Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for use against the malaria vector Anopheles gambiae. In the process of producing a library of compounds for assay against An. gambiae, it became clear that employing regioselective acylation techniques (in molecules that feature two nucleophilic, acyclic nitrogen atoms α to one another) would be imperative. Synthesis of the library derivatives proceeded rapidly and after topical assay, we found three compounds that were more toxic than the RH-series leads. One of the three displayed an LD50 value of half that of RH-1266, though patch clamp assay concluded that toxicity was not necessarily linked to inhibition of mosquito K+ channel Kv2.1. The acylation of monoarylhydrazines appears simple, but its regioselectivity is poorly understood when assumed as a function of basicity correlating to nucleophilic strength. We determined the ratio of the rate constants for distal to proximal N-acylation using 19F NMR spectroscopic analysis of reactions of 4-fluorophenylhydrazine with limiting (0.2 equiv) acylating agent in the presence of various bases. Acid anhydrides gave consistent preference for distal acylation. The selectivity of acylation by acyl chlorides when using pyridine gives strong distal preference, whereas use of triethylamine or aqueous base in conjunction with aroyl chlorides showed a moderate preference for proximal acylation. This observation yielded a convenient one-step method to synthesize proximal aroylarylhydrazines in yields comparable or superior to that provided by the standard three-step literature approach. Combined with NMR evidence of the distal nitrogen as the unambigiously stronger base of the two nitrogens, we propose a single electron transfer mechanism that predicts the regiochemistry of arylhydrazines toward acylating agents better than the nucleophilicity model based on pKa values. While synthesizing the acylhydrazine library for assay against An. gambiae, NMR spectroscopy revealed rotational isomerisms of two types: chiral helicity (M)/(P) and acyl (E)/(Z)-isomerism due to hindered rotation. Variable temperature NMR allowed the measurement of N-N bond rotational barriers, as well as estimate the barrier of (E)/(Z) interconversion. We obtained the X-ray crystal structures of four diacylhydrazines to test this hypothesis and revealed both the twist conformation around the N-N bond axis and (E)/(Z)-isomerism around the proximal acyl group. Computation (which agreed with the crystal structures) allowed us to estimate which (E)/(Z)-isomers were most likely being observed in solution at room temperature by NMR spectroscopy. In addition, we were able to calculate transition structures corresponding to N-N bond rotational barriers of (E,Z)- and (Z,Z)-isomers of model molecules and rationalize the difference in coalescence temperatures between (E,Z)- and (Z,Z)-isomers. / Ph. D.

This thesis describes stereospecific fluorination reactions, and addresses the synthesis of fluorosugars. In Chapter 1, the influence of fluorine on the physical properties of organic molecules, as well as its stereoelectronic effects, are introduced. Furthermore, an overview of nucleophilic and electrophilic fluorination reactions is given. Chapter 2 describes the dehydroxyfluorination of allylic alcohol diastereoisomers 155a and 155b, which can proceed either by direct or allylic fluorination. The regio- and stereo- selectivities were also assessed. Chapter 3 outlines the synthesis of the novel trifluoro D-glucose analogue 193 and trifluoro D-altrose analogue 216. The transport of these hexose analogues across the red blood cell membranes was then explored, to investigate the influence of polarity versus hydrogen bonding ability in carbohydrate-protein interactions. Chapter 4 describes the development and optimisation of Bio’s methodology, to promote stereospecific dehydroxyfluorination of benzylic alcohols (R)-213 and (R)-227 by addition of TMS-amine additives 226 and 229. And finally Chapter 5 reports the experimental procedures as well as the characterisation and the crystallographic data of the molecules prepared in this thesis.

