Aromatic metamorphosis: the intramolecular Diels-Alder reaction
File(s)
Author(s)
Shute, Jonathan
Type
Thesis
Abstract
This thesis details investigations into new Diels-Alder reactions primarily for the synthesis of pyridines, annulated pyridine derivatives (2,7-naphthyridin-1(2H)-ones), and oxidised pyridine derivatives (isoquinolin-1(2H)-ones). New methods for synthesis of highly substituted pyridines are in high demand because of their diverse pharmaceutical applications. In Chapter 2, investigations towards the synthesis of highly substituted pyridines involved a proposed ene-Diels-Alder cascade cyclisation. An oxazole dialkyne substrate was produced in a multistep synthesis involving early stage utilisation of the oxazole unit followed by novel metalation and allylation of the oxazole, hydroboration-oxidation, acetylide addition, protection and finally propargylation. Furan containing precursors were additionally synthesised and these were expected to undergo a related ene-Diels-Alder mechanism. However, cyclisation of this precursor led unexpectedly to the formation of a novel Diels-Alder adduct.
In Chapter 3, a lithium iodide mediated intramolecular Diels-Alder reaction has been developed for the synthesis of substituted isoquinolones from both pyrrole and furan
containing precursors (Scheme 2). In situ allene formation has been postulated to explain the formation of "abnormal" Diels-Alder adducts, and these could be synthesised in yields of 50–60%, despite their instability to fragmentation with prolonged heating to form isoquinolones. Molecules containing isoquinolone motifs are of interest because of their biological significance and their potential applications as medicinal drugs. Extension of the methodology to precursors containing oxazoles enabled the formation of annulated pyridines, and complementary conditions for the formation of annulated furans and pyridines were discovered. In conditions of an inert solvent (TCE), furans were exclusively synthesised via elimination of a nitrile component. Lithium iodide / pyridine conditions were utilised to override this inherent reactivity, and pyridines could be synthesised with both aliphatic and aromatic substituents. With an aromatic group in the 4-position, selectivity of the pyridine over the furan fragmentation products was especially high. The work in chapters 3 and 4 has been included in a patent application, which has been filed, application number 1815763.6 (I provided much of the data for the patent, I influenced the angle of the patent and the writing of the claims. My creative input was involved e.g. in proposing the direction of oxazoles to form pyridines.)
In Chapter 3, a lithium iodide mediated intramolecular Diels-Alder reaction has been developed for the synthesis of substituted isoquinolones from both pyrrole and furan
containing precursors (Scheme 2). In situ allene formation has been postulated to explain the formation of "abnormal" Diels-Alder adducts, and these could be synthesised in yields of 50–60%, despite their instability to fragmentation with prolonged heating to form isoquinolones. Molecules containing isoquinolone motifs are of interest because of their biological significance and their potential applications as medicinal drugs. Extension of the methodology to precursors containing oxazoles enabled the formation of annulated pyridines, and complementary conditions for the formation of annulated furans and pyridines were discovered. In conditions of an inert solvent (TCE), furans were exclusively synthesised via elimination of a nitrile component. Lithium iodide / pyridine conditions were utilised to override this inherent reactivity, and pyridines could be synthesised with both aliphatic and aromatic substituents. With an aromatic group in the 4-position, selectivity of the pyridine over the furan fragmentation products was especially high. The work in chapters 3 and 4 has been included in a patent application, which has been filed, application number 1815763.6 (I provided much of the data for the patent, I influenced the angle of the patent and the writing of the claims. My creative input was involved e.g. in proposing the direction of oxazoles to form pyridines.)
Version
Open Access
Date Issued
2019-04
Date Awarded
2019-09
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Parsons, Philip
Craig, Donald
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)