Les cyclopropanes sont des motifs régulièrement incorporés lors du développement de nouvelles molécules bioactives de par les propriétés qu’ils apportent à celles-ci. Cela a donc poussé les chimistes organiciens à développer de nouvelles méthodologies pour leur synthèse en modulant notamment les différentes substitutions. Les travaux de cette thèse s’inscrivent donc dans cette thématique : le développement de méthodologies permettant l’accès à des cyclopropanes hautement substitués. Afin d’accéder à des motifs 1,2,3-trisubstitués et stéréoenrichis, nous avons dans un premier temps envisagé de réaliser des couplages de Suzuki-Miyaura sur des halocyclopropanes 2,3-disubstitués synthétisés dans le groupe grâce à l’utilisation du ligand chiral de type dioxaborolane. Des conditions douces et reproductibles ont été développées, notamment grâce à la synthèse d’un pré-catalyseur de type Buchwald. Les chapitres suivants ont été consacrés à la synthèse de motifs cyclopropaniques substitués de manière plus directe en utilisant des composés diazoïques portant les groupements à introduire. Des diazoalcanes semi-stabilisés (portant des groupements possédant des liaisons π proximales tels que des aryles ou des alcènes) ont tout d’abord été employés. L’utilisation d’une porphyrine de fer a permis de réaliser des cyclopropanations d’aryldiazométhanes générés in situ à partir de 2-nosylhydrazones dans des conditions douces, ce qui a permis d’élargir la gamme de composés diazoïques semi-stabilisés utilisables en cyclopropanation. Nous avons par la suite envisagé de réaliser des cyclopropanations de dialkyldiazoalcanes générés in situ à partir d’arylsulfonylhydrazones. Des gem-diméthyl cyclopropanes, motifs d’intérêt pour l’industrie pharmaceutique, ont été synthétisés avec succès et ce sans nécessiter la présence d’un catalyseur métallique. De hautes températures ont cependant été nécessaires. À cause de ces conditions très dures, nous nous sommes tournés vers une autre stratégie pour la synthèse de composés diazoïques non-stabilisés. Nous avons alors envisagé d’oxyder des hydrazones libres, ce processus pouvant se dérouler à basses températures et générant moins de déchets. Après l’achèvement d’un projet initié par d’autres membres du groupe employant une quantité stœchiométrique d’un oxydant métallique, nous nous sommes tournés vers l’utilisation de l’iodosylbenzène. Cet oxydant organique a permis la génération de nombreux composés diazoïques aliphatiques et a été compatible avec une réaction de cycloaddition [3+2] in situ de divers accepteurs de Michael. Alors que les conditions réactionnelles ne permettaient pas la conversion spontanée de toutes les 1-pyrazolines générées en cyclopropanes, un processus de photolyse en chimie en flux continu a été développé afin d’induire ces contractions de cycle. Des dérivés d’amino acides non naturels ainsi que des gem-diméthyl cyclopropanes ont été obtenus avec de hauts rendements. En immobilisant l’iodosylbenzène dans un réacteur à garnissage et en utilisant la technologie en flux continu, nous avons par la suite généré des solutions relativement pures de phényldiazométhane. Cependant, la génération de composés diazoïques non-stabilisés en utilisant ce processus s’est avérée plus complexe en raison de diverses incompatibilités. Enfin, la synthèse de cyclopropanes substitués par des groupements amino, alkoxy ou aryloxy a été envisagée via l’utilisation de composés diazoïques substitués par ces hétéroatomes. Lors de l’initiation de ces travaux, un faible rendement en aminocyclopropane a été obtenu, indiquant néanmoins la génération et cyclopropanation du composé diazoïque déstabilisé désiré. / The cyclopropane moiety is present in a large number of bioactive molecules as its incorporation usually improves their physicochemical properties. As a result, the development of new methodologies allowing the synthesis of various substituted cyclopropanes have become of significant interest. In order to access stereoenriched 1,2,3-trisubstituted cyclopropanes, we first developed a Suzuki-Miyaura cross-coupling of 2,3-disubstituted halocyclopropanes synthesized in the group using a chiral dioxaborolane ligand. Mild and highly reproducible reaction conditions were developed, especially thanks to the synthesis of a Buchwald type pre-catalyst. The next chapters were devoted to the synthesis of substituted cyclopropanes using