Trifluoromethylierung von Mischungen hoeherer Fullerene mit CF3I wurde in Ampullen bei 400-420 Grad Celsius und 500-600 Grad Celsius durchgefuehrt. Die Produktmischungen wurden mittels mehrstufiger HPLC getrennt. In mehreren Versuchen konnten aus den isolierten HPLC-Fraktionen Kristalle fuer die Roentgenstrukturanalyse gewonnen werden. Die folgenden Strukturen der CF3-Derivate der Fullerene C84, C86 und C88 wurden bestimmt: 1 Isomer von C84(4)(CF3)12, C84(11)(CF3)10, C84(11)(CF3)12, C84(11)(CF3)16, C84(16)(CF3)8, C84(16)(CF3)14, C84(18)(CF3)10, C84(18)(CF3)12, C84(22)(CF3)20, C84(23)(CF3)8, C84(22)(CF3)10, C84(22)(CF3)12, C84(22)(CF3)18, C86(17)(CF3)10, C86(17)(CF3)16, C88(33)(CF3)16, C88(33)(CF3)18 und C88(33)(CF3)20. 2 Isomere von C84(22)(CF3)12, C84(22)(CF3)14 und C84(23)(CF3)14. 3 Isomere von C84(11)(CF3)14. 4 Isomere von C84(22)(CF3)16. Die Additionsmuster der Strukturen wurden diskutiert. Die experimentell nachgewiesenen Strukturen wurden mit berechneten Modellstrukturen verglichen. Dabei wurde auch die Stabilitaet der experimentellen Strukturen vorausgesagt. Zusaetzlich wurden die moeglichen Reaktionspfade fuer die Bildung hoeherer Derivate ausgehend von niedrigen Derivaten diskutiert. Sie zeigen, dass die Regioselektivitaet der Addition vom Kaefigisomer abhaengig ist. Die Reaktionspfade von vier Fullerenkaefigen werden in dieser Arbeit vorgestellt. C84(11)(CF3)10 --> C84(11)(CF3)16 C84(22)(CF3)2 --> C84(22)(CF3)20 C84(23)(CF3)10 --> C84(23)(CF3)18 C86(17)(CF3)10 --> C86(17)(CF3)16 / Trifluoromethylation of higher fullerene mixtures with CF3I was performed in ampoules at 400 to 420 degree Celsius and 500 to 600 degree Celsius. The obtained product mixtures were separated by multistep HPLC. Subsequent crystal growth and X-ray diffraction measurements allowed for structural characterization of the CF3 derivatives of fullerenes C84, C86 and C88 listed as the following. 1 isomer of C84(4)(CF3)12, C84(11)(CF3)10, C84(11)(CF3)12, C84(11)(CF3)16, C84(16)(CF3)8, C84(16)(CF3)14, C84(18)(CF3)10, C84(18)(CF3)12, C84(22)(CF3)20, C84(23)(CF3)8, C84(22)(CF3)10, C84(22)(CF3)12, C84(22)(CF3)18, C86(17)(CF3)10, C86(17)(CF3)16, C88(33)(CF3)16, C88(33)(CF3)18 and C88(33)(CF3)20. 2 isomers of C84(22)(CF3)12, C84(22)(CF3)14 and C84(23)(CF3)14. 3 isomers of C84(11)(CF3)14. 4 isomers of C84(22)(CF3)16. The molecular structures of isolated isomers were discussed in terms of their addition patterns and relative formation energies. DFT calculations were used to predict stable molecular structures of the CF3 derivatives. Calculated model structures have been compared with the experimental ones. In addition, the reaction pathways from the lower derivatives to higher ones of selected compounds were predicted. The pathways indicate the regioselectivity of additions depending on the fullerene cage isomer. Reaction pathways are presented for four fullerene cages in this work. C84(11)(CF3)10 --> C84(11)(CF3)16 C84(22)(CF3)2 --> C84(22)(CF3)20 C84(23)(CF3)10 --> C84(23)(CF3)18 C86(17)(CF3)10 --> C86(17)(CF3)16

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The regioespecific synthesis of a series of 14 N-acylated enaminones (52-88%) from the acylation reaction of secondary β-enamino ketones [RC(O)CH=CHNR1R2; R = Ph, 4- FC6H4, 4-NO2C6H4, thien-2-yl, CCl3, CF3; R1 = H; R2 = Bn, Ph, 4-NO2C6H4] with trifluoroacetic anhydride or ethyl oxalyl chloride in pyridine is reported. On the other hand, when tertiary enaminone precursors [R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, thien-2-yl, benzofur-2-yl, CCl3, CF3; R1,R2 = Me] were used, the acylation reaction led to a series of 17 C-acylated enaminones (75-95%). A series of 4-substituted-1H-pyrazole-5-carboxylates (73-94%) were obtained regiospecifically from the cyclocondensation reaction of non symmetrical enaminodiketones [RC(O)C(=CHNMe2)C(O)CO2Et; R = Ph, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, thien-2-yl, benzofur-2-yl, CCl3, CF3] with tert-butylhydrazine or carboxymethylhydrazine. The reaction of these pyrazole-5-carboxylates (R = 4-MeOC6H4, 4-FC6H4, benzofur-2-yl, CF3) with hydrazine lead to synthesis of 4- substituted-pyrazolo[3,4-d]pyridazinones (74-96%). In addition, the reaction of enaminodiketones (R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4- O2NC6H4, thien-2-yl, benzofur-2-yl) with 3-amino-5-methylpyrazole was performed, where a series of pyrazolo[1,5-a]pyrimidine-7-carboxylates were obtained