Reaction Steps
A suspension of O-[1,2-difluoro)phenoxathiin-3yl] N,N-diethylthiocarbamate (200 mg, 0.54 mmol) (Example 16) and H2NNH2.H2O (2.64 mL, 54.4 mmol) in 20 mL absolute EtOH was refluxed for 2 h. After cooling, to room temperature the reaction was diluted with EtOAc (75 mL), washed with 10% aqueous HCl (100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo to 130 mg of crude 1,2-difluoro-3-phenoxathiinol as a yellow-brown solid: TLC (EtOAc/hexane, 40:60) Rf =0.46; 1H-NMR (CDCI3) δ 6.53 (dd. J=6 Hz, J=2 Hz, 1 H, C4 -H), δ 6.97-7.15 (m, 4 H). A mixture of crude 1,2-difluoro-3-phenoxathiinol (110 mg, 0.44 mmol), 2-iodopropane (0.09 ml, 0.87 mmol), Cs2CO3 (0.28 g, 0.87 mmol) and 7 ml anhydrous DMF was stirred under nitrogen at 0° C. for 5 h. The reaction was diluted with Et2O (50 ml) and water (50 ml), the Et2O fraction washed with brine (50 ml), dried (Na2SO4), and concentrated in vacuo to 118 mg of an orange oil. Filtration of the crude product through 10 g of silica gel with 200 ml of EtOAc/hexane (5:95) gave 116 mg (91%) of 1,2-difluoro-3-isopropoxyphenoxathiin as a pale orange oil: TLC (EtOAc/hexane, 20:80) Rf =0.58; 1H-NMR (CDCI3) δ 1.36 (d, J=6 Hz, 6 H), δ 4.50 (m, J=6 Hz H), δ 6.50 (dd, J=Hz, J=2 Hz, 1 H, C4 -H), δ 6.96-7.15 (m, 4 H); 19F-NMR (CDCI3) C1 -F (d, J=21.4 Hz), C2 -F (dd, J=21.4 Hz, J=6 Hz). A solution of 1,2-difluoro-3-isopropoxyphenoxathiin (112 mg, 0.38 mmol) and 30% aqueous H2O2 (0.4 ml, 3.8 mmol) in 3 ml glacial AcOH was heated at 80° C. for 2.5 h. After cooling to room temperature the solution was concentrated in vacuo to a white solid. Refrigeration of the crude product in 4 ml of 1:1 EtOAc/hexane overnight afforded 79 mg (44% from O-[1,2-(difluoro)phenoxathiin-3-yl] N,N-diethylthio-carbamate) of the title compound as yellow crystals: mp 174-175° C. (EtOAc/hexane); 1H-NMR (DMSO-d6) δ 1.33 (d, J=6 Hz, 6 H), δ 4.94 (m, J=6 Hz, 1 H), δ 7.31 (dd, J=6 Hz, J=2 Hz, 1 H, C4 -H), δ 7.30-7.57 (m, 2 H), δ 8.04 (dt, J=7 Hz, J=1 Hz, 1H, C8 -H), δ 8.06 (dd, J=8 Hz, J=1 Hz, 1 H, C9 -H); 19F-NMR (DMSO-d6) C1 -F (dd, J=21.2 Hz, J=6 Hz); MS m/e (relative intensity) 327 (MH+, 100).
