Sodium hydride → (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one

Participants

Reaction Steps

To a stirred suspension of sodium hydride (60% in oil; 105 mg, 2.53 mmol) in THF (10 mL) at 0° C. under an atmosphere of N2 was added a solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 20; 68 mg, 0.21 mmol) in THF (2 mL) dropwise. The resultant mixture was stirred at 0° C. for 20 min prior to the addition of 3-bromo-2-bromomethyl-6-chloropyridine (59 mg, 0.21 mmol) as a solution in THF (1 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with H2O and was partitioned between H2O (25 mL) and EtOAC (35 mL). The aqueous layer was re-extracted with EtOAc (3×35 mL) and the combined extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazinan-2-one as a clear oil. LCMS=625.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.94-7.90 (brs, 2H), 7.83 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 5.64 (m, 1H), 5.36 (d, J=17.6 Hz, 1H), 4.46 (d, J=17.6 Hz, 1H), 3.84 (m, 1H), 2.44 (m, 1H), 2.14 (m, 1H), 1.34 (d, J=6.2 Hz, 3H).

Provenance & Evidence