Dimethylformamide → 5-((4-Methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile

Participants

Reaction Steps

An oil bath was preheated to 180° C. A mixture of 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine (19.45 g, 61.55 mmol), Zn(CN)2 (8.7 g, 73.86 mmol), and dppf (6.8 g, 12.31 mmol) in DMF (250 mL) was stirred at room temperature while bubbling nitrogen for 5 min. Pd2(dba)3 (2.8 g, 3.07 mmol, 0.05 eq.) was then added and the reaction mixture was placed inside the pre-heated bath. The bath temperature dropped to 160° C. The mixture started refluxing when the bath temperature reached 170° C. (takes 20 min). Refluxed for 10 min. The reaction mixture was cooled to room temperature and it was filtered through a pad of celite. The pad of celite was washed with EtOAc. The solvent was removed using a rotovap hooked up to a high vac. pump. The black residue was partitioned between EtOAc and water. An orange solid (some dppf by-product) precipitated and was filtered and washed with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, and concentrated to dryness. The black residue was dissolved in DCM and loaded onto a silica gel plug. The plug was washed with DCM (to get rid of some of the fast eluting impurities) followed by 1:1 EtOAc/hexanes (to move the desired). The fractions containing the desired were combined, evaporated to dryness and the residue obtained was purified by column chromatography on silica gel eluting with 0 to 50% EtOAc/hexanes to afford 15 g of 5((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile as reddish thick oily residue. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (t, 1H), 7.31 (m, 3H), 6.92 (d, 2H), 4.41 (d, 2H), 3.73 (s, 3H).

Provenance & Evidence