ABSTRACT JANG, YUJIN. Synthesis of 1-Sulfonylcyclopropanols and Their Application in New Chemical Transformations as Powerful Cyclopropanone Equivalents. (Under the direction of Dr. Vincent Lindsay). Cyclopropanone, a notoriously strained cycloalkanone (Baeyer strain ca. 49 kcal/mol), is a promising three carbon building block in organic synthesis where all three C–C bonds are labile, and can be readily involved in ring-opening or ring-expansion. Despite its tremendous potential as a strained reagent, the difficulties associated with its handling and storage have precluded its widespread use in organic synthesis. For these reasons, a majority of cyclopropanone chemistry in the literature involves the use of equivalents such as hemiketals that can equilibrate to the parent ketone in situ via base-induced α-elimination. Although the classical hemiketals are suitable in some reactions, a number of potential transformations are still inaccessible, as harsh conditions are often required to generate cyclopropanone due to the poor leaving group ability of alkoxides and the immense strain generated in the process. In order to elevate the chemistry of cyclopropanones as common building blocks in synthesis, well-behaved cyclopropanone precursors are highly demanded. Here, we describe the efficient and convenient synthesis and application of unsubstituted 1-sulfonylcyclopropanols as powerful cyclopropanone equivalents. By tuning the electronic and steric nature of leaving group, a variety 1-sulfonylcyclopropanols were furnished, and the relative propensity of their equilibration to cyclopropanone was investigated in a novel pyrazole substitution reaction. With this well-behaved class of surrogates, we explored the C–C bond activation of this strained cycloalkanone in the presence of transition metals and organocatalysts. As a result, we discovered a new Ni-catalyzed [3+2] cycloaddition of cyclopropanone and internal alkynes, affording 2,3-disubstituted cyclopentenones with complete regiocontrol. Notably, the products formed are analogous to the ones obtained in the classical Pauson-Khand reaction, but with reverse regiocontrol. In addition, we studied the NHC-umpolung chemistry of cyclopropanone to achieve formal cycloaddition via C–C activation. We currently obtained several NHC-cyclopropanone adducts in moderate to good yield and further investigation of this novel class of compounds will be conducted in the future to understand their reactivity towards cycloaddition. Considering the importance of fluorine in the field of medicinal chemistry, life sciences and agrochemicals, the development of selective fluorination is urgent. We discovered selective formal β-fluorination of carboxylic derivatives via oxidative ring opening-fluorination of cyclopropanone equivalents. Here, we adopted pyrazole as a transient leaving group, which allows further functionalization of the carboxylic derivatives obtained. © Copyright 2021 by Yujin Jang All Rights Reserved Synthesis of 1-Sulfonylcyclopropanols and Their Application in New Chemical Transformations as Powerful Cyclopropanone Equivalents. by Yujin Jang A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemistry Raleigh, North Carolina 2021 APPROVED BY: _______________________________ _______________________________ Dr. Vincent Lindsay Dr. Jonathan Lindsey Committee Chair _______________________________ _______________________________ Dr. Joshua Pierce Dr. Caroline Proulx DEDICATION I would like to dedicate this work to my parents. Without their lifelong support, I would never have reached this goal. ii BIOGRAPHY Yujin Jang was born and raised in Seoul, South Korea. She received her B.S. in Chemistry in 2010 and M.S. in Chemistry in 2012 from Kwangwoon University (South Korea), where she worked with Prof. Heung-bae Jeon, developing new synthetic methodologies for the synthesis of 1,2,3-triazoles and bistriazoles, and for the deoxygenation of sulfoxides. In 2012, she worked at Korea Institute of Ocean Science and Technology (KIOST) and conducted research on isolation of natural products and identification of their chemical structure as well as biological activities. From August 2014 until April 2016, she was a visiting scholar at the University of Kentucky, working with Prof. Kyung-Bo Kim on the development of a novel proteasome inhibitors with anti-cancer properties. She came to NC State University in August 2016 and joined the Lindsay lab, where she is working on the synthesis of 1-sulfonylcyclopropanols as cyclopropanone precursors and using them to design and develop new chemical transformations. iii ACKNOWLEDGMENTS I would like to express my deep gratitude to my advisor, Dr. Vincent Lindsay for his wonderful mentoring and advising me for the past five years, and for providing me a good research environment. I have learned a lot of things from him, and I would never have reached this goal without his support. I am also grateful to all my fellow group members for their help and sharing ideas for projects, and especially thanks to Roger Machín Rivera for helping me a lot and making it possible to work in a pleasant environment. I would like to thank Dr. Jonathan Lindsey, Dr. Joshua Pierce, Dr. Caroline Proulx and Dr. Emiel DenHartog for their willingness to serve on my committee and supporting my doctoral training. Lastly, I sincerely thank my family, especially my husband. iv TABLE OF CONTENTS LIST OF TABLES ....................................................................................................................... vii LIST OF FIGURES .................................................................................................................... viii LIST OF SCHEMES..................................................................................................................... ix LIST OF ABBREVIATIONS ........................................................................................................ x Chapter 1: General Introduction ............................................................................................... 1 1.1: Introduction to Strained Ring Systems ................................................................................... 1 1.2: Introduction to Cyclopropanone and its Derivatives .............................................................. 3 Chapter 2: Synthesis of 1-Sulfonylcyclopropanols and Kinetic Study of Their Equilibration to Cyclopropanone 2.1: Introduction to Cyclopropanone Equivalents ......................................................................... 6 2.1.1: Synthetic Approaches to Cyclopropanone Hemiketals ................................................. 7 2.2: Synthesis of 1-Sulfonylcyclopropanols .................................................................................. 9 2.3: Kinetic Study of Unsubstituted 1-Sulfonylcyclopropanols .................................................. 14 2.4: Conclusion ............................................................................................................................ 18 2.5: Experimental Details ............................................................................................................ 18 Chapter 3: Synthesis of 2,3-Disubstituted Cyclopentenones via Ni-Catalyzed C–C Activation of Cyclopropanone 3.1: Introduction to C–C bond Activation ................................................................................... 30 3.1.1: Transition Metal Catalyzed C–C Activation of Cyclobutanone .................................. 31 3.2: Investigation of Formal [3+2] Cycloaddition of Cyclopropanone ....................................... 32 3.3: Optimization of the Formation of Cyclopentenones ............................................................ 35 3.4: Scope of Accessible 2,3-Disubstituted Cyclopentenones..................................................... 41 3.5: Mechanistic Insights ............................................................................................................. 43 3.6: Conclusion ............................................................................................................................ 44 3.7: Experimental Details ............................................................................................................ 45 Chapter 4: NHC-Catalyzed Formal Cycloaddition of Cyclopropanone via Umpolung 4.1: Introduction to N-Heterocyclic Carbenes in Organocatalysis .............................................. 59 4.2: Introduction to Donor-Acceptor Cyclopropanes .................................................................. 60 4.2.1: Formal Cycloaddition of Donor-Acceptor Cyclopropanes ......................................... 61 4.3: Optimization of the Formation of NHC-Cyclopropanone Adducts ..................................... 64 4.4: Scope of Accessible NHC-Cyclopropanone Adducts .......................................................... 67 4.5: Evaluation of NHC Adducts toward Formal Cycloaddition ................................................ 68 4.6: Future Work .......................................................................................................................... 69 4.7: Conclusion ............................................................................................................................ 71 4.8: Experimental Details ..........................................................................................................