DEVELOPMENT AND APPLICATIONS OF NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) WITH TITANIUM (IV) AND GRIGNARD REAGENTS by Songye Li 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 August 2011 DEVELOPMENT AND APPLICATIONS OF NUCLEOPHILE ASSISTING LEAVING GROUPS (NAI.JGS) WITI-I TITANIUM (IV) AND GRIGNARD REAGENTS by Songye Li 1'his dissertation was prepared under the direction of the candidate's dissertation advisor, Dr. Salvatore- D. Lepore, Department of Chemistry and Biochemistry, and .has been approved by the members of her supervisory cornmittee.. It was submitted to the faculty of the Charles E. Schmidt College of Science and was accepted in partial fulfillment of the requirements for the degree ofDoctor ofPhilosophy'. SUPERVISORY COMMITTEE: _~~~ -J! In-/)~_ Dr. Salvatore D. Lepor~1 D.issertation Advisor '-"~'~~~~--'~'JZ(~~~L.,J'L-~ Dr. Guodong Sui -=--_.- fl;a!~4. r Cy Parkanyi, Ph.D. Chair, Depa en fCh y and Biochemistry Gary W. Perry, Ph.D. Dean, The Charles E. Schnlidt ollege ofScien.ce ~n:? 7~~ .__..._~._. __ Barry T. Rosson, Ph.D. Dean, Graduate College 11 ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. Salvatore D. Lepore, for his excellent guidance throughout my PhD. Dr. Lepore is truly an outstanding mentor that anyone could ask for. He taught me not only the philosophy of chemistry and also the philosophy of being a person. His talent, passion and motivation in chemistry and his kind personality have always inspired and will inspire me in the future. I want to thank my committee professors Cyril Parkanyi, 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 Deboprosad, Pradip and Mohammad for their help and friendship. I wish to express my thanks to all my family and friends who have continually supported me. The endless support, care and love from my grandparents, my parents, my brother and my sister-in-law are always the mainstay in my life. I sincerely appreciate their help and affection, I cannot achieve what I have today without them. iii ABSTRACT Author: Songye Li Title: Development and Applications of Nucleophile Assisting Leaving Groups (NALGs) with Titanium (IV) and Grignard Reagents Institution: Florida Atlantic University Thesis Advisor: Dr. Salvatore D. Lepore Degree: Doctor of Philosophy Year: 2011 We report here the development of very efficient aryl- and quinolinyl- sulfonate based leaving groups, termed Nucleophile Assisting Leaving Groups (NALGs), which substantially accelerate the rate of nucleophilic substitution reactions with metal halides. Detailed synthesis and kinetics study are described herein. Our synthesized NALGs have shown great reactivity towards poor nucleophiles and/or substrates traditionally considered too hindered to undergo nucleophilic attack. The abundant existence of halide, azide and amine in natural products demands new synthetic pathway. To fulfill this requirement, new mild stereoretentive halogenations (chlorination, bromination and iodination) reactions have also been developed for secondary cyclic alcohols using NALGs involving titanium (IV) reagents. iv The novel methodology can be extended to Azidation reactions as well with titanium (IV) azide, in which Ti (N3)4 is the first time being engaged in organic synthesis. Beased on the NALGs theory we discover the chlorosulfite can be a simplest NALG and applied as the intermediate in mild 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. Finally, an efficient mild bromination and iodination reaction for primary and secondary alcohols with Grignard reagents is also reported. This reaction exhibits the generality with substrates with various leaving groups. The important features of this reaction are that, for the first time, bromide formation using Grignard reagents without the Cu (I) catalysts. v SYNTHESIS OF NUCLEOPHILE ASSISTING LEAVING GROUPS AND NEW APPLICATIONS FOR TITANIUM (IV) AND GRIGNARD REAGENTS LIST OF FIGURES ........................................................................................................... ix LIST OF TABLES ...............................................................................................................x LIST OF SCHEMES.......................................................................................................... xi CHAPTERS 1. NUCLEOPHILE ASSISTING LEAVING GROUPS (NALGS) AND RADIOFLUORINATIONS .............................................................................................1 1.1 Leaving groups.....................................................................................................1 1.2 Sulfonate and carboxylate leaving groups ...........................................................3 1.3 Chiral leaving groups ...........................................................................................7 1.4 Organometallic leaving groups ............................................................................9 1.5 Heterocyclic leaving groups ..............................................................................10 1.6 The background of NALGs ...............................................................................11 1.7 Nucleophile Assisting Leaving Groups (NALGs) ............................................15 1.8 Nucleophilic substitutions ..................................................................................19 1.9 Pyridine and quinoline sulfonate based leaving groups .....................................21 1.10 Current progress of radiofluorination ................................................................23 vi 2. SYNTHESIS AND KINETICS STUDY ON ESTER, ETHER AND QUINOLINE-SULFONATE BASED NALGS AND COLLABORATION WITH NIH .....................................................................................................................27 2.1 First generation of aryl sulfonate based NALGs ..............................................27 2.2 Reactivity and kinetics study of first generation NALGs ..................................29 2.3 Synthesis of second generation NALGs ............................................................42 2.4 Synthesis of quinoline-sulfonate based NALGs ................................................45 2.5 Synthesis of other related NALGs .....................................................................49 2.6 Results of nucleophilic substitution reactions with lithium bromide.................51 2.7 Collaboration with NIH .....................................................................................55 2.8 Metal selectivity with HSAB theory ..................................................................57 2.9 Experimental section ..........................................................................................59 3. STEREORETENTIVE REACTIONS OF SECONDARY CYCLIC ALCOHOLS USING NALGS AND TI(IV) REAGENTS ...........................................66 3.1 Bromination and azidation with Titanium (IV) reagents ...................................66 3.2 Iodination reaction with Ti (IV) reagents ..........................................................74 3.3 Stereoretentive chlorination with chlorosulfite ..................................................77 3.4 Experimental section ..........................................................................................92 4. NEW APPLICATIONS WITH GRIGNARD REAGENTS ........................................100 4.1 Introduction of Grignard reagents ....................................................................100 4.2 Cuperate reagents facilitated carbon-carbon bond formation ..........................101 4.3 Grignard and Titanium reagents facilitated carbon-carbon bond formation ...103 4.4 Grignard substrates used as brominating reagents with the aid of Cu (I) .......106 vii 4.5 Mild bromination reaction without the addition of Cu (I) catalyst ..................106 4.6 Experimental section ........................................................................................110 5. SELECTED SPECTRA ...............................................................................................112 REFERENCES ................................................................................................................127 viii LIST OF FIGURES Figure 1 Methylating agents containing crown ether leaving groups and structure of K222 .............................................................................................13 Figure 2 Transition states for methylation reaction of a and c .......................................14 Figure 3 The hypothesis of new NALGs ........................................................................17 Figure 4 Pentavalent transition state for a bimolecular substitution reaction .................20 Figure 5 First order plot for the reactions that one of the reactants is in excess .............34 Figure 6 The second order plot for the reaction of NALG with lithium iodide ..............35 Figure 7 The crystal structure of the sodium salt of the tri (ethylene glycol) NALG 8 ...........................................................................................................44 Figure