Academic literature on the topic 'Arylation coupling'

AbstractAryl rings are ubiquitous in the core of numerous natural product and industrially important molecules and thus their facile synthesis is of major interest in the scientific community and industry. Although multiple strategies enable access to these skeletons, metal-catalyzed C–H activation is promising due to its remarkable efficiency. Commercially available organoboron reagents, a prominent arylating partner in the cross-coupling domain, have also been utilized for direct arylation. Organoborons are bench-stable, inexpensive, and readily available coupling partners that promise regioselectivity, chemodivergence, cost-efficiency, and atom-economy without requiring harsh and forcing conditions. This critical, short review presents a summary of all major studies of arylation using organoborons in transition-metal catalysis since 2005.1 Introduction2 Arylation without Directing Group Assistance2.1 Palladium Catalysis2.2 Iron Catalysis2.3 Gold Catalysis3 Arylation with Directing Group Assistance3.1 Palladium Catalysis3.2 Ruthenium Catalysis3.3 Rhodium Catalysis3.4 Nickel Catalysis3.5 Cobalt Catalysis3.6 Copper Catalysis4 Conclusion

Metal-catalyzed α-arylation of amides from α-halo amides with organometallic reagents is reviewed. The article includes Suzuki–Miyaura, Kumada–Corriu, Negishi, and Hiyama cross-coupling reactions.1 Introduction2 Suzuki–Miyaura Cross-Coupling2.1 Palladium Catalysis2.2 Nickel Catalysis3 Kumada–Corriu Cross-Coupling3.1 Nickel Catalysis3.2 Iron Catalysis3.3 Cobalt Catalysis4 Negishi Cross-Coupling5 Hiyama Cross-Coupling6 Conclusion

A convenient and highly regioselective palladium-catalyzed direct C5-arylation of 1,2,3-triazole N-oxides was developed in the presence of silver carbonate and tripotassium phosphate. This protocol allowed use of sodium arylsulfinates, diphenylphosphine oxide, and triphenylphosphine as arylating reagents to produce 2-aryl-5-aryl-1,2,3-triazole N-oxides in good to excellent yields, providing a complement to the existing methods for the direct arylation of 1,2,3-triazole N-oxides.

N-Arylated aliphatic and aromatic amines are important substituents in many biologically active compounds. In the last few years, transition-metal-mediated N-aryl bond formation has become a standard procedure for the introduction of amines into aromatic systems. While N-arylation of simple aromatic halides by simple amines works with many of the described methods in high yield, the reactions may require detailed optimization if applied to the synthesis of complex molecules with additional functional groups, such as natural products or drugs. We discuss and compare in this review the three main N-arylation methods in their application to the synthesis of biologically active compounds: Palladium-catalysed Buchwald–Hartwig-type reactions, copper-mediated Ullmann-type and Chan–Lam-type N-arylation reactions. The discussed examples show that palladium-catalysed reactions are favoured for large-scale applications and tolerate sterically demanding substituents on the coupling partners better than Chan–Lam reactions. Chan–Lam N-arylations are particularly mild and do not require additional ligands, which facilitates the work-up. However, reaction times can be very long. Ullmann- and Buchwald–Hartwig-type methods have been used in intramolecular reactions, giving access to complex ring structures. All three N-arylation methods have specific advantages and disadvantages that should be considered when selecting the reaction conditions for a desired C–N bond formation in the course of a total synthesis or drug synthesis.

Direct C-H arylation coupling is potentially a more economical and sustainable process than conventional cross-coupling. However, this method has found limited application in the synthesis of organic dyes for dye-sensitized solar cells. Although direct C-H arylation is not an universal solution to any cross-coupling reactions, it efficiently complements conventional sp2−sp2 bond formation and can provide shorter and more efficient routes to diketopyrrolopyrrole dyes. Here, we have applied palladium catalyzed direct C-H arylation in the synthesis of five new 3,6-dithienyl diketopyrrolopyrrole dyes. All prepared sensitizers display broad absorption from 350 nm up to 800 nm with high molar extinction coefficients. The dye-sensitized solar cells based on these dyes exhibit a power conversion efficiency in the range of 2.9 to 3.4%.

A new method for the synthesis of chiral α-amino acid derivatives by enantioselective C–H arylation of N-aryl glycine esters with aryl boric acids by direct C–H oxidative cross-coupling has been performed. This work successfully integrates the direct C–H oxidation with asymmetric arylation and exhibits excellent enantioselectivity.

