EXPLORING THE MECHANISM AND ENANTIOSELECTIVITY OF A LATE-STAGE C-H AZIDATION REACTION

Abstract

Organic azides are of significant importance to a variety of fields, including chemical biology, organic synthesis, pharmaceutical discovery, and materials science. Azides are used as versatile intermediates involved in organic transformations, accessing a variety of functionalities, and click chemistry. Due to their versatility, if an azide reaction could be developed via C-H activation, great progress could be made in a variety of fields. As such, a reaction would harness the ubiquity of C-H bonds in organic molecules and the synthetic versatility of azide functionality. It would be even more desirable to construct the resulting C-N\(_{3}\) bond enantioselectively, which would enable later derivation of azide to various chiral molecules. The last decade has witnessed dramatic progress in catalytic C-N bond formation especially via C-H activation. However, methods for constructing C-N\(_{3}\) from C-H bonds have been noticeably lacking. To address these gaps, the Groves laboratory has recently reported a novel C-H azidation reaction at room temperature, applicable to secondary, tertiary, and benzylic C-H bonds. Initial observations showed a moderate value for enantiomeric excess. In light of these advances, my thesis project focuses on developing a highly enantioselective C-H azidation reaction. Computational results suggested that axial ligands and radicals have an effect on reaction pathway. Experiments with a manganese salen catalyst and celestolide substrate, attained an ee value of 70%. The diamine moiety and ortho-substituents of phenoxy rings of catalysts were shown to play an important role in determining the enantioselectivity of the reaction. Additionally, substrate size relative to the bulkiness of the ortho-substituents was shown to have an impact on ee values.