University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 8-2017 The uncF tionalization of N-cyclobutylanilines under Photoredox Catalysis Jiang Wang University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Organic Chemistry Commons Recommended Citation Wang, Jiang, "The unctF ionalization of N-cyclobutylanilines under Photoredox Catalysis" (2017). Theses and Dissertations. 2416. http://scholarworks.uark.edu/etd/2416 This Dissertation is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. The Functionalization of N-cyclobutylanilines under Photoredox Catalysis A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Jiang Wang Lanzhou University Bachelor of Science in Chemistry, 2010 August 2017 University of Arkansas The dissertation is approved for recommendation to the Graduate Council. Nan Zheng, Ph.D. Dissertation Chair Matthias McIntosh, Ph.D. Committee Member Bill Durham, Ph.D. Jingyi Chen, Ph.D. Committee Member Committee Member Abstract While transition metal catalyzed cross coupling reactions have become one of the most useful strategies in constructing carbon-carbon and carbon-heteroatom bond formations, major disadvantages such as high reaction temperature, expansive metal catalysts input and limited reaction substrates scope have significantly downshifted the applications of those two electron involved transformations. Comparably, the studies on the redox coupling reactions are less investigated. Derived from single electron transfer process, the redox coupling reactions can be used to construct otherwise challenging chemical bonds efficiently, such as Csp3-Csp3 bond. Recently, visible light mediated photoredox catalysis has merged as a highly prominent tool in the development of many unconventional organic transformations. Those transformations are typically conducted in an extremely mild reaction conditions only by irradiating reaction mixtures under visible light or sunshine at room temperature and without any ligand addition. Hence, exceptional efforts are needed for further exploration of those photoredox catalyzed organic transformations. This work described an innovation approach of using visible light photoredox catalysis to develop efficient one-step syntheses for the construction of structurally diverse amine substituted novel cyclic and acyclic organic motifs from easily prepared starting materials. Amines are typically used as a sacrificial electron donor in a photoredox derived reaction. Nan Zheng recently revealed that by incorporating amine into a reductive quenching photoredox catalytic cycle, amine can be used as both the sacrificial electron donor and substrate. To accomplish this, N-cyclobutylanilines were oxidized to its corresponding amine radical cation by a photoredox catalyst upon irradiation under visible light, which would lead to a distonic radical cation through a C-C bond cleavage of cyclobutyl ring. The distonic radical cation can be trapped by a pi bond such as alkene or alkyne to reveal a novel amine substituted six membered carbon cycle through a [4+2] annulation reaction. Alternatively, by introducing a nucleophile such as trimethylsilyl cyanide and a radical acceptor such as allylsulfone derivative, a difunctionalization of N-cyclobutylanilines has been realized through a multicomponent reaction fashion. The method was further expanded to the success difunctionalization of fused cyclopropylanilines. Structurally important α-cyano pyrrolidines were synthesized with the generation of a quaternary carbon center on the α positin of pyrrolidines. © 2017 by Jiang Wang All Rights Reserved Acknowledgments I thank my mom and dad for their support and love since I was born. I would not be where I am without your unconditional love and support. I also thank my old brother, Bairong Wang for his love, support and encouragement. I am forever grateful to my advisor, Dr. Nan Zheng, for his guidance, his words and deeds throughout my graduate program, as a great mentor and advisor. His broad knowledge in chemistry and cautious attitude towards science will benefit me for my entire life as a chemist. Without his encouragement and continual support, I would not have survived in the graduate program. I express my sincere gratitude to Dr. Matt McIntosh for his excellent advice in my researches. I thank Drs. Bill Durham, Jingyi Chen for serving on my committee and for all the helpful advice and suggestions. I thank Dr. James Hinton and KZ Shein for their assistance with NMR Spectroscopy. I also thank Dr. Colin Heyes for his assistance with Fluorescence Spectroscopy and all the good suggestions. I thank