Molecular Editing of Indoles via Formal N-Atom Insertion and C–S Cross-Coupling in Micellar Solution

Valentine, Gemma (2023) Molecular Editing of Indoles via Formal N-Atom Insertion and C–S Cross-Coupling in Micellar Solution. PhD thesis, University of Nottingham.

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The research reported in this thesis consists of two distinct projects. The latter of which will be introduced in a subsequent abstract following discussion of the preliminary project.

Molecular editing is a growing research area that involves making late-stage point changes to the core of complex molecular architectures in order to alter their chemical properties. When applied to the pharmaceutical or agricultural industries, late-stage diversification can be used to rapidly expand existing compound libraries to explore new chemical space. Heterocycles have a continuingly large presence in the pharmaceutical industry, and chemistry involving heterocycles continues to be an important area of research. The insertion of a heteroatom such as nitrogen into a ring system would alter a range of physiochemical properties such as polar surface area and would result in changes in solubility and reactivity.

A 2-step route from indole to quinazoline is proposed through aziridination across the 2 and 3 positions of the indole. The first step involves the treatment of various protected indoles with a nitrogen source and phenyliodine(III) diacetate as an oxidant to form an aziridine. The deprotection of this aziridine product at the indolic nitrogen would subsequently allow a ring expansion. In this work, 5-fluoroindole was protected with a variety of protecting groups (tosyl, nosyl, acetyl, Boc, 2,4 dinitrophenyl and benzyl) and their aziridination reactions were investigated. Various nitrogen sources were explored in the aziridination step to give alternative leaving groups for the final ring-expansion step. From the range of aziridines synthesised, the ring expansion of Boc-, nosyl- and acetylprotected aziridines were focussed on and a variety of conditions were screened.

Alternative methods for conversion of indole-like structures to quinazolines were also explored. The Beckman rearrangement was first investigated, which involved the formation of an oxime of isatin followed by migration initiated under acidic conditions. Additionally, the photo-catalysed C2-C3 ring-opening of Boc-protected indole was studied, which may form quinazoline structures by addition of an ammonia source.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Ball, Liam T.
Denton, Ross M.
Keywords: molecular editing, natural products, synthesis, heterocycles
Subjects: Q Science > QD Chemistry > QD450 Physical and theoretical chemistry
R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 76631
Depositing User: Valentine, Gemma
Date Deposited: 21 Dec 2023 11:27
Last Modified: 21 Dec 2023 11:27

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