5-FLUORO-3-METHYL-PYRIDIN-2-YLAMINE

38186-84-4

886365-56-6

To a solution of 2-chloro-3-methyl-5-fluoropyridine (0.50 g, 2.82 mmol) in anhydrous toluene (12.5 mL) was added sequentially sodium tert-butoxide (0.462 g, 4.81 mmol), tris(dibenzylideneacetone)dipalladium (0.315 g, 0.344 mmol), 2,2'-bis(diphenylphosphinato)-1,1'-binaphthyl ( BINAP, 0.642 g, 1.031 mmol) and benzophenoneimine (0.692 mL, 4.12 mmol). The reaction mixture was degassed (three evacuation/nitrogen filling cycles) and subsequently heated to 80 °C and stirred for 1 hour. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with ether (400 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (34 mL) and 2 M aqueous hydrochloric acid (1.408 mL, 2.82 mmol) was added. After stirring for 1.5 h at room temperature, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate and diluted with dichloromethane (200 mL). The aqueous phase was back-extracted with dichloromethane (2 x 50 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (Biotage SP4 12M, cyclohexane/ethyl acetate 60/40). The target fraction was collected to give 2-amino-3-methyl-5-fluoropyridine (0.20 g, 1.554 mmol, 55.2% overall yield in two steps) as an orange solid. Mass spectrum (electrospray positive ion mode) m/z: 127 ([M+H]+). Elemental analysis calculated value (C6H7FN2): 126.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.73 (d, 1H), 7.23 (dd, 1H), 5.60 (broad peak, 2H), 2.04 (s, 3H).