Aluminium lithium hydride → 4-Benzyl-2-(3-methoxyphenyl)morpholine

Temperature

0 °C

In a 500 mL round-bottomed flask, 4-benzyl-6-(3-methoxyphenyl)morpholin-3-one (2.3 g, 7.74 mmol) was combined with THF (75 ml) to give a light yellow solution. The reaction was cooled to 0° C. LiAlH4 (9.67 ml of 2M solution in THF, 19.3 mmol) was added by dropwise addition. The resulting reaction mixture was allowed to warm to room temperature and then stirred at this temperature overnight. Reaction was complete as determined by LCMS. The crude reaction mixture was cooled to 0° C. and quenched carefully by sequential addition of H2O (0.75 mL), 2M NaOH (1.5 mL) and then H2O (1.5 mL). Additional THF was added during the addition of NaOH because mixture got too thick for stirring. The mixture was stirred for 1 h and filtered through Celite. The filtercake was washed several times with ethyl acetate. The combined filtrate and washes were concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 80 g, 1.5% to 2% MeOH in dichloromethane) to yield 4-benzyl-2-(3-methoxy-phenyl)-morpholine (1.32 g, 60%) as an oil. (M+H)+=284 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.14 (dd, J=11.37, 10.36 Hz, 1H) 2.31 (td, J=11.43, 3.41 Hz, 1H) 2.77 (dd, J=11.37, 1.77 Hz, 1H) 2.94 (dt, J=11.62, 2.02 Hz, 1H) 3.57 (s, 2H) 3.83 (s, 3H) 3.84-3.92 (m, 1H) 3.98-4.09 (m, 1H) 4.58 (dd, J=10.11, 2.27 Hz, 1H) 6.84 (ddd, J=8.21, 2.53, 1.14 Hz, 1H) 6.91-7.00 (m, 2H) 7.21-7.42 (m, 6H).

1. customto give a light yellow solution
2. customThe resulting reaction mixture
3. temperatureto warm to room temperature
4. customReaction
5. customThe crude reaction mixture
6. temperaturewas cooled to 0° C.
7. customquenched carefully by sequential addition of H2O (0.75 mL), 2M NaOH (1.5 mL)
8. additionAdditional THF was added during the addition of NaOH because mixture
9. stirringfor stirring
10. stirringThe mixture was stirred for 1 h
11. filtrationfiltered through Celite
12. washThe filtercake was washed several times with ethyl acetate
13. concentrationThe combined filtrate and washes were concentrated in vacuo
14. customThe residue was purified by flash chromatography (silica gel, 80 g, 1.5% to 2% MeOH in dichloromethane)

ORD record

ord-340dbf3046534d618bd9fc7cb8401b2d

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09353096B2