Sodium hydride → HCID 89762096, compound

Participants

Reaction Conditions

Reaction Steps

To a flask charged with 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Combi-Blocks) (0.321 g, 2.096 mmol) was added THF (8.38 ml). The solution was cooled in an ice water bath prior to the addition of sodium hydride (60% in mineral oil) (0.092 g, 2.306 mmol). The resulting suspension was stirred for 30 mins at 0° C., the 30 mins at room temp. The resulting pale yellow suspension was cooled in an ice water bath prior to the addition of 2-fluoro-5-(trifluoromethyl)benzonitrile (Matrix Scientific) (0.436 g, 2.306 mmol). The mixture was stirred for 5 mins at 0° C., the 1 hr at room temperature when LC-MS indicated all starting material present. The tannish suspension was heated to reflux overnight providing a brown solution with about 80% conversion to product according to LC-MS. The mixture was cooled to room temperature and carefully added to ice water which was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered and dried under reduced pressure. The crude residue was purified with a 25 g column (25 m spherical silica gel, Interchim) ramping EtOAc in heptane (0-35%, with 10% DCM throughout) providing product which had partially coeluted with starting amine. The material obtained was filtered through a 5 g SCX-2 column washing with MeOH. The MeOH wash contained product, obtained as an off-white solid 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.450 g, 1.396 mmol, 66.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-3.97 (m, 2 H) 4.22 (br. s., 2 H) 6.68 (ddd, J=10.86, 8.22, 1.37 Hz, 1 H) 6.82 (dt, J=8.41, 1.37 Hz, 1 H) 7.00 (td, J=8.31, 5.97 Hz, 1 H) 7.14 (dd, J=8.71, 2.25 Hz, 1 H) 7.67 (ddd, J=8.73, 2.23, 0.59 Hz, 1 H) 7.90 (dd, J=1.57, 0.59 Hz, 1 H). m/z (ESI) 323.3 (M+H)+.

Provenance & Evidence