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Caffeine-Derived-Iron Catalyzed Carbonyl-Ene and Diels-Alder Reactions and Development of an NHC-Diol Ligand Family

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Caffeine-Derived-Iron Catalyzed Carbonyl-Ene and Diels-Alder Reactions and Development of an NHC-Diol Ligand Family Caffeine-derived-iron catalyzed carbonyl-ene and Diels-Alder reactions and development of an NHC-diol ligand family Thè se Di Meng Doctorat en chimie Philosophiæ doctor (Ph. D.) Qué bec, Canada © Di Meng, 2018 Caffeine-derived-iron catalyzed carbonyl-ene and Diels-Alder reactions and development of an NHC-diol ligand family Thè se Di Meng Sous la direction de : Thierry Ollevier, directeur de recherche RÉ SUMÉ Cette thè se de doctorat met en é vidence l'utilisation de catalyseurs de fer qui pré sentent de nombreux avantages par rapport aux autres mé taux de transition. En effet, le fer est moins coû teux, respectueux de l’environnement et présente des activités catalytiques inté ressantes. Du fait de ces caracté ristiques, la catalyse au fer a connu un ré el essor ces 15 derniè res anné es. Cette thè se pré sente la ré action de type carbonyl-è ne intermolé culaire catalysé e par des sels de fer(II) et de fer(III), utiles pour leur rôle d’acides de Lewis, en employant plusieurs alcè nes avec le 3,3,3- trifluoropyruvate d'é thyle. Les sels de FeII, notamment FeCl2, Fe(OAc)2, Fe(NTf)2, Fe(ClO4)2·6H2O, Fe(BF4)2·6H2O et Fe(OTf)2, ont é té utilisé s pour catalyser cette transformation. Un systè me efficace utilisant le Fe(BF4)2 anhydre a é té dé veloppé pour catalyser la ré action carbonyl-è ne intermolé culaire de multiples alcè nes avec le 3,3,3-trifluoropyruvate d’éthyle, et aussi la ré action carbonyl-è ne intramolé culaire du (S)-citronellal. Des rendements entre 36-87% en produits-è ne, soit des alcools homoallyliques et de produits de cyclisation du citronellal ont été obtenus par l’utilisation de diffé rents alcè nes disubstitué s. Les carbè nes N-hé té rocycliques (NHC) sont reconnus comme des ligands prometteurs en catalyse avec des mé taux de transition. Trois sels de xanthinium dé rivé s de la café ine ont é té utilisé s comme pré curseurs NHC pour dé velopper des complexes fer-ligand NHC pour les ré actions carbonyl-è ne intra- et intermolé culaires. Les conditions optimales ont é té é tudié es, notamment le choix du sel de fer, du solvant, de la charge catalytique et du contreanion. Fe(OTf)2 est apparu comme le meilleur catalyseur lorsque complexé au ligand NHC dé rivé du sel de xanthinium café ine mé thylé . Avec [NHC-Fe]2+(SbF6)22− comme catalyseur, des rendements de 22% à 99% en alcools homoallyliques ont é té obtenus pour la ré action carbonyl-è ne en employant divers énophiles et le trifluoropyruvate d’éthyle. De plus, NHC-FeIIICl2[SbF6] s’est avéré être un catalyseur efficace et sélectif pour la transformation du citronellal en produit désiré, l’isopulé gol. L’aspect recyclable du sel de xanthinium dé rivé de la café ine lié au Fe(OTf)2 a é té é valué dans la ré action de Diels-Alder en employant des solvants verts, comme le dimé thyl carbonate. Le catalyseur a pu ê tre recyclé cinq fois et des rendements identiques ont é té obtenus. Diffé rents substrats ont é té testé s dont des composé s dicarbonylé s bidendates, cé tones, aldé hydes et esters. Les ligands NHC alkoxylé s ont é té dé veloppé s comme famille é mergente de ligands dans les réactions d’addition conjuguées énantiosélectives. Enfin, de nouveaux ligands NHC-diol ont é té synthé tisé s et testé s dans la ré action carbonyl-è ne. Ces derniers sont prometteurs en catalyse asymé trique et notamment en catalyse utilisant des mé taux de transition. iii ABSTRACT Iron has many advantages compared to other transition metals in homogeneous catalysis, such as relatively cheap price, eco-friendly, good catalytic activities. Hence, these features boosted the development of iron catalysis since 15 years ago. In this thesis, various iron salts including FeII and FeIII were examined as Lewis acid catalysts in the intermolecular carbonyl-ene reaction of various alkenes and ethyl 3,3,3-trifluoropyruvate. FeII salts, such as FeCl2, Fe(OAc)2, Fe(NTf)2, Fe(ClO4)·6H2O, Fe(BF4)2·6H2O, Fe(OTf)2, were found to be effective in catalyzing the reaction. An anhydrous Fe(BF4)2 catalytic system was developed for both of an intermolecular carbonyl-ene reaction of various alkenes and ethyl 3,3,3-trifluoropyruvate and an intramolecular carbonyl-ene reaction of (S)-citronellal. The ene-products, i.e. homoallylic alcohols, were afforded in 36-87% yields giving a scope of various with 1,1-disubstituted alkenes and the cyclization of citronellal. N- heterocyclic carbenes (NHC) are recognized as promising ligands in transition metals catalysis. Three caffeine-derived xanthinium salts were used as NHC precursors to transition metals iron for developing an NHC-iron catalyst in the intermolecular carbonyl-ene reaction and the intramolecular