Date of Award

July 2016

Degree Type


Degree Name

Doctor of Philosophy (PhD)




John Chisholm


Alkylation, AQX-1125, Etherification, Synthesis, Thioetherification, Trichloroacetimidate

Subject Categories

Physical Sciences and Mathematics


The synthesis of ethers and thioethers is necessary as the motifs are ubiquitous in natural products, pharmaceuticals, and are quite useful in numerous synthetic applications. While common methodologies prepare simple ether and thioether substrates, the harsh conditions of these techniques make them unsuitable for complex molecules. The requirement for these functional groups to be prepared by facile and efficient means has led to an investigation into O - and S – alkylations occurring solely under thermal conditions utilizing trichloroacetimidates.

The alkylation of thiols by the direct displacement of trichloroacetimidates has been accomplished under thermal conditions (heating in refluxing THF). These reactions proceed to the corresponding thioetherification product without the requirement of an added acid, base, or metal catalyst. This facile procedure provides the sulfide in excellent yields with only the formation of the neutral trichloroacetamide as the side product. Formation of the trichloroacetimidate in situ has also been studied, which provides a convenient method for the formation of sulfides from alcohols in a single flask.

A similar methodology towards obtaining etherification products has also been investigated. O – Diphenylmethyl and para-methoxybenzyl trichloroacetimidates in refluxing solvent has shown to effectively convert a variety of alcohols to their corresponding ether without disturbing pre-existing functionality. This methodology provides the subsequent etherification products in moderate to excellent yields with only the formation of the neutral trichloroacetamide as the side product.

Additionally, the development of a more efficient and concise total synthesis towards the SHIP1 activator AQX-1125 from trans-dehydroandrosterone has been studied. The synthetic approach features an allylic oxidation of the C7 position and ozonolysis to generate key intermediates. Alternative routes have also been proposed and future investigations will aim to complete this project in the future.


Open Access