Tetrahydrofuran → 4-Benzylmorpholine

Temperatur

0 °C

A solution of N-benzyl diol 4 (1.54 g, 4.02 mmol, 1.0 equiv) in 40.0 mL tetrahydrofuran was stirred at 0° C. for 10 min and was then added via cannula to sodium hydride (254.2 mg, 10.06 mmol, 2.5 equiv). The resulting white suspension was stirred vigorously at 0° C. for 5 min before removing the cooling bath. After 1 hr at 23° C., the reaction suspension was returned to a 0° C. bath for 10 min and N-tosylimidazole (894.5 mg, 4.02 mmol. 1.0 equiv) added in 3 portions over 12 min (gas evolution was observed subsequent to the addition of each portion). After stirring the resulting reaction solution for a further 10 min at 0° C., the cooling bath was again removed. After 1 hr at 23° C., excess sodium hydride was CAREFULLY quenched by the slow addition of 30 mL saturated aqueous ammonium chloride to the reaction suspension at 0° C. The reaction mixture was then partitioned between 340 mL ammounium chloride (sat., aq.) and 370 mL diethyl ether and the organic layer separated and washed further with 1×300 mL water and 1×200 mL brine. The aqueous washes were combined and extracted with 2×200 mL diethyl ether. All of the organic extracts were then combined and dried over sodium sulfate. Concentration of the extracts in vacuo provided a yellow oil, which was purified by flash column chromatography (SiO2, 20% ethyl acetate-hexanes), affording the N-benzyl morpholine product as a yellow oil (926.6 mg, 63%).

1. custombefore removing the cooling bath
2. waitAfter 1 hr at 23° C.
3. customwas returned to a 0° C.
4. customfor 10 min
5. additionwas observed subsequent to the addition of each portion)
6. stirringAfter stirring
7. customthe resulting reaction solution for a further 10 min at 0° C.
8. customthe cooling bath was again removed
9. waitAfter 1 hr at 23° C.
10. customexcess sodium hydride was CAREFULLY quenched by the slow addition of 30 mL saturated aqueous ammonium chloride to the reaction suspension at 0° C
11. customThe reaction mixture was then partitioned between 340 mL ammounium chloride (sat., aq.) and 370 mL diethyl ether
12. customthe organic layer separated
13. washwashed further with 1×300 mL water and 1×200 mL brine
14. extractionextracted with 2×200 mL diethyl ether
15. dry with materialdried over sodium sulfate
16. customConcentration of the extracts in vacuo provided a yellow oil, which
17. customwas purified by flash column chromatography (SiO2, 20% ethyl acetate-hexanes)

ORD-Eintrag

ord-c2c73cc151e649fdb7cd8f603f0b8211

Quelldatensatz

uspto-grants-2004_10

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06809099B2