Boronate Urea Activation of Nitro Compounds A Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Sonia Sung Young So, B. S. Graduate Program in Chemistry The Ohio State University 2014 Committee: Professor Anita E. Mattson (Advisor) Professor Craig J. Forsyth Professor Jovica Badjic Copyright by Sonia Sung Young So 2014 Abstract Boronate ureas have been discovered as enhanced hydrogen bond donor (HBD) catalysts for the activation of various compounds containing nitro functional groups. The enhanced ability of boronate ureas to recognize and activate nitro compounds can be attributed to the internal coordination of the strategically placed boron to the urea carbonyl. Boronate ureas have elicited rate enhancements of up to 10 times that of traditional urea and thiourea HBD catalysts in the known addition of nitrogen heterocycles to nitroalkenes. This improvement in urea catalyst activity has allowed for the discovery of two new methodologies. The urea activation of nitrocyclopropane carboxylates was discovered for nucleophilic ring opening by amine nucleophiles. The facile formation of !–amino acid precursors from nitrocyclopropane carboxylate precursors had never before been reported with HBD catalysts. This novel activation of nitrocyclopropane carboxylates led to the discovery of formal [3+3] dipolar cycloaddition reactions with nitrones for the efficient construction of oxazinanes. Additionally, boronate ureas have been demonstrated to activate nitrodiazoester compounds for N–H insertion/multicomponent coupling of anilines for the formation of !-aryl glycine compounds. Chiral phosphoric acid HBD catalysts were utilized for activation of nitrodiazoesters for stereoselective glycine formation. This methodology was expanded to develop double arylation of nitrodiazoesters through a transient N–H insertion intermediate. ii Dedication Everything leading up to and including this work is dedicated to my mom, whose patience and strength are never ending. This work is also dedicated to my husband for his support and encouragement through it all. iii Acknowledgments I would like to first thank my Ph.D. advisor, Professor Anita Mattson, for giving me the opportunity to achieve one of my life goals. Anita’s guidance and support has been integral in my development as a chemist and I am grateful for the knowledge she has imparted on me. I would like to thank Professor James Stambuli for being an advisor and an invaluable resource. I would also like to thank my undergraduate research advisor, Dr. Hamish Christie, without whom I never would have pursued chemistry. I respect and appreciate his mentorship and counsel and will continue to email him with the subject line, “update.” I would be remiss if I did not acknowledge the impact my friendships have made on my experience in graduate school and in life. I must thank Tyler, who was there from the beginning, studying, columning, complaining right alongside me, for being like a brother to me through all the ups and downs. We made it. I want to thank all my friends, especially Erica, for making grad school a little easier. I will always cherish the memories of laughing uncontrollably, talking to Kamala, racing to grab the fire extinguisher, hearing Moke’s version of historical events, going to Moy’s, the movie theater laugh, that weird noise at group meeting, Josh’s story about the Hard Rock Café, the world’s most awkward elevator ride, that time I added rhodium to my vial, and so iv many more. And, of course, I want to thank Elaine, for being so supportive and being the ultimate friend through the best and worst of it. I want to take this opportunity to thank my brother, Victor, for taking on the role of an entire family, for raising me, protecting me, and for making sacrifices no one should have to…and now that it is all done, for being my friend. I will never be able to thank my mom enough for showing me unconditional love and support. She has been an inspiration to me throughout my life and, after everything, continues to impress me. Finally, I want to thank my husband, Tommy, for listening, advising, and showing me how to be who I want to be. He is ever patient and supportive, but true enough to tell me when I am wrong. He is the most important voice in my life, and I turn to him for science, math, history, song lyrics, and nearly everything else. v Vita May 2005 ........................................................................................... Mesquite High School May 2009 ................. B.S. Biochemistry and Molecular Biophysics, University of Arizona 2009 to present ....................... Graduate Program of Chemistry, The Ohio State University Publications • So, S. S.; Mattson, A. E. “Stereoselective N–H Insertion-Arylation Reactions of Nitrodiazoesters” Asian J. Org. Chem. 2013. DOI: 10.1002/ajoc.201300285. Invited contribution. • So, S. S.; Oottikkal, S.; Badjic, J.; Hadad, C. M.; Mattson, A. E. “Urea-Catalyzed Activation of Nitrodiazoesters for N-H Insertion Reactions” J. Org. Chem. 2013. Submitted. • Auvil, T. J.; So, S. S.; Mattson, A. E. “Double Arylation of Nitrodiazo Compounds Catalyzed by a Urea/Aniline Combination” Angew. Chem. Int. Ed. 2013. 