Aluminium lithium hydride → 2-[6-(Trifluoromethyl)pyridin-3-yl]morpholine

Temperature

0 °C

In a 500 mL round-bottomed flask, 6-(6-(trifluoromethyl)pyridin-3-yl)morpholin-3-one (0.65 g, 2.64 mmol) was combined with THF (35 ml) to give a light yellow solution. The reaction mixture was cooled to 0° C. LiAlH4 (3.3 ml of a 2M solution in THF, 6.6 mmol) was added by dropwise addition. The reaction mixture was allowed to warm to room temperature and then stirred for 12 h. The reaction mixture was cooled to 0° C. and quenched carefully by sequential addition of H2O (0.27 mL), 2M NaOH (0.54 mL) and then H2O (0.54 mL). The mixture was stirred for 10 min., filtered through Celite and the Celite washed 1 time with THF and several times with ethyl acetate. The combined filtrate and washes were concentrated. The crude residue was purified by flash chromatography (silica gel, 40 g, 0.5% to 5% MeOH in dichloromethane) to afford 2-(6-(trifluoromethyl)pyridin-3-yl)morpholine (272 mg) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.92 (br. s., 1H) 2.76 (dd, J=12.38, 10.36 Hz, 1H) 2.88-3.07 (m, 2H) 3.13 (dd, J=12.25, 2.65 Hz, 1H) 3.81 (td, J=11.37, 2.78 Hz, 1H) 4.01-4.15 (m, 1H) 4.63 (dd, J=10.36, 2.53 Hz, 1H) 7.69 (d, J=8.08 Hz, 1H) 7.84-7.96 (m, 1H) 8.63-8.77 (m, 1H).

1. customto give a light yellow solution
2. temperatureto warm to room temperature
3. temperatureThe reaction mixture was cooled to 0° C.
4. customquenched carefully by sequential addition of H2O (0.27 mL), 2M NaOH (0.54 mL)
5. stirringThe mixture was stirred for 10 min.
6. filtrationfiltered through Celite
7. washthe Celite washed 1 time with THF and several times with ethyl acetate
8. concentrationThe combined filtrate and washes were concentrated
9. customThe crude residue was purified by flash chromatography (silica gel, 40 g, 0.5% to 5% MeOH in dichloromethane)

ORD record

ord-2b68b910445f4ca89f5bc90bfa50de89

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09353096B2