Ammonia → 7-bromo-2-fluoro-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine

Participants

Reaction Conditions

Reaction Steps

A solution of 7-bromo-2-fluoro-5H-chromeno[2,3-b]pyridin-5-one (150 mg, 0.510 mmol) in 5 mL of dry THF at −78° C. was added to methylmagnesium chloride, 3.0 M solution in THF (0.33 mL, 1.020 mmol) (0.33 mL) and the reaction was slowly warmed up to −30 C. At this temperature additional methylmagnesium chloride 3.0 M solution in THF (0.3 mL, 1.020 mmol) was added and stirring was continued for 1 hour. The reaction was quenched at −30° C. with saturated NH4Cl (150 mL) and extracted with EtOAc (3×150 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. The derived residue was treated with 1 mg of PPTS in CH2Cl2 at 25° C. for 0.5 h. This mixture was quenched with 0.1 g of NaHCO3 and the solvent was evaporated to dryness to give crude 7-bromo-2-fluoro-5-methylene-5H-chromeno[2,3-b]pyridine which was directly used in the next step. A solution of iodine (27.6 μL, 0.536 mmol) in THF at −25° C. was treated with silver cyanate (76 μL, 2.040 mmol). After 30 min, a solution of the above derived olefin (7-bromo-2-fluoro-5-methylene-5H-chromeno[2,3-b]pyridine) in 20 mL of THF was added dropwise. The slurry was maintained at −25° C. for 2 h at which point the slurry was filtered through celite, washing well with ether. The brown filtrate was concentrated to dryness, taken up in THF (10 mL), cooled to 0° C. and treated with ammonia (2 M solution in 2-propanol, 1.1 mL, 2.040 mmol). The reaction was allowed to slowly warm to rt and stirred overnight. Half of the solvent was evaporated in vacuo and the residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification by silica gel chromatography (CH2Cl2 to CH2Cl2/EA=3:1 to 2:1 to 1:1 to 1:2) afforded 7-bromo-2-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.

Provenance & Evidence