New methods for the construction of fluorinated cyclic amines and amides

Charlesworth, Natalie (2022) New methods for the construction of fluorinated cyclic amines and amides. PhD thesis, University of Nottingham.

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Abstract

In recent years, photoredox catalysis has emerged as a powerful tool for the synthesis of complex building blocks. Fluorine-containing saturated nitrogen heterocycles are desirable structures in medicinal and biological chemistry, as the incorporation of fluorine can be used to influence key properties of a compound such as conformation, basicity and bioavailability. This thesis explores the utilisation of a photoredox-catalysed cyclisation/hydrogen atom transfer reaction of bromodifluoroethylamines, using a modular, two-step approach.

The first chapter provides an introduction to photoredox catalysis, notable developments in the area and relevant examples from the literature of photoredox-mediated radical cyclisation reactions. Following this, the importance of fluorination in drug discovery is discussed, along with traditional methods for the introduction of the geminal difluoro- group.

The second chapter describes a photoredox radical cyclisation protocol using bromodifluoroethylamines, which are prepared through a three-component coupling. The reaction is applicable to a wide range of alkenyl- and alkynyl amines, and the utility of the products are demonstrated. Mechanistic investigations established the role of the tertiary amine base and the additional hydrogen-atom donor in the reactions. The success of the described approach relies on the strongly electron-withdrawing nature of fluorine, which prevents oxidation of the amine substrates and products under the reaction conditions. This eliminates the need for electron-withdrawing protecting groups on nitrogen and promotes cyclisation.

The third chapter builds on the developed photoredox catalysed cyclisation for the mild and efficient synthesis of γ- and δ-lactams. The protocol is applicable to a range of amide substrates, and a mechanism for the reaction is proposed, supported by computational calculations.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Denton, Ross
Keywords: Fluorinated cyclic amines, Amides
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 67503
Depositing User: Charlesworth, Natalie
Date Deposited: 02 Aug 2022 04:40
Last Modified: 02 Aug 2022 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/67503

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