carbonyl-ene reaction of citronellal. Optimized conditions were developed from the screening of iron salts, solvents, catalyst loading and counter anions. Fe(OTf)2 was found to efficiently catalyze the reaction while complexed with NHC ligand derived from methylated caffeine xanthinium salt. Caffeine-derived-[NHC-Fe]2+(SbF6)22− catalyzed carbonyl-ene reaction of various enophiles with ethyl trifluoropyruvate afforded 22-99% yields in homoallylic alcohols. NHC-FeCl2[SbF6] was efficiently and selectively used as a catalyst to convert citronellal into the desired isopulegol. Caffeine-derived xanthinium salt was designed with Fe(OTf)2 as a recyclable catalyst for Diels-Alder reaction in dimethyl carbonate used as a green solvent. Several other green solvents were examined to further study the application of green solvents in organic synthesis. The catalyst, derived from a caffeine-derived xanthinium salt and Fe(OTf)2, was recycled up to five times, while maintaining the same level of yields for the Diels-Alder reaction and recyclability. A relative large scope of substrates including bidentate dicarbonyl compounds, ketones, aldehydes, and esters were tested. Alkoxyl- NHC ligands were developed as a rising family of ligands in enantioselective conjugate addition. A series of new NHC-diol ligands were designed and tested in the carbonyl-ene reaction. These newly developed ligands are promising systems in asymmetric catalysis and transition metal catalysis. iv Table of Contents RÉ SUMÉ ......................................................................................................................................... iii ABSTRACT ..................................................................................................................................... iv Table of Contents ............................................................................................................................. v List of Schemes ............................................................................................................................... ix List of Figures ................................................................................................................................ xiv List of Tables ................................................................................................................................. xvi List of Abbreviations .....................................................................................................................xviii ACKNOWLEDGEMENTS............................................................................................................... xx Chapter one Introduction of iron and NHC-iron catalysis & Development of caffeine-derived NHC- Fe catalyst in carbonyl-ene reaction ................................................................................................ 1 1.1 Iron catalysis and the objectives of the research ................................................................... 1 1.2 General objectives of the thesis ...........................................................................................12 1.3 N-Heterocyclic carbene (NHC) chemistry .............................................................................12 1.4 The development of Iron-NHC chemistry .............................................................................16 1.4.1 Carbon−halide bond ......................................................................................................17 1.4.2 Carbon−carbon double and triple bond .........................................................................18 1.4.3 Carbon−heteroatom double bond ..................................................................................20 1.5 The development of carbonyl-ene reaction ..........................................................................21 1.5.1 Definition and advantages of carbonyl-ene reaction ......................................................21 1.5.2 Development of catalysts ..............................................................................................22 1.5.3 Development of catalysts for the ethyl trifluoropyruvate-ene reaction ...........................23 1.6 Synthetic organic chemistry of caffeine ................................................................................24 1.7 References ...........................................................................................................................27 v Chapter two Development of iron catalysis in carbonyl-ene reaction ............................................37 2.1 Iron salts as Lewis acid for carbonyl-ene reaction ................................................................37 2.2 Development of organo-iron catalyst for carbonyl-ene reactions ..........................................44 2.3 Development of caffeine-derived NHC with iron as catalyst for carbonyl-ene reactions
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