Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München METALATION AND FUNCTIONALIZATION OF 5-MEMBERED HETEROCYCLES AND THE TROPOLONE SCAFFOLD USING TMP-BASES - AND - COBALT-CATALYZED NEGISHI CROSS-COUPLING REACTIONS OF (HETERO)ARYLZINC REAGENTS von Diana Haas aus Traunstein, Deutschland 2016 Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Paul Knochel betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, ______________ ________________________ (Diana Haas) Dissertation eingereicht am: 29.04.2016 1. Gutachter Prof. Dr. Paul Knochel 2. Gutachter Prof. Dr. Konstantin Karaghiosoff Mündliche Prüfung am: 23.06.2016 This work was carried out from July 2013 to May 2016 under the guidance of Prof. Dr. Paul Knochel at the Faculty for Chemistry and Pharmacy of the Ludwig-Maximilians-Universität, Munich, Germany. I would like to thank Prof. Dr. Paul Knochel for giving me the oppurtinity of doing my Ph.D. in his research group, for his great support and for his guidance throughout the course of my scientific research. I am also very grateful to Prof. Dr. Konstantin Karaghiosoff for being my second referee. Thank you for all the discussions about mechanisms, crystal structures and Genova! I also would like to thank Prof. Dr. Manfred Heuschmann, Prof. Dr. Klaus T. Wanner, Dr. Thomas Magauer and Dr. Henry Dube for their interest shown in this manuscript by accepting to be referees. I also want to thank Jeffrey M. Hammann, Meike Simon, Dr. Daniela Sustac-Roman and Dr. Andreas Unsinn for the careful correction of this manuscript. I thank all past and present co-workers in the Knochel-group and special thanks go out for all my labmates in F2.012 during my master's and my PhD thesis: Andreas Steib, Christoph Sämann, Andreas Unsinn, Ilaria Tirotta, Olesya Kuzmina, Sarah Fernandez, Hannes Nickel, Alicia Castello-Mico, Moritz Balkenhohl and Max Hofmayer. I also would like to thank Julia Nafe for the endless discussions during our smoking breaks. Thanks go also to Varvara Morozova for the supply of Russian sweets and awesome cuddly toys. Special thanks go to Jeffrey Hammann for the collaborations, his friendship and support and all the nice moments we shared together in the lab, in conferences or by doing some sports. Also, I want to thank Marc Mosrin for the collaboration and the entertaining phone calls we had during my time in the Knochel group. I thank my former students Max, Sophia, Alan, Charly and Lucie very much for their contributions in course of their bachelor's thesis or their research internship. I am very happy that so many of you will continue their work in this group and I wish you the very best for your future! Above all I thank my great girls' soccer team from TuS Holzkirchen for spending so many hours on the soccer court and so many nights drinking beer together. Special thanks go to Franzi Sailer, just for being there, doing crazy things together and spending night over night watching Die Geissens. I also want to thank my American girl Lara Allgeier. I am very happy that our paths crossed and I hope we will share a lot more moments together in the future. Special thanks go also to Bianca Ditsch for being my invaluable friend for almost 10 years now. A heartfelt thank you goes to my mum for her love and endless support in every way. Thank you for keeping me down-home. I moja posljednja, ali najposebnija, zahvala upućena je Marku, najboljoj osobi koju sam ikada upoznala. Hvala što postojiš. Bez tvoje vjere u mene, ne bih to ikada uspjela. Parts of this PhD Thesis have been published: 1) Diana Haas, Marc Mosrin, Paul Knochel, “Regioselective Functionalization of the Oxazole Scaffold Using TMP-Bases of Mg and Zn”, Org. Lett. 2013, 15, 6162–6165. 2) Diana Haas, Tomke Bresser, Maximilian S. Hofmayer, Paul Knochel, „Zincation of 4,4- dimethyloxazoline using TMPZnCl·LiCl. A new preparation of 2-aryloxazolines”, Chem. Commun. 2015, 51, 6415–6417. 3) Jeffrey M. Hammann, Diana Haas, Paul Knochel, “Cobalt-Catalyzed Negishi Cross-Coupling Reactions of (Hetero)Arylzinc Reagents with Primary and Secondary Alkyl Bromides and Iodides”, Angew. Chem. Int. Ed. 2015, 54, 4478–4481; Angew. Chem. 2015, 127, 4560–4563. 4) Diana Haas, Jeffrey M. Hammann, Ferdinand H. Lutter, Paul Knochel, “Mild Cobalt-Catalyzed Negishi Cross-Couplings of (Hetero)arylzinc Reagents with (Hetero)aryl Halides”, Angew. Chem. Int. Ed. 2016, 55, 3809–3812; Angew. Chem. 2016, 128, 3873–3877. 5) Diana Haas, Jeffrey M. Hammann, Robert Greiner, Paul Knochel “Recent Developments in Negishi Cross-Coupling Reactions”, ACS Catal. 