Novel Selenium-Mediated Cyclisations Sohail Anjum Shahzad Ph.D. 2010 UMI Number: U584490 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U584490 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Novel Selenium-Mediated Cyclisations A thesis submitted for the degree of Doctor of Philosophy at Cardiff University By Sohail Anjum Shahzad July 2010 Declaration Declaration This work has no previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed ..................... (Sohail Anjum Shahzad) Date O ciahe& J$..,....Zo.l.a. ...... Statement 1 This thesis is being submitted in partial fulfilment of the requirements for the degree of PhD Signed ......................... (Sohail Anjum Shahzad) Date . Statement 2 This thesis is the result of my own independent investigations, except where stated otherwise. Other sources are acknowledged by explicit references. Signed.. ( ................................ (Sohail Anjum Shahzad) Date.......... Statement 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisation. Signed . V J (Sohail Anjum Shahzad) D ate Q C t ( ^ . e ^ l 9 .p .. 2 o l o . ......... Acknowledgements Acknowledgements Firstly I would like to thank my supervisor Professor Thomas Wirth for all his enthusiasm, advice, encouragement and support throughout my PhD. I would also like to thank my supervisor for giving me such an interesting and challenging project. He is a wonderful supervisor and I found him a very kind person. I would also like to thank Dr. R. Richardson for his helpful proof reading, discussions, support, advice and computational calculations of biaryls. I am highly thankful to Diana M. Freudendahl who has been helpful in proof reading my thesis. I would like to thank Simon Elmore for proof reading. I would like to thank the support staff in the department especially R. Jenkins, R. Higgins, D. Walker and B. Kariuki. Thanks to the Higher Education Commission of Pakistan and Cardiff University for funding my research. Thanks to all the technical and admin staff for their assistance. I would also like to thank all the members of the T. Wirth group for making my time in Cardiff memorable. The friends and colleagues from the Wirth group are too many to mention here, S. Altermann, D. M. Browne, B. Ojo, J. Brandt, Dr. Azhar-ul-Haq Ali Shah, Dr. U. Farooq, 0. Elhady, C. Venin, C. Vivant, M. Iwaoka, L. Zhao, Dr. M. Rasheed, and U. Farid for their support, encouragement during my stay in Wirth group. I would like to express my special gratitude to Zulfiqar Ali Khan for all his help, support and memorable discussions during my stay at Cardiff. I would also like to thank Dr. Mark Bagley and Dr. M. Elliott for their useful discussions on the chemistry during their role as assessors at Cardiff School of Chemistry. I am highly thankful to my dear friend Qamar Ali for his encouragement before and during PhD. Most importantly I would like to thank all my family especially my parents, grandmothers’ (late), brothers, sisters, auntie Arshad and uncle Ameen and Nazir for their continual support during all the stages of my life and education. I particularly want to thank my wife Summar Sohail and daughter Ayesha Sohail. They endured the many days and nights of my being presence in UK. My family provided the love, the help, and the fulfilment required for me to keep going and helped me to put this project into its proper perspective. They helped me in ways that are too numerous to mention. I thank them, and I dedicate this work to them. Sohail Anjum Shahzad Abstract Abstract The present work describes the selenium-mediated cyclofunctionalisations of alkenes. Three different areas are reported herein. Chapter 2 reports syntheses of several substrates for carbocyclisation reactions and use of selenium and Lewis acids resulting in various dihydronaphthalenes. These dihydronaphthalenes then acted as substrates for second ring forming reactions. This novel tandem double cyclisation comprises a carboannulation, a Friedel-Crafts reaction and a rearrangement. This cascade sequence has been proven to be a useful tool in the selective synthesis of dihydronaphthalenes and benzofluorenes from easily accessible stilbenes and provides fast access to polycyclic ring systems in a single step. Lewis acid, PhSeCI R Chapter 3 describes electrophilic selenium-mediated reactions which have been used to cyclise a range of /Tketo esters to corresponding biaryl compounds under very mild conditions. The products were formed by a carboannulation via addition/elimination sequence and a subsequent rearrangement of range of alkyl and aryl groups. The key starting materials stilbene /?