Sodium hydride → 2-(8-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile

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Reaction Conditions

Reaction Steps

To a flask charged with 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (AAT Pharmaceuticals) (0.237 g, 1.547 mmol) was added THF (6.19 ml). The solution was cooled in an ice water bath prior to the addition of sodium hydride (60% in mineral oil) (0.068 g, 1.702 mmol). The resulting suspension was stirred for 30 min at 0° C., the 30 min at rt. The resulting pale yellow suspension was cooled in an ice water bath prior to the addition of 2-fluoro-5-(trifluoromethyl)benzonitrile (0.322 g, 1.702 mmol). The resulting mixture was stirred for 30 min at 0° C., then 1 hr at room temperature. The mixture was heated to 60° C. overnight then at reflux for 2 hr. The mixture was cooled to room temperature and added carefully to ice water and extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, 10% DCM throughout) yielding product, obtained as a yellow oil, 2-(8-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile (0.168 g, 0.521 mmol, 33.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.89-3.97 (m, 2 H) 4.36 (dd, J=4.94, 3.86 Hz, 2 H) 6.61 (dt, J=7.78, 1.79 Hz, 1 H) 6.70-6.80 (m, 2 H) 7.50 (d, J=8.80 Hz, 1 H) 7.71-7.77 (m, 1 H) 7.92-7.95 (m, 1 H). m/z (ESI) 323.1 (M+H)+.

Provenance & Evidence