Bromoacetonitrile → Methyl 2-(6-chloro-2-methoxypyridin-3-yl)-3-cyano-2-methylpropanoate

Participants

Reaction Steps

In a dry flask containing lithium bis(trimethylsilyl)amide/toluene (1.0 M, 13.1 mL, 13.1 mmol) and THF (18 mL) at −78° C. was added methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (2.39 g, 10.4 mmol) dropwise via syringe over 12 min resulting in a bright yellow solution. After 40 min, the resulting solution was added dropwise to a dry flask containing a solution of 2-bromoacetonitrile (1.38 mL, 20.8 mmol) in THF (18 mL) at 0° C. over 15 min, resulting in a color change from colorless to yellow to dark red-brown. Subsequent rinses with THF (2×1.5 mL) were cannulated over. After 50 min, the reaction was quenched with saturated aqueous ammonium chloride (18 mL). The mixture was diluted with heptanes (4× the reaction volume). The aqueous layer was extracted 2× with 1:1 EtOAc/heptanes (200 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (220 g RediSep Gold column, 5-18% EtOAc/heptanes) provided methyl 2-(6-chloro-2-methoxypyridin-3-yl)-3-cyano-2-methylpropanoate (2.35 g, 84%) as a white solid. 1H NMR (600 MHz, CDCl3) δ: 1.74 (s, 3H), 3.07 (d, 1H), 3.14 (d, 1H), 3.67 (s, 3H), 3.95 (s, 3H), 7.00 (d, 1H), 7.57 (d, 1H); MS (AP+)(M+H) 269.

Provenance & Evidence