NEW METHODOLOGIES FOR THE SYNTHESIS OF ORGANOPHOSPHORUS COMPOUNDS by MONIKA I. ANTCZAK Master of Science, 2002 Wroclaw University of Technology Wroclaw, Poland Submitted to the Graduate Faculty of the College of Science and Engineering Texas Christian University in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2008 NEW METHODOLOGIESFOR THE SYNTHESISOF ORGANOPHOSPHORUSCOMPOLNDS by MonikaI. Antczak Dissertationapproved: Maior Professor f Scienceand Engineering Copyright by Monika I. Antczak 2008 ACKNOWLEDGMENTS I wish to acknowledge Prof. Jean-Luc Montchamp for the constant interest in the progress of my work over the past five years. I also wish to thank him for his advice and intense discussions, which helped me in expanding my knowledge and understanding of organic chemistry, and in guiding me in my educational progress at Texas Christian University. His patience and support helped me overcome some difficult situation and successfully completing my Ph.D. program. I express my gratitude to my colleagues and friends, Jennifer Tellez, Dr. Laëtitia Coudray, Yamina Belabassi and Dr. Clemence Queffelec for their help, guidance and support. I also would like to thank Dr. Onofrio Annunziata, Dr. Waldek Zerda and Dr. Dale Huckaby for their guidance and interesting discussions during these years. I wish to thank: Monika Wieligor and Dr. Mauricio Quiroz for their friendship and constant support. Finally, I wish to thank my parents for their unconditional love and support. The Chemistry Department at Texas Christian University, the National Science Foundation (CHE-0242898), the National Institute of General Medical Sciences/NIH (R01 GM067610), and the Robert A. Welch Foundation (P-1666) are gratefully acknowledged for the financial support of this research. ii TABLE OF CONTENTS ACKNOWLEDGMENT..................................................................................................... ii LIST OF FIGURES ........................................................................................................... vi LIST OF SCHEMES......................................................................................................... vii LIST OF ABBREVIATIONS .......................................................................................... xiii Chapter I: Background: Organophosphorus Chemistry. ..................................................... 1 1.1 Introduction ............................................................................................................... 1 1.2 H-Phosphinic Acid Derivatives, Useful Synthons of Organophosphorus Compounds ..................................................................................................................... 5 1.2.1 Preparation of H-phosphinic acid derivatives .................................................... 7 1.3 Phosphonic Acid Derivatives. ................................................................................. 11 1.3.1 Synthesis of phosphonic acid derivatives ........................................................ 15 1.4 Phosphine-Borane Complexes ................................................................................ 19 Chapter II: Hydrophosphinylation of Alkenes and Alkynes Using Alkyl Phosphinates .. 23 2.1 Introduction ............................................................................................................. 23 2.2 Nickel - Catalyzed Hydrophosphinylation .............................................................. 25 2.2.1 NiCl2-catalyzed addition of alkyl phosphinates to alkynes ............................. 30 2.2.2 Mechanistic considerations .............................................................................. 36 2.2.3 Tandem one-pot alkyne hydrophosphinylation-functionalization ................... 37 2.3 Radical Hydrophosphinylation. AIBN-initiated Radical Reactions of Alkyl Phosphinates. ................................................................................................................ 39 iii 2.3.1 Reaction of alkyl phosphinates with alkenes ................................................... 43 2.3.2 Reaction of alkyl phosphinates with alkynes ................................................... 47 2.4 Conclusion .............................................................................................................. 52 Chapter III: Synthesis of the GABA analogs .................................................................... 53 3.1 Introduction ............................................................................................................. 53 3.2 Phosphinic Acids as GABA Analogs ..................................................................... 54 3.3 Biological Evaluation of GABA Analogs............................................................... 62 Chapter IV: Synthesis of Functionalized Organophosphorus Compounds via Organoboranes .................................................................................................................. 63 4.1 Introduction ............................................................................................................. 63 4.2 Reaction of Phosphorus-Containing Carbenoids with Organoboranes .................. 66 4.2.1 Reactions with symmetrical trialkylboranes .................................................... 66 4.2.2 Selective migration with nonsymmetrical organoboranes ............................... 76 4.3 Transformation of -Boranophosphorus Intermediates 2: C-B Elaboration .......... 81 4.3.1 Synthesis of 1,1-bis-phosphorus compounds from organoboranes. Transformation P-C-B complex into P-C-P .............................................................. 81 4.3.2 Transformation P-C-B complex into P-C-C via acylation, aldol, conjugate adition, radical reaction cross-coupling etc. ............................................................. 87 4.3.3 Transformation P-C-B complex into P-C-X functionalities (X = Si, Se, O, I, F, N). ........................................................................................................................... 101 4.4 Asymmetric Synthesis of Functionalized Organophosphorus Compounds via Organoboranes ............................................................................................................ 110 4.5 Conclusion ............................................................................................................ 115 iv Chapter V: Borane Complexes of the H3PO2 P(III) Tautomer ....................................... 117 5.1 Introduction ........................................................................................................... 117 5.2 Synthesis and Reactivity of Diethoxyphosphine-Borane (EtO)2P(BH3)H ........... 119 5.2 Conclusion ............................................................................................................ 126 Experimental section ....................................................................................................... 128 References ....................................................................................................................... 234 VITA ABSTRACT v LIST OF FIGURES Figure 1.1 Applications of organophosphorus compounds ............................................... 1 Figure 1.2 Examples and nomenclature of some major organophosphorus compounds ... 3 Figure 1.3 Examples of biologically-active phosphinic acids ........................................... 6 Figure 1.4 2-Aminoethylphosphonic acid (AEPA) and its derivatives ........................... 11 Figure 1.5 Examples of organophosphorus compounds with antibiotics activity ........... 12 Figure 1.6 Examples of phosphonic acids with antitumor and antiviral activity ............. 12 Figure 1.7 Isosteric and isopolar ATP analog .................................................................. 13 Figure 1.8 Biologically active analogs of pyrophosphate ................................................ 14 Figure 2.1 Hydrophosphinylation of 4-octene with EtOP(O)H2 ...................................... 36 Figure 3.1 Isosteric carboxylate replacement .................................................................. 54 Figure 3.2 Phosphinic acids as GABA analogs ............................................................... 55 Figure 3.3 Structural classes and types of phosphinyl GABA analogs ........................... 57 Figure 4.1 Organophosphorus compounds used in the reaction with organoboranes ..... 68 Figure 4.2 Chiral auxiliaries which were investigated ................................................... 114 vi LIST OF SCHEMES Scheme 1.1 Phosphorus compounds containing phosphinylidene moiety (P(=O)H) ........ 4 Scheme 1.2 Transformations of H-phosphinic acid derivatives ......................................... 5 Scheme 1.3 Methods for the preparation of H-phosphinates ............................................. 8 Scheme 1.4 Cross-coupling vs. transfer hydrogenation competing pathways ................... 9 Scheme 1.5 Montchamp’s methods for the synthesis of H-phosphinates ........................ 10 Scheme 1.6 Montchamp’s tandem reaction for the preparation of phosphonic acids ...... 15 Scheme 1.7 Phosphonic acids from chlorophosphines ..................................................... 16 Scheme 1.8 Mechanism of Michaelis-Arbuzov reaction ................................................. 17 Scheme 1.9 Hydrophosphonylation of alkenes, alkynes and allenes ............................... 18 Scheme 1.10 Methods for the synthesis of phosphine-borane complexes