Lithium Hexamethyldisilazide → 4-(2-Methoxyethoxy)pyridin-2-amine

Participants

Reaction Conditions

Reaction Steps

2-Chloro-4-(2-methoxyethoxy)pyridine (30.0 g; 159.9 mmol), X-PHOS (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. LHMDS (325 mL, 325.0 mmol) was added by addition funnel while 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 reparatory funnel with the addition of methyl t-butyl ether (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).

Provenance & Evidence