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Synthesis of α-thio-β-chloroacrylamides including continuous processing and application to the formation of sulfur containing heterocycles
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Date
2018
Authors
Cacheux, Valérie M. Y.
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
α-Thio-β-chloroacrylamides are formed from the analogous α-thioamides through an oxidative reaction cascade. In this work, enhanced insight into the mechanistic pathway leading to these highly functionalised compounds has been achieved, in addition to demonstration of their potential as intermediates in the synthesis of pharmaceutically significant heterocycles. The first chapter is an extensive literature review of the synthesis of sulfur containing heterocycles including 1,4-oxathiin, 1,4-dithiin, 1,4-thiazine and 1,4- benzothiazine derivatives. After an initial brief discussion of the importance of these compounds as therapeutic agents, common synthetic strategies and more exotic approaches are described. In some instances, the mechanisms involved in these transformations are outlined. The second chapter focuses on a detailed investigation of a series of α-thio-β- chloroacrylamides and of the intermediates involved in the reaction cascade leading to their formations. A previously unseen pathway leading to the β- chlorosulfide has been revealed. The advantages associated with used of a continuous flow process enabled for the first time the scale up of the α-thio-β- chloroacrylamide transformation. Notably, the reaction cascade can be controlled through this continuous system, leading to selective recovery of individual components from the reaction. Efficient rapid quantification of reaction products, intermediates, starting material and by-products within the process through HPLC underpinned the development of an efficient flow process. The third chapter discusses the synthesis of a range of functionalised α-thio-β- chloroacrylamides. The stereoselectivity and the efficiency of the transformation involved were seen to be highly sensitive to the precursor substituents and the solvent system employed. These novel derivatives enabled formation of 1,4- oxathiin, 1,4-thiazine and 1,4-benzothiazine derivatives via intramolecular cyclisation processes. Extension of the strategy to dithiin synthesis has also been investigated. The novel thiazine synthesised in this project was subsequently derivatised providing a broad range of new thiomorpholines. Investigation into the potential of these sulfur containing heterocycles as anti-cancer agents is described.
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Keywords
Thiazine , α-Thio-β-chloroacrylamide , Organic chemistry , Flow chemistry
Citation
Cacheux, V. M. Y. 2018. Synthesis of α-thio-β-chloroacrylamides including continuous processing and application to the formation of sulfur containing heterocycles. PhD Thesis, University College Cork.