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Ruthenium Catalysts for the Synthesis of Quinolines and Enol Esters

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Ruthenium Catalysts for the Synthesis of Quinolines and Enol Esters Faculty of Science Department of Inorganic and Physical Chemistry Centre for Ordered Materials, Organometallics and Catalysis Ruthenium catalysts for the synthesis of quinolines and enol esters Hans Vander Mierde Promoter: Prof. Dr. F. Verpoort Proefschrift voorgelegd tot het behalen van de graad van Doctor in de Wetenschappen: Scheikunde ii Members of the jury Prof. Dr. F. Verpoort (Promoter) Prof. Dr. P. Van Der Voort Prof. Dr. J. Van der Eycken Prof. Dr. R. Willem Prof. Dr. Ir. C. Stevens Dr. R. Drozdzak Prof. Dr. K. Strubbe (Chairman) iii Science only starts to get interesting at the point where it stops. Wetenschap wordt eigenlijk pas interessant op het punt waar ze ophoudt. Dankwoord/Acknowledgements “PLOF!!” Daar ligt hij dan: mijn doctoraatsproefschrift, de exponent van jaren puffen, zwoe- gen en zweten. Gelukkig heb ik al die jaren kunnen rekenen op de onvoorwaardelijke steun van een heleboel mensen. Hier komen hun welverdiende ‘two pages of fame’. Mijn eerste ‘dankjewel’ zou ik willen richten aan mijn promotor, professor Francis Verpoort, om mij de mogelijkheid te geven dit onderzoek te verrichten. Ook in de moeilijke eerste jaren met tegenvallende resultaten, die soms eigen zijn aan wetenschappelijk onderzoek, wist hij mij steeds te verrassen met nieuwe idee¨en. Uiteraard mag ik ook de financi¨ele steun van de Universiteit Gent niet vergeten. In mijn job als assistent heb ik niet alleen studenten iets proberen bij te brengen, maar heb ik ook zelf enorm veel geleerd. Verder ben ik dank verschuldigd aan de leden van de jury, voor het kritisch lezen en beoordelen van dit werk. Al die jaren heb ik het geluk gehad te kunnen samenwerken met fantastische colle- ga’s. In het bijzonder wil ik Bart, Nele en Carl bedanken voor hun wetenschappelijk bijdragen, de uitstekende sfeer in het labo en de zomerse ijsjes. Natuurlijk mag ik Stijn, Jeroen, Fu, Steven, Siegfried en David niet overslaan. De samenwerking met de groep van professor Pascal Van Der Voort verliep zeer vlot. De nieuwe lichting doctorandi Els, Ilke, Matthias, Frederik en Karen zorgden voor een aangename frisse wind in het schrijflokaal wat het extra jammer maakt dat “Welkom” zo snel plaats moet maken voor “Tot ziens”. Ook bedankt aan ‘vaste stoffers’ Klaartje, Veerle en Jonas en alle andere mensen die ik hier niet persoonlijk vermeld heb, voor de vele leuke momenten en losse bab- bels . Verder verdienen ook alle ATP’ers en praktijkassistenten hun plaatsje op deze pa- gina. Bedankt Pat voor de constructie van mijn aluminium ‘multi-mini-kolom- filtratie-houder’ en Danny voor assistentie en onderhoud van het GC toestel. Een speciaal woordje van dank gaat uit naar Claudine, ‘moeder van alle doctoraatsstu- denten’ voor een luisterend oor bij grote en kleine zorgen. Daarnaast wil ik ook Marc Schelfaut bedanken van de onderzoeksgroep Chroma- tografie voor het uitvoeren van GC-MS metingen. Mieke, liefste Mieke. Hoeveel van onze conversaties gingen niet als volgt: “Wacht schat, ik zal je helpen met wassen/strijken/poetsen/...” waarop jij evenveel keer antwoordde “Nee hoor, dat is niet nodig. Werk jij maar hard door aan je doc- toraat.” Duizendmaal dank voor alle steun en begrip tijdens die zware laatste v vi maanden. Gelukkig waren er ook nog de ontspanningsmomenten met goede vrienden Bram en Valerie om eens een kaartje te leggen of op een zonnige avond te keuvelen over de dingen des levens. Af en toe moest de frustratie er ook een keer uit en dat zul- len David en Sven geweten hebben tijdens onze badmintonwedstrijdjes. Gelukkig waren het vooral de pluimpjes die het moesten ontgelden. Eindigen doe ik met een woordje van lof voor mijn ouders. Tijdens mijn univer- sitaire ‘carriere’ stonden zij steeds op de eerste rij om voor mij te supporteren. Hun tomeloze inzet en grenzeloze liefde waren steeds een stuwende kracht in mijn leven. Hopelijk kan ik hen daarvan met het volbrengen van dit werk een stukje teruggeven. Table of Contents Dankwoord/Acknowledgements v Table of Contents vii Preface: Setting the stage xi Outline xiii List of abbreviations xv List of numbered compounds xvii 1 Introduction to quinoline synthesis 1 1.1 What is quinoline? . 1 1.2 Traditional methods of synthesis . 2 1.2.1 Skraup/Doebner-von Miller reaction . 2 1.2.2 Combes quinoline synthesis . 3 1.2.3 Friedlander quinoline synthesis . 3 1.2.4 Other named reactions . 4 1.2.5 Classic organic synthesis . 5 1.3 Transition metal-catalyzed approaches . 5 1.3.1 The modified Friedlander quinoline synthesis . 6 1.3.2 Other transition metal catalyzed methods . 