Novel Synthesis of TV-Heterocycles A thesis submitted to Cardiff University by Damian Gordon Dunford BSc (Hons.) A thesis submitted for the Degree of Doctor of Philosophy December 2010 School of Chemistry Cardiff University UMI Number: U516902 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 U516902 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 DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed ..................... (candidate) Date . I ^ STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD Signed. 2) 22. .......................(candidate) Date . STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed... J <2 .. ‘. .O .V (candidate) 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 organisations. Sig ned. ^ 2.\ ...2 (candidate) Date1 Contents Title Page i Acknowledgements ii Dedication Page iii Abbreviations iv Abstract vii Chapter one: Introduction 1 1.1 Introduction to metal-catalysed heterocyclic synthesis 2 1.2 Previous work in the Knight group 2 1.3 Current work 5 1.3.1 Indoles 5 1.3.2 Pyrazoles 5 1.3.3 Pyrroles 5 Chapter two: Indoles 6 2.1 Aims 7 2.2 Literature Review 8 2.2.1 Fischer indole synthesis 8 2.2.2 From 2-alkynyl anilines 10 2.2.2.1 Alkoxide-mediated cyclisations 11 2.2.2.2 Copper-mediated synthesis 12 2.2.2.3 Palladium-mediated synthesis 16 2.2.2.4 Methods using other metals 18 2.2.2.5 Iodocyclisations 19 2.2.3 By reductive cyclisation 20 2.2.4 Other methods 21 2.2.4.1 Bartoli indole synthesis 21 2.2.4.2 Madelung indole synthesis 22 2.2.4.3 Gassman indole synthesis 22 2.2.4.4 Intramolecular Heck cyclisation 23 2.2.5 Aza-indole synthesis 23 2.2.5.1 Copper-catalysed synthesis of azaindoles 24 2.2.5.2 Palladium-catalysed synthesis of azaindoles 24 2.3 Indoles: Results and Discussion 26 2.3.1 Synthesis of 2-alkynyl anilines and azaanilines 26 2.3.2 Cyclisation of indole and azaindole precursors 29 2.4 Mechanistic elucidation 35 2.5 Computational studies 37 2.6 Significance of a propargylic alcohol 42 2.7 Flow chemistry 44 2.8 Conclusions 48 Chapter three: Pyrazoles 49 3.1 Introduction 50 3.2 Literature methods to make pyrazoles 51 3.2.1 Synthesis of pyrazoles from hydrazines 51 3.2.2 By reaction between Huisgen zwitterions and Electron-deficient alkenes 51 3.2.3 Palladium-catalysed synthesis 53 3.2.4 Silver(I)-catalysed synthesis 53 3.3 Pyrazoles: Results and Discussion 55 3.3.1 Origins of the current work 55 3.3.2 Synthesis of 4,5-dihydropyrazoles via Mitsunobu Coupling of phthalimides with alcohols 56 3.3.3 Limitations 58 3.3.4 A change in hydrazine-hopes for a regioselective Mitsunobu reaction 59 3.4 Conclusions 68 Chapter four: Pyrroles 69 4.1 Introduction 70 4.2 Literature methods 71 4.2.1 Some classical methods 71 4.2.2 Iodocyclisation 72 4.2.3 Metal-catalysed pyrrole synthesis 73 4.2.4 Synthesis from isocyanides 79 4.3 Pyrroles: Results and Discussion 80 4.3.1 Aims 80 4.3.2 Copper(II)-catalysed 5-endo-dig cyclisations 81 4.3.2.1 Sharlands origionol method 81 4.3.2.2 Synthesis of P-hydroxyamino esters 81 4.3.2.3 Stereochemistry 85 4.3.2.4 Assessing and improving Sharland’s Copper-mediated cyclisations 86 4.3.2.5 Synthesis of other pyrrole precursors 89 4.3.2.6 Assessing the optimised copper(II) catalysed methodology 90 4.3.2.7 Scope and limitations 92 4.3.2.8 Silver(I)-catalysed cyclisations and Comparisons with copper(II) 93 4.3.3 Extension of silver cyclisation methodology- Synthesis of annulated pyrroles 94 4.3.3.1 General method towards annulated pyrroles 95 4.3.3.2 Stereochemistry 96 4.3.3.3 Cyclisations 98 4.3.4 Extension towards the synthesis of N-bridgehead pyrroles 99 4.3.4.1 General method towards N-bridgehead pyrroles 100 4.3.4.2 Stereochemistry 102 4.3.4.3 Silver(I) cyclisations of 2-propargylic pyrrolidines and piperidines 103 4.3.4.4 Limitations 107 4.3.4.5 Future work 108 4.3.4.6 Possible applications to natural products 109 4.3.5 Applications of the silver(I)-catalysed cyclisations towards a natural product 115 4.3.5.1 Introduction to pyrrolostatin 115 4.3.5.2 Previous synthesis of pyrrolostatin 116 4.3.5.3 Proposed synthesis of pyrrolostatin 117 4.3.5.4 Our synthesis of pyrrolostatin 119 4.4 Conclusions 126 Chapter five: Experimental 127 5.1 General Experimental 128 5.2 Indole Experimental 131 5.3 Pyrazole Experimental 5.4 Pyrrole Experimental References Appendix