A New Synthetic Approach to Substituted Hydroquinoline-8-carboxylic Acids and 1,3-Oxazino[5,4,3-ij]quinolines

This is the authors' abstract. We don't add key points for this paper.

Tricyclic systems derived from partially hydrogenated quinolines exhibit a broad spectrum of physiological activity. Biologically active compounds have also been identified among 1,3-oxazine derivatives. In particular, 1,3-oxazino[5,4,3-ij]quinolines exhibit antibacterial activity. This prompted us to construct novel tricyclic structures in which a 1,3-oxazine moiety is annulated to the hydroquinoline core at the i- and j-positions, expecting that such systems would exhibit broad-spectrum practical potential. To develop an efficient and a simple synthetic approach to 1,3-oxazino[5,4,3-ij]quinoline-1-ones, we performed an alternative synthesis of hydroquinoline-8-carboxylic acids and investigated their reaction with formaldehyde under various conditions. Substituted hydroquinoline-8-carboxylic acids, including previously undescribed ones, were prepared by alkaline hydrolysis of the corresponding 1,3-oxazino[5,4,3-ij]quinoline-1,3-diones. It was found that the reactions with formalin in boiling methanol in the when the quinolinecarboxylic acid contained a substituent on the aromatic ring. Under these conditions, substituted 1,3-oxazino[5,4,3-ij]quinolin-1-ones were obtained in yields of 60–76%. When paraformaldehyde was used as the cyclizing agent in the presence of zinc chloride, the reaction selectively proceeded selectively in methylene chloride at room temperature and was complete within 4 h. Neither presence nor the nature of substituents in the starting carboxylic acids significantly affected the reaction outcome; all target oxazinoquinolines were formed in high yields of 68–87%. These findings allowed us to develop a simple and an efficient two-stage protocol for the synthesis of substituted 1,3-oxazino[5,4,3-ij]quinoline-1-ones involving alkaline hydrolysis of 1,3-oxazino[5,4,3-ij]quinoline-1,3-diones to form hydroquinoline-8-carboxylic acids, followed by their acid-catalyzed cyclocondensation with formaldehyde or paraformaldehyde.