diazo compounds bearing the groups to introduce. Semi-stabilized diazoalkanes (bearing π-system-containing groups such as aryl or alkene moieties) were first employed. The use of an iron porphyrin allowed the cyclopropanation of aryldiazomethanes generated in situ from 2-nosylhydrazones under mild conditions, enabling a broader scope of semi-stabilized diazo compounds that can be used in cyclopropanation reactions. Then, we investigated the cyclopropanation of dialkyldiazoalkanes generated in situ from arylsulfonylhydrazones. Gem-dimethyl cyclopropanes, motifs of particular interest in medicinal chemistry, were synthesized under metal-free conditions. However, high temperatures were needed to decompose the diazo precursors. Because of these harsh reaction conditions, we moved to another strategy enabling the synthesis of non-stabilized diazo compounds. We envisioned the oxidation of free hydrazones, being a more atom economical process that typically requires lower temperatures. After the completion of a project initiated by other group members employing stoichiometric amounts of a metallic reagent, we investigated the use of an organic oxidant. Iodosylbenzene allowed the generation of numerous aliphatic diazo compounds and was compatible with the in situ [3+2] cycloaddition of various Michael acceptors. Conversion of the 1-pyrazolines into the corresponding cyclopropanes was not always spontaneous under these reaction conditions, and therefore a photolysis process using continuous flow was developed in order to induce the ring contractions. Unnatural amino acids and gem-dimethyl cyclopropanes were synthesized in high yields using methodology. Immobilizing the iodosylbenzene in a packed bed reactor using a continuous flow set up allowed us to rapidly generate clean solutions of phenyldiazomethane. However, the production of non-stabilized diazo compounds using this process turned out to be more complicated due to numerous incompatibilities. Finally, the syntheses of amino-, alkoxy- or aryloxycyclopropanes were attempted by generating heteroatom-substituted diazo compounds from the corresponding free hydrazones. An aminocyclopropane was obtained during the initial investigation of this reaction. Although in low yield, this result showed the feasibility of each and every step.

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Die vorliegende Arbeit ist in zwei Teile gegliedert und befasst sich im ersten Abschnitt mit der stöchiometrischen und katalytischen Aktivierung von Element-Element-Bindungen an NHC-stabilisierten Eisen(II)-Komplexen. Im Fokus der Untersuchungen steht hierbei sowohl die Isolierung und Charakterisierung neuartiger NHC-stabilisierter Eisen-Komplexe sowie deren Nutzung als Katalysatoren in der Hydrosilylierung von Carbonylverbindungen und der Hydrophosphanierung von Mehrfachbindungssystemen. Der zweite Teil dieser Arbeit ist der Reaktivität N-heterocyclischer Carbene gegenüber Hauptgruppenelement-Verbindungen wie beispielsweise Chlorsilanen, Stannanen, Phosphanen und Alanen gewidmet. Neben der Aufklärung mechanistischer Details der Reaktionen ist die übergangsmetallfreie Hydrodefluorierung von Fluoraromaten zentraler Bestandteil dieser Untersuchungen. / The present thesis is divided into two parts, the first of which is concerned with the stoichiometric and catalytic activation of element-element bonds at NHC-stabilized iron(II) complexes. The focus of these investigations is on the isolation and characterization of novel NHC-stabilized iron complexes and on their utilization as catalysts in the hydrosilylation of carbonyl compounds, as well as in the hydrophosphination of unsaturated hydrocarbons. The second part of this thesis addresses the reactivity of N-heterocyclic carbenes towards main-group element compounds such as chlorosilanes, stannanes, phosphines and alanes. Besides the elucidation of mechanistic details, the transition-metal-free hydrodefluorination of fluorinated aromatic compounds is a central part of this work

