| Various 2-position substituted imidazoles were employed as electron rich dienophiles in inverse electron demand Diels-Alder (IEDDA) chemistry with 1,2,4-triazines, leading to a variety of biologically interesting heterocyclic compounds. Intramolecular [4+2] cycloadditions of trimethylene-tethered imidazole/1,2,4-triazine pairs readily produced 1,2,3,4-tetrahydro-1,5-naphthyridines as a major product, instead of forming the anticipated deazapurines. Microwave-promoted cycloadditions of trimethylene-tethered imidazole/triazine pairs were briefly examined and showed promising results in promoting these cycloadditions. The intramolecular cycloadditions of imidazole/triazine pairs with four-methylene tethers were also successful, though these reactions were more sluggish than those with trimethylene tethers, and only worked under thermal conditions to provide 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines along with small yet reproducible amounts of aromatized deazapurines. Furthermore, all the cycloadditions were sensitive to substituent electronic effects.; Some of the 1,2,3,4-tetrahydro-1,5-naphthyridines were shown to be active against the drug resistant Mycobacterium avium complex, M. tuberculosis, as well as several fungal species. The efficiency and the ease of IEDDA methodology to prepare these naphthyridines together with their promising biological activities led to the use of these heterocycles as scaffolds to develop a diverse chemical library. Several reactions were tested mainly on the N-1 position of the tetrahydronaphthyridines to confirm the suitability of these heterocycles as library structural cores. Indeed, the N-1 position of the tetrahydronaphthyridines proved to be reactive, and a small 24-membered naphthyridine dimer library was successfully developed, setting the stage for a larger library.; In order to expand the scope and the application of this methodology, cycloadditions of imidazoles and isatin-derived 1,2,4-triazines were intended to synthesize the complete core of the grossularines, anticancer natural products with an alpha-carboline subunit. Extensive efforts were put in to this project, however, both inter- and intramolecular cycloadditions of imidazoles and isatin-derived 1,2,4-triazines were unsuccessful. Nevertheless, a novel and facile route to alpha-carbolines and 6H-indolo[2,3-b][1,5]naphthyridines by intramolecular IEDDA reactions between isatin-derived 1,2,4-triazines with alkynes and imidazoles, respectively, was developed. |
