Monash University

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New advances in the [3,3]-sigmatropic rearrangement

posted on 2017-02-21, 04:42 authored by Lagiakos, Helen Rachel
For the past century, the [3,3]-sigmatropic rearrangement has been a valuable and evolving transformation, providing a direct, effective process for the formation of new C–C, C–O and C–N bonds. The studies discussed in this thesis continue this rich history, describing a number of ways in which this rearrangement has been applied to the synthesis of various useful molecules, such as α hydroxy amides, spiro orthoamides and pyrimidinediones. To accomplish this, four variants of the reaction have been employed: Chapters 1 and 2 explore the 3 aza 4,6 dioxa [3,3]-sigmatropic rearrangement, while chapters 3 and 4 discuss work based upon the 3 aza 4 oxa-, 3,4 diaza- and 3,4-dithia-[3,3]-sigmatropic rearrangement. In Chapter 1, work on a 3 aza 4,6 dioxa [3,3]-sigmatropic rearrangement of hydroxamic acid derivatives is described. In such a reaction, a new C–O bond is forged upon rearrangement as opposed to the traditional C–C bond, and is therefore classified as a hetero [3,3]-sigmatropic rearrangement. Limited precedents exist for such a transformation, and the presented method improves on the available protocols by both widening the scope of the reaction to include substrates that were previously inaccessible, and in the ease in which the transformation occurs. It was also found that the amount of reagent used influenced the outcome of the reaction: a stoichiometric amount of reagent with respect to substrate favored the formation of α acyloxyamides, while an excess of reagents favored cyclic orthoamides. This represents a new method for the synthesis of these cyclic compounds. Lastly, attempts were made to control the diastereoselectivity of the rearrangement, making use of amino acids as chiral auxiliaries in the reaction. The studies described in Chapter 2 apply the rearrangement developed in Chapter 1 towards the synthesis of novel spirocyclic molecules. Occurring through a unique hetero-[3,3] sigmatropic rearrangement – spirocyclization cascade, attempts to develop a reproducible method and insights into the possible mechanism are discussed. Chapter 3 introduces a new method for the preparation of derivatized pyrimidine nucleobases based on either a 3 aza 4 oxa- or a 3,4 diaza-[3,3]-sigmatropic rearrangement – Curtius rearrangement – dehydrogenation cascade. The N,N’-diacylhydrazine or N,O-diacylhydroxylamine starting materials can be easily prepared, the major steps are both simple and tolerant of a wide range of substituents, and the sequence allows for regiocontrol of the substituent placement on the pyrimidine ring, making for an attractive method into pyrimidine nucleobase analogs. An application was envisioned in which these molecules could be used as fluorescent probes; as such, the first in a new class of pro-fluorescent nucleobases has been efficiently prepared using this method, with in vitro and in vivo efficacy soon be tested. Chapter 4 evaluates the coupling reaction of thioenolates. There is only one literature precedent that describes such a transformation and its mechanism is unconfirmed, however, it was proposed to occur either through a 3,4-dithia-[3,3]-sigmatropic rearrangement or an oxidative enolate coupling. The preceding chapters of this thesis demonstrate the power of the [3,3]-sigmatropic rearrangement in the formation of new bonds between enolates; this last chapter evaluates an alternative approach: the oxidative enolate coupling reaction. The oxidative enolate coupling of thioamides and thioesters was achieved in poor to good yields, with reaction success being highly substrate specific. During the course of synthesizing the starting materials required for the reaction, a novel method for the thionation of amides and esters was developed. This method improves on the available literature by expanding the reaction scope; drastically reducing the reaction time; and providing a simplified, cleaner work-up and purification procedure.


Campus location


Principal supervisor

Patrick Perlmutter

Year of Award


Department, School or Centre



Doctor of Philosophy

Degree Type



Faculty of Science