regiospecifically (53-79%). / A síntese de uma série de 14 enaminonas N-aciladas regioespecificamente (52-88%) foi realizada a partir da reação de acilação de enaminonas secundárias [RC(O)CH=CHNR1R2; R = Ph, 4-FC6H4, 4-NO2C6H4, tien-2-il, CCl3, CF3; R1 = H; R2 = Bn, Ph, 4-NO2C6H4] com anidrido trifluoracético e com cloreto de etil oxalila em piridina. Quando foram utilizados como precursores enaminonas terciárias [R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, tien-2-il, benzofur-2-il, CCl3, CF3; R1,R2 = Me] a reação de acilação levou à obtenção regioespecífica de 17 enaminonas C-aciladas (75-95%). Uma série de 5-carboxietil-1H-pirazol 4-substituídos foi obtida regioespecificamente (73-94%) a partir da ciclocondensação das enaminodicetonas não simétricas [RC(O)C(=CHNMe2)C(O)CO2Et; R = Ph, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, tien-2-il, benzofur-2-il, CCl3, CF3] com tert-butilidrazina ou carboximetilidrazina. A reação destes pirazóis (R = 4-MeOC6H4, 4-FC6H4, benzofur-2-il, CF3) com hidrazina monoidrato levou à síntese de pirazolo[3,4-d]piridazinona 4- substituídas (74-96%). Também foi realizada a reação de ciclocondensação de enaminodicetonas (R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, tien-2-il, benzofur-2-il) com 3-amino-5-metilpirazol onde as 7-carboxietilpirazolo[1,5-a]pirimidinas 6-substituídas foram obtidas regioespecificamente (53-79%).

Cette thèse présente différents aspects de la cyclonickellation des phosphinites de type Aryl-OP(i-Pr)2, leur potentiel dans la fonctionnalisation et leur utilité pour former des nouveaux types de complexes de types pincer de nickel. Le Chapitre 1 constitue une introduction générale sur l’importance de la liaison carbone-nickel en chimie organométallique. Diverses stratégies de formation des liens C-Ni dans des composés classiques (monodentés), des composés de types pincer (tridentés) et des composé cyclonickellés (bidentés et tridentés) y sont présentées, incluant des réactions impliquant des précurseurs de Ni0, de NiII ou de NiIV. Ce chapitre présente également la réactivité de ces composés comportant des liens C-Ni, et met l’emphase sur la réactivité des liaisons carbone-nickel, en particulier dans les processus catalytiques destinés à la fonctionnalisation des liens C-H, en utilisant des groupes directeurs. Les phosphinites sont ensuite présentées comme des groupes directeurs intéressants en catalyse, bien qu’elles aient surtout été utilisé avec d’autres métaux que le nickel. La dernière partie de ce chapitre pose les questions qui tenterons de trouver réponse dans les travaux présentés aux chapitres suivants. Les Chapitres 2 et 4, basés sur des articles publiés, présentent l’isolation et la caractérisation de composés dimériques de type [{κP,κC-(i-Pr)2POAr}Ni(μ-Br)]2 issus de l’ortho-nickellation des phosphinites dérivées des phénols et des naphtols substitués, ainsi que de certains de leurs adduits monomériques d’acétonitrile ou du ligand lui-même. Ces discussions cherchent à répondre à la question de régiosélectivité de la cyclonickellation : on y démontre que cette réaction est gouvernée par les facteurs stériques, menant à la métallation préférablement (pour les substituants fluor) ou exclusivement (pour les substituants plus volumineux) aux carbones les moins encombrés, lorsque deux positions ortho sont disponibles, et que la réaction mène toujours à la formation de nickellacycles à 5 chainons. Ainsi, les phénols C3-substitués subissent la métallation au carbone C6, alors que les 1- et 2-naphtols subissent la nickellation aux positions C2 et C3, respectivement. Ces deux chapitres démontrent que la métallation peut avoir lieu sur des carbones qui possèdent déjà un voisin encombrant (F, OMe, benzo), menant à des structures relativement distordues, mais que la nickellation n’est pas produite dans les conditions standard au voisinage des substituants Me et Cl qui sont plus volumineux, ni au carbone C8 du 1-naphtol qui mènerait à un nickellacycle à 6 chainons. L’étude structurale permet de rationaliser les régiosélectivités observées, et les études par diverses méthodes RMN complètent la caractérisation de ces nouveaux composés. Le Chapitre 2 démontre que lorsque les sites potentiels de nickellation sont bloqués par des substituants ortho Me ou Ph, la réaction ne prend pas place sur ces substituants en raison de la formation de nickellacycles à 6 ou 7 chainons respectivement. Ceci met en lumière