Applications of radical reactions for the synthesis of β-amino acids and carbonyl compounds Xuan Chen To cite this version: Xuan Chen. Applications of radical reactions for the synthesis of β-amino acids and carbonyl com- pounds. Organic chemistry. Institut Polytechnique de Paris, 2020. English. NNT : 2020IPPAX042. tel-02983194 HAL Id: tel-02983194 https://tel.archives-ouvertes.fr/tel-02983194 Submitted on 29 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Applications of radical reactions for the synthesis of β-amino acids and carbonyl compounds 42 0 Thèse de doctorat de l’Institut Polytechnique de Paris AX préparée à École Polytechnique IPP 20 20 École doctorale n°626 Ecole Doctorale de l’Institut Polytechnique de : Paris (ED IP Paris) Spécialité de doctorat: Chimie NNT Thèse présentée et soutenue à Palaiseau, le 15 Septembre 2020, par M. Xuan CHEN Composition du Jury : Isabelle GILLAIZEAU Professeur, Université d'Orléans (UMR 7311) Présidente Luc NEUVILLE Docteur, University Paris-Saclay Rapporteur Benoît CROUSSE Docteur, University Paris-Sud (UMR 8076) Rapporteur Samir Z. ZARD Professeur, Ecole Polytechnique (UMR 7652) Examinateur, Directeur de thèse Acknowledgements I First of all, I am going to express my gratitude to my supervisor Professor Samir Z. Zard who gave me an opportunity to learn in a top university of the world and guided me on the right pathway in my academic career. I still remember the first day that I went to his office, he taught me the basic principle of xanthate chemistry and outlined the research topics in the next three years with profound knowledge. From that time, I changed my view on radical chemistry and realized xanthate transfer process is a powerful tool in organic synthesis. He not only gave me many helps in my research and daily life but also taught me the philosophy of life, the word “you should happy for your success, but more importantly, you should learn from your failure” impressed me the most. I really appreciate everything that he did for me and it is a great honor to work as his Ph.D student. I would like to thank all the members of jury committee, Prof. Isabelle Gillaizeau, Dr. Luc Neuville and Dr. Benoît Crousse for your precious time to evaluate this manuscript and come to my defense. Thank you for your suggestions. I want to thank Dr. Alexis Archambeau and Dr. Sébastien Prévost who have made great efforts on the problem sessions part, it is helpful to me and push me forward, I learned a lot from these exercises during the three years. My special thanks to Dr. Qi HUANG, a former Ph.D student in LSO. He gave me countless help at the beginning of my abroad life, both in my research projects and some trivial personal things and taking time to read and correct this manuscript. The two years we shared is unforgettable in my life. I also want to thank Vincent R. and Richard L. for providing me many solutions to the problem I encountered in my experiments and gave me some practical tips in my research projects. And also thank them for reading and correction of this manuscript. I would like to thank all of the LSO members: Dr. Yvan, Dr. Bastien Nay, Antoine, Anaïs, Wei, Oscar, Quentin, Gabriela, Dung, Xianzhu, Jean, Benjamin, Valentin, Nicolas, Paula, Cristina, Thomas, Kieu, Eloi, Pjotr. And also express my grateful to Julien for his warm help in many administrative matters and Vincent L. for HRMS analysis. I would like to thank my family, relatives and friends, they always stand behind me and help me to achieve the goals. I express my deepest gratitude to my parents and my wife for their support. Finally, I especially want to thank my little daughter, her cute face and sweet smile give me the courage and confidence to overcome any difficulties I encountered, and bring me a joyful life. Thank you all! II Contents III Acknowledgements ................................................................................................................... I Abbreviations ....................................................................................................................... VII Avant-Propos .......................................................................................................................... IX General introduction ........................................................................................................... XII Chapter 1 Introduction to radical chemistry ........................................................................ 1 1.1 Introduction .................................................................................................................... 2 1.2 Physical properties of radicals ....................................................................................... 2 1.2.1 The geometry: planar or pyramidal? ..................................................................... 2 1.2.2 Radical stability .................................................................................................... 3 1.3 Chemical properties of radicals ..................................................................................... 5 1.3.1 Thermal cleavage .................................................................................................. 5 1.3.2 Photochemical cleavage ........................................................................................ 6 1.3.3 Radicals arising from organoboranes .................................................................... 7 1.3.4 Radicals generated by single electron transfer process (SET) .............................. 8 1.4 Radical reactions ............................................................................................................ 8 1.4.1 Radical chain reactions ......................................................................................... 8 1.4.2 Hydrogen abstraction ............................................................................................ 9 1.4.3 Addition to unsaturated bonds ............................................................................ 10 1.4.4 Fragmentation ..................................................................................................... 10 1.4.5 Rearrangement ..................................................................................................... 11 1.4.6 Radical Oxidation ................................................................................................ 11 1.5 Conclusion ................................................................................................................... 12 Chapter 2 Xanthate based radical chemistry ...................................................................... 15 2.1 Introduction .................................................................................................................. 16 2.2 The Barton-McCombie deoxygenation ........................................................................ 16 2.2.1 An overall view: from alcohol to alkane ............................................................. 16 IV 2.2.2 The mechanism ................................................................................................... 17 2.2.3 Applications ........................................................................................................ 17 2.3 Development of the Barton-McCombie deoxygenation .............................................. 18 2.4 Radicals generation from carbon-sulfur bond disconnection: the degenerate transfer of xanthates .............................................................................................................................. 20 2.5 Preparation of xanthates ............................................................................................... 22 2.5.1 By a simple substitution ...................................................................................... 22 2.5.2 Using a radical procedure ................................................................................... 23 2.5.3 Other radical approaches ..................................................................................... 24 2.6 Applications of xanthate chemistry .............................................................................. 25 2.6.1 Applications of radical additions to the synthesis of ketones ............................. 25 2.6.2 Formation of cyclopropanes ............................................................................... 27 2.6.3 The xanthate route to amines and anilines .......................................................... 28 2.6.4 Stabilization of Radicals by Imides. ................................................................... 30 2.6.5 Synthesis of protected amino acid derivatives .................................................... 31 2.6.6 Modification of heterocycles .............................................................................. 32 2.7 Conclusion ................................................................................................................... 36 Chapter 3 A Convergent Route to β-Amino Acids and