Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Ellman, Jonathan
Abstract
Nitrogen heterocycles are present in almost two-thirds of U.S. FDA approved pharmaceuticals. For this reason, methods for the rapid synthesis of nitrogen heterocycles are highly valued. The first two chapters of this dissertation will discuss the development of Cp*Rh(III)-catalyzed imidoyl C–H activation methods to rapidly access two different pharmaceutically relevant classes of fused bicyclic nitrogen heterocycles. The third chapter describes the Cp*Rh(III)-catalyzed, imine directed N–H functionalization/annulation for the synthesis of piperazinones, a nonaromatic, monocyclic nitrogen heterocycle that has become one of the most extensively used in drug discovery and development.Chapter 1 describes a three-component reaction for the rapid assembly of pyrido[1,2-a]pyrimidin-4-ones from readily available aldehydes, 2-aminopyridines, and diazo esters. This method proceeds by Cp*Rh(III)-catalyzed imidoyl C–H activation of an imine formed in situ to provide a [6,6]-bicyclic heterocycle. The method was optimized for setup without the use of an inert atmosphere and with the use of a microwave reactor to allow for fast reaction times. A wide variety of functional groups were found to be compatible with the reaction conditions, including acidic and basic functionality. Chapter 2 describes a method for coupling hydrazones, derived from N-amino-pyrroles or N-aminoazoles and aldehydes, with alkynes to access pyrrolo- and azolopyridazines. This transformation represents a rare example of hydrazoyl C–H activation. Additionally, the C–H activation occurs without the use of a heteroatom directing group. To access a tricyclic ring system, hydrazones with tethered alkynes were synthesized and subjected to the reaction conditions. Studies were performed, including the isolation and NMR characterization of a catalytically competent rhodacycle, to further understand the reaction mechanism. Chapter 3 describes a three-component reaction for the rapid assembly of piperazinones from readily available α-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. In addition to demonstrating the first instance of transition metal-catalyzed multicomponent N–H functionalization, this method represents the first instance of imine directed N–H functionalization. Further studies were performed, including X-ray crystallographic characterization of a catalytically competent five-membered rhodacycle with imine and amide nitrogen chelation, to understand the reaction mechanism. Future directions include a highly diastereoselective synthesis of diketopiperazines and a multicomponent synthesis of densely substituted morpholines.
Recommended Citation
Zoll, Adam Jacob, "Cp*Rh(III)-Catalyzed Syntheses of Nitrogen Heterocycles from Imines" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1149.
https://elischolar.library.yale.edu/gsas_dissertations/1149
