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Continuous Flow Metalations of Arenes, Heteroarenes and Formamides Using Lithium and Zinc Reagents

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Continuous Flow Metalations of Arenes, Heteroarenes and Formamides Using Lithium and Zinc Reagents Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Continuous Flow Metalations of Arenes, Heteroarenes and Formamides Using Lithium and Zinc Reagents von Matthias Richard Becker aus Karlsruhe, 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, 16. September 2016 …..…………………………………… Matthias Richard Becker Dissertation eingereicht am: 16. September 2016 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Konstantin Karaghiosoff Mündliche Prüfung am: 18. Oktober 2016 This work was carried out from March 2014 to July 2016 under the guidance of Prof. Dr. Paul Knochel at the Department of Chemistry at the Ludwig-Maximilians-Universität Munich. First of all, I would like to thank Prof. Dr. Paul Knochel for giving me the great opportunity to carry out my PhD thesis in his group, for his support, the exciting research projects, the advice in the course of my scientific research and his interest in this work. I also would like to express my gratitude to Prof. Dr. Konstantin Karaghiosoff for being the person he is and for agreeing to be second reviewer of my thesis. Moreover, I would like to thank Prof. Dr. Franz Bracher, Dr. Henry Dube, Prof. Dr. Manfred Heuschmann and Dr. Thomas Magauer for their interest shown in this manuscript by accepting to be members of my defense committee. I really would like to thank Mariia Karpacheva, Andreas ‘Bernd’ Bellan and Maximilian Ganiek for the careful correction of this manuscript. Furthermore, I would like to thank all the past and present members I have met in the Knochel group for all the moments and activities inside and outside the lab and for making my three years in the group a great experience. Especially I want to consider all my former and actual lab mates of F2.001b, Dr. Nadja Barl, Dr. Andreas Steib, Laura Kohout, Dr. Julia Nafe, Maximilian Ganiek, Andreas Bellan and Mariia Karpacheva, who gave me the best working and living atmosphere one can imagine. Moreover, I would like to thank Peter Dowling, Sophie Hansen, Dr. Vladimir Malakhov and Yulia Tsvik for their huge helps organizing everyday life in the lab and the office. Finally, I would like to thank my whole family, my parents, my sister and Masha bear for every possible support, for their love, patience and believe in me. Parts of this PhD thesis have been published Communications 1. Matthias R. Becker, Paul Knochel, “Practical Continuous-Flow Trapping Metalations of Functionalized Arenes and Heteroarenes Using TMPLi in the Presence of Mg, Zn, Cu, or La Halides”, Angew. Chem. Int. Ed. 2015, 54, 12501; Angew. Chem. 2015, 127, 12681. 2. Matthias R. Becker, Maximilian A. Ganiek, Paul Knochel, “Practical and economic lithiations of functionalized arenes and heteroarenes using Cy2NLi in the presence of Mg, Zn or La halides in a continuous flow”, Chem. Sci. 2015, 6, 6649. 3. Matthias R. Becker, Paul Knochel, “High-Temperature Continuous-Flow Zincations of Functionalized Arenes and Heteroarenes Using (Cy2N)2Zn∙2LiCl”, Org. Lett. 2016, 18, 1462. 4. Maximilian A. Ganiek, Matthias R. Becker, Paul Knochel, “Continuous flow in situ trapping functionalizations of N,N-disubstituted formamides using LDA”, manuscript in preparation. Reviews 1. Andreas D. Benischke, Mario Ellwart, Matthias R. Becker, Paul Knochel, “Polyfunctional Zinc and Magnesium Organometallics for Organic Synthesis: Some Perspectives”, Synthesis 2016, 48, 1101. Patents 1. Matthias R. Becker, Paul Knochel, “Kontinuierliche Durchfluss-Metallierungen organischer Verbindungen mit Lewis-acidem Wasserstoff” 2015, patent pending. 2. Matthias R. Becker, Paul Knochel, “Kontinuierliche Durchfluss-Zinkierungen organischer Verbindungen mit Lewis-acidem Wasserstoff unter Verwendung einer Bis(dicyclohexylamino)zink-Base” 2015, patent pending. Abbreviations Ac acetyl acac acetylacetonate aq aqueous Ar aryl Bn benzyl Boc tert-butyloxycarbonyl Bu butyl c cyclo calcd calculated conc concentrated Cy Cyclohexyl dba trans,trans-dibenzylideneacetone DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DPP diphenylphosphine E electrophile EI electron ionization equiv equivalent Et ethyl eV electronvolt FG functional group g gram GC gas chromatography h hour Hal halogen i Het heteroaryl HRMS high resolution mass spectrometry i iso id inner diameter IR infrared J coupling constant (NMR) LDA lithium diisopropylamide M mole/L Me methyl mg milligram MHz megahertz min minute mL milliliter mm millimeter mmol millimole mol% mole percent mp melting point MS mass spectrometry NMP N-methylpyrrolidone