Citric Acid → (S)-2-(tert-butyldimethylsilyloxy)-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide

Participants

Reaction Conditions

Reaction Steps

A solution of trimethylaluminium (2M in hexane, 2.75 mL, 5.49 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (0.594 g, 5.49 mmol) in toluene (10 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. The resulting solution was stirred for 15 minutes. A solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-ethoxypropanoate (Intermediate G3) (1.31 g, 4.99 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was allowed to warm to ambient temperature and then heated to reflux for 7 hours then allowed to cool to room temperature and 1M citric acid (20 mL) added, diluted with water (25 mL) and the mixture extracted with ethyl acetate (25 mL). The aqueous was re-extracted with ethyl acetate (25 mL), the organic phases combined, washed with water (5 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 10 to 100% EtOAc in isohexane to give (2S)-2-(tert-butyl-dimethylsilyl)oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (1.1 g, 65%). 1H NMR (400 MHz, CDCl3) δ 0.18 (3H, s), 2.00 (3H, s), 0.99 (9H, s), 1.18 (3H, t), 2.30 (3H, s), 3.51-3.61 (2H, m), 3.63-3.67 (1H, m), 3.78-3.81 (1H, m), 4.41-4.43 (1H, m), 7.51 (1H, dd), 8.13-8.18 (2H, m), 9.03 (1H, s); m/z (ESI+) (M+H)+=339; HPLC tR=3.31 min.

Provenance & Evidence