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The N-heterocyclic carbene (NHCs) based pincer ligands field is still in its infancy after decades. They are known for their applications in organocatalysis, coordinating with transition metals and p-block elements, catalysis, and material chemistry. Among all NHCs, CCC-NHC-based on late-transition metal complexes were first developed by our group in 2005 with a unique metalation/transmetalation strategy. Our group also designed the chiral version of these CCC-NHC ligands to synthesize its metal complexes. However, their asymmetric catalytic applications were unknown. Wanting to expand on this work, we first successfully synthesized achiral CCC-NHC pincer complexes and their new catalytic application, as it is economically cheaper than directly working on developing a chiral version for catalysis. Then, different chiral CCC-NHC salts were synthesized based on different chiral arms and N-substituents on NHCs to modify their steric hindrance and electronic structure properties. These precursors were used for their enantioselective application in nucleophilic catalysis. In Chapter II, we will discuss the synthesis of the CCC-NHC pincer Ir (III) dimer complex and its first catalytic application in C−H functionalization of N-methylindoles with alpha-aryl-alpha-diazoacetates at the C-3. The best reaction conditions involve a combination of catalysts and substrates in a specific order. It resulted in the activation of the C-H bond with the formation of a new C-C bond to generate alpha-aryl-alpha-indolyl acetates with more than 99% conversion at room temperature without requiring any additives. The substrate scope and limitations of N-methyl indoles and diazoacetates were also explored. Chapter III will focus on a new modified synthetic route to synthesize and characterize chiral CCC-NHC chloride salts in a shorter synthetic route than the known one. The metalation/transmetalation of chiral CCC-NHC ligands with late transition metals and the initial attempt in asymmetric catalysis will be discussed in Chapter IV. Chapter, V, demonstrated nucleophilic catalysis of CCC-NHC precursors in benzoin condensation of aldehyde. The study started with the evaluation of fifteen different achiral bis-CCC-NHC salts based on triazole, imidazole, and benzimidazole. Further studies with chiral CCC-NHC salts also resulted in more than 99% conversion and 99% ee in benzoin products. The substrate scope of benzaldehyde with different substituents was also explored

This thesis describes our physical organic and mechanistic investigations into N Heterocyclic Carbene (NHC) mediated organocatalytic transformations, through a collaboration with the research group of Dr AnnMarie O'Donoghue and PhD student Richard Massey at Durham University. Initial research focused upon the determination of kinetic acidities and associated pKₐ values for a range of triazolium salts using C(3) H/D exchange, monitored by ¹H NMR spectroscopy. Estimates for pKₐ values in the range 16.6 17.4 were obtained, which are some ~2 and ~3 5 pK units lower than analogous imidazolium and thiazolium species respectively, with modest N substituent (0.3 pK units) effects observed. At lower pD values, an altered pD dependence indicates a dicationic triazolium species is formed (through N(1) protonation) with an estimated pKₐᴺ¹ of -0.2-0.5 and C(3) H pKₐ values at least 2 units lower than their monocationic analogues. This methodology was subsequently extended to mesoionic NHCs, where pKa values of 23.0 27.1 for a range of triazolium and 30.2 31.0 for a range of imidazolium salts were estimated. A detailed study of the NHC catalysed intramolecular Stetter reaction was also undertaken using ¹H NMR spectroscopy. A range of 3 (hydroxybenzyl)azolium salts (adducts), formed from the addition of NHC to aldehyde were isolated, enabling the generation of reaction profiles and the determination of rate constants. The reaction proceeds via rapid and reversible adduct generation, followed by rate limiting Breslow intermediate formation, with electron withdrawing N aryl substituents increasing the rate of product formation. Consistent with rate limiting deprotonation, deuterium exchange studies of O methylated adduct analogues found electron withdrawing N-aryl units gave faster exchange. Examination of the equilibrium constants for adduct formation revealed that both in the case of NHCs bearing 2,6 disubstituted N aryl units and aldehydes bearing a 2 ether substituent, the equilibrium position is significantly shifted towards adduct. Finally, studies at sub-stoichiometric NHC concentrations, monitored by HPLC, imply the reaction is first order with respect to NHC precursor, but zero order in aldehyde, again indicative of rate limiting deprotonation.

