Development of Three Reaction Methodologies En Route to Nitrogen Containing Heterocycles: a Diels-Alder/Schmidt, a DIels-Alder/Acylation and a Catalytic Intramolecular Schmidt

Abstract

This thesis describes three new advances in the synthesis of nitrogen containing heterocycles. The first two chapters discuss the development of two different domino reaction sequences: a Diels-Alder/Schmidt and a Diels-Alder/acylation sequence. The third chapter then explores the development of a first-generation catalytic Schmidt reaction. The domino Diels-Alder/Schmidt reaction exploits two modes of reactivity. The first method reacted the azide and ketone groups on separate molecules, since it had been established in previous work that intermolecular Schmidt reactions only occur under special circumstances. An initial Diels¬-Alder reaction followed by a subsequent intramolecular Schmidt reaction was observed. This mode of reactivity was used to synthesize several interesting alkaloid-like skeleta. The second method was to deactivate the ketone for intramolecular azide attack by converting it into an enone. The Schmidt reaction did not occur until the enone had participated in a Diels-Alder reaction, thus providing control of this domino reaction. The enone deactivation method was used to form trans-hexahydroindoles and homopyrrolo[2.1-j]quinolin-5-ones. Also described herein is the development of a one-pot domino Diels-Alder/acylation strategy to form octahydroisoquinolinone scaffolds. The reaction exploits the reactivity of maleic anhydride toward variously substituted amino dienes providing exclusively the endo product. This work resulted in a scalable synthetic sequence tolerant of a wide range of substitution. The products also contain olefin and carboxylic acid groups suitable for further functionalization. Finally, studies towards the development of a catalytic, intramolecular Schmidt reaction of ketones and azides are described. Building on an initial positive result employing 50 mol% Sc(OTf)3 in water, conditions were explored for promoting this reaction sequence. Reaction surveys exploring solvents, Lewis and protic acids, and reaction conditions were completed. These studies led to the identification of conditions using a phase transfer catalyst (n-Bu4NOH or n-Bu4NCl) and microwave irradiation that accelerate the reaction with a broader range of substrates.