Intramolecular azide-alkyne [3 + 2] cycloaddition: versatile route to new heterocyclic structural scaffolds

Abstract

Investigating the relatively unexplored intramolecular version of the azide-alkyne [3 + 2] cycloaddition, the present studies demonstrate the utility of the above reaction in the synthesis of a variety of as yet unreported heterocyclic structural scaffolds. The approach involved initial installation of strategic azide and alkyne moieties on a common structural framework, followed by their intramolecular cycloaddition studies. The pivotal azidoalkyne intermediates were efficiently accessed from a variety of easily available starting materials such as olefins, epoxides, amino acids, amino alcohols, ketones etc. The key reactions for incorporation of the azide functionality into the desired framework involved azidolysis of epoxides, displacement of hydroxy groups with azide nucleophiles, and diazo transfer on amine. Attachment of the desired alkyne functionalities was accomplished by either N-, or, O-alkylation with appropriate propargylic halides. The azidoalkynes thus prepared underwent smooth intramolecular cycloaddition, resulting in a variety of novel triazolooxazine and triazolopyrazine derivatives. Interestingly, unlike in the intermolecular version, metal catalysis was not necessary for the performance of the above cycloadditions. It is expected that the results from the present studies and its further extension will provide a potentially fertile pathway to a variety of unique chemical entities of structural and biological significance.