Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.769245
Title: Functionalisation of saturated heterocycles at unactivated positions by palladium-catalysed directed C(sp3)-H arylation
Author: Affron, Dominic Paul
ISNI:       0000 0004 7656 884X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Abstract:
Saturated heterocycles are vital components of many biologically active compounds that are central to life, and offer great potential as pharmaceuticals for complex targets. Therefore, synthetic methods to efficiently synthesise a range of saturated heterocycles are highly desirable. In this thesis, palladium-catalysed directed C(sp3)-H arylation methodology to functionalise unactivated positions of heteroaliphatic rings is explored for the first time. Initially, the synthesis of a range of novel 2,3-difunctionalised pyrrolidines is described. These pyrrolidines are synthesised as single stereoisomers via directed C−H functionalisation at the unactivated 3-position of proline derivatives, representing the first direct functionalisations of unactivated C-H bonds on the pyrrolidine ring. A variety of functionalised and heterocyclic iodoarenes are employed with minimal excess, and the resulting 3-(hetero)arylproline derivatives are transformed in to compounds that comply with desirable criteria for drug discovery. Subsequently, this C-H arylation approach is applied to the synthesis of 3-aryl tetrahydrofuran, tetrahydropyran and piperidine derivatives, where subtle differences in substrate structures were found to alter reactivity significantly. High yields were obtained for each substrate, through the development of a condensed optimisation procedure that employs a limited set of reaction variables designed to cover appropriate reaction space. Reactivity and selectivity is compared across these substrates, and a comparison of the success of different directing groups was undertaken on the THP substrate, which was the only substrate to form trans-configured products as minor components. This condensed optimisation approach was also demonstrated on carbocyclic and acyclic derivatives to demonstrate the flexibility and applicability of this process, enabling direct comparison with literature results. Stereoselective removal of the directing group was also demonstrated on both nitrogen and oxygen heterocycles. Preliminary studies into reaction kinetics and the viability of directing groups at the 3-position of saturated heterocycles are described. The final section provides full experimental details.
Supervisor: Bull, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.769245  DOI:
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