反应详情

温度

-78 °C

A solution of tert-butyl pyrrolidine-1-carboxylate (4.09 mL, 23.4 mmol) and (−)-sparteine (6.44 mL, 28.0 mmol) in MTBE (50 mL) was cooled to −78° C. and sec-BuLi (20 mL, 28.0 mmol, 1.4 M in cyclohexane) was introduced drop-wise by cannula, keeping the internal temperature under −78° C. The resulting solution was stirred for 3 hours at −78° C., followed by addition of a solution of ZnCl2 (21.0 mL, 21.0 mmol, 1M in Et2O) drop-wise with rapid stirring, keeping the internal temperature below −65° C. The resulting light suspension was stirred at −78° C. for 10 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 3-bromo-5-fluoro-2-methoxypyridine (5.05 g, 24.5 mmol), Pd(OAc)2 (0.262 g, 1.17 mmol) and t-Bu3P-HBF4 (0.407 g, 1.40 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (1 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite® and washed with Et2O. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5% EtOAc/hexanes to give product (R)-tert-butyl 2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidine-1-carboxylate as yellow oil (4.34 g, 63% yield).

1. customunder −78° C
2. customthe internal temperature below −65° C
3. stirringThe resulting light suspension was stirred at −78° C. for 10 minutes
4. temperaturewarmed to ambient temperature
5. stirringAfter stirring overnight at ambient temperature
6. stirringthe reaction was stirred for 1 hour
7. filtrationThe resulting slurry was filtered through Celite®
8. washwashed with Et2O
9. filtrationThe organic layer was filtered
10. concentrationconcentrated
11. customthe crude product was purified by silica column chromatography
12. washeluting with 5% EtOAc/hexanes