également l’impossibilité d’isoler les composés nickellés aux carbones sp³ des substituants ortho, et le Chapitre 4 démontre par des expériences d’échange H/D que la nickellation à ces positions n’est pas seulement thermodynamiquement défavorisée, mais qu’elle est aussi cinétiquement inexistante. Ce chapitre dévoile également les réactions qui sont observables à 80 °C sont radicalement accélérées à haute température (120 ou 160 °C), et que les produits de nickellation y sont thermodynamiquement stables. Le Chapitre 4 présente également une réaction de fonctionnalisation in situ des liens carbone-nickel de la phosphinite cyclonickellée dérivée du 1-naphthol. Dans cette réaction, qui se produit à haute température en absence de base, la bromophosphine Br-P(i-Pr)2 se génère in situ et permet l’insertion formelle d’un phosphènium [(i-Pr)2P]+ dans le lien carbone-nickel, menant à un complexe phosphine-phosphinite de type {κP,κP’-1-(i-Pr)2PO-2-naphtyl-P(i-Pr)2}NiBr2. Lorsque la position C2 du 1-naphtol est bloquée par un substituant Et, un genre similaire de fonctionnalisation à la position C8 est observé, menant à l’obtention de 8-(i-Pr)2P(O)-2-Et-1-naphtol, ainsi qu’à des sous-produits qui ont été identifiés et caractérisés. Cette réaction démontre l’accessibilité cinétique de la position C8 à haute température, mais démontre également l’instabilité du nickellaycle généré. Les conditions réactionnelles pour l’obtention des phosphinites nickellées dévoilées au Chapitre 2 (utilisant l’acétonitrile comme solvant) ont démontré une efficacité supérieure que celle présentée précédemment (dans le toluène). Ainsi, le Chapitre 3, également basé sur un article publié, cherche à décrire les aspects mécanistiques de cette cyclométallation et démontre que les espèces initialement présentes dans l’acétonitrile sont des adduits mono-phosphinites du nickel au contraire des espèces présentes dans le toluène. Cette étude démontre qu’une base externe est nécessaire pour conduire à l’isolation des composés nickellés, mais qu’elle n’est pas impliquée dans le mécanisme de métallation car la formation des liens C-Ni se produit réversiblement en absence de base. Des suivis cinétiques indiquent que la réaction est de premier ordre et qu’un excès de base ralentit la réaction en formant des espèces non réactives, et que les bases idéales sont fortes et peu coordonnantes. Une étude mécanistique expérimentale révèle que l’étape de nickellation est de nature électrophile (pente de Hammett ρ ≈ –4) et associative (ΔH⧧ = 18(1) kcal·mol–1 and ΔS⧧ = −27(4) cal·mol–1·K–1) et que le transfert de proton est l’étape limitante (kH/kD ≈ 11). Ces résultats sont appuyés par une étude computationnelle par DFT qui démontre que la dissociation d’un ligand Br- mène à une paire d’ions comme intermédiaire, depuis lequel la déprotonation est réalisée par l’anion Br- dans un mécanisme de type CMD. Les résultats de ces calculs théoriques permettent également d’appuyer la thèse d’un état fondamental triplet pour les espèces présentes avant la nickellation dans l’acétonitrile. Les études sur la régiosélectivité ont mené à un résultat surprenant : à la place de subir la nickellation C-H, la phosphinite dérivée du 2-vinylphénol subit une attaque nucléophile sur le groupe vinyle afin de donner un composé tridenté portant un lien Csp³-Ni. Le Chapitre 5 présente ainsi une nouvelle stratégie de préparation des composés pincers par des réactions de type Umpolung. Le ligand 2-vinylphényl-OP(i-Pr)2 réagit avec des amines et des phosphines portant au moins un proton, pour donner des complexes pinceurs de type 6,4-POCY-NiBr (Y = P, N). Ce chapitre dévoile l’étendue des composés qui peuvent être produits par cette méthode, et offre une caractérisation de ces composés par RMN, diffraction des rayons X et par électrochimie, afin de comparer leurs caractéristiques avec les autres pincers décrits dans la littérature. Enfin, alors que le Chapitre 6 présente quelques résultats additionnels reliés aux divers axes de recherche de cette thèse, le Chapitre 7 rappelle les grandes lignes des découvertes présentées aux Chapitres 2-5. Ce chapitre de conclusion générale présente également des perspectives basées sur les résultats de la thèse, et sur les quelques résultats préliminaires. Au menu : une discussion sur la relation entre régiosélectivité et la stabilité, des nouvelles stratégies de nickellation à étudier (à partir de liens carbone-halogène), la