Aspects of Organoselenium Chemistry A thesis presented for the degree of Doctor of Philosophy by Virginia R. Ward B.Sc. (Hons) School of Chemistry and Physics November 2012 TABLE OF CONTENTS ABSTRACT iii STATEMENT OF ORIGINALITY v ACKNOWLEDGEMENTS vi ABBREVIATIONS vii 1 INTRODUCTION 1 1.1 SELENIUM 1 1.2 ORGANOSELENIUM CHEMISTRY 5 1.2.1 Selenium dioxide 5 1.2.2 Electrophilic Selenium Reagents 7 1.2.3 Nucleophilic Selenium Reagents 15 1.2.4 Radical Chemistry of Organoselenium Compounds 21 1.2.5 The Selenoxide syn-Elimination 26 1.2.5 Biotransformation of Organoselenium Compounds 29 2 THE AMIDOSELENATION OF ALKENES 32 2.1 INTRODUCTION 32 2.2 INVESTIGATION OF THE FORMATION OF THE trans-OXAZOLINE (2.9) 34 2.3 ONE-POT PREPARATION OF -AMIDO SELENIDES 40 2.4 ALTERNATIVE SOLVENTS FOR THE AMIDOSELENATION REACTION 46 2.5 TWO-STEP PREPARATION OF -AMIDO SELENIDES 49 2.6 PREPARATION OF THE trans-OXAZOLINE (2.9) 56 3 CYCLISATION OF -AMIDOALKYL PHENYL SELENIDES 59 3.1 INITIAL ATTEMPTS TO OPTIMISE THE FORMATION OF N-ACYLAZIRIDINES 59 3.2 CYCLISATION OF -AMIDO SELENIDES AT LOW TEMPERATURE 67 3.3 SUMMARY OF RESULTS FROM THE CYCLISATION OF -AMIDO SELENIDES 76 3.4 FACTORS DETERMINING THE FORMATION OF 3- VERSUS 5-MEMBERED RINGS 77 3.5 OCCURRANCE AND UTILITY OF N-ACYLAZIRIDINES 79 4 AMIDOSELENATION via ADDITION OF ‘PHENYLSELENENYL PERCHLORATE’ 83 4.1 INTRODUCTION 83 4.2 PREPARATION OF -(PHENYLSELANYL)CYCLOHEXYL AMIDES 86 4.3 ALTERNATIVES TO THE -AMIDO SUBSTITUENT 88 5 CLOSER EXAMINATION OF A SELENOXIDE AND A SELENONE 92 5.1 PREPARATION OF N-[2-(PHENYLSELENINYL)CYCLOHEXYL]BENZAMIDE AND N-[2-(PHENYLSELENONYL)CYCLOHEXYL]BENZAMIDE 92 5.2 HYDROGEN-BONDING IN THE SELENIDE (2.5), SELENOXIDE (5.1) AND SELENONE (5.9) 98 5.3 NMR-SCALE OXIDATION OF N-[2-(PHENYLSELANYL)CYCLOHEXYL]BENZAMIDE (2.5) 101 6 PREPARATION AND CYCLISATION OF -HYDROXY SELENIDES 107 6.1 INTRODUCTION 107 6.2 ATTEMPTED ONE-POT PREPARATION OF 2-PHENYLOXETANE 110 6.3 PREPARATION AND ATTEMPTED CYCLISATION OF 3-PHENYL-3-PHENYLSELENOPROPANOL 112 6.3 PREPARATION AND CYCLISATION OF -HYDROXY SELENIDES BEARING A PRIMARY SELENIUM MOIETY 115 6.4 OXETANES IN NATURAL PRODUCTS AND DRUG DESIGN 124 7 EXPERIMENTAL 128 7.1 GENERAL EXPERIMENTAL 128 7.2 WORK DESCRIBED IN CHAPTER 2 131 7.3 WORK DESCRIBED IN CHAPTER 3 160 7.4 WORK DESCRIBED IN CHAPTER 4 182 7.5 WORK DESCRIBED IN CHAPTER 5 187 7.6 WORK DESCRIBED IN CHAPTER 6 196 REFERENCES 212 PUBLICATIONS 230 ABSTRACT A range of-amidoalkyl phenylselenides were prepared in order to explore their cyclisation via oxidation of the selenium moiety to the selenone followed by intramolecular displacement. At first, the -amidoalkyl phenylselenides were prepared in one-step from the alkenes. However, the one-step preparation was complicated by side-reactions and a two-step method was found to give clean reactions and higher yields of a wide range of the desired amido selenides. Along with the expected oxazolines, isomeric N-acylaziridines were obtained from the cyclisation reaction. Formation of N-acylaziridines by cyclisation of amides is unusual, and variation of the conditions was explored in order to optimise this novel aziridine-forming reaction. It was found that conducting the oxidation reaction at low temperature favoured the aziridine products. In this way, the aziridines derived from all prepared -amido selenides were obtained in good to excellent yield. From some substrates, the aziridine was obtained as the exclusive product. The low temperature generation of a selenone from the corresponding selenide had not been reported previously. Experiments were carried out which provided evidence for the supposition that the intermediate in the cyclisation reaction was the selenone. The preparation of -amido selenides was also investigated using silver ion to sequester the halide of the selenium reagent, rendering the selenium species more electrophilic and its addition to the alkene to give a seleniranium ion, irreversible. The seleniranium ion was generated in the presence of nitrile to allow attack by the iii weak nitrile nucleophile upon the seleniranium ion, giving a nitrilium ion. With addition of water to the nitrilium ion, -amido selenides were formed in moderate yield. Thus, it was shown that the -amido selenides could be prepared without the use of strong acid. Addition of azide to the nitrilium ion gave a tetrazole, which demonstrated that this methodology could provide access to selenides substituted at the -position with groups other than the amido group. -Benzamidocyclohexyl phenyl selenoxide and -benzamidocyclohexyl phenyl selenone were prepared, and hydrogen bonding in the two compounds was examined spectroscopically. An X-ray crystal structure of the selenoxide showed