ABSTRACT Title of Dissertation: SYNTHESIS OF FUNCTIONALIZED DIAZOACETOACETATES VIA MUKAIYAMA-TYPE CONDENSATIONS Yu Liu, Doctor of Philosophy, 2012 Dissertation directed by: Professor Michael P. Doyle Department of Chemistry and Biochemistry Mukaiyama-type condensation reactions of 3-tert -butyldimethylsiloxy-2-diazo-3- butenoate and different electrophiles are effective methods for the synthesis of highly substituted diazoacetoacetates. With 0.5-3 mol% of Zn(OTf) 2 as Lewis acid catalyst, Mukaiyama-Michael reactions of vinyldiazoacetates and α,β– unsaturated ketones proceed at ambient temperature to afford functionalized diazoacetoacetates in good yields. By carefully choosing the reaction conditions, both Mukaiyama-Michael adducts in either silyl enol ether form or in ketone form can be synthesized. Addition products obtained from these Mukaiyama-Michael reactions are investigated in dirhodium(II) catalyst induced dinitrogen extrusion reactions. Enedione-diazoester derived from Mukaiyama-Michael reaction of 3-tert - butyldimethylsiloxy-2-diazo-3-butenoate and 4-methoxy-3-bute-2-one can be converted to resorcinol derivatives under base catalysis. This novel transformation was investigated and developed into a synthetic methodology for the preparation of poly-substituted resorcinol compounds. Orthoesters also react with 3-tert -butyldimethylsiloxy-2-diazo-3-butenoate in the presence of Lewis acid catalysts. Diazoacetoacetates that contain acetal functionality can be assembled by these reactions. Rhodium(II) acetate promoted dinitrogen extrusion reactions of these adducts can give β–alkoxycyclbutanone products, which are useful synthons in organic synthesis. SYNTHESIS OF FUNCTIONALIZED DIAZOACETOACETATES VIA MUKAIYAMA-TYPE CONDENSATIONS by Yu Liu Dissertation submitted to the Faculty of the Graduate School of the University of Maryland, College Park in partial fulfillment Of the requirements for the degree of Doctor of Philosophy 2012 Advisory Committee: Professor Jeffery Davis, Chair Professor Michael Doyle Professor Anderi Vedernikov Professor Herman Sintim Professor Srinivasa Raghavan © Copyright by Yu Liu 2012 DEDICATION To my grandfather, Qingyun Liu, and to my parents, Guangxing Liu and Anli Wang ii ACKNOWLEDGEMENTS Now that I am at the finishing line of this journey to a PhD degree, looking back at what I have experienced during this five-year adventure, there are just so many people that I am truly grateful to. I wish I would be able express my deepest appreciation to all these people in this acknowledgement, but I would have to write another chapter in order to do so. Therefore, I will try my best to express my gratitude to those very special individuals in this short paragraph, although what they have done to help and support me in this pursue for a doctoral degree goes well beyond these simple words. First of all, I would like to thank Professor Michael Doyle for his support throughout my graduate study. Mike is such a great mentor that he makes all the effort that I spent on coming to a foreign country far from home, and seeking for guidance and motivation in learning science worthwhile. His passion about science will always be an inspiration for me in my future career. I would like to thank Mike especially for his tremendous effort spent on helping me improve my English writing. I have to admit that reading through a paragraph in English wrote by me is probably not a pleasant thing. However, Mike never gave me up on that. Time and time again, he helped me go through my writing, sentence by sentence, word by word. His dedication, relentlessness and attentiveness to details reflected in this process are truly amazing to me. I know I have say this many times, but I am obligated to say it here one more time: Thanks Mike. Thank you very much for everything you have done for me. iii I would like to thank my undergraduate research advisor Professor Jianbo Wang at Peking University, China. He is the person who opened the door to scientific research for me, and showed the beauty of organic chemistry to me. Professor Wang is really a great scientist, incredible mentor, and very nice person to work with. I am very fortunate to have had the opportunity to work under his directions, and I really benefit from his insights on science, his advice on career development, and many other things. I would like to thank Professor Jeffery Davis, Professor Anderi Vedernikov, Professor Herman Sintim and Professor Srinivasa Raghavan for serving on my committee. It is my great pleasure to have the opportunity to discuss my work with you. I have to say that this long trip to graduation from graduate school would be dreadful without all those fantastic friends that I have run into along the way. I am blessed with so many considerate