Hydrochloric Acid → HCID 14939422, compound

Participants

Reaction Conditions

Reaction Steps

The following is based on the procedure disclosed in B. Lygo, Tetrahedron, 51, pp. 12859-12868 (1995). To an oven dried 5 liter flask was added sodium hydride (60% dispersion in mineral oil, 1.21 mmoles, 48.55 g) under nitrogen gas. The hydride was washed with hexanes (4×250 mL). The hydride was then suspended in dry tetrahydrofuran (THF) (2000 mL) and the mixture cooled to 0° C. in an ice bath. To this solution was added t-butylacetoacetate (160 g, 1.01 mmol) via an addition funnel dropwise over 2 hours at 0° C. with a constant flow of nitrogen gas. After the addition was complete the reaction was allowed to stir at 0° C. under nitrogen for an additional 30 minutes. To this mixture was added n-butyllithium (2 M in cyclohexane, 556 mL, 1.11 mmol) via addition funnel dropwise over 3 hours. After the addition was complete the reaction mixture was allowed to stir at 0° C. for an additional 30 minutes. Ethylpropionate (85.94 mL, 1.01 mmol) was loaded into an addition funnel and added to reaction slowly over 1.5 hours. At this point the reaction was allowed to warm up to room temperature while stirring overnight. The reaction was once again cooled to 0° C. in an ice bath and 2 N HCl (1.15 liters, cooled to 0° C. before addition) was added dropwise via an addition funnel over 2 hours. The reaction pH was checked to ensure neutralization. If needed, more 2 N HCl was added by pipette to adjust the solution to pH 7. At this point the major portion of THF/cyclohexane was decanted away from the aqueous layer and the organic solvent was reduced by ˜75% using rotary evaporation. The aqueous layer was extracted with ethyl acetate (3×200 mL). The residue obtained from volume reduction was diluted with ethyl acetate (500 mL) and combined with the organic pool from aqueous extraction. This organic pool was washed with saturated sodium chloride (3×250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was then subjected to high vacuum distillation (140 microns, short path distillation head) to yield 131 g of crude compound U as a clear oil. 1H NMR CDCl3 δ: 15.16 (bs, 1H), 5.59 (s, 1H), 3.24 (s, 2H), 3.22 (q, 2H, J=8.0 Hz), 1.46 (s, 9H), 1.14 (t, 3H, J=8.0 Hz). ESMS m/z: 237 [M+Na+], 159 [M-t-butyl]+.

Provenance & Evidence