| New applications of inverse electron demand Diels-Alder chemistry to the synthesis of heterocyclic core structures have been explored. To this end imidazoles substituted at the 2-position were employed as dienophiles in these cycloadditions with 1,2,4-triazines, culminating in the preparation of a variety of biologically interesting heterocyclic compounds. Intermolecular cycloadditions of 2-substituted imidazoles with triethyl 1,2,4-triazine-3,5,6-tricarboxylate produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimidines (8-deazapteridines), the ratio of which was proven to be highly dependent on the reaction conditions and imidazole substituent. In order to expand the scope of this methodology, cycloadditions with other 1,2,4-triazines were examined. A novel method for the preparation of 5,6-unsymmetric 1,2,4-triazine-3-carboxylates was also devised, through which the highly sought-after diethyl 1,2,4-triazine-3,5-dicarboxylate was synthesized for the first time. Employing this triazine, a remarkable dependence on the triazine C-6 substituent in the outcome of the Diels-Alder reaction with imidazoles was uncovered: imidazo[4,5-c]pyridines were produced exclusively. With the knowledge of substrate requirements necessary for the production of 8-deazapteridine cycloaddition products, a novel analog of 8-deazafolic acid was prepared. As analogs of folic acid have long been known to possess clinically useful levels of inhibition of dihydrofolate reductase and thymidylate synthase, enzymes often targeted in cancer chemotherapy, this synthesis demonstrated that the Diels-Alder approach to the 8-deazapteridine skeleton can provide rapid access to an important building block for such substrates.; The analogous intramolecular inverse electron demand Diels-Alder reactions of imidazoles with 1,2,4-triazines were also studied. Employing the aforementioned method of 1,2,4-triazine synthesis, a C-3 imidazole-tethered triazine bearing a single ester group was prepared and the intramolecular [4+2] cycloaddition provided the 1,2,3,4-tetrahydro-1,5-naphthyridine skeleton to be used as the scaffold for chemical library development. In order to examine the analogous Diels-Alder reactions of imidazoles tethered to triazine C-6 position, a novel synthetic route to such substrates was developed. |
