反应详情

温度

2.5 °C

2-Chloro-4-(2-methoxyethoxy)pyridine (30.0 g; 159.9 mmol), X-PHOS (dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine) (3.03 g, 6.356 mmol), and Tris(dibenzylideneacetone)dipalladium (2.26 g; 2.468 mmol) were combined in a reaction flask under an atmosphere of dry nitrogen. Anhydrous tetrahydrofuran (150 mL) was added. The mixture was degassed by alternately evacuating the flask followed by filling with dry nitrogen (three times). The mixture was cooled to 0-5° C. using an ice/water bath. Lithium hexamethyldisilazide (LHMDS) (325 mL, 325.0 mmol) was added via addition funnel maintaining the temperature below 5° C. The ice/water bath was removed and the mixture was heated to reflux (60-65° C.) for 1.5 hours. After allowing the mixture to cool an ice/water bath was put in place. Hydrochloric acid (2N; 300 mL) was added with stirring, maintaining the temperature below 30° C. After stirring for 15 minutes the mixture was transferred to a separatory funnel with the addition of methyl t-butyl ether (MTBE) (300 mL) and water (20 mL). The phases were separated. The aqueous phase was basified by the addition of sodium hydroxide (50%; 10 mL) and then extracted with dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and filtered. Heptane (300 mL) was added. The solution was concentrated under vacuum to about one third the initial volume. Heptane (200 mL) was added. Further concentration resulted in solids precipitating. The solids were collected by filtration and washed with heptane (100 mL). The solids were dried under vacuum at 55° C. to give 4-(2-methoxyethoxy)pyridin-2-amine as an off white solid (23.62 g).

1. customThe mixture was degassed
2. customby alternately evacuating the flask
3. temperaturemaintaining the temperature below 5° C
4. customThe ice/water bath was removed
5. temperaturethe mixture was heated
6. temperatureto reflux (60-65° C.) for 1.5 hours
7. temperatureto cool an ice/water bath
8. additionHydrochloric acid (2N; 300 mL) was added
9. temperaturemaintaining the temperature below 30° C
10. stirringAfter stirring for 15 minutes the mixture
11. additionwas transferred to a separatory funnel with the addition of methyl t-butyl ether (MTBE) (300 mL) and water (20 mL)
12. customThe phases were separated
13. additionThe aqueous phase was basified by the addition of sodium hydroxide (50%; 10 mL)
14. extractionextracted with dichloromethane
15. dry with materialThe combined dichloromethane extracts were dried over sodium sulfate
16. filtrationfiltered
17. additionHeptane (300 mL) was added
18. concentrationThe solution was concentrated under vacuum to about one third the initial volume
19. additionHeptane (200 mL) was added
20. concentrationFurther concentration
21. customresulted in solids
22. customprecipitating
23. filtrationThe solids were collected by filtration
24. washwashed with heptane (100 mL)
25. customThe solids were dried under vacuum at 55° C.