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Synthetic Applications of Nitrile Oxide/Isoxazoline Chemistry Ewan

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Synthetic Applications of Nitrile Oxide/Isoxazoline Chemistry Ewan Synthetic Applications of Nitrile Oxide/Isoxazoline Chemistry Ewan Campbell Boyd Thesis submitted for Degree of Doctor of Philosophy University of Edinburgh 1992 Declaration I declare that this thesis was composed by myself and that it describes my own work except where specifically stated in the text. The work was carried out from October 1987 to October 1990 in the department of chemistry at the University of Edinburgh under the supervision of Dr R.M. Paton. Ewan C. Boyd Acknowledgements I would like to thank Dr Mike Paton for his help, encouragement and advice during the course of this work. Thanks are also due to those who provided structural and analytical services in the chemistry department: John Millar, Heather Grant and David Reed (NMR), Elizabeth Stevenson and Alan Taylor (mass Spec.), Elaine McDougal (CHN) and Dr R.O Gould and Dr A.J. Blake (X-Ray analysis). I would also like to thank Castrol Research Ltd for their generous funding of this work and John Porter and Graham Warrellow who diligently proof read this thesis. Postgraduate Lectures (1987-1990) Departmental Seminars, three years attendance. Fatty Acids and Lipids, (Prof. F.D. Gunstone) 1988, 10 lectures. Disconnections (Dr I. Gosney) 1988, 5 lectures. Modern Synthetic Strategies (Dr G. Tennant) 1988, 5 lectures. Medicinal Chemistry (Dr R.M. Paton) 1989, 5 lectures. Medicinal Chemistry (Prof. R. Baker and Dr P. Leeson, MSD) 1989, 5 lectures. Medicinal Chemistry (Prof. A. Baker) 1990 5 lectures. Recent Advances in Organic Chemistry (various lecturers) 1989, 5 lectures. Departmental German course passed (1987). Abbreviations Boc t-butoxycarbonyl Boc2O di-t-butyl dicarbonate b.p. boiling point BuLi butyllithium CBZ benzyloxycarbonyl DIBAL di-isobutylaluminium hydride DMP 2,2-dimethoxypropane DMSO dimethylsuiphoxide ether diethyl ether FAB Fast Atom Bombardment FMO Frontier Molecular Orbital HMPA hexamethylphosphoramide HOMO Highest Occupied Molecular Orbital HPLC High Pressure Liquid Chromatography IR Infra-red LAH lithium aluminium hydride LDA lithium di-isopropylamide LDEA lithium diethylamide lit, literature value LUMO Lowest Unoccupied Molecular Orbital mmol millimole MO Molecular Orbital M.P. melting point NBS N-bromosuccinimide NCS N-chlorosuccinimide NMR Nuclear Magnetic Resonance PCC pyridinium chlorochromate TFA trifluoroacetic acid THF tetrahydrofu ran tic thin layer chromatography Ts tosyl (toluenesuiphonyl) TsCI p-toluenesulphonyl chloride TsOH p-toluenesulphonic acid Abstract Three alkenes, (R/S)-2-phenyl-4-vinyl-4,5-dihydro-oxazole (11), (4R)-3- N-t-butoxycarbonyl-2,2-dimethyl-4-vinyloxazolidine (1 2) and (2F)-2-(N-t- butoxycarbonyl)aminobut-3-en-1-ol (13), have been prepared from (S) serine and used in cycloaddition reactions with some common nitrile oxides, to investigate the effect of an allylic nitrogen at an a-chiral centre on it-facial selectivity. Alkene (11) was prepared in racemic form after an unexpected racemisation during its synthesis. Cycloaddition reactions with three nitrile oxides (benzonitrile oxide, ethoxycarbonylformonitrile oxide and bromonitrile oxide) furnished the isoxazoline/oxazoline adducts in poor to good yield. it-facial selectivity