intermolecular hydrogen bonding between the amide hydrogen and the seleninyl oxygen, in contrast to proposals in the literature that analogous selenoxides were stabilised by intramolecular hydrogen bonding in the solid state. Three -hydroxy selenides were prepared and their low-temperature oxidation and cyclisation was explored with a view to obtaining the corresponding oxetanes. The low-temperature procedure did not translate successfully to the cyclisation of - hydroxy selenides to oxetanes, instead giving complex mixtures. However, with reference to literature conditions for the preparation of methoxy-substituted oxetanes, the -hydroxy selenides were cyclised to the corresponding oxetanes by oxidation in methanol at room temperature, demonstrating that the scope of this method could be widened to a more generalised preparation of oxetanes. iv STATEMENT OF ORIGINALITY I certify that this work contains no material which has been accepted for the award of any other degree or diploma in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference has been made in the text. In addition, I certify that no part of this work will, in the future, be used in a submission for any other degree or diploma in any university or other tertiary institution without the prior approval of the University of Adelaide and where applicable, any partner institution responsible for the joint-award of this degree. I give consent to this copy of my thesis, when deposited in the University Library, being made available for loan and photocopying, subject to the provisions of the Copyright Act 1968. I also give permission for the digital version of my thesis to be made available on the web, via the University’s digital research repository, the Library catalogue and also through web search engines, unless permission has been granted by the University to restrict access for a period of time. Virginia Ward November, 2012 v ACKNOWLEDGEMENTS I thank David Ward for giving me the opportunity to work with this intriguing element, for sagely guiding my experimental endeavours, for generously editing my thesis chapters, and for being a steadfast presence throughout this long journey. I have many happy memories of working in Lab 6, thanks to the good company of our postdocs, Matt Lucas and Pasquale Razzino. Thanks also to Herbert Foo for much helpful advice and assistance during my brief stay in Lab 3. I wish him a happy and successful career. Thanks to the staff of the Chemistry Department, particularly Phil Clements for his expert assistance in obtaining NMR and mass spectra. Many thanks to John Bowie and Simon Pyke for overseeing the final stages and making it possible for me to complete this work. And thanks to Tricia, Hugh, Vanessa, Edward and Graham, and to my mother for their encouragement and the constant distractions. vi ABBREVIATIONS General Ac acetate AIBN azobisisobutyronitrile Bn benzyl, C6H5CH2 Bu3SnH tri-butyltin hydride CH2Cl2 dichloromethane CHCl3 chloroform de diastereomeric excess DMF dimethyl formamide DMSO dimethyl sulfoxide ee enantiomeric excess Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol HMPA hexamethylphosphoramide i-PrOH isopropanol KOH potassium hydroxide LDA lithium diisopropylamide m-CPBA meta-chloroperbenzoic acid Me methyl, CH3 MeOH methanol MgSO4 magnesium sulfate N2 nitrogen NaBH4 sodium borohydride NaCl sodium chloride vii NaH sodium hydride NaHCO3 sodium hydrogen carbonate Nu nucleophile OTf trifluoromethanesulfonate, triflate Ph phenyl, C6H5 Pr propyl, C3H7 r.t. room temperature t-BuOK potassium tertiary-butoxide TfOH trifluoromethanesulfonic acid, triflic acid THF tetrahydrofuran TLC thin layer chromatography NMR d doublet Hz hertz m multiplet MHz megahertz ppm parts per million q quartet qn quintet s singlet sept septet t triplet chemical shift viii IR br broad cm-1 wavenumbers (reciprocal centimeters) KBr potassium bromide pressed disc s strong w weak MS EI electron impact ESI electrospray FAB fast atom bombardment HRMS high resolution mass spectrum M molecular ion m/z mass per unit charge ix Chapter 1 1 INTRODUCTION 1.1 SELENIUM Selenium was discovered in 1818 by Jöns Jakob Berzelius who observed a powdery red deposit which precipitated from the burning of sulfur at his sulfuric acid plant in the Swedish mining town of Fahlun.[1] Upon heating the red powder Berzelius noted that it gave off a strong odour of decayed radishes.[1] The German chemist Martin Heinrich Klaproth had observed a similar odour upon heating a sample of tellurium. Subsequently, Berzelius showed that the tellurium sample must have been contaminated with a new substance which he named ‘selenium’ after the moon to recall its association with tellurium which Klaproth had named