mL) and stirred for 15 minutes under N2. 4-tert-Butoxystyrene (25 g, 142 mmol) is added and the mixture cooled to −10° C. (internal temperature) under N2. Ethyldiazoacetate (24.75 g, 184.4 mmol) is dissolved in 50 mL of tert-butyl methyl ether and 5 mL of the resulting solution is added dropwise with cooling over 30 minutes using a syringe pump. The addition is then stopped and the mixture stirred at −10° C. until the reaction starts (effervescence and color change). Once the reaction has started the mixture is cooled to −20° C. and the remaining solution added dropwise using a syringe pump over 3 hours maintaining the temperature at −20° C. Once the addition is completed the mixture is allowed to slowly warm to room temperature and stirred overnight. NMR of a reaction sample shows approx. 30% of unreacted starting material, therefore the mixture is cooled to −20° C. and a further 14.1 g of ethyl diazoacetate in 30 mL of tert-butyl methyl ether is added dropwise over 90 minutes, stirred for 1 hour at −20° C. and then allowed to warm to room temperature. The solvent is removed under vacuum and the residue is purified by flash chromatography (0-5% ethyl acetate in cyclohexane) to give the title compound (yield 29.7 g). GC (METHOD 1): tR=11.47 min; Mass spectrum (EI+): m/z=262 [M]+, e.e. 96% by chiral HPLC (Column: Daicel Chiralcel OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=9.87 (9.13) min.

Provenance & Evidence