Exploiting the power of continuous flow chemistry in the synthesis and reactivity of alpha-diazosulfoxides

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dc.contributor.advisor Maguire, Anita R. en
dc.contributor.advisor Collins, Stuart G. en
dc.contributor.author McCaw, Patrick G.
dc.date.accessioned 2018-09-26T10:53:16Z
dc.date.issued 2018
dc.date.submitted 2018
dc.identifier.citation McCaw, P. G. 2018. Exploiting the power of continuous flow chemistry in the synthesis and reactivity of alpha-diazosulfoxides. PhD Thesis, University College Cork. en
dc.identifier.endpage 467 en
dc.identifier.uri http://hdl.handle.net/10468/6909
dc.description.abstract The research described in this thesis is an extensive study on the synthesis and reactivity of α-diazosulfoxides utilising continuous flow processing, and contrasting the outcomes from a synthetic perspective with traditional batch reaction conditions. Using continuous flow processing leads to increased efficiency and yields of the α-diazosulfoxides. Inducing the hetero-Wolff rearrangement of α-diazosulfoxides to form α-oxo sulfines in both batch and continuous flow conditions was also explored, together with subsequent trapping in cycloaddition reactions. Both Diels-Alder cycloadditions and 1,3-dipolar cycloadditions with sulfines acting as the dipolarophiles were carried out. Overall it was established that although the diastereomeric ratios for Diels-Alder cycloadditions are comparable in batch and flow, the yields are significantly enhanced from the flow process in addition to the benefit of a metal free process. The study of 1,3-dipolar cycloadditions with nitrones and nitrile oxides led to isolation of a number of novel heterocycles, and highlighted interesting differences in reactivity patterns between the lactone and ketone derived α-oxo sulfines. The introductory chapter is an extensive review of sulfines with a focus on both the synthesis and reactivity of sulfines and α-oxo sulfines. The methods discussed for the generation of sulfines include oxidation of thioketones, sulfenylation with sulfur dioxide, rearrangement reactions and dehydrochlorination reactions. The physical properties of the compounds are also summarised, and the final portion of the review focuses on the diverse reaction pathways which are observed with sulfines and α-oxo sulfines, including the most widely reported Diels-Alder cycloadditions. Other reaction pathways covered include, 1,3-dipolar cycloadditions, in which the sulfine can act as the dipole or dipolarophile, oxygen extrusion, sulfur extrusion, and dimerization. The results of this research programme are discussed in the second chapter. While the synthesis of α-diazosulfoxides has been explored for many years in the research team, the synthetic potential has been limited by very poor yields, typically less than 30%. A major advance in this work demonstrated that through use of continuous flow processing, the exposure of the α-diazosulfoxide products to the basic reaction conditions could be controlled and reduced, resulting in significant yield enhancement, up to three fold, in both the ketone and lactone derived series. Building on the insight developed through optimisation in continuous flow, a modified set of batch conditions was developed which resulted in enhanced yields through reduction in product deterioration by ameliorating exposure to base. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile and potential to scale up. Generation of the α-oxo sulfines from α- diazosulfoxides has been explored in continuous flow using transition metal catalysis, thermolysis and photolysis; this process is more amenable to scale up in continuous flow than in traditional batch conditions. The thermolytic conditions are the most advantageous synthetically, leading to the cycloadducts in a metal free process. Diels-Alder trapping of the α-oxo sulfines has been demonstrated under continuous flow, in general leading to similar diastereoselectivities to those seen in batch but with higher yields, improved safety and potential for scale up. Critical to the success of the α-oxo sulfine cycloaddition was use of a sufficiently concentrated diene trap; in the absence of this, alternative α-oxo sulfine reaction pathways competed with the Diels-Alder cycloaddition. Reactivity differences between the lactone and ketone series of α-diazosulfoxides was explored. One of the highlights of this work was the demonstration of proof of concept in telescoping the diazo transfer to generate the α-diazosulfoxide, with the thermal rearrangement to the α-oxo sulfine, and Diels-Alder cycloaddition to provide direct access to a stable thiopyran-S-oxide, with clear potential benefits from a safety and scale up perspective. Investigation of 1,3-dipolar cycloadditions of α-oxo sulfines with nitrile oxides and nitrones, proved very interesting from both a synthetic and mechanistic perspective. Focusing initially on the nitrile oxides the 1,3-dipolar cycloadditions with lactone and ketone derived α-oxo sulfines exhibited opposite regiochemical outcomes leading to isolation of 1,2,5-oxathiazole-S-oxides, only two of which have previously been reported, and 1,4,2-oxathiazole-S-oxides. An interesting and unanticipated epimerisation was seen in the 1,2,5-oxathiazole-S-oxides. Cycloaddition of the α-oxo sulfines with nitrones leads to both approaches to form regioisomeric cycloadducts, but in this case both of the novel heterocycles undergo subsequent spontaneous reaction to aziridines and other products. Detailed analysis of the spectroscopic features of the novel heterocycles is a key element of this investigation. Representative examples of compounds from across the research programme including 1,2,5-oxathiazole-S-oxides and 1,4,2-oxathiazole-S-oxides were sent to U.S. National Cancer Institute (NCI) for anticancer screening. The third chapter details the full experimental procedures which were used throughout the project and includes all the spectroscopic characterisation and analytical data which were obtained for the novel compounds synthesised. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2018, Patrick G. McCaw. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Diazo en
dc.subject Sulfoxide en
dc.subject Continuous flow en
dc.subject Dipolar cycloaddition en
dc.subject Sulfine en
dc.subject Reactive intermediates en
dc.subject Carbene en
dc.title Exploiting the power of continuous flow chemistry in the synthesis and reactivity of alpha-diazosulfoxides en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD en
dc.internal.availability Full text not available en
dc.check.info Restricted to everyone for five years en
dc.check.date 2023-09-25T10:53:16Z
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council en
dc.description.status Not peer reviewed en
dc.internal.school Chemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Apply the embargo to both hard bound copy and e-thesis (If you have submitted an e-thesis and a hard bound thesis and want to embargo both) en
ucc.workflow.supervisor stuart.collins@ucc.ie
dc.internal.conferring Autumn 2018 en
dc.internal.ricu Analytical and Biological Chemistry Research Facility en

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