varied from 69:31 (BrCNO) to 82:18 (Et02CCNO) in favour of the (5R,4'S) erythro product. The stereoselectivity has been explained by both a steric transition state model and by the existence of a stereoelectronic contribution to the stability of the transition state. Alkene (12) afforded good yields of cycloadducts with the same three nitrile oxides, but only gave moderate it-facial selectivity (ca. 66:34); the (5R,4'S) eiythro products were again favoured. The diastereomeric products were separated after partial deprotection of the n-amino-alcohol moiety (deacetonisation). The observed it-facial selectivity has been explained by a steric transition state model. The N-protected vinylarnino-alcohol (13) has been reacted with benzonitrile oxide and ethoxycarbonylformonitrile oxide to give the corresponding cycloadducts in moderate yield. it-facial selectivity was poor, and the (5S,2'S) threo isomer was favoured. The reduction and reversal of it-facial induction has been explained by a hydrogen bonding interaction in the transition state. Two examples of chiral heterocyclic nitrile oxides (39) and (41) which correspond to the two heterocyclic alkenes have also been prepared, each of which represents a protected chiral j3-amino-alcohol nitrile oxide. (4R)-3-N-t-butoxycarbonyl-2,2-dimethyloxazolidi ne-4-carbonitrile oxide (39) was generated from the corresponding oxime (40) and reacted with three olefins: styrene, oct-1-ene and diethylfumarate, affording the cycloadducts in poor to good yield. (R/S)-2-phenyl-4,5-dihydro-oxazole-4-carbonitrile oxide (41) was generated by dehydration of the corresponding nitromethyl heterocycle (42) and reacted, when formed in a low steady state concentration, with styrene and oct-1-ene to give moderate yields of the bis-heterocyclic adducts. When the concentration of the nitnie oxide was not controlled by the slow addition of the precursor, the diastereomeric furazan- N-oxides (45a & b) were the only isolated products. Isomer ratios for both nitrile oxides were Ca. 1:1. Finally, five examples of isoxazole- and isoxazoline-3-aldoximes have been prepared, and conditions established for their conversion to the corresponding 3-carbonitrile oxides. In situ generation with sodium hypochlorite and N-chlorosuccinimide/triethylamine proved most successful. A series of bi-isoxazoles, isoxazole/isoxazolines and bi- isoxazolines have been prepared in moderate yield as potential lubricant additives. Contents 1 Introduction 1.1 1,3-Dipoles i 1.2 1,3-Dipolar Cycloaddition Reactions 3 1.2.1 Mechanism 3 1.2.2 Concerted vs Diradical 7 1.2.3 Reactivity 9 1.2.4 Regioselectivity 10 1.2.5 Stereoselectivity 12 1.3 Nitrile Oxides 13 1.3.1 History 13 1.3.2 Electronic Structure 13 1.3.3 Generation 14 1.3.3.1 Oxidation of Aldoximes 14 1.3.3.2 Dehydration of Primary Nitroalkanes 15 1.3.3.3 Other Methods of Generation 16 1.3.4 Reactions 18 1.3.4.1 Dimerisation 18 1.3.4.2 Rearrangement to Isocyanates 19 1.3.4.3 Cycloaddition Reactions 19 1.4 Asymmetric Induction in Nitrile Oxide Cycloaddition Reactions 22 1.5 Ring Opening Reactions of 2-Isoxazolines 24 1.5.1 3-Hydroxyketones 24 1.5.2 y-Hydroxyamines 26 1.5.3 3-CyanoalcohoIs and a,f-Unsaturated Nitriles 29 1.6 Modification of 2-1soxazolines via endo- and exo-Azaenolates 30 2 Results and Discussion 2.1 Cycloaddition Reactions of Nitrile Oxides with Alkenes Bearing an Allylic Nitrogen Substituent at the Asymmetric Centre 33 2.1.1 