Lakehead University Knowledge Commons,http://knowledgecommons.lakeheadu.ca Electronic Theses and Dissertations Retrospective theses 2002 Reactivity and mechanistic study of the Sonogashira coupling and Grignard-Sonogashira coupling reactions Aguirre, Andrea Adelia http://knowledgecommons.lakeheadu.ca/handle/2453/3210 Downloaded from Lakehead University, KnowledgeCommons A Reactivity and Mechanistic Study of the Sonogashira Coupling and Grignard-Sonogashira Coupling Reactions A Thesis Presented to The Faculty of Graduate Studies of Lakehead University by ANDREA A. AGUIRRE In partial fulfilment of requirements for the degree of Masters of Science August 20, 2002. © Andrea Aguirre, 2002 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. National Library Bibliothèque nationale of Canada du Canada Acquisitions and Acquisisitons et Bibliographic Services services bibliographiques 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 0-612-83398-4 Our file Notre référence ISBN: 0-612-83398-4 The author has granted a non­ L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts from it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou aturement reproduits sans son permission. autorisation. Canada Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT A Reactivity and Mechanistic Study of the Sonogashira Coupling and Grignard-Sonogashira Coupling Reactions Andrea Aguirre Supervisor: Lakehead University Dr. Gottardo The interest in studying enediyne systems was stimulated by the discovery of anti-cancer agents containing enediyne functionalities, such as esperamicin and dynemicin. These compounds have potential for use as anti-tumour antibiotics, however, they are not sufficiently selective to he used clinically. Many attempts to synthesize analogs of the natural enediynes with improved selectivity and reduced toxicity have been made. A number of synthetic methodologies have been employed toward the synthesis of the analogs, including Stephens- Castro Coupling and Sonogashira Coupling. In this thesis, a reactivity study involving coupling reactions using PdfPPh^)^ and a series of electron donating and electron withdrawing substituted aryl halides is presented. The positions of these substituents relative to the coupled alkyne (i.e., ortho, meta, para) were studied and the changes these substituents had on reactivity (i.e., electronic and steric effects) were investigated. All of the substituted alkynyl benzenes were successfully synthesized in all positions and fully characterized. High yields were obtained for both electron withdrawing and electron donating substituents. In competitive reactions electron Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. withdrawing groups in the para position reacted preferentially over electron donating groups. In general, substituents in the ortho position decreased the rate of reaction. When the starting halides were converted to Grignard reagents, high yields were obtained for electron donating groups as well as some hindered electron withdrawing groups. Mechanistic studies for the Grignard coupling reaction reveal that a transmetallation reaction occurs, and the same catalytic intermediate that is present in the standard Sonogashira coupling reaction also exists in the modified Grignard coupling process. 11 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS First and foremost I would like to express my extreme gratitude to Dr. Gottardo for her encouragement, guidance and support without which this thesis could not be completed. Her insights and suggestions have been a supreme influence on the outcome of this thesis because without her inspiration this thesis would not have been a success. Secondly, I would like to thank Dr. Spivak for his input on the mechanistic approaches and possibilities regarding the Pd and Pt NMR spectroscopic studies. In addition, special thanks is also deserving of Debbie and Ainsley for their patience and expert assistance with the HPLC and various other techniques. Finally, I would like to express gratitude to all those that I have had the privilege of sharing the lab with over the years for making my experience relaxing and fim. I l l Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF ABBREVIATIONS Cul Cuprous Iodide DNA Deoxyribonucleic Acid EtjN Triethy lamine EtOAc Ethyl Acetate FTIR Fourier Transform Infrared GC-MS Gas Chromatography Mass-Spectrometry GLC Gas Liquid Chromatography HPLC High Performance Liquid Chromatography ICP Inductively Coupled Plasma IR Infrared KI Potassium Iodide NCS Neocarzinostatin NMR Nuclear Magnetic Resonance Pd(PPh3)4 T etrakistriphenylphosphine Palladium(O) PPhj Triphenylphosphine Pt(PPh3)4 Tetrakistriphenylphosphine Platinum(O) TEMPO 2,2,6,6-Tetramethyl-l-Piperidinyloxy Free Radical THF T etrahydrofuran TEC Thin Layer Chromatography TMS Trimethylsilyl IV Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS PAGE ABSTRACT.......................................................................................................................................... i ACKNOWLEDGEMENTS................................................................................................................ iii LIST OF ABBREVIATIONS .......................................................................................................... iv LIST OF TABLES.............................................................................................................................viii CHAPTER ONE: A REVIEW OF ENEDIYNE STRUCTURE AND ACTIVITY 1.1 Introduction........................................................................................................................ 1 1.2 Enediyne Anticancer Agents .............................................................................................1 1.2.1 Mode of Action...................................................................................................2 1.2.2 Calicheamicin/Esperamicin ..............................................................................6 1.2.3 Dynemicin........................................................................................................... 6 1.2.4 Kedarcidin Chromophore..................................................................................7 1.2.5 C-1027 Chromophore........................................................................................ 7 1.2.6 Neocarzinostatin Chromophore ....................................................................... 8 1.2.7 Enediyne A nalogs...............................................................................................9 1.2.8 Synthesis of Enediynes.................................................................................... 10 CHAPTER TWO: REACTIVITY STUDY INVOLVING THE PALLADIUM CROSS-COUPLING REACTION 2.1 Palladium Catalysed Coupling Reactions ....................................................................11 2.1.1 Stephens-Castro Coupling ............................................................................ 12 V Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.1.2 Sonogashira Coupling Procedure....................................................................13 2.1.3 Coupling hy Thorand and Krause ................................................................15 2.2 Reactivity Study Toward the Synthesis of Alkvnvl Aromatics Involving Sonogashira Coupling.............................................................................................................................17 2.3 Results and Discussion ...................................................................................................20 2.3.1 Percent Yield Trends........................................................................................ 20 2.3.2 Optimization of the Catalytic System and Coupling R eaction.....................23 2.3.3 Rates of Reactivity ...........................................................................................29 2.3.4 Conclusion ....................................................................................................... 38 CHAPTER 3: REACTIVITY STUDY INVOLVING THE GRIGNARD-SONOGASHIRA REACTION 3.1 Grignard Coupling Reactions.......................................................................................... 40 3.2 Reactivity Study on the Synthesis of Alkvnvl Aromatics Involving Grignard Coupling........................................................................................................... 41 3.3 Results and Discussion