Novel Process Windows: Reactions Using Tricky Reagents

Novel Process Windows: Reactions Using Tricky Reagents

Novel Process Windows: Reactions Using Tricky Reagents A Thesis Submitted to Cardiff University in Fulfilment of the Requirements for the Degree of Doctor of Philosophy by Matthew John Hutchings PhD Thesis October 2016 Cardiff University I II DECLARATION This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ................................................ (Matthew Hutchings) Date .............................. STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for: the Degree of Doctor of Philosophy Signed ................................................ (Matthew Hutchings) 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. The views expressed are my own. Signed ................................................ (Matthew Hutchings) 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. Signed ................................................ (Matthew Hutchings) Date ............................ III CANDIDATES LAST NAME HUTCHINGS CANDIDATES FIRST NAME(S) MATTHEW CANDIDATES ID NUMBE R 0704493 SCHOOL CHEMISTRY Please circle appropriate degree title TITLE OF DEGREE EdD, EngD, DSW, DClinPsy, DHS, MCh, MD, MPhil, MScD by Research, PhD Novel process windows: reactions using tricky FULL TITLE OF THESIS reagents IS THIS A RESUB MISSION? YES / NO Permanent binding [ ] THESIS SUBMITTED FOR EXAMINATION IN Temporary binding [ ] CANDIDATES DATE SIGNATURE IV Acknowledgments Firstly, I would like to thank my supervisor Professor Thomas Wirth who gave me the opportunity to research the field of flow chemistry within his group. His guidance and tutorship has been invaluable. Furthermore, I would like to thank the members of my research group Dr. Fateh, Dr Munawwer, Dr Ravi, Dr Pushpak, Dr. Kenta, Dr Nida, Dr Mike, Dr Umar, Dr Kevin, Dr Guillaume, Richard, Alastair, Simon, Florence, Ana, Filipa, Mohammad. I would further like to acknowledge the technical support staff at the Cardiff School of Chemistry, Dr Rob Jenkins, Sham Ali, Robin Hicks, Dave Walker and Simon Waller. Lastly I would like to give a big thanks to the engineering department Alun Davies and Steven Morris for their help in repairs of flow equipment within my time here. V List of Abbreviations Å Angstrøm Ac Acetyl AIBN Azobisisobutyronitrile Ar Aryl BPR Back Pressure Regulator CV Column volumes DBN 1,5-Diazabicyclo(4.3.0)non-5-ene DBU 1,8-Diazabicycloundec-7-ene (DHQ) 2PHAL Hydroquinine 1,4 -phthalazinediyl diether DIAD Diisopropyl azodicarboxylate DIB Diacetoxyiodobenzene DMF Dimethylformamide DMP Dess –Martin periodinane DPPA Diphenylphosphoryl azide dppp 1,3-Bis(diphenylphosphino)propane DMSO Dimethylsulfoxide Et Ethyl FIBX (2,4,5,6-Tetra -fluoro) 2-iodoxybenzoic acid GPR Gas Pressure Regulator h Hour/hours HPLC High pressure liquid chromatography HRMS High resolution mass spectrometry IBX 2-Iodoxybenzoic acid iNOC isonicotinyloxycarbonyl IR Infra-red Hz Hertz mA milliamp µm micrometre m-CPBA m- Chloroperoxybenzoic acid VI Me Methyl MFC Mass Flow Control MHz Megahertz min Minute m.p. Melting point m/z Mass over charge ratio NIS N-iodosuccinimide NMR Nuclear magnetic resonance o.n. overnight PET Positron emission tomography PIFA [Bis(trifluoroacetoxy)iodo]benzene pKa Acid dissociation constant ppm parts per million Ph Phenyl Pr Propyl PTC phase transfer catalysis/catalyst Re Reynold’s Number rt Room temperature T3P Propylphosphonic anhydride TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene t-Bu t-Butyl TEA Triethylamine TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxyl TFA Trifluoroacetic acid THF Tetrahydrofuran TMEDA N,N,N′,N′ -Tetramethylethylenediamine TMS Trimethylsilyl TTMS Tetramethylsilane VII Abstract Flow chemistry has been increasingly used in the last decade as an alternative method to batch chemistry. This methodology allows for conditions that would be unattainable under batch techniques due to the high temperature control, selectivity and safety that flow chemistry allows. The diazidation of styrenes has been investigated under continuous flow conditions, where the inherent safety of flow chemistry allows the use of azides without the concerns usually associated with these reagents. Secondly, the nitroaldol reaction has been transferred to flow conditions. This highlights the safety of continuous flow procedures, as the use of a highly energetic reagent such as nitromethane is easily possible.. The Koch-Haaf carbonylation reaction was investigated to demonstrate the use of gases in flow chemistry and the safe handling of toxic gases such as carbon monoxide. Finally the Ritter reaction was used to further demonstrate the suitability of flow chemistry for highly exothermic reactions using concentrated acids; where the temperature control allows for high selectivities. VIII 2.1 Contents Acknowledgments ......................................................................................................................... 5 List of Abbreviations ..................................................................................................................... 6 Abstract ......................................................................................................................................... 8 1.1 Advantages of Flow Chemistry...................................................................................... 1 1.2 Organic s ynthesis promoted by flow chemistry’s properties ....................................... 4 1.1.1 Single Phase Reactions .......................................................................................... 4 1.1.2 Liquid-Liquid Biphasic Reactions ........................................................................... 6 1.3 Heterogeneous conditions ............................................................................................ 8 1.1.3 Gas liquid conditions ............................................................................................. 8 1.1.4 Solid liquid conditions ......................................................................................... 11 1.4 Miscellaneous techniques ........................................................................................... 13 1.5 Multi-Step Synthesis ................................................................................................... 16 1.6 In-line Analysis and automated control ...................................................................... 18 1.7 Scaling up .................................................................................................................... 21 2.1 Introduction to diazidation reactions ............................................................................. 23 2.1.1 Azides in organic synthesis.................................................................................. 23 2.1.2 Azide chemistry in microreactors ....................................................................... 25 2.1.3 Iodine reagents and their use in diamination reactions ..................................... 31 2.1.4 Hypervalent iodine compounds in combination with azides.............................. 36 2.1.5 Aims of project .................................................................................................... 44 2.2 Results and Discussions .................................................................................................. 46 2.2.1 Initial diazidation conditions ............................................................................... 46 2.2.2 Stereoselective diazidations ............................................................................... 50 2.2.3 Catalytic diazidations .......................................................................................... 54 2.2.4 Flow conditions ................................................................................................... 56 2.2.5 Azido thiocyanation. ........................................................................................... 61 2.2.6 Results ................................................................................................................. 65 IX 2.3 Concluding remarks and Future work ............................................................................. 67 3.1 Introduction to nitroaldol reactions ............................................................................... 68 3.1.1 Nitromethane: A highly energetic chemical ........................................................... 68 3.1.2 Synthesis of compounds containing nitro groups................................................... 70 3.1.3 The Nitroaldol Reaction .......................................................................................... 72 3.1.4 Utilization of the nitro group .................................................................................. 76 3.2 Results and Discussion .................................................................................................... 77 3.2.1 Initial Flow Conditions ............................................................................................. 77 3.2.2 Chiral synthesis ......................................................................................................

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