Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2009 5-Endo-Dig Cyclization of a Carbon- Centered Radical and Utility of Cyclopentene Bromosulfone Product Jason Nathaniel Abrams Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES 5-ENDO-DIG CYCLIZATION OF A CARBON-CENTERED RADICAL AND UTILITY OF CYCLOPENTENE BROMOSULFONE PRODUCT By JASON N. ABRAMS A Dissertation submitted to the Department of Chemistry & Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Fall Semester, 2009 The members of the committee approve the dissertation of Jason N. Abrams defended on July 22, 2009. ___________________________________ Igor Alabugin Professor Directing Dissertation ___________________________________ William Landing University Representative ___________________________________ Gregory Dudley Committee Member ___________________________________ Brian Miller Committee Member Approved: __________________________________ William Copper, Assistant Chair, Department of Chemistry and Biochemistry __________________________________ Joe Travis, Dean, College of Arts and Sciences The Graduate School has verified and approved the above-named committee members. ii ACKNOWLEDGEMENTS I would like to acknowledge fellow graduate student Abdul Baroudi who performed the computational calculations on reaction energies for the tandem Claisen/Cope rearrangement followed by endocyclic double bond isomerizations as well as David Jones for help in interpreting the spectra of this product. I would like to thank Dr. Vitaliy Tymokhin for his significant efforts on our 5-endo-dig radical cyclization project. Special thanks to Dr. Ion Ghiviriga of the University of Florida and Dr. Tom Gedris of Florida State University who provided NMR spectroscopic interpretation for our 5-endo-dig radical cyclization products, as well as Professor Ronald Clark of Florida State University who performed X-ray crystallographic analysis on some of our compounds. Finally I would like to acknowledge Professor Igor Alabugin as a mentor, my research group, and the chemistry faculty at Florida State University. iii TABLE OF CONTENTS List of Tables……………………………………………………………………………………………..vii List of Figures……………………………………………………………………………………………viii Abstract…………………………………………………………………………………………………..xvi Chapter 1: Introduction: 5-Endo Cyclization…………………………………………………………...1 1.1 Examples of 5-Endo-Dig cyclization .................................................................................... 4 Chapter 2: Our Initial Studies on Digonal Systems .................................................................................................................................................... 15 2.1 Attempts to Induce 6-Endo-Dig Cyclization with a Carbon-Centered Radical ................................................................................................................................................ 18 2.2 Computational Studies of Ideal Substrates for undergoing 5-Endo-Dig Cyclization ................................................................................................................................................ 21 2.3 Preparation of Substrate for Subsequent 5-Endo-Dig Cyclization with In Situ Generated Carbon-Centered Radical ………………………………………………………………………………………………………. 23 Chapter 3: 5-Endo-Dig Cyclization Attempts with Tethered Carbon-Centered Radicals ................................................................................................................................................. 25 3.1 Cyclization Attempts with Alkyl Radicals ................................................................................................................................................ 25 3.2 Preparation of Substrates which can Generate Vinyl Radicals ............................................................................................................................................. 25 3.3 Different Radical Sources which can attack Alkynes and Generate Vinyl Radicals for 5- Endo-Dig Cyclization . ............................................................................................................................................ 31 3.4 Initial Success in forming Products from 5-Endo-Dig Cyclization with Carbon-Centered Radical ................................................................................................................................................ 32 iv 3.5 Breakthrough Discovery in First Efficient 5-Endo-Dig Cyclization with Carbon-Centered Radical ................................................................................................................................................ 33 3.6 Mechanistic Rationale for Efficient 5-Endo-Dig Cyclization with Carbon-Centered Radical ................................................................................................................................................ 35 3.7 Optimization of Conditions for 5-Endo-Dig Cyclization ................................................................................................................................................ 36 Chapter 4: Alternative Mechanistic Scenarios in Lieu of 5-Endo-Dig Cyclization Pathway .................................................................................................................................................... 43 4.1 Ring-expansion of 4-exo-products ............................................................................................................................................. 44 Chapter 5: Construction of Other Diyne Systems for Undergoing 5-Endo-Dig Cyclization .................................................................................................................................................... 47 Chapter 6: Synthesis of Vinyl Sulfones: Literature Background .................................................................................................................................................... 67 6.1 Literature Methods for the Preparation of Vinyl Sulfones ................................................................................................................................................ 69 Chapter 7: Literature Transformations of Vinyl Sulfones .................................................................................................................................................... 78 7.1 Other Vinyl Sulfone Transformations/ Removal ................................................................................................................................................ 84 Chapter 8: Biomedical Applications: Vinyl Sulfones as Biological Warheads .................................................................................................................................................... 89 Chapter 9: Methodologies Incorporating the Vinyl Sulfone Moiety .................................................................................................................................................... 92 Chapter 10: Vinyl Sulfone Methodology Used Towards Natural Product Syntheses .................................................................................................................................................... 98 Chapter 11: Discussion of Properties of our Cyclopentene Bromosulfone Product .................................................................................................................................................. 102 Chapter 12: Successful Reactions with Acetonide Protected Cyclopentene Bromosulfone .................................................................................................................................................. 105 Chapter 13: Tandem Reactions with Acetonide Protected Cyclopentene Bromosulfone .................................................................................................................................................. 116 v 13.1 Computations for Predicting the Product of Allyl Vinyl Ether Rearrangement Under Thermal Conditions .............................................................................................................. 126 13.2 Attempts at Thermal Rearrangement of Allyl Amine Product .............................................................................................................................................. 127 13.3 Other Successful Reactions with Carbon-Centered Nucleophiles .............................................................................................................................................. 129 Chapter 14: Unusual Product Formation .................................................................................................................................................. 130 Chapter 15: Sulfone Removal .................................................................................................................................................. 134 Chapter 16: Compounds with Best Utility .................................................................................................................................................. 136 Chapter 17: Summary of Successful Reactions with Acetonide Protected Cyclopentene Bromosulfone .................................................................................................................................................