2016, 6, 1540–1552. All my life through, the new sights of nature made me rejoice like a child. Marie Curie Table of Contents A INTRODUCTION 1 1 Overview 3 2 Preparation of Zinc Organometallics 4 2.1 Oxidative Addition of Zinc Powder to Organic Halides 4 2.2 Metal-Catalyzed Preparation of Organozinc Reagents 7 2.3 Transmetalation of Magnesium, Aluminum or Lithium Organometallics 8 2.4 Preparation of Zinc Reagents by Directed Metalation 9 3 Negishi Cross-Coupling Reactions 14 3.1 Palladium-Catalyzed Negishi Cross-Coupling Reactions 14 3.2 Negishi Cross-Coupling Reactions Using Nickel-Catalysts 19 3.3 Negishi Cross-Coupling Reactions Using other Transition-Metal Catalysts 22 4 Applications of Negishi Cross-Couplings in Natural Product Synthesis 26 5 Objectives 29 B RESULTS AND DISCUSSION 31 1 Regioselective Functionalization of the Oxazole Scaffold Using TMP-Bases of Mg and Zn 33 1.1 Introduction 33 1.2 Zincation of Oxazole in Position C-2 35 1.3 Zincation or Magnesiation of 2-Arylated Oxazole Derivatives 37 1.4 Zincation of 2,5-Disubstituted Oxazole Derivatives 40 2 Zincation of 4,4-Dimethyloxazoline Using TMPZnCl·LiCl. A New Preparation of 2- Aryloxazolines 43 2.1 Introduction 43 2.2 Metalation of 4,4-Dimethyloxazoline 44 2.3 Oxazoline as a Directing Group for Further Functionalizations 47 3 Metalation and Functionalization of the Tropolone Scaffold Using TMPZnCl·LiCl 51 3.1 Introduction 51 3.2 Metalation and Functionalization of 5-Bromo-2-methoxytropone Using TMPZnCl·LiCl 52 3.3 Metalation and Functionalization of 2-Benzyloxytropone using TMPZnCl·LiCl 53 4 Cobalt-Catalyzed Negishi Cross-Coupling Reactions of (Hetero)Aryl-zinc Reagents with Primary and Secondary Alkyl Bromides and Iodides 57 4.1 Introduction 57 4.2 Design of the Coupling Procedure 58 I 4.3 Cobalt-Catalyzed Cross-Coupling of Zincated Ethyl 3-fluorobenzoate with Various Alkyl Halides 59 4.4 Cobalt-Catalyzed Cross-Coupling of Di(hetero)arylzinc Reagents with Alkyl Iodides 61 5 Mild Cobalt-Catalyzed Negishi Cross-Couplings of (Hetero)arylzinc Reagents with (Hetero)aryl Halides 64 5.1 Introduction 64 5.2 Design of the Procedure 65 5.3 Cobalt-Catalyzed Cross-Coupling of 2-Halogenated Aromatic Ketones 67 5.4 Cobalt-Catalyzed Cross-Coupling of 2-Chloropyridines 69 5.5 Cobalt-Catalyzed Cross-Coupling of Various N-Heterocycles 71 6 Summary 74 C EXPERIMENTAL PART 79 1 General Considerations 81 1.1 Solvents 81 1.2 Reagents 81 1.3 Chromatography 83 1.4 Analytical Data 83 2 Regioselective Functionalization of the Oxazole Scaffold Using TMP-Bases of Mg and Zn 85 2.1 Typical Procedures 85 2.2 Metalation of Oxazole and Oxazole Derivatives and Subsequent Reaction with Electrophiles 85 3 Zincation of 4,4-Dimethyloxazoline Using TMPZnCl·LiCl. A New Preparation of 2- Aryloxazolines 111 3.1 Typical Procedures 111 3.2 Zincation of 4,4-Dimethyloxazoline and Subsequent Reaction with Electrophiles 111 3.3 Magnesiation of Aryloxazolines and Reaction with Electrophiles 122 4 Metalation and Functionalization of the Tropolone Scaffold 132 4.1 Preparation of Starting Materials 132 4.2 Typical Procedures 134 4.3 Metalation and Functionalization of 5-Bromo-2-methoxytropone 135 4.4 Metalation of 2-Benzyloxytropone 140 4.5 Addition of Grignard Reagents to 7-Aryl-2-benzyloxytropones 147 5 Cobalt-Catalyzed Negishi Cross-Coupling of (Hetero)Arylzinc Reagents with Primary and Secondary Alkyl Bromides and Iodides 150 5.1 Preparation of Starting Materials 150 5.2 Typical Procedures 152 II 5.3 Cobalt-Catalyzed Negishi Cross-Coupling Reactions of (Hetero)Arylzinc Reagents with Alkyl Halides 153 6 Cobalt-Catalyzed Negishi Cross-Couplings of (Hetero)Arylzinc Reagents with (Hetero)Aryl Halides 169 6.1 Preparation of Organometallic Reagents 169 6.2 Preparation of Starting Materials 169 6.3 Typical Procedure 170 6.4 Kinetic Investigation of the Cross-Coupling Reaction 171 6.5 Cobalt-Catalyzed Cross-Coupling of (Hetero)Arylzinc Reagents with (Hetero)Aryl Halides 172 D APPENDIX 191 1 X-Ray Structures 193 2 List of Abbreviations 196 3 Curriculum Vitae 198 III A INTRODUCTION INTRODUCTION A INTRODUCTION In 2010, Richard Heck, Ei-ichi Negishi, and Akira Suzuki joined the prestigious circle of Nobel laureates for their roles in discovering and developing highly practical methodologies for C-C bond forming reactions.1 From their contributions the landscape of methods for organic synthesis irreversibly changed for chemists, both in academia and in industry. Until today, the transition metal-catalyzed transformations continue to find great attention from the chemical community. As Negishi picted out in his Nobel lecture, the goal of organic chemists in the 21st century is the synthesis of every imaginable compound to seek for new structures that could possibly solve mankind’s problems in the near or far future.2 1 Overview Pd-catalyzed cross-coupling reactions between unsaturated halides and organometallics have found broad applications. Cross-coupling reactions using boronic acids or esters, known as Suzuki cross- coupling reactions,3 have been extensively used due to the broad availability and relative air- and moisture-stability of unsaturated boronic acid derivatives.4 Nevertheless, the fast transmetalation of organozinc reagents to palladium compared to boronic acids often allows the achievement Negishi cross-couplings2 between a broad range of unsaturated halides and zinc organometallics under very mild conditions (Scheme 1).