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4-Π Photocyclisation: a New Route to Functionalised Four-Membered Rings

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4- Photocyclisation: A New Route to Functionalised Four-Membered Rings Thomas Britten This dissertation is submitted for the degree of Doctor of Philosophy April 2019 School of Chemistry Dedicated to Elsie Daisy Alice Moore (1916-2018) and Karin Dixon Wilkins (1962-2015) i Declaration This thesis has not been submitted in support of an application for another degree at this or any other university. It is the result of my own work and includes nothing that is the outcome of work done in collaboration except where specifically indicated. Many of the ideas in this thesis were the product of discussion with my supervisor Dr Susannah Coote. Thomas K. Britten MChem Lancaster University, UK ii Abstract The work disclosed within this thesis describes the use of photochemistry to develop efficient and scalable methodology to access functionalised four-membered rings. Chapter 2 examines the synthesis and synthetic potential of 1,2-dihydropyridazines. The feasibility of the current literature syntheses of 1,2-dihydropyrdazines on multigram scales has been investigated, which has resulted in the development of a novel, scalable route to unsubstituted 1,2-dihydropyridazines. Currently, the synthesis is not amenable to the synthesis of substituted 1,2-dihydropyridazines. 1,2-Dihydropyridazines are precursors to interesting molecular scaffolds through double bond transformations, however in some cases the isolated product was not the expected product. Chapter 3 investigates the optimisation and scale up of the 4-π photocyclisation of 1,2- dihydropyridazines using commercially available batch and flow photoreactors. The use of a batch photoreactor gave better yields, purity and productivity for the synthesis of bicyclic 1,2- diazetidines compared to the flow photoreactor. The photophysical properties of 1,2- dihydropyridazines have been studied and the data has provided guidance for optimisation and rationale for the observed results. Chapter 4 explores the stability and synthetic potential of bicyclic 1,2-diazetidines to access functionalised 1,2-diazetidines, cyclobutenes and other products that were not expected at the outset of the project. Attempts to access cyclobutenes (through N-N cleavage) were unsuccessful due to a facile 4-π electrocyclic ring opening, whereas it was possible to synthesis a range of novel monocyclic functionalised 1,2-diazetidines. Chapter 5 provides overall conclusions, as well as a comparison of the synthesised compounds to Lipinski’s “rule of five” and lead-like space using open access software and ideas for future work Chapters 6 and 7 will provide the experimental details and characterisation of novel compounds that have been reported in this thesis. The appendix gives details on the X-ray crystal structures and differential scanning calorimetry traces for a select few examples. iii Acknowledgements Firstly, I would like to thank my supervisor Dr Susannah Coote for all her help, support and guidance throughout my PhD. In the same manner, I would like to thank my industry supervisor Dr Paul Kemmitt for your support, input into the project and making me feel welcome when I completed my placement at AstraZeneca. A special thank you my second supervisor Dr Mike Coogan, Dr Nicholas Evans, as well as my appraisal panel members Dr Vilius Franckevicius and Dr Verena Görtz. In addition, I would like to thank Lancaster University and AstraZeneca for funding my PhD project, as well as the Society of Chemical Industry (SCI) for a scholarship to support my studies. The most important thanks must go to my partner, Izzy, who has been unbelievably supportive, understanding, motivating and patient over the last 3.5 years. You took a leap of faith moving here, much like me, but you have been truly fantastic and now we can move forward into an exciting future. Thank you to my family (Sally, Russell, Nan, Emily, Jamie, Jack, Archie, James, Catherine, Edison, Brenda, Louise) for your unwavering support, not only throughout my PhD but throughout my entire academic career thus far. Thank you to my fantastic pets (Peanut, Cashew, Duchess and Poppy) for helping to take my mind off my PhD and providing a rare cuddle, though I am not thankful for all the rabbit fur that has gotten everywhere! Thank you to my boys from university (Dipen, Rob, Josh, Jack, Kam, Ross, Baines, Pete) for helping