and supportive friends around me. The first group of people appears in my mind are those I have overlapped with in Doyle Research Group. Thanks to all the post doctoral fellows: Dr Yuanhua Wang, Dr Yu Zhang, Dr Hojae Choi, Dr Emily Mclaughlin, Dr Richard Duffy, Dr Jianhua Xie, Dr Lei zhou, Dr Colin White, Dr Dmitry Shabashov, Dr Ryan Burgin, Dr Xinfang Xu and Dr Charles Shanahan. All of them are very resourceful and extremely helpful, and they are great people to work with. Thanks to other graduate students in Doyle Research Group: Jason Nichols, Deana Jaber, Xiaochen Wang, Maxim Ratnikov, Phong Truong, and Xichen Xu. Working alongside with you folks in the lab through all these years have been a rather pleasant experience. iv Thanks to undergraduate students and visiting students in the group: Noel Jee, Grace Chiou, Kanwarpal Bakshi, Arnold Romero Bohorquez, Carolin Weigl, Petra Goldmann, Barbara Steingenberger, and Yu Qian. I would like to thank Noel and Kanwarpal (Paul) particularly since they worked together with me. Thank you for your enthusiasm and hard work. It is my pleasure to be your mentor in the research lab. I consider myself lucky to be a member of a very lively class of graduate students came to the Chemistry Department in 2006. There are many names and familiar faces come out from my memory at this point: Dennis, Matt, Fred, Derrick, Irene, Catherine, Seth, Chengyun, Jingxin, Jinxi. sorry I can’t name all of you here, but I just want to say thanks to all of you. With your company, all the classes, exams, presentations that we had to go through were not that bad. I would like to thank the Chinese community in the Chemistry Department. I have already mentioned many of them, but there are still a few more to add: Dr Huan Wang, Dr Yang Liu, Jing Wu, Jia Liu, Sijia Qin, and Xiaoyu Wang. Chinese people would say it is yuan fen that we are able to get together in the U.S. far from our home country. I am really glad that I had the chance to know all of you. Since you are all here with me, I rarely feel lonely although I am far away from home. Last but not least, I would like to thank all my family members, especially my father Guangxing Liu and my mother Anli Wang. Thank you so much for your encouragement and support over the years. Even though you are on the other v side of the earth, I know that your hearts are always here with me. It is your love that carries me through this adventure, and gives me confidence to continue moving forward from here on. vi TABLE OF CONTENTS Dedications.............................................................................................................ii Acknowledgement.................................................................................................iii Table of Contents.................................................................................................vii List of Tables.......................................................................................................xiv List of Figures......................................................................................................xvi List of Schemes.................................................................................................xviii Chapter 1: Mukaiyama-Michael Additions of vinyldiazoacetate with α,β–Unsaturated Ketones....1 1.1 Introduction.....1 1.1.1 Structure and Reactivity of Dazocarbonyl Compounds...........1 1.1.2 Different Categories of Diazocarbonyl Compounds................6 1.1.2.1 Diazoketones....................................................................7 1.1.2.2 Diazoacetates...............................................................8 1.1.2.3 Diazoacetoacetates.................................................12 1.1.3 Synthesis of Functionalized Diazoacetoacetates...............14 1.1.3.1 Synthesis of Functionalized Diazoacetoacetates from β-Ketoesters........................................................15 1.1.3.2 Synthesis of Functionalized Diazoacetoacetates from Diazoacetates......................................................17 1.1.3.3 Synthesis of Functionalized Diazoacetoacetates from Diazoacetoacetic Acid........................................18 1.1.3.4 Synthesis of Functionalized Diazoacetoacetates vii from Vinyldiazoacetates..............................................19 1.1.4 Mukaiyama-aldol Reactions of vinyldiazoacetates.............23 1.2 Results and Discussion.........................................................28 1.2.1 Previous Results (work done by Dr Yu Zhang)....29 1.2.1.1 General Information.. ......29 1.2.1.2 Catalyst Screening..........................30 1.2.1.3 Substrate Scope of α,β–Unsaturated Ketones 47 .......32 1.2.1.4 Mechanistic Perspective......34 1.2.2 Discovery and Synthesis of Diazoacetoacetate