Introduction 33 2.1.2 Synthesis of (4F-3-(N-t-butoxycarbonyI)-2,2-di- methyl-4-vinyloxazolidi ne (1 2) and (4R)-2-(N-t- butoxycarbonylamino)but-3-en-1 -01 (13) 39 2.1.3 Cycloaddition Reactions of Nitrite Oxides with (4R)-3- (N-t-butoxycarbonyl)-2,2-di methyl-4-vinyloxazolidi ne (12) 44 2.1.4 Explanation for the Observed it-Facial Selectivity 50 2.1.5 Nitrile Oxide Cycloaddition Reactions with (2R)-2- (N-t-butoxycarbonylamino)but-3-en-1 -ol (13) 52 2.1.6 Synthesis of (R/S-2-phenyl-4-vinyl-4,5-di hydro- oxazole(11) 57 2.1.7 Racemisation of (R/S)-2-phenyl-4-vinyl-4,5-dihydro- oxazole (11 ) 60 2.1.8 Cycloaddition Reactions of Nitrile Oxides with (R/S)- 2-phenyl-4-vinyl-4,5-di hydro-oxazole (11) 66 2.1.9 Some Observed Trends in the Characteristics of the Cycloadducts of (11) 67 2.1.10 Assignment of Stereochemistry 70 2.1.11 Explanation for the Observed Stereoselectivities 72 2.1.12 Conclusion W. 2.1.12.1 Summary of Results 76 2.1.12.2 Future Work 77 2.2 Synthesis and Cycloaddition Reactions of Oxazoline- and Oxazolidine-4-carbonitrile Oxides 81 2.2.1 Introduction 81 2.2.2 Synthesis of (R/S)-4- nitro met hyl-2-phenyl-4,5-di- hydro-oxazole (42) 81 2.2.3 Preparation of (4R)-4-aldoxi mi no-3-(N-t-butoxycar- bonyl)-2,2-dimethyloxazolidine (40) 82 2.2.4 Cycloaddition Reactions of (R/S)-2-phenyl-4,5-dihydro- oxazole-4-carbonitrile oxide (41) 85 2.2.5 Features of (RS/SR)-5-phenyl-3-(2-phenyl-4,5-dihydro- oxazol-4-yl)-2-isoxazoline (46a) from the X-Ray Crystal Structure 90 2.2.6 Features of (RR/SS)-3,4-di-(2-phenyl-4,5-dihydro- oxazol-4-yI)furazan-N-oxide (45b) from the X-Ray Crystal Structure 91 2.2.7 Cycloaddition Reactions of (4F-3-(N-t-butoxycar- bonyl)-2,2-di methyl-4-carbonitrile oxide (39) 92 2.2.8 Assignment of Configuration 96 2.2.9 Final Comments on the 1 H-NMR Spectra of the Chiral Nitrile Oxide Adducts 98 2.2.10 Conclusion 99 2.3 Synthesis of 3,3'-bi-isoxazoles and Lower Oxidation State Analogues via Isoxazole- and 2-lsoxazoline-3-carbonitrile Oxides 101 2.3.1 Introduction ioi 2.3.1.1 Use of oxalodinitrile oxide in the Synthesis of 3,3'-bi-isoxazoles 103 2.3.1.2 Use of Isoxazole- and 2-lsoxazoline-3-hydroxi- moyl halides 105 2.3.2 Preparation of Substituted Isoxazole- and 2-lsoxazo- Iine-3-aldoximes 110 2.3.3 Generation and Cycloaddition Reactions of Isoxazole- and 2-lsoxazoline-3-carbonitrile Oxides 119 2.3.4 Observations from the X-Ray Structure of (RS/SR) meso-5-phenyl-3-(5-phenyl-2-isoxazolin-3-yI)-2-isox- azoline(66a) 137 2.3.5 Conclusion 139 3 Experimental 3.1 General Experimental Conditions 141 3.2 Compounds for General Use 143 3.3 Synthesis and Cycloaddition Reactions of (4R)-3-(N-t- butoxycarbonyl)-2,2-di methyl-4-vinyloxazo lid in e (1 2) and (2R)-2-(N-t-butoxycarbony lam i no) but-3-en- 1 -01 (1 3) 144 3.4 Synthesis of (R/S)-2-phenyl-4-vinyl-4,5-dihydro-oxazole (11) 161 3.5 Cycloaddition Reactions of (RIS)-2-phenyl-4-vinyl-4 ,5-di hydro- oxazole(11) 171 3.6 Preparation of Nitrile Oxide Precursors (40) and (42) 175 3.7 Cycloaddition Reactions of (RfS)-2-phenyl-4 ,5-di hydro-oxa- zole-4-carbonitrile oxide and (4f-3-(N-t-butoxycarbonyl)-2,2- dimethyloxazolidine-4-carbonitrile oxide 176 3.8 Deprotection of (50b) 185 3.9 Synthesis of Isoxazole and 2-lsoxazoline-3-aldoximes 186 3.10 Cycloaddition Reactions of Isoxazole- and 2-lsoxazoline-3- carbonitrile Oxides 199 Bibliography 220 Appendix (Selected X-Ray Data) 229 1 1.
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