University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2019 Part I: The Study Of 2-Aryl-1,3-Dithiane Derivatives As Pronucleophiles In Palladium-Catalyzed Allylic Alkylation And Propellylation Part Ii: Ligand-Free Palladium-Catalyzed Allylic Amintion Of Hydrazone Derivatives Part Iii: Synthesis Of Criegee Intermediate Precursors Nisalak Trongsiriwat University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Inorganic Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Trongsiriwat, Nisalak, "Part I: The Study Of 2-Aryl-1,3-Dithiane Derivatives As Pronucleophiles In Palladium-Catalyzed Allylic Alkylation And Propellylation Part Ii: Ligand-Free Palladium-Catalyzed Allylic Amintion Of Hydrazone Derivatives Part Iii: Synthesis Of Criegee Intermediate Precursors" (2019). Publicly Accessible Penn Dissertations. 3502. https://repository.upenn.edu/edissertations/3502 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3502 For more information, please contact [email protected]. Part I: The Study Of 2-Aryl-1,3-Dithiane Derivatives As Pronucleophiles In Palladium-Catalyzed Allylic Alkylation And Propellylation Part Ii: Ligand-Free Palladium-Catalyzed Allylic Amintion Of Hydrazone Derivatives Part Iii: Synthesis Of Criegee Intermediate Precursors Abstract Chapter 1 and 2 detail studies of 2-aryl-1,3-dithianes as pronucleophiles in palladium-catalyzed allylic alkylation and propellylation to access skeletally diverse aryl alkyl ketone cores. Allylic carbonate and [1.1.1]propellane electrophiles successfully couple with in situ generated 2-sodio-1,3-dithiane nucleophiles to afford the corresponding products in good to excellent yields. Deprotection of these products leads to valuable aryl alkyl ketones. The palladium-catalyzed allylic alkylation of 2-aryl-1,3-dithianes is examined in chapter 1. A direct synthesis of ????unsaturated ketones via a one-pot allylation-oxidation protocol is also presented. Additionally, the utility of this method is demonstrated through a sequential one-pot allylation-Heck cyclization to produce asterogynin derivatives which are important bioactive compounds in medicinal chemistry. Chapter 2 discloses a general method for the synthesis of bicyclo[1.1.1]pentane (BCP)-containing dithianes which, upon deprotection, provide access to BCP analogues of medicinally abundant diarylketones. Transformation of the dithiane part into a variety of functional groups such as BCP aryl difluoromethanes and BCP esteare demonstrated. A computational study indicates that the reaction of 2-aryl-1,3-dithianes and [1.1.1]propellane proceeds via a two-electron pathway. Chapter 3 focuses on a protocol for ligand-free palladium catalyzed allylic amination of in situ generated hydrazone nucleophiles at room temperature. This method is effective and applicable for a variety of hydrazones in excellent yields and also economical due to low palladium loading and ligand-free conditions. In addition, we demonstrated an example of tandem allylation-Fischer indole cyclization to afford the core structure of antifungal drug. In chapter 4, we introduce detailed on novel synthesis of (Z/E)-1,3-diiodobut-2-ene and (E)-1,3-diiodo-2-methylprop-1-ene which are considered as precursors of Criegee intermediates methyl vinyl ketone oxide (MVK-oxide) and methacrolein oxide (MARC-oxide) respectively. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Chemistry First Advisor Patrick J. Walsh Subject Categories Inorganic Chemistry | Organic Chemistry This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/3502 PART I: THE STUDY OF 2-ARYL-1,3-DITHIANE DERIVATIVES AS PRONUCLEOPHILES IN PALLADIUM-CATALYZED ALLYLIC ALKYLATION AND PROPELLYLATION PART II: LIGAND-FREE PALLADIUM-CATALYZED ALLYLIC AMINTION OF HYDRAZONE DERIVATIVES PART III: SYNTHESIS OF CRIEGEE INTERMEDIATE PRECURSORS Nisalak Trongsiriwat A DISSERTATION in Chemistry Presented to tHe Faculties of tHe University of Pennsylvania in Partial Fulfillment of tHe ReQuirements for tHe Degree of Doctor of PhilosopHy 2019 Supervisor of Dissertation ______________ Dr. Patrick J. WalsH, Professor of Chemistry Graduate Group CHairperson _________________ Dr. David W. Christianson, Roy and Diana Vagelos Professor in Chemistry and Chemical Biology Dissertation Committee Dr. Virgil Percec, P. Roy Vagelos Professor of Chemistry Dr. Ivan J. DmocHowski, Alan G. MacDiarmid Professor of Chemistry Dr. Neil C. Tomson, Assistant Professor of Chemistry PART I: THE STUDY OF 2-ARYL-1,3-DITHIANE DERIVATIVES AS PRONUCLEOPHILES IN PALLADIUM-CATALYZED ALLYLIC ALKYLATION AND PROPELLYLATION PART II: LIGAND-FREE PALLADIUM-CATALYZED ALLYLIC AMINTION OF HYDRAZONE DERIVATIVES