Development of a Deoxygenative Ring Contraction Reaction for Nitrogen Heterocycle Synthesis

Atkinson, Nick (2023) Development of a Deoxygenative Ring Contraction Reaction for Nitrogen Heterocycle Synthesis. PhD thesis, University of Nottingham.

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Small nitrogen-containing saturated heterocycles are ubiquitous motifs found in a vast number of organic molecules that include natural products, active pharmaceuticals and agrochemicals. Hence, inexpensive, accessible and practical strategies for making these heterocycles is of great interest to the chemical industry. Fortunately, deoxygenative ring contractions provide a novel way of synthesising substituted amines of this type that would otherwise be very hard to obtain by classical synthesis methods. 3,6-Dihydro-2H-1,2-oxazines can be valuable synthesis precursors to highly functionalised heterocycles. Hence, they constitute attractive starting points for the synthesis of unsymmetrical substituted 3-pyrrolines and pyrrolidines that would represent challenging targets using more conventional strategies.

An iridium-catalysed deoxygenative ring contraction of N─O containing heterocycles using phenylsilane as a terminal reductant has been demonstrated. The N─O containing heterocycles were largely obtained from the nitroso Diels-Alder reaction between a nitroso compound and a diene. This deoxygenative ring contraction reaction has been applied to a range of different 1,2-oxazine and 1,2-oxazinane substrates to give the ring contracted heterocycles in 19-76% yield without the rigorous exclusion of air and moisture. Hence, this represents a unique convergent strategy in which these saturated nitrogen heterocycles can be built up rapidly from a sequential cycloaddition/deoxygenative ring contraction process. Investigations towards the total synthesis of the natural product (±)-DMDP have been outlined, in which the deoxygenative ring contraction is used as the key step.

A plausible mechanism has been proposed based on experimental and spectroscopic observations that accounts for the formation of observed intermediates. During these studies a novel alkylation of amines with non-racemic alcohols has been discovered. Preliminary optimisation of this reaction has enabled a chiral tertiary amine product to be obtained in 43% yield and 89% e.e with an inversion of configuration.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Denton, Ross
Keywords: heterocycles, alkylation, amines, organosilicon compounds
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Chemistry
Item ID: 73048
Depositing User: Atkinson, Nicholas
Date Deposited: 26 Jul 2023 04:40
Last Modified: 26 Jul 2023 04:40

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