8 1.4 The development of the modified Friedlander method . 15 1.4.1 Introduction . 15 1.4.2 Catalytic transfer hydrogenation . 15 1.4.3 Extension to the Friedlander reaction . 17 2 Ruthenium catalyzed synthesis of quinolines 21 2.1 Introduction . 21 2.2 Ruthenium catalysts . 22 2.2.1 Synthesis of Ruthenium-arene complexes . 22 2.2.2 Quinoline synthesis with Ru-arene complexes . 26 2.2.3 Quinoline synthesis with Ru-carbene complexes . 28 2.2.4 Quinoline synthesis from other ketones . 31 2.2.5 Isolation and characterization of the quinolines . 33 2.3 Influence of the base . 34 2.4 Solvent preparation: flushing with argon . 36 vii viii TABLE OF CONTENTS 2.5 Turn-over number and turn-over frequency . 37 2.6 The influence of a hydrogen acceptor . 39 2.7 Reaction mechanism . 42 2.7.1 General reaction scheme . 42 2.7.2 Reaction mechanism concerning the catalyst . 44 2.8 Synthesis of 3-substituted quinolines . 45 2.8.1 Introduction . 45 2.8.2 Development of a new method for the synthesis of 3-substituted quinolines . 47 2.8.3 Optimization of the reaction parameters . 48 2.8.4 Reaction mechanism . 50 2.9 Conclusions on Ru-catalyzed quinoline synthesis . 52 3 Base-mediated synthesis of quinolines 55 3.1 Introduction . 55 3.2 Synthesis of quinolines from ketones . 57 3.3 Reaction mechanism . 61 3.4 Synthesis of 3-substituted quinolines . 62 3.5 Conclusions on the base-mediated synthesis of quinolines . 63 4 Introduction to enol esters 65 4.1 Definition . 65 4.2 Applications of enol esters . 66 4.3 Synthesis of enol esters . 68 4.3.1 Addition of carboxylic acids to alkynes . 68 4.3.2 Enol esters via enolates . 75 4.3.3 Other methods for the synthesis of enol esters . 76 4.3.4 Reaction mechanism of the ruthenium-catalyzed synthesis of enol esters . 77 5 Ruthenium catalyzed synthesis of enol esters 79 5.1 Introduction . 79 5.2 Screening of ruthenium catalysts . 80 5.2.1 Model reaction 1: phenylacetylene and acetic acid . 80 5.2.2 Model reaction 2: 1-octyne and acetic acid . 85 5.2.3 Phenylacetylene and the dimerization problem . 88 5.3 Broadening the scope of the reaction . 90 5.3.1 Phenylacetylene and trichloroacetic acid . 91 5.3.2 Phenylacetylene and benzoic acid . 91 5.3.3 1-Octyne and trichloroacetic acid . 93 5.3.4 1-Octyne and benzoic acid . 93 5.3.5 3,3-Dimethyl-1-butyne and acetic acid . 95 5.3.6 3,3-Dimethyl-1-butyne and trichloroacetic acid . 95 5.3.7 3,3-Dimethyl-1-butyne and benzoic acid . 95 5.3.8 Cyclic enol esters from 4-pentynoic acid (Lactones) . 96 5.3.9 The alkynes 4-octyne and 2-methyl-3-butyn-2-ol . 98 5.3.10 Influence of the pKa on the stereochemistry . 99 5.4 Tweaking the reaction conditions . 100 TABLE OF CONTENTS ix 5.4.1 Introduction . 100 5.4.2 Sodium acetate instead of acetic acid . 100 5.4.3 The addition of NHC ligands . 100 5.4.4 The addition of bases . 102 5.5 Mechanistical considerations for the synthesis of enol esters. 103 5.6 Conclusions on ruthenium-catalyzed synthesis of enol esters . 105 6 General conclusions and outlook 107 7 Experimental 111 7.1 General remarks . 111 7.1.1 Chemical compounds and synthesis . 111 7.1.2 Experimental techniques and analysis . 111 7.2 Synthesis of Schiff base ligands . 112 7.2.1 Schiff base SB1 .......................... 112 7.2.2 Schiff base SBN1 ........................ 112 7.2.3 Schiff base SB2 .......................... 113 7.2.4 Schiff bases SB6 ......................... 113 7.2.5 Schiff bases SBN2, SB3, SBN3, SB4, SBN4, SB5, SBN5 and SBN6 ............................ 113 7.3 Synthesis of the Schiff base thallium salts . 114 7.4 Synthesis of the catalysts . 114 7.4.1 Synthesis of RuCl(p-cymene)SchiffBase complex . 114 7.5 Ru-catalyzed quinoline synthesis from ketones . 117 7.5.1 General experimental procedure . 117 7.5.2 Isolation of quinolines . 117 7.5.3 Properties and spectral data of quinolines . 117 7.5.4 Synthesis of 3-phenylpropiophenone . 119 7.6 Ruthenium-catalyzed synthesis of 3-substituted quinolines . 119 7.6.1 Method A: slow addition of the aldehyde . 119 7.6.2 Method B: oxazine formation followed by ring closing . 120 7.6.3 Spectral data of oxazines . 120 7.6.4 Properties and spectral data of quinolines . 121 7.7 Base-mediated quinoline synthesis . 122 7.7.1 Procedure for quinoline synthesis from ketones . 122 7.7.2 Procedure for the synthesis of 3-substituted quinolines . 122 7.7.3 Synthesis of 2-acetamidobenzyl acetate (ABA”)....... 122 7.7.4 Self-condensation of 2-heptanone . 123 7.8 Ruthenium-catalyzed synthesis of enol esters . 123 7.8.1 General experimental procedure . 123 7.8.2 Procedure for the addition of NHC ligands . 123 7.8.3 Procedure for the addition of bases . 124 7.8.4 Isolation of enol esters . 124 7.8.5 Properties and spectral data of enol esters .
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