A short and practical arylation of imidazo[1,2-a]pyridine and imidazole derivatives with aryl halides or aryl boronic acids as coupling partners was successfully carried out using phosphine-free (SIPr)Pd(allyl)Cl as the catalyst [SIPr: (N,N’-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)] ((SIPr)Pd(allyl)Cl complex). 3,6-disubstituted imidazo[1,2-a]pyridine and 5-substituted imidazole compounds were obtained in good to excellent yields in only 1h under microwave-assisted C-H arylation and Suzuki-Miyaura coupling reaction conditions.

A simple and efficient copper-catalyzed S-arylation of aryl­thioureas was developed. Arylthioureas were smoothly converted into aryl-isothioureas with good yield by copper-catalyzed S-arylation. The features of this method include the use of a ligand-free catalyst, good yield, short reaction time, and broad substrate scope. The method provides a facile and convenient preparation of some potentially biologically active compounds.

Direct arylation is an appealing method for preparing π-conjugated materials, avoiding the prefunctionalization required for traditional cross-coupling methods. A major effort in organic electronic materials development is improving the environmental and economic impact of production; direct arylation polymerization (DArP) is an effective method to achieve these goals. Room-temperature polymerization would further improve the cost and energy efficiencies required to prepare these materials. Reported herein is new mechanistic work studying the underlying mechanism of room temperature direct arylation between iodobenzene and indole. Results indicate that room-temperature, Pd/Ag-catalyzed direct arylation systems are radical-mediated. This is in contrast to the commonly proposed two-electron mechanisms for direct arylation and appears to extend to other substrates such as benzo[b]thiophene and pentafluorobenzene.

A direct arylation to furnish diarylmethanes from benzyl alcohols was realized through Pd(PPh₃)₄-catalyzed Suzuki–Miyaura coupling via benzylic C–O activation in the absence of any additives. The arylation is compatible with various functional groups. This development provides an atom- and step-economic way to approach a diarylmethane scaffold under mild and environmentally benign conditions.

The research conducted for this thesis has led to the development of an intramolecular gold-catalysed direct arylation protocol whereby tethered arenes and aryltrimethylsilanes are coupled (Scheme 1). In Chapter 1, the key synthetic and mechanistic studies that have ultimately led to the conception of this project are introduced. In Chapter 2, the substrate scope of intramolecular direct arylation is assessed. The reaction tolerates a wide range of substrates with tether lengths between one and five units (containing C, N and O) generating 5- to 9- membered rings. Substrates that lead to 5-membered rings (1 → 2) can tolerate a broad electronic range of substituents and proceed under the mildest reaction conditions (≤ 1 mol% catalyst, room temperature) and with excellent yields. A smaller collection of examples is demonstrated for the cyclisation to 6- and 7- membered rings (3 → 4, 5 → 6), but no heating is required and good yields are maintained throughout the series. The synthetically challenging synthesis of 8- and 9- membered rings (7 → 8, 9 → 10) is successful, albeit with slightly more forcing conditions (4 mol%, up to 50 °C). The methodology was subsequently applied in the successful 10-step synthesis of natural product allocolchicine 11. In Chapter 3, the operative reaction mechanism is elucidated. Reaction monitoring techniques allowed for the detailed study of linear free energy relationships (LFERs) and kinetic isotope effects (KIEs), which in turn allowed for deduction of the reaction turnover-limiting step (TLS) and thus the first quantitative experimental data on the effects of aryl electron demand and conformational freedom on the rate of reductive elimination from diarylgold(III) species. The mechanistic investigation led to the observation of complex kinetic profiles for specific substrates. The origin of these unusual effects is the focus of Chapter 4. By combining experiment with kinetic simulation, an off-cycle catalyst inhibition pathway was identified and the understanding of this process allowed for a re-optimisation of reaction conditions. In Chapter 5, the general kinetic parameters that could govern any domino reaction combining inter- and intramolecular direct arylation are deduced through kinetic analysis and simulation of hypothetical systems. The results of the kinetic analysis were proved experimentally through the successful combination of intra- and intermolecular gold-catalysed direct arylation. The products of intramolecular cyclisation 2, generated in-situ, are demonstrated to couple with intermolecular aryltrimethylsilanes 12, resulting in a rapid increase in molecular complexity from simple substrates in one pot.

