Degree Name

Doctor of Philosophy


School of Chemistry


The N-acyliminium ion has long been an important tool in the synthesis of nitrogen containing heterocycles, capable of forming both carbon-carbon and carbon-heteroatom bonds. Recent advances in the chemistry of N-acyliminium ions has seen the development of α,β-unsaturated N-acyliminium ions, capable of reacting through sequential 1,4- and 1,2-addition reactions to yield optically active heterocyclic spirocycles, generating high molecular complexity in a one-pot reaction. The α-cyclopropyl N-acyliminium ion under the right conditions reacts in an analogous way, capable of sequential homoconjugate-addition and 1,2-addition reactions, resulting in ring opening of the cyclopropyl group and its incorporation into a spirocyclic heterocycle. To the authors knowledge, only one report of an α-cyclopropyl N-acyliminium ion is in the literature where the chemistry was briefly mentioned in 1975, but the reactivity of α-cyclopropyl N-acyliminium ions had not been properly explored until this Thesis.

In this thesis (Chapter 2), the synthesis of several α-cyclopropyl N-acyliminium ion precursors is described, from which an α-cyclopropyl N-acyliminium ion is generated in situ with BF3·Et2O and reacted with 1,2-dimethoxybenezne to furnish the desired spirocycle. Optimisation studies were carried out for the reaction of an α-cyclopropyl N-acyliminium ion precursor and 1,2-dimethoxybenzene, where complications arose due to the BF3OH- anion ring opening the cyclopropyl group through homoconjugate addition, which led to an undesired spirocyclic furan.

The reaction scope is then expanded to include other aromatic nucleophiles and allyltrimethylsilanes, which give a variety of novel homoconjugate addition products and 1,2-addition products, as well as the undesired spirocyclic furan.

From these reactions, indole proves to be the most promising, and so a range of substituted indoles were reacted with the α-cyclopropyl N-acyliminium ion precursors synthesised earlier. These results are reported in Chapter 4. The reaction product outcomes appear to be dependent on the electron richness (nucleophilicity) of the indole nucleophile, where highly electron rich nucleophiles result in 1,2-addition reactions to the α-cyclopropyl N-acyliminium ions, and electron poor nucleophiles result in the undesired spirocyclic furan, that is they do not react with the α-cyclopropyl N-acyliminium ion. Homoconjugate addition occurs somewhere between these two afore mentioned levels of nucleophilicity. It was discovered however, that steric effects from the substituents close to the iminium carbon during the addition transition state favoured homoconjugate addition over 1,2-addition products.

Finally, a high throughput biological assay was carried out by Eli Lily on a subset of the products made in this thesis, with promising results in PCSK9 inhibition and in the identification of potential anti-malaria therapeutics.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.