4-Amino-2-methylpyridine → 6-bromo-N-(2-methylpyridin-4-yl)isoquinolin-3-amine

Participants

Reaction Steps

A dry 40 mL scintillation vial equipped with a screw cap with a teflon insert was cooled under nitrogen, equipped with a stir bar and charged with 2-methylpyridine-4-amine (263 mg, 3.32 mmol) and anhydrous THF (27 mL) and maintained under a N2 atmosphere. LiHMDS was added as a solid (0.925 g, 5.53 mmol). The reaction mixture was stirred at RT under nitrogen for 5 min. To the mixture was added 6-bromo-3-fluoro isoquinoline (500 mg, 2.21 mmol), the vial was flushed with N2, tightly capped and placed in a pre-heated oil bath at 85° C. After 4 h at 85° C., additional 2-methylpyridine-4-amine (96 mg, total: 359 mg, 3.32 mmol) and LiHMDSi (185 mg, total: 1.11 g, 6.64 mmol) were added, and the reaction was heated an additional 2 h at 85° C. The reaction was cooled, and the THF was removed in vacuo. The crude reaction mixture was partitioned between water and DCM containing 10% MeOH. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was absorbed onto Celite® and purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0 to 10% MeOH) to afford 196 mg (28%) of 6-bromo-N-(2-methylpyridin-4-yl)isoquinolin-3-amine (94) as a yellow solid, which was used in the next step without further purification.

Provenance & Evidence