Development of Copper-catalyzed Processes towards the Synthesis of Tetrahydroquinolines, Benzoxazinones and Fused Triazoles

The Lautens group has a long-standing interest in the application of transition metal catalyzed reactions in developing strategies towards synthesizing biologically relevant heterocycles. This thesis focuses on the development of various copper-catalyzed transformations that enable the efficient syntheses of tetrahydroquinoline, benzoxazinone, and fused trisubstitued triazole heterocycles. Chapter 1 describes a process to synthesize borylated tetrahydroquinoline scaffolds using a copper-catalyzed borylation of Michael acceptors in tandem with a Mannich-type cyclization. The use of Michael acceptors as π-systems in copper-catalyzed borylation reactions is well known, however their application to generate heterocycles in domino processes remains largely underdeveloped. This strategy is feasible with a broad range of Michael acceptors, and can be leveraged to generate versatile borylated tetrahydroquinoline scaffolds bearing three contiguous stereocenters in a diastereo- and enantioselective fashion. Chapter 2 details the development of a multi-step strategy enabling the synthesis of benzoxazinone scaffolds. The developed method relies on an initial selective copper-catalyzed borylation across an α,β-unsaturated ester or amide, subsequent C−B bond oxidation to generate the reactive alcohol intermediate, and a cyclization to generate the desired heterocyclic product. The application of chiral ligands in this strategy was also demonstrated, generating the benzoxazinone moiety in an enantioselective fashion. Chapter 3 focuses on the utilization of the copper-catalyzed azide alkyne cycloaddition reaction in the synthesis of trisubstituted 1,2,3-triazoles. The mechanism of the copper-catalyzed azide alkyne cycloaddition involves the generation for a nucleophilic copper-triazolide intermediate. Typically, this intermediate undergoes protodemetallation to generate 1,4-disubstituted 1,2,3-triazole compounds. However, the tethering of carbamoyl chloride functional group enables an intramolecular cyclization generating novel, fully-substituted, fused 5-acyl 1,2,3-triazoles.Ph.D