52, 11317- 11320. (Highlighted in SynFacts) • Hardman, A. M.; So, S. S.; Mattson, A. E. “Formal [3+2] Dipolar Cycloaddition Reactions of Nitrocyclopropane Carboxylates” Org. Biomol. Chem. 2013, 11, 5793- 5797 • Nickerson, D. M.; Angeles, V. V.; Auvil, T. J.; So, S. S.; Mattson, A. E. “Internal Lewis Acid Assisted Ureas: Tunable Hydrogen Bond Donor Catalysts” Chem. Commun. 2012, 49, 4289-4291. Invited Contribution • So, S. S.; Mattson, A. E. “Urea Activation of !-Nitrodiazoesters: An Organocatalytic Approach to N–H Insertion Reactions” J. Am. Chem. Soc. 2012, 134, 8798-8801. (Highlighted in SynForm, Highlighted in SynFacts) vi • So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. “Boronate Urea Activation of Nitrocyclopropanes” Org. Lett. 2012. 14, 444-447. (Highlighted in SynFacts) • So, S. S.; Burkett, J. A.; Mattson, A. E. “Internal Lewis Acid Assisted Hydrogen Bond Donor Catalysis” Org. Lett. 2011, 4, 716-719. Fields of Study Major Field: Chemistry Organic Chemistry vii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iii Acknowledgments .............................................................................................................. iv Vita ..................................................................................................................................... vi List of Tables ................................................................................................................... xiii List of Figures ................................................................................................................... xv List of Schemes ............................................................................................................... xvii Chapter 1: Boronate Ureas as Enhanced Hydrogen Bond Donor Catalysts ....................... 1 1.1 Dual Hydrogen Bond Donor Catalysts: A History ................................................... 1 1.1.1 Ureas and Thioureas in HBD Catalysis ............................................................. 3 1.1.2 Recent Advances in Asymmetric Dual HBD Catalysis ..................................... 6 1.1.3 Enhanced HBD Catalysts ................................................................................. 10 1.2 Ureas For Molecular Recognition ........................................................................... 15 1.2.1 Boronate Ureas for Molecular Recognition ..................................................... 18 1.3 Internal Lewis Acid-Assisted Boronate Urea Catalysts .......................................... 20 1.3.1 Preparation of Boronate Ureas ......................................................................... 21 viii 1.3.2 Examination of Boronate Urea Structure and Features with Select NMR Spectra ....................................................................................................................... 23 1.4 Activation of Nitroalkenes for Conjugate Addition ................................................ 28 1.4.1 Scope of Addition of Nitrogen Heterocycles to Nitroalkenes ......................... 31 1.4.2 Investigation into the Relative Rates of Urea Catalysts ................................... 32 1.4.3 Asymmetric Addition to Nitroalkenes Using Chiral Boronate Ureas ............. 33 1.5 Activation of Nitrocyclopropane Carboxylates ...................................................... 34 1.5.1 Development of Nucleophilic Ring-Opening Reactions ................................. 36 1.5.2 Scope of Nucleophilic Ring-Opening Reactions ............................................. 39 1.5.3 Investigations into the Proposed Reaction Pathway ........................................ 41 1.5.4 Synthesis of 3-(1-Methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino)-5-(3- trifluoromethyl-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one ............... 43 1.6 Formal [3+3] Dipolar Cycloadditions ..................................................................... 45 1.6.1 Dipolar Cycloadditions of 1,1-Diestercyclopropanes .....................................