fonctionnalisation des liens C-Ni par des composés isolobaux aux phosphèniums et des stratégies pour la fonctionnalisation des oléfines dans les composés de type alcool. / This thesis presents various aspects of the cyclonickelation of phosphinites Aryl-OP(i-Pr)2, as well as their potential in functionalization processes and applications in the preparation of new types of pincer-Ni complexes. Chapter 1 consists of a general introduction on the importance of the carbon-nickel bond in organometallic chemistry. Various strategies leading to C-Ni bonds in classical (monodentate) compounds, pincer complexes (tridentate), and cyclonickelated species (bi- and tridentate) are disclosed, including reactions implicating Ni0, de NiII ou de NiIV precursors. This chapter also presents the reactivity of species featuring C-Ni bonds C-Ni and underlines the reactivity of C-Ni bonds, especially in catalytic processes targeting C-H bonds functionalization, through the use of directing groups. Next, phosphinites are displayed as interesting directing groups in catalysis even though they have been used mostly with metals other than nickel. The last part of this chapter outlines the questions that are meant to be addressed in the next chapters. Chapters 2 and 4, based on published articles, display the isolation and characterization of dimeric complexes of the type [{κP,κC-(i-Pr)2POAr}Ni(μ-Br)]2 arising from the ortho-nickelation of phosphinites derived from substituted phenols and naphthols, as well as some of their acetonitrile or phosphinite adducts. These studies are meant to address the question of regioselectivity in the cyclonickelation. The results obtained prove that when two ortho sites are available for reactivity, the nickelation is governed by steric factors and leads to metalation preferably (in case of F substituents) or exclusively (in case of larger substituents) at the least hidered C-H bond; moreover, the nickelation always leads to 5-membered nickelacycles. Thus, C3-substituted phenols undergo nickelation at the C6 position, while 1- and 2-naphthols undergo nickelation at C2 and C3 positions, respectively. Together, Chapters 2 and 4 show that metalation can take place at the carbon next to a F-, MeO- or benzo substituent, but such nickelation at the hindered sites leads to distorted structures in the products. One the other hand, nickelation never occurs at carbons neighbouring the larger Me- or Cl- substituents, nor at the C8 position of 1-naphthol which would lead to a 6-membered nickelacycle. The structural study allows us to rationalize the observed regioselectivities, and NMR studies complete the characterization of these new compounds. Chapter 2 also reveals that when the ortho sites are blocked by Me or Ph functional groups, no nickelation takes places on these substituents due to the unfavored generation of 6- or 7-membered metallacycles, respectively. This finding also rationalizes why it has not been possible to isolate complexes arising from the nickelation at sp³ carbons of ortho substituents. This point is confirmed in the studies described in Chapter 4, which shows how H/D exchange experiments helped us prove that reactivity at these aliphatic C-H sites is disfavored not only thermodynamically, but also kinetically. This chapter also reveals that reactions observed at 80 °C can be accelerated dramatically at higher temperatures (120 or 160 °C), and that nickelated products are stable in these conditions. Chapter 4 also presents some examples of in situ functionalization of the C-Ni bonds in cyclonickelated 1-naphthyl phosphinites. Conducting these reactions in the absence of base at high temperatures allowed the in situ generation of bromoposphine, Br-P(i-Pr)2, that promotes the formal insertion of a phosphenium fragment [(i-Pr)2P]+ into the C-Ni bond, thus leading to a phosphine-phosphinite complex of Ni, of the following formula: {κP,κP’-1-(i-Pr)2PO-2-naphtyl-P(i-Pr)2}NiBr2. When the C2 position in the naphthyl phosphinite is blocked by an Et substituent, a similar functionalization occurs at the C8 position leading to 8-(i-Pr)2P(O)-2-Et-1-naphtol, along with by-products which have been identified and characterized. These findings demonstrated the kinetic accessibility of the C8 position at high temperatures, while proving the instability of the generated nickelacycle. The reaction conditions used for the syntheses of cyclonickelated phosphinites