DEVELOPMENT OF NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) AND NEW STEREOSELECTIVE REACTIONS USING TITANIUM(IV) REAGENTS by Deboprosad Mondal A Dissertation Submitted to the Faculty of The Charles E. Schmidt College of Science in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Florida Atlantic University Boca Raton, Florida December 2010 ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. Salvatore D. Lepore, for his excellent guidance throughout my PhD. Dr. Lepore has opened for me a door to the art and science of chemical synthesis and methodology development. His talent, passion and motivation in synthesis and his kind personality have always inspired me to improve myself; I am grateful for his encouragement, patience and financial support. I want to thank my committee professors Predrag Cudic, Stanislaw Wnuk and Guodong Sui for their time and insightful advice on my research. I would also like to express my gratitude towards all the past and current members of the Lepore Research Group, especially Change He, Pradip, Ravi and Songye for their help and friendship throughout my PhD. Finally, I thank Drs. Anjan Bhunia and Maximilian Silvestri for their guidance during first year of my PhD. Now I wish to express my thanks to all my friends who have continually inspired me. I am deeply indebted to my parents, especially my father who was my ‘Guru’, my inspiration; my dada for his affection and love; maa-bapi, bhai, kaka for their unconditional love, support and inspiration. Finally, my wife Pinki, I am really proud of her for her love, inspiration and support. iii ABSTRACT Author: Deboprosad Mondal Title: Development of Nucleophile Assisting Leaving Groups (NALGs) and New Stereoselective Reactions Using Titanium(IV) Reagents Institution: Florida Atlantic University Thesis Advisor: Dr. Salvatore D. Lepore Degree: Doctor of Philosophy Year: 2010 We report here the development of very efficient sulfonate based leaving groups, termed Nucleophile Assisting Leaving Groups (NALGs), to accelerate the rate of nucleophilic substitution reactions involving poor nucleophiles and/or substrates traditionally considered too hindered to undergo nucleophilic attack. Indeed NALGs have shown exceptional ability in improving rate of nucleophilic substitution reactions. New very mild stereoretentive halogenations and azidation reactions have also been developed for secondary cyclic alcohols using NALGs involving titanium(IV) reagents. This reaction is particularly significant since the carbon-halogen bond is found widely in natural products and is used extensively as a synthesis intermediate. Azide is also a synthetically important functional group from which a variety of biologically important functional groups are conveniently obtained. Though stereoretentive chlorination and bromination reactions are known, we have developed, for the first time, iv a stereoretentive azidation reaction using titanium(IV) azide, a reagent not previously used in organic synthesis. During our development of stereoretentive reactions, we eventually developed very efficient, mild, two-step one-pot stereoretentive halogenations (chlorination and bromination) using titanium(IV) halides as catalysts or stoichiometric reagents. These reactions were found to be particularly efficient for cyclic alcohols. An efficient one pot stereoretentive amidation reaction for secondary cyclic alcohols is also reported. The important features of this reaction are that, for the first time, chlorosulfite (prepared in situ from alcohol using thionylchloride) has been used as a leaving group and titanium(IV)fluoride as an activator. Utilization of those two reagents is unique as thionylchloride has never been used for nucleophilic substitution reactions except in chlorination procedures. In addition, this work has found new and creative applications for titanium(IV) fluoride, a reactant rarely used in organic synthesis. Further exploiting the unique reactivity of titanium(IV), reactions of alkenes with various nucleophiles have been developed with this reagent in both catalytic and stoichiometric quantities. It was observed that α-substituted aromatic conjugated alkenes dimerize to generate important indan class of compounds which are very important in the polymer industry. In addition, non conjugated unactivated alkenes react with various nucleophiles to yield the adduct. v To My Parents and Beloved Wife Pinki DEVELOPMENT OF NUCLEOPHILE ASSISTING LEAVING GROUPS AND NEW STEREOSELECTIVE REACTIONS USING TITANIUM(IV) REAGENTS LIST OF FIGURES ......................................................................................................... viii LIST OF TABLES............................................................................................................. ix LIST OF SCHEMES .......................................................................................................... x CHAPTER ONE NEW LEAVING GROUPS - NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) ............................................... 1 1.1 Introduction..................................................................................................... 1 1.2 Nucleophile Assisting Leaving Groups (NALGs).......................................... 2 1.3 The background of NALGs............................................................................ 3 1.4 First aryl sulfonate based NALGs from Lepore’s group: First generation NALGs and their synthesis................................................... 7 1.5 Synthesis of second generation NALGs......................................................... 9 1.6 Results of nucleophilic substitution reactions with lithium bromide ........... 10 1.7 Experimental section..................................................................................... 13 CHAPTER TWO TWO STEP STEREORETENTIVE REACTIONS OF SECONDARY CYCLIC ALCOHOLS USING NALGS AND Ti(IV) REAGENTS............................................................................. 20 2.1 Introduction................................................................................................... 20 2.2 The stereoretentive chlorination reactions.................................................... 21 2.3 Stereoretentive bromination and azidation reactions.................................... 23 2.4 Experimental section..................................................................................... 29 vi CHAPTER THREE ONE-POT STEREORETNTIVE HALOGENATION REACTIONS OF CHIRAL SECONDARY ALCOHOLS CATALYZED BY Ti(IV) HALIDES .......................................................... 35 3.1 Introduction................................................................................................... 35 3.2 The background of chlorination using thionylchloride................................. 35 3.3 Development of very mild stereoretentive chlorination reactions: Results and discussion .................................................................................. 38 3.4 Mechanistic Discussion................................................................................ 47 3.5 Experimental section..................................................................................... 62 CHAPTER FOUR ONE-POT TWO STEP STEREORETENTIVE AMIDATION REACTIONS OF SECONDARY CYCLIC ALCOHOLS ................................................................................................ 67 4.1 Introduction................................................................................................... 67 4.2 Development of stereoretentive amidation reactions: Results and discussion ............................................................................................... 68 4.3 Mechanistic discussion................................................................................. 76 4.4 Experimental section..................................................................................... 79 CHAPTER FIVE TiF4 MEDIATED REACTIONS OF ALKENE WITH NUCLEOPHILES......................................................................................... 87 5.1 Introduction................................................................................................... 87 5.2 Cyclodimerization of styrene: synthesis of indan class of compounds ........ 87 5.3 Addition of nitrile to unactivated alkene ...................................................... 90 5.4 Addition of carboxylic acid to alkene........................................................... 92 5.5 Experimental section..................................................................................... 93 CHAPTER SIX REFERENCES.............................................................................. 96 CHAPTER SEVEN SELECTED SPECTRA........................................................ 101 vii LIST OF FIGURES Figure 1. Methylating agents containing crown ether leaving groups and structure of K222 ............................................................................................ 5 Figure 2. Transition state for methylation of 8 and 10 ................................................... 6 Figure 3. Possible transition state for stereoretentive halogenation and azidation reactions ........................................................................................ 27 Figure 4. General structure of indan class of copounds ............................................... 88 viii LIST OF TABLES Table 1. Bromination reaction times with 3-phenylpropyl substrates containing various leaving groups ...............................................................