Catalyst-free aza-Michael addition of azoles to 3-hydroxypyridine-based quinone methides

We have studied the reaction of various 1H-azoles with 2-((dimethylamino)methyl)pyridin-3-ol and 2-bromo-6-(hydroxymethyl)pyridin-3-ol as precursors of ortho- and para-quinone methides of 3-hydroxypyridine series, correspondingly. This process proved to be convenient and efficient for the synthesis of hybrid heterocycles containing both pyridine and azole moiety - 2-and 6-[(azolyl)methyl] pyridin-3-ols. The protocol has been successfully extended to 2,6-bis-(hydroxymethyl)pyridine-3-ol, which is simultaneously ortho- and para-quinone methide precursor, involving both functionalities. Finally, two new heterocyclic systems 9H-pyrazolo[5,1-b]pyrido[2,3-e][1,3]oxazine and 12H-benzo[4,5] imidazo[2,1-b]pyrido[2,3-e][1,3]oxazine were obtained as a result of cascade aza-Michael/intramolecular nucleophilic substitution reactions from 2-((dimethylamino)methyl)pyridin-3-ol and 2-(methylthio) benzimidazole or 3,4,5-tribromopyrazole, correspondingly.

Automated summary

We investigated the reaction of 1H-azoles with precursors of ortho- and para-quinone methides of 3-hydroxypyridine series. The synthesis of hybrid heterocycles containing both pyridine and azole moieties was convenient and efficient. Two new heterocyclic systems were obtained through cascade aza-Michael/intramolecular nucleophilic substitution reactions.