A facile and novel synthesis of 1,6‐naphthyridin‐2(1H)‐ones

A new and convenient procedure for the synthesis of 1,6‐naphthyridin‐2(1H)‐ones and their derivatives is described. In the first scheme 5‐acetyl‐6‐[2‐(dimethylamino)ethenyl]‐1,2‐dihydro‐2‐oxo‐3‐pyridinecarbonitrile (4) obtained by the reaction of N,N‐dimethylformamide dimethyl acetal with 5‐acetyl‐1,2‐dihydro‐6‐methyl‐2‐oxo‐3‐pyridinecarbonitrile (3) was cyclized to 1,2‐dihydro‐5‐methyl‐2‐oxo‐1,6‐naphthyridine‐3‐carbonitrile (5) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5‐methyl‐1,6‐naphthyridin‐2(1H)‐one (8) and its dimer 9. Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3‐amino‐5‐methyl‐1,6‐naphthyridin‐2(1H)‐one (12) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3‐hydroxy‐5‐methyl‐1,6‐naphthyridin‐2(1H)‐one (13). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5‐acyl(aroyl)‐6‐methyl‐2(1H)‐pyridinones (21) which in turn were treated with Bredereck's reagent to produce 5‐acyl(aroyl)‐6‐[2‐(dimethylamino)ethenyl]‐2(1H)‐pyridinones (22). Treatment of 22 with ammonium acetate led to the formation of 1,6‐naphthyridin‐2(1H)‐ones 23.