me to get through my PhD and I apologise that I have not seen some of you all that much. Finally, I would like to thank everybody here in the Chemistry Department at Lancaster University for helping to create a great working environment and I will miss you all. I would like to personally thank Henry, Mark, Josh, Charlie, James, Bette, Abbie, Patch, Callum, Miles, Gillian, Eleanor, Vassilis, Dhruv, Ross, Ben, Olivia, Izaak, Stuart, Weronika, Bara, Chloe, Pip, Jack, Craig and Sapphire for making my PhD enjoyable and providing some fantastic memories. iv Contents 1. Chapter 1: Introduction 1 1.1 The Growing Interest In sp3-Rich Compounds 2 1.2 Project Aims and Objectives 6 1.3 The Synthesis of 1,2-Diazetidines 7 1.3.1 Synthesis of 1,2-Diazetidines via [2+2] Cycloaddition 7 1.3.2 Other Methods to Synthesise 1,2-Diazetidines 12 1.3.2.1 Synthesis of 1,2-Diazetidine 12 1.3.2.2 Synthesis of 3-Substituted-1,2-Diazetidines 14 1.3.2.3 Synthesis of Other Substituted-1,2-Diazetidines 15 1.3.2.4 Peripheral Functionalisation of 1,2-Diazetidines 17 1.4 The Thermal Stability of Substituted Cyclobutenes 19 1.4.1 Torquoselectivity – Theory 20 1.4.2 Torquoselectivity – Experimental Evidence 23 1.5 Conclusions 30 2. Chapter 2: Synthesis and Reactions of 1,2-Dihydropyridazines 32 2.1 Introduction 33 2.1.1 Synthetic Approaches to 1,2-Dihydropyridazines 33 2.1.2 Conformational Studies 42 2.1.3 Conclusions 43 2.2 Aims 43 2.3 Results and Discussion 44 2.3.1 Synthesis of 1,2-Dihydropyridazines Through Literature Procedures 44 2.3.1.1 Synthesis of 1,2,3,6-Tetrahydropyridazines 44 2.3.1.2 Synthesis of 1,2-Dihydropyridazines from Tetrahydropyridazines 46 2.3.1.3 Synthesis of 1,2-Dihydropyridazines from 2-Pyrones 48 2.3.2 Novel Synthesis of 1,2-Dihydropyridazines from O-Substituted Dienes 49 2.3.2.1 Diene Synthesis 49 2.3.2.2 Diels-Alder Optimisation 51 2.3.2.3 Synthesis of 1,2-Dihydropyridazines 52 2.3.2.4 Scope 57 2.3.2.4.1 Synthesis of Hydrazines 58 2.3.2.4.2 Synthesis of Azo Compounds 59 2.3.2.4.3 Diels-Alder Reactions 62 2.3.2.4.4 Palladium-Catalysed Elimination Reactions 64 2.3.3 Variable-Temperature NMR of 1,2-Dihydropyridazines 66 2.3.4 Reactions of 1,2-Dihydropyridazines 71 2.4 Conclusions 77 3. Chapter 3: Photochemistry of 1,2-Dihydropyridazines 79 3.1 Introduction 80 v 3.1.1 4-π Photocyclisation of 1,2-Dihydropyridazines 80 3.1.2 Organometallic Complexes with Azo Compounds 81 3.1.3 Cyclobutadiene and Azo Compounds 82 3.1.4 Photochemistry of Other 1,2-Dihydropyridazines 85 3.1.5 Conclusions 89 3.2 Aims 90 3.3 Results and Discussion 90 3.3.1 Ultraviolet-Visible (UV-Vis) of 1,2-Dihydropyridazine 9b 90 3.3.2 Optimisation in a Batch Photoreactor 93 3.3.3 Optimisation in a Flow Photoreactor 105 3.4 Conclusions 109 4. Chapter 4: Reactions of Bicyclic 1,2-Diazetidines 110 4.1 Introduction 111 4.1.1 Derivatisation of Bicyclic 1,2-Diazetidines 111 4.1.2 Conclusions 114 4.2 Aims 114 4.3 Results and Discussion 115 4.3.1 Thermal Stability of Bicyclic 1,2-Diazetidines 115 4.3.2 Synthesis of Functionalised 1,2-Diazetidines 121 4.3.3 Synthesis of Functionalised Cyclobutenes 126 4.4 Conclusions 132 5. Chapter 5: Conclusions and Future Work 133 5.1 Conclusions 134 5.1.1 Synthesis and Reactions of 1,2-Dihydropyridazines 134 5.1.2 Synthesis and Reactions of Bicyclic 1,2-Diazetidines 136 5.2 Future Work 138 6. Chapter 6: Experimental 142 6.1 General Information 143 6.2 General Procedures 144 6.3 Synthetic Procedures 148 7. Chapter 7: References 205 8. Chapter 8: Appendix 224 7.1 X-Ray Data 225 7.2 Differential Scanning Calorimetry (DSC) Traces 238 vi List of Abbreviations and Acronyms A absorbance Ac acetyl ADMET absorption, distribution, metabolism, excretion and toxicity AIBN 2,2’-azobis(2-methylpropionitrile) Aq aqueous Ar unspecified aryl group APCI atmospheric pressure chemical ionization ATR attenuated total reflection BBN 9-borabicyclo[3.3.1]nonane Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl c concentration C centigrade CAN cerium ammonium nitrate COSY correlation spectroscopy Cy cyclohexane d doublet D dimensional DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBAD di-tert-butyl azodicarboxylate DBB di-tert-butylbiphenyl DBU 1,8-diazabicycloundec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DMAD dimethyl azodicarboxylate DMAP 4-dimethylaminopyridine vii DME 1,2-dimethoxyethane DMEDA 1,2-dimethylethylenediamine DMF dimethylformamide DMSO dimethyl sulfoxide DPAD diphenyl azodicarboxylate dppp 1,3-bis(diphenylphosphino)propane DSC differential scanning calorimetry EDG electron donating group ee enantiomeric excess Eq equivalents ESI electrospray ionization Et ethyl FTIR fourier transform infrared h Planck’s constant (6.626 x 10−34 Js) HMBC heteronuclear multiple-bond coherence HMDS bis(trimethylsilyl)amine HOMO highest occupied molecular orbital HRMS high resolution mass spectrometry hr(s) hour(s) HSQC heteronuclear single quantum coherence Hz hertz i iso IBDA iodobenzene diacetate IBX 2-iodoxybenzoic acid IR infrared ISC intersystem crossing IT ion trap J coupling constant l path length LED light-emitting diode LLAMA lead-likeness and