-keto esters were readily prepared by Heck coupling and hydrolysis followed by condensation with potassium ethyl malonate. ZrCI4or FeCI3, PhSeCI Ar Chapter 4 describes work on catalytic selenium reagents with stoichiometric amount of hypervalent iodine to convert a range of stilbene carboxylic acids into their corresponding isocoumarins. The work also describes the selective synthesis of dihydroisocoumarins using diphenyl disulfide and dimethyl diselenide. Ph-S-S-Ph or Ph-Se-Se-Ph (10%) CHg-Se-Se-CH COOH Phl(OCOCF3)2 rAr 'Ar X = SeMe v Phl(OCOCF3)2 81—99% X = SPh 57—97% Abbreviations List of Abbreviations Ac acetyl acac acetyl aceton ate AEBN azo-fo's-isobutyronitrile Ar aryl group 5 chemical shift °C degree (s) Celsius A reflux BOC f-butoxycarbonyl br broad Bu butyl calc. calculated CDCI3 deuterated chloroform cod 1,5-cyclooctadienyl Cp cyclopentadienyl CSA camphorsulfonic acid d doublet dba dibenzylidene acetone DCE 1,2-dichloroethane DHP dihydropyran DMAD dimethylacetylene dicarboxylate DMAP 4-(dimethylamino)pyridine DMF dimethylformamide DMSO deuterated dimethylsulfoxide dppe 1,2 -bis(diphenylphosphino)ethane dppf bis(diphenylphosphino)ferrocene Dr diastereomeric ratio E electrophile ee enantiomeric excess EI+ electron impact (mass spectrometry) ESI electrospray ionisation (mass spectrometry) equiv. equivalent EtsN triethylamine Abbreviations Et ethyl h hours HRMS high resolution mass spectrometry Hz Hertz IR infrared J coupling constant LDA lithium diisopropylamide LRMS low resolution mass spectrometry mCPBA 77 ieta-chloroperbenzoic acid Me methyl mp melting point Ms methanesulfonyl n- normal (linear alkyl group) NMR nuclear magnetic resonance (spectroscopy) Nu nucleophile o- ortho p- para Ph phenyl Pr propyl p-To\ 4-methylphenyl A-PSP A-(phenylseleno)phthalimide q quartet qn quintet R general (alkyl) group rt room temperature sec secondary tert- or t- tertiary THF tetrahydrofuran THP tetrahydropyran(yl) TLC thin layer chromatography TMU tetramethylurea Z or EWG electron withdrawing group v Contents List of Contents Declaration ............................................................................................................................ i Acknowledgements ...............................................................................................................ii Abstract..................................................................................................................................iii Abbreviations ........................................................................................................................iv Contents ................................................................................................................................. vi Chapter 1 General Introduction on Selenium 1.1 History of Selenium .................................................................................................. 1 1.2 Properties of Selenium .............................................................................................. 1 1.3 Sources of Selenium ................................................................................................. 1 1.4 Uses of Selenium ...................................................................................................... 1 1.5 Health Effects........................................................................................................... 2 1.6 Development of Organoselenium Chemistry ........................................................ 2 1.7 Allylic Oxidation Using Selenium Dioxide .......................................................... 4 1.8 The Use of Selenium in Carbocyclisations ........................................................... 5 1.9 Literature Examples of Selenium-Mediated Carboyclisations ........................... 6 Chapter 2 The Synthesis of Novel Dihydronaphthalenes and Benzofluorenes 2.1 Introduction to Dihydronaphthalenes ..................................................................14 2.2 Introduction to Benzofluorenes ............................................................................. 26 2.3 Aims of the Project................................................................................................