NMR nuclear magnetic resonance Oct octyl p para Pent pentyl PEPPSI pyridine-enhanced precatalyst preparation stabilization and initiation PFA perfluoroalkoxy alkane Ph phenyl pin pinacolate piv pivaloyl ii ppm parts per million Pr propyl PTFE polytetrafluoroethylene R organic substituent rt room temperature s second sat saturated S-Phos 2-dicylohexylphosphino-2’,6’-dimethoxybiphenyl t tert TBAB tetra-n-butylammonium bromide TFA trifluoroacetic acid tfp tri(2-furyl)phosphine THF tetrahydrofuran TLC thin layer chromatography tmet metalation time Tmet metalation temperature TMP 2,2,6,6-tetramethylpiperidyl TMS trimethylsilyl TP typical procedure Ts tosyl UV ultraviolet X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl iii Table of contents A. Introduction ............................................................................................................................. 1 1. Overview ......................................................................................................................................... 2 2. Preparation of organometallic reagents ........................................................................................... 3 2.1 Oxidative insertion .................................................................................................................... 3 2.2 Halogen-metal exchange ........................................................................................................... 5 2.3 Directed metalation ................................................................................................................... 8 3. Continuous flow reactions in organometallic chemistry ............................................................... 11 4. Objectives ...................................................................................................................................... 17 B. Results and discussion ............................................................................................................ 20 1. Practical continuous flow trapping metalations of functionalized arenes and heteroarenes using TMPLi in the presence of Mg, Zn, Cu, or La halides........................................................................ 21 1.1 Introduction ............................................................................................................................. 21 1.2 Continuous flow in situ trapping metalations of arenes .......................................................... 22 1.3 Continuous flow in situ trapping metalations of heteroarenes ................................................ 26 2. Practical and economic lithiations of functionalized arenes and heteroarenes using Cy2NLi in the presence of Mg, Zn or La halides in a continuous flow .................................................................... 33 2.1 Introduction ............................................................................................................................. 33 2.2 Continuous flow in situ trapping metalations of arenes .......................................................... 34 2.3 Continuous flow in situ trapping metalations of heteroarenes ................................................ 38 3. High temperature continuous flow zincations of functionalized arenes and heteroarenes using (Cy2N)2Zn·2LiCl ............................................................................................................................... 42 3.1 Introduction ............................................................................................................................. 42 3.2 High temperature zincations of functionalized heteroarenes................................................... 43 3.3 High temperature zincations of functionalized arenes ............................................................ 48 4. Convenient in situ trapping functionalizations of N,N-disubstituted formamides using LDA in the presence of electrophiles in a continuous flow .................................................................................. 51 4.1 Introduction ............................................................................................................................. 51 4.2 Functionalizations of N,N-disubstituted formamides .............................................................. 52 5. Summary ....................................................................................................................................... 56 5.1 Practical continuous flow trapping metalations of functionalized arenes and heteroarenes using TMPLi in the presence of Mg, Zn, Cu, or La halides .......................................................... 56 5.2 Practical
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