Reaction Steps
To a solution of (3 aS,4S,5R,6S,7aS)-6-(difluoromethyl)-4-fluoro-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (46.5 mg, 0.182 mmol) in EtOH (3 mL) was added azetidine hydrochloride (51.2 mg, 0.547 mmol). The mixture was heated at reflux for 9 h. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 65% EtOAc in hexane and then 10% 1.8 M NH3 MeOH solution in DCM to give (3aS,4S,5R,6S,7aS)-2-(azetidin-1-yl)-6-(difluoromethyl)-4-fluoro-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (37.2 mg, 77%). MS m/z 265.1 (M+1, 100%); 1H NMR (500 MHz, MeOD) δ 6.16 (td, J=56.7 Hz, 1.8 Hz, 1H), 4.63-4.59 (m, 1H), 4.60 (dm, J=52.5 Hz, 1H), 4.03 (t, J=7.6 Hz, 4H), 3.88 (ddd, J=26.3 Hz, 7.1 Hz, 3.8 Hz, 1H), 3.61 (dd, J=29.4 Hz, 10.2 Hz, 1H), 2.45-2.30 (m, 4H), 1.94 (ddd, J=15.8 Hz, 10.8 Hz, 5.2 Hz, 1H); 13C NMR (100 MHz, MeOD) δ 165.68, 118.32 (t, J=238.5 Hz), 92.92 (d, J=179.3 Hz), 79.59, 68.84 (dd, J=18.8 Hz, 8.7 Hz), 64.22 (d, J=17.3 Hz), 51.87, 37.90 (td, J=19.7 Hz, 6.7 Hz), 22.41 (t, J=4.5 Hz), 17.77.