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  • United States Patent Office Patented July 1, 1969

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    3,453,337 United States Patent Office Patented July 1, 1969 1. 2 3,453,337 FLUORINATION OF HALOGENATED The presence in the reaction mixture of the two fluo ORGANIC COMPOUNDS rides, or the complex fluoride enables better yields of Royston Henry Bennett and David Walter Cottrell, Ayon highly fluorinated products to be obtained under less mouth, England, assignors to Imperial Smelting Cor severe reaction condions, markedly increases the amount poration (N.S.C.) Limited, London, England, a British of fluorination reagent reacted under otherwise similar company conditions and enables the fluorination reaction to be No brawing. Filed Feb. 19, 1965, Ser. No. 434,128 carried out (for the same yield of product) at a lower Claims priority, application Great Britain, Feb. 26, 1964, temperature with the consequent use of less costly ma 7,932/64 terials and techniques of reactor construction. The pres Int, C. C07c 25/04 10 ence of the fluorides enables the vapor phase reaction U.S. C. 260-650 2 Claims to be carried out (for the same yields) at lower pressure This invention relates to the fluorination of organic than the pressure involved in the reactions using only halogen compounds and more especially to a process the alkali metal fluorides as proposed hitherto. The fur for the production of highly fluorinated aromatic com ther possibility of using a continuous flow apparatus such pounds by the replacement of higher halogen atoms in 15 as a fluidised reactor will be apparent to those familiar halogeno-aromatic compounds by fluorine atoms. with the art. The presence of the two fluorides or com Aromatic halogenocarbons containing carbon and halo plex fluoride enables a lower temperature to be em gen atoms only can be reacted with alkali fluorides ployed than was hitherto believed to be necessary, with under various conditions to give yields of halofluoro a consequent reduction in the extent of thermal degrada aromatic compounds.
  • Dulaneyspr15.Pdf (409.1Kb)

    Dulaneyspr15.Pdf (409.1Kb)

    Adventures in Organophosphorus Chemistry James W. Dulaney, III (Faculty Mentor: David E. Lewis) Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702-4004 Background Challenges with the Mitsunobu reaction What is required in a replacement to make the reaction Azodicarboxylates, an important component of the re- “green”? Organophosphorus compounds have been an increasingly important part of organic synthesis since the discovery action, are very hazardous: of the Arbuzov rearrangement in 1905. In the century that followed this discovery, the applications of phosphorus- O Green? based reagents in synthesis has grown to incorporate the Wittig and Horner-Wadsworth-Emmons reactions for OEt • They are highly explosive (especially diethyl azodi- N alkene formation, as well as the Mitsunobu inversion reaction, which is used to convert alcohols to a wide range carboxylate). N Green reactions are run under more environmentally sustainable conditions with a view to of products with inversion of configuration. O minimizing environmental impact: • They are highly toxic (especially diethyl azodicar- OEt boxylate). diethyl azodicarboxylate • They are highly regulated. (DEAD) • Wherever possible, renewable sources are used • Wherever possible, hazardous materials are eliminated completely or replaced by The Wittig reaction Ph Ph Ph BuLi Ph less hazardous materials P R P R Regulations have been put into place by the DOT that O Ph Ph O-i-Pr • Wherever possibler, catalytic reactions are used Reaction between an ylide and an aldehyde or ketone to give an alkene. make azodicarboxylic esters even more difficult to ob- N • Hazardous waste is minimized wherever possible (e.g. organic solvents can be re- Reaction gives mainly the Z isomer with aldehydes O tain and use.