Acknowledgements Firstly I would like to express my gratitude to Professor David W. Knight. Throughout the course of this project he has been a constant source of knowledge, support and encouragement. I would also like to thank EPSRC and GlaxoSmithKline for their funding as well as Rob and Ian at GSK in Stevenage for their ideas and coffee breaks during my three month placement. I would also like to thank members of the Knight group: Laura Henderson, Andy Smith, Ian King and Jessica Hatherley and ERASMUS students Andreas and Tobius for their support and discussions as well as Rob Richardson at the POC for his helpful advice and ideas during the course of my PhD. I am also grateful to Terrie, Trish, Jo, Alison and Stephanie for their help with clerical matters. I would also like to thank Dr Benson Kariuki for X-ray crystallography and the technicians Rob, Robin and Dave for their help with NMR and mass spectrometry. I would also like to thank Gaz and Jamie for keeping our lab well stocked. I would also like to thank Larry for being there for me through all the difficult times and always being able to make me smile no matter how bad things looked. I also want to thank Larries family for their support throughout all the difficult times. I would also like to thank Jamie and Derek for their support and allowing me to stay during my last few months writing. To anyone else I missed out I thank you very much. With all my love To my big sister Carla Abbreviations: Abbreviations used in this text: Ac Acetyl Ad Adamantane Alloc Allyloxycarbonyl APCI Atmospheric Pressure Chemical Ionisation (mass spectrometry) Ar Aromatic atm Atmosphere (unit of pressure) Ax Axial Aq. Aqueous Binap 2,2’-bis(diphenylphospino)-1,1 ’-binaphthyl Bu Butyl /Bu /so-Butyl /Bu ter/-Butyl Boc /er/-Butyloxycarbonyl bp Boiling point BU4NOH Tetrabutylammonium hydroxide «-BuLi Butyl lithium f-BuOH tert- butanol °C Degrees Centigrade (Celcius) Cat Catalytic CCDC No Cambridge Crystallographic Data Centre number mCPBA /weta-chloroperoxybenzoic acid DABCO 1,4-Diazabicyclo[2.2.2]octane dap N, 7V-D imethy lam i nom ethyl pyrro ly 1 DCC Dicyclohexylcarbodiimide DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyanobenzoquinone DFT Density functional theory DIAD Diisopropyl azodicarboxylate dig Digonal DMA Dimethylacetamide DMF Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(\H) pyrimidinone DMSO Dimethyl sulfoxide dppm 1,1 -Bis(diphenylphosphino)methane EDA Ethylenediamine El Electron impact (mass spectrometry) Eq Equitorial Equiv/eq Equivalents ES Electrospray ionisation (mass spectrometry) Et20/ether Diethyl ether g Grams G2 Gauss ian-2 h Hours HMPA Hexamethylphosphoramide HRMS High Resolution Mass Spectrometry IBX o-iodoxybenzoic acid ICPMS Inductively coupled plasma mass spectrometry IR Infrared J Coupling constant (in Hertz) LDA Lithium diisopropylamide Ln Ligand LUMO Lowest unoccupied molecular orbital m Meta M Molar (moles L'1) Me Methyl MeCN Acetonitrile MEM J3-Methoxyethoxymethyl ether Min Minutes Moc Methoxycarbonyl M.p. Melting Point ms Mass Spectrometry MW Microwave NaHMDS Sodium bis(trimethylsilyl)amide NMP jV-methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance Nosyl or Ns para -N itrobenzenesulfonyl NsCl /?ora-Nitrobenzenesulfonyl chloride o Ortho p Para PDC Pyridinium dichromate Ph Phenyl Phen Phenanthroline pKa Acid dissociation constant Ppm Parts per million /Pr wo-Propyl Pyr Pyridine RT Room Temperature (Sia)2BH Disiamylborane Si02 Silica gel t or tert Tertiary TBAF Tetrabutylammonium fluoride TBDMS or TBS ter/-Butyldimethylsilyl TFA Trifluoroacetic acid Tf20 ' Trifluoromethansulfonic anhydride THF Tetrahydrofuran TMS Trimethylsilyl Tosyl or Ts /?ora-Toluenesufhonyl TsCl /?ara-Toluenesulfonyl chloride Abstract The Knight group has been working on the synthesis of substituted heterocycles via 5-endo-d\g cyclisation for some time. In particular, the use of metals [M]n+ such as silver(I) and copper(I) have been employed to catalyse these cyclisations to give heterocyclic products in near quantitative yields and cleanly without any need for purification. In a continuation of these studies into metal-catalysed 5-endo-d\g cyclisations, we investigated their application to the synthesis of a range of TV-heterocycles: indoles, pyrazoles and pyrroles.