Phosphorus oxychloride → 3-(3-chloro-1H-pyrazol-1-yl)pyridine

Participants

Reaction Steps

A 250 mL, 3-neck round bottom flask was charged with methyl 2-acetamidoacrylate (4.91 g, 34.3 mmol) and ethanol (40 mL). 3-Hydrazinopyridine dihydrochloride (5 g, 27.5 mmol) was added, followed by sodium ethoxide (7.48 g, 110 mmol) and the reaction was stirred at 60° C. for 6 hours, at which point thin layer chromatography analysis [Eluent: 10% methanol/dichloromethane] indicated that the starting material had disappeared and a major product had formed: ESIMS m/z 221 ([M+H]+). The reaction was allowed to cool to room temperature and concentrated to afford a yellow solid. The resulting solid was slowly charged with phosphoryl chloride (29.2 g, 191 mmol). The reaction was stirred at 60° C. for 3 hours, at which point a sample of the reaction mixture was diluted with water and basified with 50 wt % sodium hydroxide solution. The resulting solution was extracted with ethyl acetate and the organic layer was analyzed by thin layer chromatography [Eluent: ethyl acetate], which indicated that the reaction was complete. The reaction mixture was concentrated at 40° C. to remove phosphoryl chloride and the residue was slowly quenched with water (40 mL) at <30° C. The resulting solution was basified with 50 wt % sodium hydroxide solution and the resulting suspension was extracted with ethyl acetate (3×50 mL). The organic layers were concentrated to dryness and the residue was purified by flash column chromatography using 40-50% ethyl acetate/hexanes. The fractions containing the pure product were concentrated to dryness to afford a white solid, which was further dried under vacuum at room temperature to afford the desired product as a white solid (2.4 g, 49%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.08; EIMS m/z 179 ([M]+).

Provenance & Evidence