Dr. Yongmin Liang from Lanzhou University and Dr. Aiqin Wang from Lanzhou Institute of Chemical Physics, Chinese Academy of Science for their guidance on my undergraduate study and their ultimate support since then. I thank the members of the Zheng group, especially Dr. Samaresh Jana, Dr. Jie Hu and Scott Morris for being such great friends to me. I also thank Lucas Whisenhunt for being a great friend and roommate. I thank my wonderful wife, Tianshu Zhang, for her unconditional love and support. Thanks for showing up in my life and being my life partner. Last, I thank Chemistry & Biochemstry department for all the support. Dedication I dedicate this dissertation to my dearest parents, Shulan Zhang and Xiaoyi Wang. Table of Contents Chapter 1: Visible Light Mediated Photoredox Catalysis 1.1. Photoredox Chemistry……………………………………………………………………1 1.2. Photoredox Catalyst………………………………………………………………………4 1.3. Homogeneous Photoredox Catalysis in Organic Synthesis………………………………7 1.3.1. Oxidative Quenching Cycle…………………………………………………….10 1.3.2. Reductive Quenching Cycle…………………………………………………...14 1.3.3. Energy Transfer Process……………………………………………………….19 1.4. Amine Radical Cations…………………………………………………………………..21 1.5. Ring Opening Strategies of Cyclobutanes……………………………………………….27 1.5.1. Transition Metal Catalyzed Activation of C-C Bond on Cyclobutane………...28 1.5.2. Radical Mediated C-C bond cleavage on Cyclobutane………………..……….32 1.5.3. Donor-Acceptor (DA) Mediated Ring Opening of Cyclobutane………………35 1.6. Conclusion………………………………………………………………………………..37 1.7 References………………………………………………………………………………...38 Chapter 2: Intermolecular [4+2] Annulation of N-Cyclobutylanilines with Alkynes 2.1. Introduction………………………………………………………………………………49 2.2. [4+2] Annulation of N-cyclobutylanilines with Alkynes under Photoredox Catalysis…..50 2.2.1. Reaction Optimization of the [4+2] Annulation………………………………..50 2.2.2. Substrates Scope of Monocyclic and Bicyclic N-Cyclotbulanilines……………52 2.2.3. Mechanism Study……………………………………………………………….58 2.2.4 Experimental Section……………………………………………………………61 2.2.5 Summary ………………………………………………………………………..87 2.3. [4+2] Annulation of N-Cyclobutylanilines with Pi bonds under Continuous Flow……...88 2.3.1. Results and Discussion…………………………………………………………89 2.3.2. Gram Scale Synthesis…………………………………………………………..93 2.3.3 Experimental Section…………………………………………………………....93 2.3.4 Summary……………………………………………………………………….102 3+ 2.4. [4+2] Annulation under Heterogeneous Ti @TiO2 Catalysis………………………….102 2.4.1. Reaction Optimization………………………………………………………...106 2.4.2. Substrates Scope………………………………………………………………109 2.4.3. Catalyst Recycle and Stability Study………………………………………….111 2.4.4. Reaction Mechanism Study…………………………………………………...113 2.3.5. Experimental Section………………………………………………………….120 2.3.6 Summary……………………………………………………………………….130 2.5. References……………………………………………………………………………….131 Chapter 3: Difunctionalization of N-Cyclobutylanilines under Photoredox Catalysis 3.1. Introduction……………………………………………………………………………...139 3.2 Results and Discussion…………………………………………………………………...141 3.2.1. Reaction Optimization…………………………………………………………141 3.2.2. Substrates Scope……………………………………………………………….143 3.2.3. Products Derivatization………………………………………………………..146 3.2.4. Reaction Mechanism Study……………………………………………………147 3.2.5. Experimental Section…………………………………………………………..148 3.3. Summary…………………………………………………………………………………182 3.4. References……………………………………………………………………………….183 List of Tables Table 2.2.1 Opimization of [4+2] Annulation …………………………………………….…...52 Table 2.2.2 Scope of [4+2] Annulation with Phenylacetylene…………………………………53 Table 2.2.3 Scope of [4+2] Annulation with various Alkynes………………………………....55 Table 2.2.4 [4+2] Annulation with Bicyclic cyclobutylanilines…………………………….…57 Table 2.3.1 Optimization of [4+2] Annulation under Flow……………………………….……90 Table 2.3.2 [4+2] Annulation with various pi bonds…………………………………………..91 3+ Table 2.4.1 Optimization of Ti @TiO2 Catalyzed [4+2] Annulation………………………...107 3+ 3+ Table 2.4.2 Evaluation of Ti influence in Ti @TiO2...........................................................109 Table 3.1 Difunctionalization Reaction Optimization…………………………………….…...142 Table 3.2 The absorbance of the Actinometry at 510 nm………………………………….….179 List of Figures Figure 1.1 The Synthesis of Carvone Camphor under Sunlight………………………………..1 Figure 1.2. Different Pathways of Photoexcited Molecules……………………………………2 Figure 1.3. Absorption Spectrum of Ru(bpy)3(PF6) in CH3CN…………………………….…...4 Figure 1.4. Depiction of Working Protocol of Ru(bpy)3(PF6)2…………………………….……5 Figure 1.5. Ligand Effects on Redox Properties……………………………………….………...7 Figure 1.6. Oxidative Quenching