THESE Présentée à : L’Institut National des Sciences Appliquées de Rouen En vue de l’obtention du grade de : Docteur en « Chimie Organique » Par Xiaoyang DAI Hydride Transfer Reactions of Trifluoromethylated Allylic Alcohols and Ketimines & Nucleophilic Trifluoromethylthiolation of Morita-Baylis-Hillman Carbonates Date de soutenance 12 Décembre 2014 Devant le jury composé de : Dr Thierry BILLARD (Rapporteur) Directeur de recherche CNRS, Université de Lyon 1 Dr Barbara MOHAR (Rapporteur) Directrice de recherche, National Institute of Chemistry, Ljubljana, Slovénie Dr Christine BAUDEQUIN (Examinatrice) Maître de conférences, Université de Rouen Dr Dominique CAHARD (Directeur de thèse) Directeur de recherche CNRS, Université de Rouen Acknowledgements Acknowledgements First and foremost, I would like to express my sincere appreciation to the juries of my PhD defense: Dr. Thierry Billard, Director of research CNRS in University of Lyon 1; Dr. Barbara Mohar, Director of research in the National Institute of Chemistry, Ljubljana, and Dr. Christine Baudequin, lecturer in University of Rouen. I would like to give my deep gratitude to my supervisor Dr. Dominique Cahard, research director in CNRS, who always has plenty of sparkling ideas in chemistry. He provided me many useful suggestions and encouraged me to think around and go ahead when there were difficulties in my Ph.D. subject. Without his incredible patience and enthusiasm, I would have given up the pursuit of my thesis work. I would like to thank the Chinese Scholarship Council who gave me a financial support for my whole Ph.D period. I am also grateful to my colleagues and all the members of the fluorine group in IRCOF who helped me a lot with the chemical experiments. Besides, my dear friend Dr. Sophie Letort always came to help me in volunteer to adapt to the life in France and bring laughter; my big brother Dr. Vincent Bizet gave me lots of advices in the hydride transfer part of work; Dr. Natalie Fresneau, who worked with me around two years in the lab, taught me french frequently. With her company, I had a happy time in the first two years of my Ph.D. My deep gratitude extends to my family, especially my husband Haibin Zhu who was always ready to give me a warm hug and told me that I was not alone. Thanks to their unconditional supports, I had the motivation to finish my Ph.D work without any delay. 1 Contents Contents Acknowledgements............................................................................................................................................1 Contents............................................................................................................................................................. 2 Abbreviations and acronyms............................................................................................................................. 4 1. General introduction...................................................................................................................................... 6 1.1 Brief history of fluorine.......................................................................................................................6 1.2 Fluorine on earth..................................................................................................................................7 1.3 The properties of fluorine and fluorine effects....................................................................................8 1.4 Fluorinated pharmaceuticals..............................................................................................................11 1.5 Synthesis of fluorinated compounds................................................................................................. 13 1.5.1 Direct fluorination.................................................................................................................. 13 1.5.2 Direct trifluoromethylation.....................................................................................................14 1.5.3 The association of CF 3 group with a heteroatom (XCF 3)...................................................... 16 2. Objectives of the PhD work.........................................................................................................................17 3. Transition-metal catalyzed hydride transfer reactions of CF 3 compounds................................................. 19 3.1 Isomerization of CF 3 allylic alcohols catalyzed by iron (II) complexes...........................................20 3.1.1 Literature data and objective.................................................................................................. 20 3.1.2 Synthesis of CF 3 dihydrochalcones by isomerization of CF 3 allylic alcohols.......................22 3.1.2.1 Preparation of CF 3 allylic alcohols..............................................................................23 3.1.2.2 Optimization of reaction conditions for isomerization of CF 3 allylic alcohols..........25 3.1.2.3 Substrate scope for isomerization of CF 3 allylic alcohols.......................................... 28 3.1.2.4 Comparison CF 3 versus CH 3 allylic alcohols..............................................................30 3.1.2.5 Asymmetric version: stereospecificity versus stereoselectivity..................................30 3.1.2.6 Mechanism investigation.............................................................................................31 3.1.3 Conclusion and perspectives.................................................................................................. 32 3.2 Asymmetric transfer hydrogenation of CF 3 ketimines catalyzed by Ru (II) complexes.................. 34 3.2.1 Literature data and objective.................................................................................................. 34 3.2.2 Synthesis of trifluoromethylated ketimines........................................................................... 39 3.2.3 Asymmetric transfer hydrogenation: optimization of the reaction conditions...................... 44 3.2.3.1 Screening of the hydrogen source and ligand’s type.................................................. 45 3.2.3.2 Screening of chiral ligand and ruthenium arene......................................................... 49 3.2.3.3 Screening of base, temperature, concentration, and ratio of reaction partners...........52 3.2.3.4 Screening of the nitrogen substituent..........................................................................55 3.2.4 Substrate scope....................................................................................................................... 57 3.2.5 Comparison with non-fluorinated imine................................................................................ 60 3.2.6 Mechanism investigation........................................................................................................61 3.2.7 Application of ATH.................................................................................................................63 3.2.8 Conclusion.............................................................................................................................. 64 4. Nucleophilic trifluoromethylthiolation of Morita-Baylis-Hillman carbonates...........................................65 4.1 Literature data and objective............................................................................................................. 65 2 Contents 4.1.1 Brief introduction of trifluoromethylthiolated compounds....................................................65 4.1.2 Allylic substitution of Morita-Baylis-Hillman carbonates.....................................................68 4.1.3 Objective.................................................................................................................................70 4.2 Synthesis of Morita-Baylis-Hillman derivatives...............................................................................70 4.3 Attempts using Me 4NSCF 3 and MSCF 3 (M = Ag, Cu) as nucleophilic SCF 3 transfer reagents.......73 4.4 Metal-free nucleophilic trifluoromethylthiolation of Morita-Baylis-Hillman carbonates................76 4.4.1 Combination of S8/CF 3SiMe 3/KF as nucleophilic SCF 3 transfer reagent..............................76 4.4.1.1 Introduction................................................................................................................. 76 4.4.1.2 Optimization of reaction conditions............................................................................76 4.4.1.3 Substrate scope............................................................................................................ 82 4.4.1.4 Mechanism investigation by 19 F NMR and GC-MS...................................................85 4.4.2 Use of Zard’s reagent as nucleophilic SCF 3 transfer reagent.................................................88 4.4.2.1 Introduction................................................................................................................. 88 4.4.2.2 Optimization of reaction conditions............................................................................89 4.4.2.3 Mechanism investigation.............................................................................................91 4.4.2.4 Asymmetric version.....................................................................................................92 4.5 Conclusion and perspectives............................................................................................................