displayed in Chapter 2 (using acetonitrile as the solvent) have been proven more efficient than that previously reported (in toluene). Thus, Chapter 3, also based on a published article, describes the mechanistic aspects of the new procedure and reveals that acetonitrile generates more reactive species at the pre-nickelation stage, namely mono-phosphinite nickel adducts, as opposed to the bis-phosphinite nickel complexes observed in toluene. This study demonstrates that an external base is required for isolating the nickelated complexes, but that this base is not implicated in the metalation process, since the formation of the C-Ni bond occurs reversibly in the absence of base. Kinetic monitoring reveals that the reaction is 1st order and that an excess of base in fact slows down the rate by generating non-reactive species. Ideal bases for the nickelation are thus strong bases but weakly coordinating nucleophiles. An experiment-based mechanistic investigation shows that the nickelation is of electrophilic (Hammett slope ρ ≈ –4) and associative (ΔH⧧ = 18(1) kcal·mol–1 and ΔS⧧ = −27(4) cal·mol–1·K–1) nature, and that the proton transfer is rate limiting (kH/kD ≈ 11). These results are supported by a DFT-based computational study that points towards an ion pair formation that allows the dissociated Br- anion to capture the proton, in a CMD mechanism. The theoretical calculation also supported a triplet ground state in acetonitrile for the species present in the pre-nickelation mixture in acetonitrile. Regioselectivity studies of a phosphinite bearing an ortho-vinyl substituent led to a surprising finding: instead of undergoing C-H nickelation, the phosphinite derived from 2-vinylphenol is attacked by nucleophiles on the vinyl moiety and give a Ni complex featuring a tridentate pincer-type ligand with a central Csp³-Ni bond. Chapter 5 thus discloses a new Umpolung-based strategy leading to new pincer complexes. Reaction of the ligand 2-vinylphenyl-OP(i-Pr)2 with primary or secondary amines and phosphines produces novel pincer-Ni complexes of the type 6,4-POCsp3Y-NiBr (Y = P, N). This chapter discloses the variety of new complexes that can be prepared by this new synthetic strategy. The characterisation of the new complexes by NMR, XRD and electrochemical analysis allowed us to compare their structural and redox properties to pincer-Ni complexes reported in the literature. While Chapter 6 discloses additional results related to various research axes of this thesis, Chapter 7 recalls the main findings revealed in Chapters 2-5. This conclusion also discloses research perspectives based on the results presented in this thesis, as well as phosphinite-related preliminary results gathered during my Ph. D. studies. The main proposed ideas touch on the following aspects: (a) the relationship between regioselectivity and stability towards functionalization; (b) new nickelation strategies based on the metalation of carbon-halogen bonds; (c) C-Ni functionalization by isolobal compounds to phosphenium ions; and (d) strategies towards the functionalization of alcohols bearing alkene moieties.

Synthesis of cyclodextrin derivatives for practical applications Abstract The first part of this PhD thesis is focused on the synthesis of a series of monosubstituted tetraalkylammonium cyclodextrin (CD) derivatives. The emphasis was placed on the possible applicability of the synthetic process to multigram or even industrial scale. Monotosylation of the native cyclodextrins (-, -, -) on the primary side of the macrocycle afforded the starting materials. Derivatives with one cationic group were prepared by the reaction with aqueous trimethylamine. The reaction of the mono-Ts-CD with neat N,N,N'-trimethylethane-1,2-diamine or N,N,N'-trimethylpropane-1,3-diamine and subsequent methylation led to derivatives with the substituent bearing two cationic groups (PEMEDA- and PEMPDA-β-CD). Analogs bearing a moiety with three tetraalkylammonium sites were synthesized by reaction of mono-Ts-CD with bis(3-aminopropyl)amine with subsequent methylation. 1,3-Dipolar cycloaddition of mono-6- azido--CD with diaminoacetylenes followed by methylation led to analogs with a avariable distance of the charged substituent from the CD core. Majority of the presented reactions are straightforward, relatively high-yielding and the workup does not require chromatographic steps. The second part of the work is dealing with the...

