Single-Carbon Atom Insertion into Aromatic Heterocycles

Joynson, Ben (2023) Single-Carbon Atom Insertion into Aromatic Heterocycles. PhD thesis, University of Nottingham.

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The desire for highly selective and general methods for the functionalisation of complex molecules is particularly prevalent in the field of drug discovery, as the facile modification of pre-existing entities can lead to the rapid diversification of existing drug libraries. In turn, this could lead to the more efficient identification of potential drug candidates. Building upon the general theme of skeletal editing, this thesis details the development of methodologies to transform heteroaromatic scaffolds – namely indoles and pyrroles - by the insertion of a single carbon atom.

The work described in Chapter 2 outlines the development of a methodology to achieve the ring expansion of indoles via a cyclopropanation/fragmentation strategy to the corresponding quinoline with the use of zinc carbenoids. While the desired transformation was achieved in modest yields, the highly reactive nature of the carbenoid intermediate led to poor compatibility with unprotected indoles, while protected indoles proved inert in most cases.

Chapter 3 details the development and application of a robust protocol to achieve carbon atom insertion by a similar strategy, employing arylchlorodiazirines as photo-activated carbene precursors. Protection of the indole nitrogen proved key to high conversion and – along with the tuning of the reaction solvent – allowed for precipitation of the azinium salt product and facile isolation by filtration. An extensive substrate scope revealed tolerance of a range of functional groups, both on the azole and diazirinyl partners. The exploration of substrate scope was assisted by a robustness screen of a number of medicinally-relevant functional groups, revealing the potential application to complex molecules. Consequently, the methodology was applied to the modification of tryptophan and tryptophan-containing peptides. Functionalisation of the azinium salt products was also explored, focusing in particular on reduction chemistry to give access to a range of three-dimensional architectures.

A hazard assessment of arylchlorodiazirines was also carried out as literature reports have often noted their thermal instability though extensive analysis has not yet been undertaken. The explosive nature of arylchlorodiazirines was analysed by the use of differential scanning calorimetry (DSC). From this data, along with predictors derived from it, the thermal stability of these diazirines was assessed and measures to avoid potential hazards were proposed and discussed.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Ball, Liam
Keywords: Skeletal Editing, Diazirines, Carbenes, Heterocycles, Heterocyclic chemistry
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 74157
Depositing User: Joynson, Benjamin
Date Deposited: 12 Dec 2023 04:40
Last Modified: 12 Dec 2023 04:40

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