Abstract
Primary amines are widely used in organic synthesis, but their reactivity is typically governed by the nucleophilicity of the nitrogen lone pair. This bias favours C−N bond formation, particularly in reactions with electrophilic heteroarenes, such as those proceeding via nucleophilic aromatic substitution (SNAr) reactions. As a result, direct C−C bond formation at the α-position remains challenging without prior N-protection. Recent work from the Cresswell lab has shown that α-amino radicals, generated from unprotected amines under visible-light photoredox catalysis, can react with electrophilic partners to form new C−C bonds.This thesis applies that strategy to the functionalisation of heteroaromatics, focusing on α-aminoalkylation strategies of two pharmaceutically relevant classes: indoles and 1,3-azoles. These scaffolds present distinct challenges due to their varied reactivity with nucleophilic α-amino radicals.
Chapter 1 surveys the reactivity of indoles and 1,3-azoles, with a focus on C(2) functionalisation via radical-mediated C–H activation, including both aromatic substitution and dearomatisation. Relevant examples of α-aminoalkylation are discussed within this context.
Chapter 2 details a radical SNAr reaction between primary amines and azolyl chlorides. By employing continuous flow photochemistry, otherwise inaccessible C-selective heteroarylations are achieved using azolyl chlorides that typically undergo exclusive N-arylation under batch conditions.
Chapter 3 describes the photocatalytic synthesis of spirocyclic tetrahydropyrrolo[3,4-b]indolines, as a new class of pseudo natural products, via the direct addition of primary or secondary amines to C(3)-ester-substituted indoles, affording complex scaffolds in a single step.
| Date of Award | 12 Nov 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Alex Cresswell (Supervisor) & Frank Marken (Supervisor) |