Abstract
N-heterocycles are of vital importance in both organic chemistry and pharmaceutical research, due to their structural diversity and functional versatility. Their unique electronic properties enable them to participate in key chemical reactions, making them essential scaffolds for drug discovery and development. Among them, bicyclic, partially saturated, (hetero)aromatic-fused N-heterocycles, which incorporate polar functionality, enhanced Fsp3 character, and fixed-orientation of group on the aromatic framework that offers important binding interactions with targeted proteins. However, the synthesis of such N-heterocycles is often labour-intensive and engages the heavy use of transition-metal-catalysis.Recent advancement of photocatalysis has facilitated unconventional bond disconnections in organic chemistry, providing new reactivities and allowing reactions to proceed under milder conditions. This thesis explores the use of photoredox catalysis in the synthesis of N-heterocycles such as tetrahydronaphthyridines, indolines, and benzomorpholines, offering transition-metal-free, scalable routes to a diverse library of high-value compounds.
Chapter 1 introduces the foundational theories of photoredox catalysis, photocatalytic hydrogen or halogen atom transfer reactions, contemporary techniques for aryl radical generation, and catalytic aryl amination reactions driven by visible light.
Chapter 2 details the automated synthesis of a series of isomeric tetrahydronapthyridines from unprotected primary amines and halogenated vinylpyridines via a photoredox-catalysed α hydroaminoalkylation and thermal SNAr cyclisation sequence in continuous flow. The developed methodology is applied to a concise synthesis of Pfizer’s Phase I drug candidate (PF-07258669).
Chapter 3 outlines the development of a novel strategy for the synthesis of indolines and benzomorpholines via photocatalytic, intramolecular C–N bond formation of aryl iodides. Mechanistic investigations into the reaction are also discussed.
Date of Award | 26 Mar 2025 |
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Original language | English |
Awarding Institution |
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Supervisor | Alex Cresswell (Supervisor) & Simon Lewis (Supervisor) |
Keywords
- Photoredox Catalysis
- Amine Functionalisation