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Toward the Synthesis of Novel Benzisoselenazolones

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Toward the Synthesis of Novel Benzisoselenazolones TOWARD THE SYNTHESIS OF NOVEL BENZISOSELENAZOLONES by Vassilios Kanellis Bachelor of Science Chemistry, Ryerson University Toronto, ON, Canada, 2012 A thesis presented to Ryerson University in partial fulfillment of the requirements for the degree of Master of Science in the Program of Molecular Science Toronto, Ontario, Canada, 2016 ©Vassili Kanellis 2016 Author’s Declaration I hereby declare that I am the sole author of this thesis. This is a true copy of the thesis, including any required final revisions, as accepted by my examiners. I authorize Ryerson University to lend this thesis to other institutions or individuals for the purpose of scholarly research I further authorize Ryerson University to reproduce this thesis by photocopying or by other means, in total or in part, at the request of other institutions or individuals for the purpose of scholarly research. I understand that my thesis may be made electronically available to the public. ii Abstract Ebselen is a synthetic selenium-containing organic compound that has been studied as a potential treatment for a number of conditions. Ebselen is an antioxidant, capable of scavenging peroxide and other reactive oxygen species. This research is focused on the preparation of novel ebselen derivatives towards biologically active compounds with tunable redox properties and pharmacokinetics. Currently we are exploring different synthetic routes towards ebselen, which are compatible with desired modifications to the ebselen scaffold including replacement of the phenyl group with different aryl or heteroaryl moieties, as well as functional group substitution on the benzisoselenazolone ring. The pathways investigated include a recently published transition metal-mediated method as well as a novel approach using isocyanates. iii Acknowledgements I would like to thank my supervisor, Dr. Viirre, for his unwavering support. I’d also like to thank my committee members, Dr. Robert Gossage and Dr. Stephen Wylie, for their feedback and assistance; Nande Wright for her assistance, patience and friendship; and my former and current lab mates, Bashar Alkhouri, Robert Denning, Daniyl Oleynik and Kevin Paul for helping make the lab a pleasant place to work. I would also like to thank my grandparents, Katina and Vasili Kanellis and Daphne Edmunds; my mother, Monica; my father, Steve; and my brother, Demetri. Lastly I would like to mention my friends Glen-Thomas Totton, Hardeep Bhachhoo, Zahraa Kerawala and all my friends in East York who made life a little more enjoyable with their good humour and support. iv Table of Contents Abstract .......................................................................................................................................... iii Acknowledgements ........................................................................................................................ iv List of Figures ............................................................................................................................... vii List of Schemes .............................................................................................................................. ix List of Tables ................................................................................................................................ xii List of Abbreviations ................................................................................................................... xiii 1 Introduction .......................................................................................................................... 1 1.1 Reactive Oxygen Species ............................................................................................. 1 1.2 Control of Oxidative Stress .......................................................................................... 4 1.3 Project Goals............................................................................................................... 11 1.4 Synthesis of Ebselen ................................................................................................... 12 2 Results and Discussion ...................................................................................................... 16 2.1 Attempting the Cross-Coupling Procedure................................................................. 16 2.2 Attempts at Ebselen via Directed Lithiation............................................................... 22 2.3 Attempts at Ebselen via Diazonium Displacement .................................................... 30 2.4 Possible Route From o-lithiation of Protected Selenol .............................................. 34 2.5 Possible Route via C-H Bond Activation ................................................................... 41 2.6 Generation of Selenium Nucleophiles ........................................................................ 43 2.7 Engman Synthesis Revisited ...................................................................................... 46 v 2.8 Preparation of Amide Precursors ................................................................................ 46 2.9 Future Work ................................................................................................................ 49 3 Conclusion ......................................................................................................................... 51 4 Experimental ...................................................................................................................... 53 4.1 Benzamides ................................................................................................................. 53 4.2 BOC-Protected Benzamide ......................................................................................... 57 4.3 Selenides ..................................................................................................................... 58 4.4 Diselenides.................................................................................................................. 61 4.5 Benzisoselenazolones ................................................................................................. 62 5 Appendix ............................................................................................................................ 66 References ............................................................................................................................... 111 vi List of Figures Figure 1: Selenocysteine ................................................................................................................. 2 Figure 2: Glutathione (GSH) .......................................................................................................... 3 Figure 3: Edaravone ........................................................................................................................ 4 Figure 4: N-acetylcysteine .............................................................................................................. 5 Figure 5: Ebselen ............................................................................................................................ 5 Figure 6: Selenium Naming Conventions ....................................................................................... 6 Figure 7: Origin of Ebselen’s IUPAC Name .................................................................................. 6 Figure 8: Nitro Ebselen ................................................................................................................. 10 Figure 9: Deoxyebselen ................................................................................................................ 10 Figure 10: Donepezil and its Ebselen Hybrid ............................................................................... 10 Figure 11: Tacrine and its Ebselen Hybrid ................................................................................... 11 Figure 12: 2,2'-Selenobis(N-phenylbenzamide) ........................................................................... 17 Figure 13: 2-Hydroseleno-N-phenylbenzamide ............................................................................ 19 Figure 14: 1H-NMR of Unintended Product ................................................................................. 24 Figure 15: 13C{1H}-NMR of Unintended Product ........................................................................ 25 Figure 16: 1H-1H COSY of Unintended Product .......................................................................... 26 Figure 17: HSQC of Unintended Product ..................................................................................... 27 Figure 18: HMBC of Unintended Product .................................................................................... 28 Figure 19: 1H-NMR of MOM-Protected Selenol.......................................................................... 36 Figure 20: 13C-NMR of MOM-Protected Selenide ....................................................................... 37 Figure 21: Expansion of 1H-NMR Spectrum for 4-t-butylphenyl MOM Selenide ...................... 38 Figure 22: Possible Byproducts of Selenide Synthesis ................................................................. 39 vii 1 Figure 23: H-NMR of Crude Product in DMSO ......................................................................... 48 1 Figure 24: H-NMR of Crude Amide in DMSO + D2O ............................................................... 49 Figure
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