University of Groningen Carbon-carbon bond formations using organolithium reagents Heijnen, Dorus IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. 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Credits : Dusan Kolarski The work described in this thesis was carried out at the Stratingh Institute for Chemistry (University of Groningen, The Netherlands) and was financially supported by a NWO-TOP grant Printed by : Ipskamp Printing, Enschede, The Netherlands ISBN (printed) 978-94-028-1146-9 Carbon-Carbon Bond Formations Using Organolithium Reagents Proefschrift Ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties De openbare verdediging zal plaatsvinden op Vrijdag 7 september 2018 om 16:15 door Dorus Heijnen Geboren op 16 juli 1988 te Nijmegen Promotor Prof. dr. B.L. Feringa Copromotor Prof. dr. S. R. Harutyunyan Beoordelingscommissie Prof. dr. J.H. van Maarseveen Prof. dr. K. Barta Prof. dr. I. Marek Table of Contents Chapter 1: Introduction Organolithium Reagents : Discovery, Preparation, Properties and Applications ............................................................................................................................................. 9 1.1 Discovery and preparation .......................................................................................................... 10 1.2 Properties .................................................................................................................................... 11 1.3 Transmetallations and catalysis .................................................................................................. 14 Direct cross coupling with organolithium compounds ................................................................. 16 Faster ............................................................................................................................................. 18 Cheaper ......................................................................................................................................... 20 Functional group compatibility ..................................................................................................... 21 Applications ................................................................................................................................... 22 1.4 References. .................................................................................................................................. 25 Chapter 2: Palladium-Catalyzed Cross-Coupling of (Trimethylsilyl)methyllithium with (Hetero)-Aryl Halides ................................................................................................................................................... 28 2.1 Introduction ................................................................................................................................. 29 2.2 Catalyst optimization ................................................................................................................... 30 2.3 Substrate scope with aryl chlorides ............................................................................................ 31 2.4 Substrate scope with aryl bromides ............................................................................................ 32 2.5 Selectivity .................................................................................................................................... 33 2.6 The sequential coupling of TMS-substituted toluene derivatives............................................... 34 2.7 Conclusions .................................................................................................................................. 35 2.8 References ................................................................................................................................... 36 2.9 Experimental section ................................................................................................................... 39 Chapter 3: Pd-Catalyzed, tBuLi-Mediated Dimerization of Aryl Halides and its Application in the Atropselective Total Synthesis of Mastigophorene .............................................................................. 47 3.1 Introduction ................................................................................................................................. 48 3.2 Optimization and Scope .............................................................................................................. 50 3.3 Synthesis of Mastigophorene ...................................................................................................... 53 3.4 Conclusions .................................................................................................................................. 57 3.5 References ................................................................................................................................... 57 3.6 Experimental section ................................................................................................................... 60 Chapter 4 : One-Pot Strategies for Developing Synthetic Methods with Organolithium Reagents ..... 78 4.1 Introduction ................................................................................................................................. 79 4.2 One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation ................................................................... 79 4.2.1 Introduction .......................................................................................................................... 79 4.2.2 Optimization ......................................................................................................................... 80 4.2.3 Scope of the reaction ........................................................................................................... 83 4.2.4 Competition studies ............................................................................................................. 84 4.2.5 Other use of the tetrahedral intermediate .......................................................................... 85 4.2.6 Conclusions ........................................................................................................................... 86 4.2.7 References ............................................................................................................................ 86 4.2.8 Experimental section ............................................................................................................ 88 4.3 The Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot Reduction/Cross-Coupling Procedure .......................................................................................................................................... 99 4.4.1 Introduction ........................................................................................................................ 100 4.4.2 Optimization ....................................................................................................................... 101 4.4.3 Substrate scope .................................................................................................................. 102 4.4.4 In situ reduction of ketones................................................................................................ 105 4.4.5 Conclusions ......................................................................................................................... 105 4.4.6 References .......................................................................................................................... 105 4.4.7 Experimental section .......................................................................................................... 107 4.4 Conclusions and outlook ..........................................................................................................