Methyl isobutyrate → Tert-butyl 2-(3-chloropyrazin-2-yl)-2-methylpropanoate

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Reaction Steps

Sodium tert-butoxide (7.2 g, 74.9 mmol) was suspended in diethyl ether (2500 mL) under argon. Methyl isobutyrate (6.0 ml, 58.7 mmol) was added and the mixture stirred at room temperature for 3 hours. The suspension was filtered through a pad of neutral alumina and concentrated under reduced pressure to −50 mL. The crude product was placed under argon and bromo[tri-tert-butylphosphine]dipalladium(1)dimer (0.282 g, 0.363 mmol) was added. The solution was cooled in an ice/acetone bath and lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 55 ml, 55.0 mmol) was added. The solution was stirred for minutes. 2,3-Dichloropyrazine (5.0 ml, 48.0 mmol) was added neat and after another 5 minutes the mixture was heated at 50° C. for 40 hours. The mixture was cooled and partitioned between water (400 mL), saturated ammonium chloride (100 mL) and ethyl acetate (400 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was purified using silica chromatography (hexane to ethyl acetate gradient) to give tert-butyl 2-(3-chloropyrazin-2-yl)-2-methylpropanoate (8.51 g, 33.1 mmol, 69.0% yield).

Provenance & Evidence