Utilisation of rearrangement chemistry in the synthesis of novel fluorinated ring systems : a computational and experimental study

Orr, David George Alexander

Thesis

Utilisation of rearrangement chemistry in the synthesis of novel fluorinated ring systems : a computational and experimental study

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Creator

Orr, David George Alexander.

Awarding institution

University of Strathclyde

Date of award

2016

Thesis identifier

T14356

Person Identifier (Local)

201282866

Qualification Level

Doctoral (Postgraduate)

Qualification Name

Doctor of Philosophy (PhD)

Department, School or Faculty

Department of Pure and Applied Chemistry.

Abstract

The rearrangement of vinylcyclopropanes to cyclopentenes (the vinylcyclopropane rearrangement, VCPR) has developed rapidly from its initial discovery and has become an important transformation in the synthesis of a variety of natural products. The beneficial effect of fluorine atom substitution on vinylcyclopropanes has been well documented but the rearrangement has yet to be deployed as an effective method for the synthesis of difluorocyclopentenes.Work towards developing an efficient, building-block approach to difluorocyclopentenes by using the VCPR is presented. Two distinct precursors were selected as synthetic targets; focusing on accessing compounds with either gem-difluoroalkene or gem-difluorocyclopropane motifs. These routes relied on the successful development of novel cross-coupling chemistry and the utilisation of the most effective difluorocyclopropanation techniques.Accessible precursors were subjected to thermal, photochemical and Ni-mediated VCPR conditions showing that difluorocyclopropane substitution underwent more efficient rearrangements than difluorovinyl precursors. Overall, a novel difluorocyclopentene could be accessed in 70% yield over 4 steps using commercial reagents and further functionalised to more complex molecules.The ease of rearrangement was intriguing, and was investigated using a variety of physical organic chemistry tools such as spectroscopy, kinetic studies, density functional theory and reaction simulations. Reaction monitoring of the rearrangements uncovered both competing cyclopropane stereoisomerisation and an alternative [3,3]-sigmatropic rearrangement pathway which ultimately afforded a novel fluorinated benzocycloheptadiene. Furthermore, a dramatic reactivity difference was observed when different alkene isomers were subject to VCPR conditions.Experimental activation energies for the rearrangements could be obtained and used to conduct methodology screening for electronic structure calculations, leading to the development of a computational model which could triage synthetic targets.This work contributes to better understanding of the VCPR and the synthetic limitations of accessing fluorinated precursors. The development of a computational model which can be effectively utilised by non-specialists is an excellent tool for aiding synthetic projects which utilise the VCPR.

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