ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Thesis Submitted to The College of Arts and Sciences of the UNIVERSITY OF DAYTON In Partial Fulfillment of the Requirements for The Degree of Master of Science in Chemistry By Batool J. Murtadha Dayton, Ohio May 2020 ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Name: Murtadha, Batool J. APPROVED BY: __________________________________ Jeremy Erb, Ph.D. Research Advisor Assistant Professor Department of Chemistry University of Dayton ___________________________________ Vladimir Benin, Ph.D. Professor of Chemistry Department of Chemistry University of Dayton ___________________________________ Justin C. Biffinger, Ph.D. Committee Member Assistant Professor Department of Chemistry University of Dayton ii © Copyright by Batool J. Murtadha All rights reserved 2020 iii ABSTRACT ASYMMETRIC SYNTHESIS OF ORGANOPHOSPHATES AND THEIR DERIVATIVES Name: Murtadha, Batool J. University of Dayton Advisor: Dr. Jeremy Erb Organophosphorus compounds (OPs) are widely used in the agricultural industry especially in the pesticide market. Phosphates play a huge role as biological compounds in the form of energy carrier compounds like ATP, and medicine as antivirals. OPs have become increasingly important as evidenced by the publication of new methods devoted to their uses and synthesis. These well-established studies lay the basis for industrial organic derivatives of phosphorus preparations. The current work explored methods of synthesizing chiral organophosphate triesters. We experimented with different processes roughly divided into either an electrophilic or nucleophilic strategy using chiral Lewis acids, organocatalysts (HyperBTM), activating agents, and chiral auxiliaries with the goal of control stereoselectivity. These methods were explored through the use of different starting materials like POCl3, triethyl phosphate, methyl phosphordichloradate, and PSCl3. My research results suggest that most of the reactions only went to partial completion. Furthermore, most of the experiments were either non-effective product or the scientific data were not productive in the reaction, in fact, the product could not be isolated iv or purified. The synthesis reaction steps were evaluated through TLC, 1H NMR, and 31P NMR. v ACKNOWLEDGMENTS Foremost, I would like to express my sincere gratitude to my advisor Dr. Jeremy Erb for the continuous support of my master's study and research, for his patience, motivation, enthusiasm, and immense knowledge. His guidance helped me all the time in research and writing of this thesis. Besides my advisor, I would like to thank the rest of my thesis committee: Dr. Vladimir Benin and Dr. Justin C. Biffinger for their encouragement. I would also like to thank the University of Dayton and, specifically, the Department of Chemistry for their advice and aid as I performed this research. Thank you to others who helped me with obscure questions, instrumentation issues, and simply listened to me complain as my research progressed. I wish to thank all the people whose assistance was a milestone in the completion of the thesis. Also, I would like to thank my friends and My colleagues at the chemistry department, who have supported me and had to put up with my stresses and moans for the past three years of study. Last but not the least, I would like to thank my family: my parents who supported me and offered deep insight into the study and always were by my side and motivate me through the hard nights. vi TABLE OF CONTENTS ABSTRACT ....................................................................................................................... iv ACKNOWLEDGMENTS ................................................................................................. vi LIST OF FIGURES ……………………………………………………………………...xi LIST OF TABLES ............................................................................................................ xv LIST OF ABBREVIATION ............................................................................................ xvi CHAPTER ONE INTRODUCTION ................................................................................. 1 1.1 Nomenclature of Organophosphorus Compounds ............................................. 1 1.2 Industrial Importance Of Organophosphorus Compounds ................................. 2 1.2.1 Pesticides......................................................................................................... 2 1.2.2 Nerve-Agents .................................................................................................. 3 1.2.3 Fertilizers ........................................................................................................ 4 1.3 Medical Importance of Organophosphorus Compounds ................................... 5 1.3.1 The Role of Phosphorus in Biology ................................................................ 5 1.3.2 Medicines That Use Organophosphorus Compounds..................................... 7 1.4 General Synthetic Methods to Control Chirality .............................................. 10 1.4.1 Lewis Acid Catalysis .................................................................................... 10 1.4.2 Organocatalytic ............................................................................................. 13 1.4.3 Chiral Auxiliaries .......................................................................................... 14 1.5 Methods to Synthesize Organophosphorus Compounds .................................. 15 1.5.1 Synthesis Of P(V) Species ............................................................................ 15 1.5.2 Other OP Synthetic Reactions ...................................................................... 18 vii 1.5.3 Tf2O Activating Regent of Phosphorus (V) Starting Material ..................... 20 1.6 Methods to Synthesize Chiral Organophosphorus Species .............................. 21 1.6.1 Palladium-Catalyzed Cross-Coupling ........................................................... 21 1.6.2 Biomaterial Methods ..................................................................................... 25 1.6.3 Electrophilic Phosphorus .............................................................................. 26 1.7 Previous Work .................................................................................................. 28 CHAPTER TWO RESULTS AND DISCUSSION ......................................................... 30 2.1 Attempted Synthesis of 3,5-dimethoxyphenyl (4-methoxyphenyl) (4-benzyl-2-oxazolidine-3-yl) phosphonate, 4.............................................................. 30 2.2 Attempted Synthesis of 4-benzyl-2-oxooxazolidin-3-yl ethyl methyl phosphate, 6 .................................................................................................................. 36 2.3 Attempted Synthesis of 4-benzyl-2-oxazolidin-3-yl methyl phenyl phosphate, 13 ................................................................................................................ 40 2.4 Attempted Synthesis of 4-benzyl-2-oxazolidin-3-yl ethyl phenyl phosphate, 19 ................................................................................................................ 41 2.5 Attempted Synthesis of ethyl methyl phenyl phosphorothioate, 23…………...43 CHAPTER THREE EXPERIMENTAL .......................................................................... 47 3.1 Reagents ............................................................................................................ 47 3.2 The Synthesis of Chiral Organophosphate from POCl3 ................................... 48 Distillation of the Phosphorus Oxychloride, 1 ........................................................... 48 3.2.1 The Synthesis Of 3,5-Dimethoxyphenyl (4-Methoxyphenyl) (4-Benzyl-2- Oxazolidin-3-yl) Phosphonate, 4 .............................................................................. 48 3.2.2 The Synthesis of 4-Benzyl-2-Oxazolidin-3-yl Ethyl Methyl viii Phosphate, 6 .............................................................................................................. 52 3.2.3 The Synthesis Of 4-Benzyl-2-Oxazolidin-3-yl Decyl Methyl Phosphate, 10 ............................................................................................................ 58 3.3 The Synthesis Of P-Chiral Organophosphates From Alkyl Phosphorus .......... 60 3.3.1 The Synthesis Of 4-Benzyl-2-Oxazolidin-3-yl Methyl Phenyl Phosphate, 13 ............................................................................................................ 60 3.3.2 The Synthesis of Benzyl Ethyl Methyl Phosphate, 16 .................................. 64 3.4 Synthesis Of P-Chiral Organophosphates In Presence of Trialkyl Phosphorus and Tf2O/Pyridine ......................................................................................................... 66 3.4.1 The Synthesis of 4-Benzyl-2-Oxazolidin-3-yl Ethyl Phenyl Phosphate, 19 ............................................................................................................ 66 3.4.2 The Synthesis of Benzyl Ethyl Phenyl Phosphate, 24: ................................. 67 3.5 Synthesis of P-Chiral Thiophosphate ............................................................... 69 REFERENCES ................................................................................................................. 72 APPENDIX A - 31P NMR Distilled Phosphorus Oxychloride ......................................... 81 APPENDIX