Hydrochloric Acid → 3-Chloro-4-methyl-1,8-naphthyridine

Participants

Reaction Conditions

Reaction Steps

N-(5-chloro-4-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (18.3 g, 0.081 mol) from Step 2 was placed in a flame-dried three-neck 1 L flask fitted with an overhead stirrer, under nitrogen. To this solid was added anhydrous diethyl ether (170 mL) and the mixture stirred until a solution, whereupon it was cooled in a dry ice/acetone bath for 20 min (slurry formed). To the resulting slurry was dropped in tert-butyl lithium (1.7 M in pentane, 100 mL) via cannula over an 8 min period. The flask was removed from the cooling bath and allowed to stir until it reached RT, at which time 3-dimethylamino-propenal (10 mL, 0.10 mol) was added neat. The resulting mixture was stirred overnight at RT under a nitrogen stream; by morning a dry powder resulted. To this was added water (80 mL) followed by slow addition of conc. HCl (40 mL) while cooling the flask in an ice/water bath. After the acid addition, the ice bath was removed and the flask was heated to 80° C. for 1 h, cooled in an ice/water bath and treated with NaOH (solid pellets) until basic. The basic aqueous mixture was subsequently extracted with DCM (4×100 mL)—patience and brine were required to help break the resulting emulsions. The combined extracts were dried over Na2SO4 and concentrated under vacuum to yield crude product, which was further purified by SGC (EtOAc eluant) to yield pure 3-chloro-4-methyl-[1,8]naphthyridine (10 g, 0.056 mol). Note: owing to weak UV activity, it was found more efficacious to monitor column fractions with MS rather than UV. MS (ESI+) for m/z 179 (M+H)+. 1H NMR (CDCl3) δ 9.06 (m, 1 H), 8.96 (s, 1 H), 8.34 (d, 1 H), 7.51 (m, 1H), 2.72 (s, 3H).

Provenance & Evidence