PART III: SYNTHESIS OF CRIEGEE INTERMEDIATE PRECURSORS COPYRIGHT 2019 Nisalak Trongsiriwat This work is licensed under tHe Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of tHis license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ To my family iii ACKNOWLEDGMENTS I would like to thank my advisor, Prof. Patrick J. WalsH for giving me the opportunity to join His laboratory. I first came at UPenn as a visiting scholar and got an opportunity to work witH Him for tHree montHs. WitHin tHat period of time, I learnt not only cHemistry knowledge from him, but also, the way to do research, to think chemistry. These encouraged me coming back as a graduate student in his laboratory. I really appreciate his support and his generous guidance throughout my graduate career. In past four years, Pat gave me tHe freedom in researcH, so I can pursue every interesting direction from my work. I wisH I can be sucH a good mentor as Him in tHe future. Being a part of tHe WalsH group has been a great honor and I will enjoy watching the lab develop during the upcoming years. I would like to thank my dissertation committee members, Professor Virgil Percec, Professor Ivan J. DmocHowski and Professor Neil C. Tomson for tHeir kind support and helpful suggestions over past three years. A special thanks to Professor Marisa Kozlowski for her helpful suggestions in joint group meeting and Professor Marsha Lester for her kind support on our collaboration. I would also like to thank all members in WalsH group and alumni for making our laboratory a great working environment. It Has been sucH a pleasure to work with these people. First, I would like to thank Dr. Jiadi Zhang, my first mentor when I was undergraduate visiting scholar. I learnt so much from him and I really missed working with him. I also tHank Dr. Minyan Li for his great help in the beginning of my PhD career. Many thanks Dr. CHen Wu, ZHipHeng ZHang, Grace Panetti, Russell Shelp, and Bowen Hu who have been my great colleagues and friends. Many thanks to my collaborators for their hard iv working and important input; Dr. Ana Pascual-Escudero, Dr. Yexenia Nieves-Quinones, Youge Pu, Victoria Barber and MicHael Vansco and many otHers. A special tHanks to my coffee buddy, Jennifer Lee for Her kind support, encouragement and friendship over past five years. It has been a wonderful time having fun with Her at UPenn. I would also like to thank ‘Party every week” group, the THai community at UPenn and Drexel University, for kind support, friendship and good foods. Special tHanks “Party every day” group to Dr. IttHipHol Sungwienwong, Dr. Parawee Kasitinon and Dr. WeerapHa Panaddasirisuk. I really appreciate tHeir Help and incredible support. I’ve also enjoyed time spent with them cooking and playing games. This tHesis certainly would not Have been possible without the love and encouragement of my family and friends in Thailand. Special thanks to the best parents in the world, my dad and mom. THeir endless love, understanding and devotion mean the world to me. I am tHankful to my sister and brotHer for their love and support. Finally, I would like to tHank tHe Royal Thai government for financial support for my undergraduate and PhD life. v ABSTRACT PART I: THE STUDY OF 2-ARYL-1,3-DITHIANE DERIVATIVES AS PRONUCLEOPHILES IN PALLADIUM-CATALYZED ALLYLIC ALKYLATION AND PROPELLYLATION PART II: LIGAND-FREE PALLADIUM-CATALYZED ALLYLIC AMINATION OF HYDRAZONE DERIVATIVES PART III: SYNTHESIS OF CRIEGEE INTERMEDIATE PRECURSORS Nisalak Trongsiriwat Professor Patrick J. WalsH Chapter 1 and 2 detail studies of 2-aryl-1,3-dithianes as pronucleophiles in palladium-catalyzed allylic alkylation and propellylation to access skeletally diverse aryl alkyl ketone cores. Allylic carbonate and [1.1.1]propellane electropHiles successfully couple with in situ generated 2-sodio-1,3-dithiane nucleophiles to afford the corresponding products in good to excellent yields. Deprotection of these products leads to valuable aryl alkyl ketones. The palladium-catalyzed allylic alkylation of 2-aryl-1,3-ditHianes is examined in chapter 1. A direct synthesis of b,g-unsaturated ketones via a one-pot allylation-oxidation protocol is also presented. Additionally, the utility of this method is vi demonstrated through a sequential one-pot allylation-Heck cyclization to produce asterogynin derivatives which are important bioactive compounds in medicinal chemistry. Chapter 2 discloses a general metHod for tHe syntHesis of bicyclo[1.1.1]pentane (BCP)-containing dithianes which, upon deprotection, provide access to BCP analogues of medicinally abundant diarylketones. Transformation of tHe ditHiane