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Iron-Catalyzed Synthesis of Unprotected Primary Amines

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Iron-Catalyzed Synthesis of Unprotected Primary Amines Iron-catalyzed Synthesis of Unprotected Primary Amines Dissertation Zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften Vorgelegt der Fakultät für Chemie und Biochemie der Ruhr-Universität Bochum von Luca Legnani aus Saronno, Italien Bochum, 2018 "I carried the book a hundred yards into the desolation, towards the southeast. With all my might I threw it far out in the direction she had gone. Then I got into the car, started the engine, and drove back to Los Angeles." John Fante, Ask the dust Die vorliegende Arbeit wurde im Zeitraum von Oktober 2014 bis April 2018 am Max- Planck-Institut für Kohlenforschung unter Anleitung von Dr. Bill Morandi angefertigt. Supervisor: Dr. Bill Morandi Co-supervisor: Prof. Dr. Wolfram Sander Acknowledgments i Acknowledgments The acknowledgements are going to be the most difficult pages to write. My sincere gratitude goes in the first place to Bill. In the last four years he passed on a lot of experience and enthusiasm for organic chemistry. However, before being an excellent supervisor, he has been an older brother. Entering his office, I have always found a nice word or a joke and I have never been afraid to discuss with him a reaction mechanism or a concern in private life. I will always be thankful to him for what he taught me and for the nice environment he built. I truly believe he is a wonderful boss and a great person. I would also like to thank Prof. Sander who agreed to supervise my thesis. His class at the Bochum University has been inspiring and convinced me to pursue my studies in organic chemistry, investigating reaction mechanisms. I am thankful to Prof. List for sharing the equipment of his group and for the nice activities organized at the Department. I thank the MPI für Kohlenfoschung for the economic and scientific support during these years. I have had a great time during my PhD thanks to the old and present members of the Morandi group. More than colleagues they have been a group of friends with who you can share ideas, chemicals, stories, fun and laughs. I have been lucky to have met Bastien that made the time in the lab so pleasant. Thanks also for keeping my feet warm with the heat gun. With Nikos, following the tradition of ancient Greek philosophers, I have shared many chats and discussions about life. In case of an issue with DAK I will call your help. Thanks to Gabri, that has been a close friend during these years. I have always counted on him for outdoor activities, a discussion about chemistry or a song to sing together. Thanks also for working with me on the amino chlorination project. I promise I will try my best to support Valentino Rossi and Francesco Totti in the future. I have been lucky to have met Ben. He always had valuable suggestions for any question in lab and his contribution during the proofreading of this thesis has been priceless. The time spent with him has always been pleasant, full of stories, movies and looking-up dogs. The time spent with him has always been pleasant also because I could usually understand half of his words. I will truly miss Peng. He taught me that a different culture ii Iron-catalyzed synthesis of unprotected primary amines can mean a great friendship. I hope I will soon have the chance to visit China with him. In case of an issue with bureaucracy I am sure you will be ready to help me. I am sincerely thankful, in a random order, also to: Erhan and his funny videos, Dr. Fang and delicious fishes, Rodeo Rod and his latino intensity, Suzanne and the Dutch directness, Szabo because he is a real NeRD, Tobias for his tough questions, Yong Ho and the tidy glovebox, Eckhard and the google translated emails, Julia that wants to go for lunch at 10:30, Tristan because he can whistle the same song for few days in row, Lin and the Lineneintopf, quick quick Zhong, Sophia, Emrah, Sarah. I am very happy that I had the chance to work with these people because in the morning, on the way to the institute, I have always worn a smile. During the last years, despite the many kilometers, my Italian friends and I managed to keep a close relationship. Every time I went back to my Alps I have always found a warm welcome, hugs and laughs. I am thankful to them for reminding me that there is no place like home. I am grateful to my family for having always supported me. They have trusted any decision I have taken during these years and they have never stopped to help me. I am sure Monica and Giuliano will become fantastic grandparents, Anna an incredible aunt, Francesco and Carla wise great-grandparents. I am lucky to have such wonderful uncles and cousins as Walter, Bobo, Giorgio, Roberto, Elga, Francesco. The memories and teachings of nonna Fernanda and nonno Antonio are still vivid in our loud family. This thesis would have not been written without the constant help, support and love of Tanja. I am incredibly lucky to have met a person that shares with me the same World view. I am thankful to her for deciding to follow me in Mülheim, quitting a ten-year life in Regensburg, friends and jobs. I am sure our next adventure across the ocean will be exciting and will make us even closer. I thank the little kicker for already donating us new and wonderful emotions. I will do the best that I can to make the two of you happy. Table of Contents iii Table of Contents 1. Introduction: recent progress in the synthesis of unprotected primary amines ....................................... 1 1.1. About amines ............................................................................................................................. 2 1.2. Hydroamination ......................................................................................................................... 3 1.3. Reductive amination .................................................................................................................. 6 1.4. Dehydrogenative coupling with alcohols ................................................................................... 10 1.5. Allylic amination ....................................................................................................................... 13 1.6. Amination of prefunctionalized arenes ...................................................................................... 16 1.6.1. Amination of halides and pseudohalides................................................................................ 16 1.6.2. Amination of boronates ......................................................................................................... 19 1.7. C−H amination ......................................................................................................................... 21 1.7.1. Directed C−H amination ........................................................................................................ 22 1.7.2. Innate C−H amination ........................................................................................................... 23 1.8. Aminofunctionalization ............................................................................................................. 27 1.9. Conclusion and project outline ................................................................................................. 29 2. Direct synthesis of unprotected amino alcohols .................................................................................. 31 2.1. Background ............................................................................................................................. 32 2.2. Literature precedents ............................................................................................................... 33 2.3. Reaction design and optimization ............................................................................................. 36 2.4. Scope of the reaction ............................................................................................................... 38 2.5. Extension of the reaction to different nucleophiles .................................................................... 41 2.6. Potential applications in medicinal chemistry ............................................................................ 42 2.7. Mechanistic experiments .......................................................................................................... 44 2.8. Extension of the reaction to the synthesis of SLAP reagent ...................................................... 46 2.9. Conclusion and outlooks .......................................................................................................... 48 3. Direct synthesis of primary anilines through C−H amination ................................................................ 51 3.1. Background ............................................................................................................................. 52 3.2. Literature precedents in innate C−H amination ......................................................................... 52 3.3. A matter of chemoselectivity .................................................................................................... 56 iv Iron-catalyzed synthesis of unprotected primary amines 3.4. Scope of the reaction ............................................................................................................... 58 3.5. Late stage functionalization ...................................................................................................... 61 3.6. Mechanistic experiments ........................................................................................................
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