Photokontrolle von Eigenschaften einzelner Moleküle und größerer Molekülvereinigungen ist ein faszinierendes Feld aktueller chemischer Forschung. Das schlichte Potential der genauen Adressierbarkeit von chemischer Reaktivität sowie die Möglichkeit durch Ausnutzen des katalytischen Zyklus einen Lichtstimulus in ein verstärktes chemisches Signal zu übersetzen, machen die Photokontrolle über katalytische Aktivität zu einem besonders attraktiven Ziel. Daher wurde im Rahmen dieser Dissertation ein allgemeines Konzept zur Realisierung von photoschaltbaren Katalysatoren entwickelt, das auf der reversiblen sterischen Abschirmung eines katalytisch aktiven Zentrums durch eine photochrome Abschirmungsgruppe beruht. Durch Vorgabe des Schaltzustandes des Photochromes kann die Aktivität des Katalysators bestimmt werden. Das Konzept wurde durch die Entwicklung von konformativ eingeschränkten, photoschaltbaren Piperidinbasen umgesetzt, die synthetisch leicht durch einen in hohem Maße modularen Zugang erhalten werden konnten. Die Piperidinbasen erlaubten die Photokontrolle der Katalysatoraktivität in der Nitroaldol-Reaktion (Henry-Reaktion). Durch die Optimierung der Substituenten konnten bemerkenswerte katalytische AN/AUS-Verhältnisse erreicht werden. Die Reaktivitätsunterschiede konnten mit Änderungen der Basizität in Abhängigkeit vom Schaltzustand korreliert werden. Systematische NMR-spektroskopische und theoretische Untersuchungen der strukturellen Dynamik des Katalysators in Lösung ermöglichten die Formulierung von detaillierten Struktur-Reaktivitäts-Beziehungen. Eine Erweiterung des Konzepts auf intrinsisch reaktivere Katalysatoren sollte zu einer verbesserten Anwendbarkeit beitragen. Daher wurde das Konzept der reversiblen sterischen Abschirmung auf katalytisch aktive N-heterozyklische Carbene übertragen. Eine erfolgreiche Synthese wurde durch ungünstige sterische Wechselwirkungen zwischen den abschirmenden Gruppen an den Stickstoffatomen des Carbens verhindert. / Photocontrol over properties of single molecules and assemblies thereof is an appealing area of current chemical research. The mere potential to selectively address chemical reactivity as well as the possibility to transform an incoming light stimulus into an amplified chemical signal by exploiting the associated catalytic cycle renders photocontrol of catalytic activity a particularly attractive goal. In this dissertation, a general concept for the realization of photoswitchable catalysts was developed, based on reversible steric shielding of a catalyst’s active site by a photochromic blocking group. Dictating the photochrome’s switching state enables gated access to the active site, thereby photocontrolling the catalyst’s chemical reactivity. The concept was realized by designing conformationally restricted, photoswitchable piperidine bases, which were easily synthesized exploiting a highly modular approach. Indeed, the developed piperidine bases allowed to photocontrol the catalysts’ activities in the nitroaldol reaction (Henry reaction) and by tuning of the substituents significant catalytic ON/OFF-ratios were achieved. The reactivity differences could be correlated with changes of basicity depending on the photochrome’s switching state. Systematic NMR-spectroscopic and computational studies of the catalysts’ structural dynamics in solution enabled the formulation of detailed structure-reactivity relationships. Strategies for the implementation of the concept of reversible steric shielding into the N-heterocyclic carbene (NHC) motif were devised to exploit the high reactivity of NHCs in numerous catalytic processes, which is expected to greatly enhance the utility of the concept. However, profound steric shielding of the active site to suppress unwanted OFF-state reactivity prevented the synthetic realization of the concept due to unfavorable steric interactions upon formation of the heterocyclic carbene from suitable precursors.