8-bromo-2-chloro-4-fluoro-10H-chromeno[3,2-b]pyridin-10-one → 8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine

Participants

Reaction Conditions

Reaction Steps

To a solution of 8-bromo-2-chloro-4-fluoro-10H-chromeno[3,2-b]pyridin-10-one (44 mg, 0.134 mmol) in 10 mL of dry THF was added dropwise methylmagnesium chloride (3M in THF, 0.12 mL, 0.335 mmol) in at −78° C. The reaction was slowly warmed up to 0° C. over 2 hours. The reaction was quenched at 0° C. with saturated NH4Cl (20 mL) and extracted with EtOAc (2×10 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. The derived tertiary alcohol was taken up in 10 mL of CH2Cl2 treated with 1 mg of PPTS. After stirring for 30 minutes the mixture was cooled to 0° C. and 0.1 g of NaHCO3 was added. The solvent was evaporated to dryness to give crude 8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine which was directly used in the next step. A solution of iodine (7.24 μL, 0.141 mmol) in THF at −25° C. was treated with silver cyanate (20.07 μL, 0.536 mmol). After stirring for 30 minutes, a solution of the derived olefin (8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine) in THF (10 mL) was added dropwise. The slurry was maintained at −25° C. for 2 h at which point the slurry was filtered through celite. The brown solution was concentrated to dryness, taken up in 10 mL THF, cooled to 0° C. and treated with ammonia (2M in 2-propanol (0.3 mL, 0.536 mmol). The reaction was allowed to slowly warm to rt and stirred overnight. The solvent was evaporated and the residue was purified by flash column (CH2Cl2 to CH2Cl2/EA=2:1 to 1:1 to CH2Cl2/MeOH=100:5) to give 8-bromo-2-chloro-4-fluoro-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine as an off white solid.

Provenance & Evidence