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Synthesis of Nitrogen-Containing Heterocycles Via Carbenoid Insertion/Ring-Closing

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Synthesis of Nitrogen-Containing Heterocycles Via Carbenoid Insertion/Ring-Closing Synthesis of Nitrogen-Containing Heterocycles via Carbenoid Insertion/Ring-Closing Metathesis Sequence A dissertation presented to the faculty of the College of Arts and Sciences of Ohio University In partial fulfillment of the requirements for the degree Doctor of Philosophy Oksana M. Pavlyuk June 2011 © 2011 Oksana M. Pavlyuk. All Rights Reserved. 2 This dissertation titled Synthesis of Nitrogen-Containing Heterocycles via Carbenoid Insertion/Ring-Closing Metathesis Sequence by OKSANA M. PAVLYUK has been approved for the Department of Chemistry and Biochemistry and the College of Arts and Sciences by Mark C. McMills Associate Professor of Chemistry and Biochemistry Benjamin M. Ogles Dean, College of Arts and Sciences 3 ABSTRACT PAVLYUK, OKSANA M., Ph.D., June 2011, Chemistry and Biochemistry Synthesis of Nitrogen-Containing Heterocycles via Carbenoid Insertion/Ring-Closing Metathesis Sequence Director of Dissertation: Mark C. McMills A series of five- to nine-membered nitrogen-containing heterocycles were prepared via a general and efficient sequence featuring rhodium-catalyzed insertions of !- diazocarbonyls into the N-H or C-H bonds of a series of tert-butoxy-(Boc)-protected amines, followed by ring-closing metathesis catalyzed by ruthenium benzylidene complexes. The newly developed methodology allows easy and convenient access to highly functionalized azacycloalkenes in good yields and excellent selectivities. Vinyl diazoacetoacetate and styryl diazoacetate were found to undergo exceptionally chemoselective carbenoid insertions into the N-H bonds of a series of Boc- protected amines in good yields; however, no stereoselectivity was observed for this process. In contrast, diastereo- and enantioselective C-H insertions and cyclopropanations were observed for the decomposition of styryl diazoacetate catalyzed by the same rhodium catalyst. Based on these findings, reactivity trends of rhodium carbenoids derived from styryl diazoacetate were postulated. Approved: _____________________________________________________________ Mark C. McMills Associate Professor of Chemistry and Biochemistry 4 To my husband, Dr. Joe Slocik 5 ACKNOWLEDGEMENTS I would like to thank my Ph.D. advisor, Professor Mark Chad McMills for agreeing to oversee my doctoral work. Under Professor McMills’ supervision, I have grown both as a scientist and as a person. During my time in Professor McMills’ group I have acquired invaluable knowledge, and for this priceless experience I will be eternally grateful. I feel that the skills I have learned during my time with Professor McMills have prepared me for the future and the world outside of Athens. I would also like to thank my former undergraduate supervisor, Professor Tomá! Hudlick" for introducing me to the field of organic chemistry and encouraging me to pursue the highest academic degree attainable. I am very thankful to all the present and past group members in Professor McMills’ lab. I would like to gratefully acknowledge Dr. Jason Stengel, who has helped me tremendously when I first joined the group; as well as the future graduates, John Bougher and Alicia Frantz. I would like to thank all the undergraduate research associates, including Ross Humes, Katie Castor, Austin Doyle and John Feltenberger. It has been fun to have the German exchange students and I would really like to thank Henrik Teller and Daniel Becker, with whom I was fortunate to work with. I am grateful to my friends and colleagues, Shannon Cook and Dr. Crina Orac, for sharing our graduate experience together. I would never be able to graduate without my committee members, and I am very grateful they have guided me through my journey. I appreciate advice given by Professor Stephen Bergmeier, as well as various reagents and solvents borrowed from his lab over 6 the years. I am very grateful to Professor Shawn Chen for his valuable discussions and suggestions. I am thankful for Professor Glen Jackson’s patience and understanding. I am very appreciative of the Department and all the people who work here, including Carolyn Khurshid, Marlene Jenkins, Rollie Merriman and many others. My family has always been there for me and I am very thankful for their continuours love and support. Last but not least, I would like to thank my husband, Dr. Joe Slocik. His love and support give meaning to my undertakings and his professional expertise does not hurt either. Joe has always been insistent on me getting my work done during our trips to Panera and although at the time I thought it was ruining our weekends, I know now that my dissertation would not have been written otherwise. I would like to acknowledge Ohio University and Biomolecular Innovation and Technology (BMIT) Group for financial support. 7 TABLE OF CONTENTS Page Abstract................................................................................................................................3 Dedication............................................................................................................................4 Acknowledgments ...............................................................................................................5 List of Abbreviations .........................................................................................................10 List of Figures....................................................................................................................11 List of Schemes .................................................................................................................13 List of Tables .....................................................................................................................15 Chapter 1: Introduction......................................................................................................16 1.1 Olefin Metathesis.........................................................................................................18 1.1.1 General Aspects of Olefin Metathesis ......................................................................18 1.1.2 Historical Perspective ...............................................................................................19 1.1.3 Mechanism and Catalytic Cycle ...............................................................................22 1.1.4 Methodological Studies and Applications in Synthesis ...........................................27 1.1.4.1 Synthesis of 5- to 7-membered Azacycles via RCM.............................................28 1.1.4.2 Synthesis of 8- and 9-membered Azacycles via RCM ..........................................33 1.2 Diazocarbonyl Chemistry ............................................................................................36 1.2.1 General Aspects of Diazocarbonyl Chemistry .........................................................36 1.2.2 Historical Perspective ...............................................................................................42 1.2.3 Mechanism and Catalytic Cycle ...............................................................................44 1.2.3.1 Cyclopropanation Mechanism...............................................................................46 8 Page 1.2.3.2 C-H Insertion Mechanism .....................................................................................48 1.2.3.3 N-H Insertion Mechanism .....................................................................................48 1.2.4 Methodological Studies and Applications in Synthesis ...........................................49 1.2.4.1 Cyclopropanations .................................................................................................50 1.2.4.2 C-H Insertions........................................................................................................52 1.2.4.3 N-H Insertions .......................................................................................................54 Chapter 2: Results and Discussion ....................................................................................57 2.1 Synthetic Strategy........................................................................................................57 2.2 Synthesis of N-containing Heterocycles via N-H Insertion/RCM Sequence ..............59 2.2.1 Preparation of Substrates ..........................................................................................59 2.2.2 Intermolecular N-H Insertions..................................................................................61 2.2.2.1 Acceptor/acceptor-substituted Diazocarbonyls .....................................................65 2.2.2.2 Acceptor/donor-substituted Diazocarbonyls .........................................................67 2.2.3 RCM of N-H Insertion Products...............................................................................69 2.2.3.1 Synthesis of 6- to 9-membered N-containing Heterocycles..................................70 2.2.3.2 Synthesis of 5- to 8-membered N-containing Heterocycles..................................72 2.2.4 One-pot Carbenoid N-H Insertions/RCM.................................................................74 2.3 Synthesis of N-containing Heterocycles via C-H Insertion/RCM Sequence ..............79 2.3.1 Preparation of Substrates ..........................................................................................79 2.3.2 Intermolecular C-H Insertions and Cyclopropanations ............................................79 2.3.3 RCM of C-H Insertion Products...............................................................................85
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