Chapter 1.<br />1-Ethynyl-2-phenyltetramethyldisilanes HCºCSiMe2SiMe2C6H4-p-X [X = NMe2(1.1), Me (1.2), H (1.3), Br (1.4), CF3 (1.5)] are accessible from ClSiMe2SiMe2Cl, BrMgC6H4X and HCºCMgBr in a two step Grignard reaction. The crystal structure of 1.1 as determined by single crystal X-ray crystallography exhibits a nearly planar PhNMe2 moiety and an unusual gauche array of the phenyl and the acetylene group with respect to rotation around the Si-Si-bond. Full geometry optimization (B3LYP/6- 31+G**) of the gas phase structures of 1.1 and 1.3 affords minima for the gauche and the trans rotational isomers, both being very close in energy with a rotational barrier of only 3 – 5 kJ/mol. Experimental and calculated (time-dependent DFT B3LYP/TZVP) UV absorption data of 1.1 – 1.5 show pronounced electronic interactions of the HCºC- and the C6H4X p-systems with the central Si-Si bond.<br /><br />Chapter 2.<br />A family of [( 5-Cp*)Ru( 6-arene)]+ (Cp* = C5Me5) sandwich complexes of 1- and 1,4-substituted phenyl and naphthyl systems are described along with the regioselectivities of the reactions under various conditions. Finally, the (h 5-Cp*) Ru+ arenophile was found to act as a gate to the flow of electrons between para-substituted termini. When it is complexed onto the phenyl or A naphthyl ring, the gate is closed. On the contrary, when it is complexed onto the B naphthyl ring, the gate is open.<br /><br />Chapter 3.<br />Regioselective complexation reactions of the organoiron acetylide derivatives (h 2- dppe)(h 5-Cp*)Fe-C C-Ar (Ar = phenyl, 1-naphthyl; dppe = 1,2- bis(diphenylphosphino)ethane) with [(h 5-Cp*Ru(CH3CN)3][PF6] to afford heterobimetallic complexes formulated as [(h 2-dppe)(h 5-Cp*)Fe-C C-{(h 6-Ar)Ru(h 5- Cp*)}][PF6], were achieved. In the case of the FeII-RuII 1-naphthyl derivative, the (h 5-Cp*)Ru+ arenophile was complexed both onto the substituted ring and free rings of the acetylide 1-naphthyl linker. The first redox-driven h 6-h 6 inter-ring haptotropic migration of the (h 5-Cp*)Ru+ moeity was shown to occur. Crystal structures of all of the seven new iron acetylenes were resolved, including both haptotropomers of the naphthyl compound.<br /><br />Chapter 4.<br />The diorganoiron [{(h2-dpppe)(h5-Cp*)Fe-CC-}2(1,4-naphthyl)] (4.12) was synthesized in good yield in two steps via the vinylidene, and oxidation led to the mixed valence (MV) and iron(III)-iron(III) species in good to excellent yields. This exhaustive empirical study on the family of complexes 4.12[PF6]n (n = 0,1,2) includes a crystal structure for the case in which n = 2. This work clearly establishes good electronic and magnetic communication between the iron centers across the bis(ethynyl)naphthalene bridge. All empirical measurements of these naphthyl compounds reveal that their properties fall between those of known phenyl and anthracenyl derivatives. In some cases, the naphthyl derivative behaves as an average of the phenyl and anthracenyl complexes. For example, the comproportionation constant of the naphthyl species falls at the midpoint between those for the phenyl and anthracenyl compounds. The same is true for the UV absorption maxima in all three oxidation states (Fe[II]- Fe[II], MV, and Fe[III]- Fe[III]). The large electronic (2043 cm-1) and magnetic (-526 cm-1) coupling constants were determined via NIR spectroscopy and SQUID magnetometry, respectively. As for the heterotrinuclear species, the iron(II) acetylene, 4.14B[PF6] [{Cp*(dppe)Fe-C C}2-(h 6 – [1,4-napthyl])RuCp*](PF6), [Cp* = h 5 - C5Me5; Fe = FeII] was prepared in high yields with an adapted, regioselective synthesis via the trinuclear vinylidene. Complete characterization, including a crystal structure, of this sandwich complex reveals that the arenophile perturbs the organoiron ligand more in the bis(iron) than in the previously reported mono(iron) case.

Les imidazo[1,2-b]pyrazoles tout comme les imidazo[1,2-a]imidazoles sont des entités présentant diverses applications intéressantes notamment dans le domaine pharmacologique. Cependant, malgré ce potentiel, ces structures hétérobicycliques ont été, jusqu’à ce jour, relativement peu étudiées tant au niveau de leur préparation que de leur fonctionnalisation. De ce fait, ces travaux de thèse ont pour objet la mise au point de nouvelles voies d’accès à ces systèmes bicycliques et ce, au départ de substrats facilement accessibles. Des stratégies de fonctionnalisation de ces charpentes moléculaires ont ensuite été développées dans le but de concevoir des librairies diversifiées de ce type de composés, librairies destinées à être évaluées biologiquement. Les premiers résultats d’évaluation sur des lignées cancéreuses de dérivés imidazo[1,2-b]pyrazoliques sont également présentés. / Imidazo[1,2-b]pyrazoles and imidazo[1,2-a]imidazoles are entities with some interesting applications in pharmacology. However, despite this potential, few methods of preparation and direct functionalisation of the heterocyclic moiety have been described. In this context, the overall goal of our research is to develop new routes to these bicyclic systems from readily available starting materials. Strategies of functionalisation of the heterocyclic moiety were then explored in order to design diversified libraries for the evaluation of potential biological activities. Herein, the results of the tests of imidazo[1,2-b]pyrazole series against various cancer lines are reported.

