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Synthesis Towards Fulminic Acid and Its Derivatives in 1, 3-Dipolar Cycloaddition Reactions

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Synthesis Towards Fulminic Acid and Its Derivatives in 1, 3-Dipolar Cycloaddition Reactions East Tennessee State University Digital Commons @ East Tennessee State University Electronic Theses and Dissertations Student Works 8-2008 Synthesis Towards Fulminic Acid and Its Derivatives in 1, 3-Dipolar Cycloaddition Reactions. Ophilia Ndi Toh East Tennessee State University Follow this and additional works at: https://dc.etsu.edu/etd Part of the Organic Chemistry Commons Recommended Citation Toh, Ophilia Ndi, "Synthesis Towards Fulminic Acid and Its Derivatives in 1, 3-Dipolar Cycloaddition Reactions." (2008). Electronic Theses and Dissertations. Paper 1982. https://dc.etsu.edu/etd/1982 This Thesis - Open Access is brought to you for free and open access by the Student Works at Digital Commons @ East Tennessee State University. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Digital Commons @ East Tennessee State University. For more information, please contact [email protected]. Synthesis Towards Fulminic Acid and Its Derivatives in 1,3-Dipolar Cycloaddition Reactions ______________ A thesis presented to the faculty of the Department of Chemistry East Tennessee State University In partial fulfillment of the requirement for the Degree Master of Science in Chemistry ______________ by Ophilia Ndi Toh August 2008 ______________ Professor David G. J. Young, Ph.D., Chair Professor Jeffery G. Wardeska, Ph.D. Professor Yu Lin Jiang, Ph.D. Keywords: isoxazoline, cycloaddition, fulminic acid, nitrile oxides ABSTRACT Synthesis Towards Fulminic Acid and Its Derivatives in 1,3-Dipolar Cycloaddition Reactions by Ophilia Ndi Toh A new approach to fulminic acid cycloadditions has been developed. At reduced temperatures, fulminic acid is generated in situ and undergoes 1, 3-diploar cycloaddition reactions with dipolarophiles to form isoxazolines and/or its dimers. This procedure represents a novel, safe general method for the one-step generation of fulminic acid, which complements existing potentially explosive protocols. 2 DEDICATION This work is dedicated to my late father; Peter TOH, my mom Helen AFOR 3 ACKNOWLEDGMENTS I owe a lot to ETSU (Faculty and Staff) for the knowledge impacted on me during the master’s degree program through their friendliness, collaboration, and willingness to help at any time. My sincere thanks go to my supervisor, Dr. David G.Young, who is always there to explain some of the basic concepts underlying the research and as a result I was able to differentiate between theory and practical. Also, many thanks to Dr. Yu Lin Jiang and Dr. Jeff G. Wardeska for being members of my thesis committee. My brothers and sisters; Dr. Toh Ephraim and wife, Mr/Mrs Ngangyet Clement, Mr/Mrs Toh Hans, Mr/Mrs Otengong Helaria, Mr/Mrs Chick Stella, and Mr Toh Oswin for their relentless support and prayers. My cousin; Mr/Dr Wini Akam for the relentless support, thanks and may God richly bless you. Classmates/friends who have contributed to this journey and the hope to light each of mile: Arrey B. Enyong, Nadine K. Njoya, Mark-Henry Kamga, Jennifer Ashie, Laude A. Bannerman, William E. Ghann, Charles Odame-Ankra, Aaron Apawu, Ernest Jum, etc. May the spirit of togetherness continue to abide in us wherever we may happen to find ourselves. Our mother of the department, Mrs Susan Campbell is not left out. Your encouragements, gentleness, kindness, and pretty smiles and above all love has contributed immensely to my success. Thank you all. 4 CONTENTS Page ABSTRACT……………………………………………………………………………….…………….2 DEDICATION…………………………………………………………………………………………..3 ACKNOWLEDGMENTS……………………………………………………………. ..........................4 LIST OF FIGURES……………………………………………………………………..........................8 LIST OF SCHEMES……………………………………………………………………………............9 LIST OF TABLES……………………………………………………………......................................10 ABBREVIATIONS……………………………………………………………………………............11 Chapter 1. INTRODUCTION AND LITERATURE REVIEW……………………….……….............15 Discovery of Fulminic Acid…….……………………………………………………..16 Previous Method of Fulminic Acid Synthesis…………………………………............16 Methods of Nitrile Oxide Generation………………………………………………….21 Classical Method……………………………………………………….............21 Mukaiyama-Hoshino method………………………………………………….22 Oxidation with Catalyst………………………………………………………..22 Thermolysis of Furoxans………………………………………………............23 Nitrile Oxides from O-silylhydroxamates……………………………………………..23 Methods of Nitrile Oxide Cycloaddition …..………………………………………….23 Allene –Nitrile Oxide Cycloaddition…….. ………………………………...................23 5 Intramolecular Nitrile Oxide Cycloaddition …..……………………...……….24 Intermolecular Nitrile Oxide Cycloaddition…..