Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Ellman, Jonathan

Abstract

Nitrogen heterocycles are privileged scaffolds found in 82% of FDA approved pharmaceuticals approved from 2013 – 2023. Thus, modular and efficient methods to synthesize these motifs are valuable for drug discovery and development. Chapters 1 and 2 will discuss the use of Cp*Rh(III)-catalyzed N–H functionalization to synthesize two types of non-aromatic nitrogen heterocycles. Chapter 3 discusses ongoing work for a Cu(I)-catalyzed three-component synthesis of piperazines. Chapter 1 describes a three-component synthesis of piperazinones from readily available amino amides, aldehydes, and diazo compounds. This method proceeds by a new mode of reactivity: imine directed Cp*Rh(III)-catalyzed N–H functionalization/annulation. This method represents the first instance of multi-component transition-metal catalyzed N–H functionalization as well as the first instance of imine-directed N–H functionalization. Mechanistic studies, including the isolation and characterization of a catalytically competent five-membered rhodacycle showing chelation to the imine and amide nitrogens, provide support for the proposed mechanism. Chapter 2 describes a synthetic sequence to produce a diverse set of diketopiperazines and a related scaffold. The first step uses Cp*Rh(III)-catalyzed amine directed N–H functionalization/annulation of amino amides with the appropriate diazo compound to give diketopiperazines substituted with a phosphonate group. These compounds were further elaborated by coupling with readily available carbonyl compounds to give a diverse set of monodehydro-diketopiperazines. Face-selective hydrogenation of monodehydro-diketopiperazines to give enantioenriched diketopiperazines was also demonstrated. Chapter 3 describes current work on a Cu(I)-catalyzed synthesis of piperazines from the three-component coupling of diamines, aldehydes, and diazo compounds. Initial optimization of a two-step, one-pot protocol is described. A preliminary scope is presented. Future work in optimization, substrate scope, and product diversification is discussed.

Download

Share

COinS