Les hétérocycles oxygénés, azotés et soufrés sont des motifs présents dans de nombreux produits naturels possédant des activités biologiques intéressantes. Plusieurs publications décrivant la synthèse de ces hétérocycles en particulier oxygénés et azotés reposent sur l’utilisation des métaux de transition en tant que catalyseur.Dans notre cas, nous nous sommes intéressés dans un premier temps à la synthèse cupro-catalysée des pyrano[3’,4’:4,5]imidazo[1,2-a]pyridin-1-ones selon une réaction tandem impliquant un couplage et une hétérocyclisation, à partir des dérivés de l’acide 3-iodo-, 3,6- ou (3,8) diiodoimidazo[1,2-a]pyridine-2-carboxylique et d’alcynes vrais en présence de sels de cuivre (I) dans le DMF. Les réactions développées ne nécessitent aucune utilisation de métaux de transition plus coûteux comme les complexes au palladium par exemple. / Heterocycles of oxygen, nitrogen and sulfur are patterns found in many natural products possessing interesting biological activities. Several researchers describe the synthesis of oxygen and nitrogen based heterocycles using transition metals as catalyst.In the present study, we focused initially on the copper-catalyzed synthesis of pyrano[3',4':4,5]imidazo[1,2-a]pyridin-1-ones by a tandem coupling-heterocyclisation reaction from derivatives of 3-iodo-, 3,6- or (3,8) diiodoimidazo[1,2-a]pyridine-2-carboxylic acid and terminal alkynes in the presence of copper (I) salts as catalyst in DMF. This procedure does not require the use of any expensive transition metal complexes like palladium and supplement any additives. The extension of this methodology to 2,3,5-triiodobenzoic acid allowed the regioselective synthesis of new isocoumarins substituted in positions 3, 5 and 7. Regioselective reactivity of iodine atoms in position 5 and 7 has been studied by palladium coupling reactions and nucleophilic substitution to broad its synthesis to a wide variety of new substituted isocoumarins.

Les symbioses bactérie-légumineuse (nodulation) et champignon-plante (mycorhization) présentent un intérêt agrobiologique et écologique majeur ; elles permettent aux plantes de croître naturellement sur un sol aride et peu fertile. Il a été démontré très récemment que les signaux impliqués dans la mise en place de la symbiose endomycorhizienne à arbuscule (facteurs "Myc") sont très proches de ceux de la nodulation. Il s'agit de molécules appartenant à la famille des lipo-chitooligosaccharides. Afin de réaliser la synthèse de ces molécules, deux nouvelles méthodologies ont été développées. L'ouverture oxydante d'acétals de 4,6-O-benzylidène de plusieurs glycopyranosides (en série gluco, galacto et manno) par le diméthyldioxirane (DMDO) a été étudiée. Le contrôle de la régiosélectivité a été effectué grâce au groupement protecteur introduit sur la fonction alcool de la position 3. La formation directe de β-glycosides de la N-acétyl-D-glucosamine par catalyse au triflate de fer (III) a été étudiée. La réaction a été menée sous irradiation micro-ondes ou en flux continu (système minifluidique Vapourtec®). Une nouvelle stratégie pour la synthèse du facteur [Myc-IV (C16:0, S)] a ensuite été établie. Nous avons utilisé un réactif peu toxique et non odorant pour introduire le motif thio nécessaire à la formation de deux liaisons glycosidiques. Le disaccharide précurseur de l'unité réductrice a été obtenu grâce à la première méthodologie développée au cours de cette thèse. / Arbuscular mycorrhiza (AM) is a root endosymbiosis between plants and fungi. It has an agrobiological interest and a crucial ecological importance because it allows plants to grow on aride and infertile soil. Recently, the structure of the symbiotic signal "Myc factor" was identified as a mixture of lipochitooligosaccharides (LCOs). In order to propose a new synthesis of LCOs, we developed two green methodologies in glycochemistry. We performed the oxidative cleavage of 4,6-O-benzylidene acetals of various glycopyranosides (gluco, manno and galacto series) with dimethyldioxirane (DMDO) and its regioselective control with a suitable protecting group at position 3. We investigated the formation of β-glycoside of N-acetyl-D-glucosamine using catalytic iron (III) triflate. The reaction can be performed using microwave irradiation or, for scale-up synthesis, flow chemistry using Vapourtec® minifluidic system. We establish a new strategy for the total synthesis of the most abundant Myc factor [Myc-IV (C16:0, S)]. We used odorless and few toxic MbpSH reagent to introduce the activated thio residue involved in two glycosylation reactions. The disaccharide acceptor precursor of the reducing end was obtained after oxidative cleavage of the 4,6-O-benzylidene moiety by DMDO.