……………………………….25 Dimerization of Nitrile Oxides………………………………………………………...26 Other Methods of Isoxazoline Synthesis……………………………………................27 Uses of Isoxazolines in the Synthesis of Natural Products and Related Structures……27 Reactions of Isoxazolines……………………………………………….......................28 Reduction……………………………………………………………………………....28 Oxidation……………….……………..………………………………………….……29 Applications of Nitrile Oxides………………………………………………………....29 2. RESULTS AND DISCUSSION…………….……………………………………….……...33 3. EXPERIMENTAL………………………………………......................................................37 General Methods……………………………………………………………………….37 GC-Analysis……………………………………………………………………............37 General procedure for method A……………………………………………................38 General method for method B………………………………………………………….38 General procedure for method C……………………………………………………….39 5-phenyl-4,5-dihydroisoxazoline..……………………………………………………..39 5,5'-Bisbromoethyl-4,5,4,'5'-tetrahydro-[3,3']biisoxazolyl ……………………………40 5,4',5'-Hydroxymethyl-4,5,4',5'-tetrahydro-[3,3']biisoxazolyl-4-yl)- methanol…….....41 1-(tert-butyldiphenylsiloxy) pent-4-ene ……………….………………………………41 (1-diazo-2-phenylethyl)trimethylsilane ………………………………….....................42 2,2,2-trichloroethyl-4-pentanoate……………………………………………………...43 6 3-[5'-(5,5,5-Trichroro-3-oxo-pentyl)-4,5,4',5'-tetrahydro-[3,3']biisoxazolyl-5-yl]- propionic acid-2,2,2-trichloro-ethyl ester…………………………...............................43 Tert-butyldimethylsiloxyl pent-1-ene …………………………………………………44 3-[5'-(-Hydroxy-propyl)-4,5,4',5'-tetrahydro-[3,3']biisoxazolyl-5-yl]-propan-1-ol........45 5,4',5',-Tris-hydromethyl-4,5,4,'5'-tetrahydro-[3,3]biisoxazolyl-4-yl)-Methanol……...46 4. CONCLUSION……………………………………………………………………………...47 REFERENCES………………………………………………………………………………………...48 APPENDICES…….…………………………………………………………………………………...49 Appendix A: 1H-NMR for 5,4',5',-Tris-hydromethyl-4,5,4,'5'-tetrahydro-[3,3] biisoxazolyl-4-yl)- methanol…………………………………………………………...49 Appendix B: 13C-NMR for 5,4',5',-Tris-hydromethyl-4,5,4,'5'-tetrahydro-[3,3] biisoxazolyl-4-yl)- methanol…………………………………………………………...50 Appendix C: 1H-NMR for 2,2,2-trichloroethyl-4-pentanoate…………………………………..51 Appendix D: 13C-NMR for 2,2,2-trichloroethyl-4-pentanoate….................................................52 Appendix E: 1H-NMR for 3-[5'-(-Hydroxy-propyl)-4,5,4',5'-tetrahydro-[3,3']biisoxazolyl- 5-yl]-propan-1- ol…………………………………………………………………..…..53 Appendix F: 1H-NMR for 3-[5'-(-Hydroxy-propyl)-4,5,4',5'-tetrahydro- [3,3']biisoxazolyl-5-yl]-propan-1- ol…………………………………………………..54 Appendix G:13C- NMR for 3-[5'-(-Hydroxy-propyl)-4,5,4',5'-tetrahydro[3,3']biisoxazolyl-5-yl]- propan-1- ol…………………………………….............................................................55 Appendix H: 1H-NMR for P-toluenesulfonulhydrazide……………………………………….56 Appendix I :13C-NMR for P-toluenesulfonulhydrazide………………………….......................57 Appendix J: 1H-NMR for 5-phenyl-4,5-dihydroisoxazoline……………………………………58 7 Appendix K: 13C-NMR for 5-phenyl-4,5-dihydroisoxazoline………………………………….59 Appendix L: 1H-NMR for Tert-butyldimethylsiloxyl pent-1-ene……………………………...60 Appendix M: 13C-NMR for Tert-butyldimethylsiloxyl pent-1-ene……………………………..61 Appendix N: 1H-NMR for (5'-Hydroxymethyl-4,5,4',5'-tetrahydro-[3,3']biisoxasolyl-5-yl)- methanol………………………………………………………………………………..62 Appendix O: 1H-NMR for 3-[5'-(5,5,5-Trichroro-3-oxo-pentyl)-4,5,4',5'-tetrahydro- [3,3']biisoxazolyl- 5-yl]-propionic acid-2,2,2-trichloro-ethyl ester………………...63 Appendix P: 13C-NMR for 3-[5'-(5,5,5-Trichroro-3-oxo-pentyl)-4,5,4',5'-tetrahydro- [3,3']biisoxazolyl- 5-yl]-propionic acid-2,2,2-trichloro-ethyl ester………………...64 Appendix Q: 1H-NMR for 5,5'-Bisbromoethyl-4,5,4,'5'-tetrahydro-[3,3']biisoxazolyl………...65 Appendix R: 1H-NMR for (1-diazo-2-phenylethyl)trimethylsilane………………………….....66 Appendix S: 1H-NMR for Metafulminic acid………………………………..………………....67 Appendix T: Mass Spectrum for 5,5'-Bisbromoethyl-4,5,4,'5'tetrahydro-[3,3']biisoxazolyl…...68 Appendix U: Mass Spectrum for 5,4',5'-Hydroxymethyl-4,5,4',5'-tetrahydro- [3,3']biisoxazolyl-4-yl)-methanol……………………...………………………………69 Appendix V: Mass Spectrum for 3-[5'-(-Hydroxy-propyl)-4,5,4',5'-tetrahydro- [3,3']biisoxazolyl-5-yl]-propan-1- ol………………………..………………………….70 VITA…………………………………………………………………………………………………...71 8 LIST OF FIGURES Figure Page 1. Biologically Active Isoxazolines …………………………………………………………..18 2. Natural Products Isoxazolines ……………………………………......................................27 9 LIST OF SCHEMES Schemes Page 1. Polymerization of Fulminic Acid ………………………………………………..................15 2. Previous Synthesis of Fulminic Acid………..…………........................................................16 3. Mesomeric Structure of Nitrile Oxides……………………………………………………...17 4. Isoxazoline from Substituted Nitrile Oxide…………………………………………............20 5. Proposed Route to Fulminic Acid Synthesis………………………………..........................20 6. Two-Step Generation of a Nitrile
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