La sérotonine ou 5-hydroxytryptamine (5-HT) est un neurotransmetteur impliqué dans un grand nombre de fonctions physiologiques (thermorégulation, mémoire, sommeil, humeur…). La pluralité des troubles engendrés par un dysfonctionnement sérotoninergique s’explique par le grand nombre de récepteurs associés (5-HT1 à 5-HT7, eux-mêmes divisés en sous-groupes). Parmi eux, les récepteurs 5-HT6 et 5-HT7 sont les derniers à avoir été identifiés. A ce jour bien que leurs rôles biologiques restent méconnus, ils sembleraient être impliqués dans certaines pathologies psychiatriques (dépression, anxiété, schizophrénie…) et pourraient représenter de nouvelles cibles thérapeutiques. Ainsi, dans un premier temps, une étude bibliographique présentera l’ensemble des récepteurs sérotoninergiques et détaillera les travaux relatant des 5-HT6 et 5-HT7. La seconde partie sera consacrée à la synthèse de ligands potentiels des 5-HT7 et à l’étude de relation structure-activité associée. L’exemplification d’une réaction de C2-arylation d’indole inédite catalysée par le cuivre fera l’objet de la troisième partie. La quatrième partie sera consacrée à la synthèse de ligands antagonistes connus des récepteurs 5-HT6 afin de les employer comme radiotraceurs potentiels. Cette partie exposera également la synthèse de ligands potentiels inédits de ces récepteurs. Enfin, les premiers résultats de radiosynthèse et de leur application TEP (Tomographie à Emission de Positons) seront exposés
Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter involved in many physiological functions (thermoregulation, memory, sleep, mood ...). The plurality of disorders caused by a serotonergic dysfunction due to the large number of receptors involved (5-HT1 to 5-HT7, divided themselves into sub-groups). Among them, the 5-HT6 and 5-HT7 are the last to be identified. To date, although their biological roles remain unknown, they appear to be involved in some psychiatric disorders (depression, anxiety, schizophrenia ...) and could represent new therapeutic targets. Thus, initially, a bibliographic study will present all the serotonin receptors and detail work on the 5-HT6 and 5-HT7. The second part will be devoted to the synthesis of potential ligands of 5-HT7 and the study of structure-related activity. The exemplification of a reaction of C2-arylation of indole catalyzed by copper will be the third party. The fourth part will be devoted to the synthesis of antagonists ligands known of 5-HT6 receptors in order to use them as potential radiotracers. This part also describes the synthesis of novel potential ligands of these receptors. Finally, preliminary results of radiosynthesis and their application PET (Positron Emission Tomography) are exposed

Les performances des catalyseurs à base de palladium dans diverses réactions de couplage croisé ont suscité un intérêt croissant depuis les années soixante-dix et le développement de versions énantiosélectives a fait l’objet de recherches intensives. Dans ce domaine, les ligands auxiliaires N-hétérocycliques carbènes (NHCs) monodentates possédant de bonnes propriétés σ donneur et π-accepteur confèrent au métal d’excellentes réactivités. Les ligands NHCs sont appelés ligands intelligents, car leurs propriétés électroniques et stériques peuvent être finement ajustées à des transformations catalytiques spécifiques. Par conséquent, les complexes chiraux NHC-Pd sont une classe de catalyseurs chiraux qui se sont développés rapidement au cours des dernières décennies. Néanmoins, de nouveaux catalyseurs avec une réactivité et une énantiosélectivité améliorées sont nécessaires car seules quelques applications sont réellement développées dans l’industrie. L’objectif de mon doctorat était d’étudier un nouveau concept de complexes chiraux NHC-Pd et leurs applications pour explorer de nouvelles transformations catalytiques. Le premier chapitre expose la chimie du carbène en tant que ligands des métaux de transition avec les principales réalisations décrites dans la littérature. Les propriétés chimiques des NHCs sont également brièvement présentées. Dans ce chapitre, les différents designs de ligands chiraux NHC pour la catalyse à base de palladium sont résumés ainsi que les applications dans la catalyse énantiosélective. Enfin, des études antérieures sur les complexes chiraux NHC-palladium réalisées dans notre laboratoire sont présentées afin de définir les objectifs et les enjeux de mon travail de doctorat. Dans le deuxième chapitre de ce manuscrit, nous analysons les avantages et les inconvénients des catalyseurs développés dans notre groupe, afin de simplifier les étapes de synthèse et d’améliorer l’activité catalytique. En conséquence, certains nouveaux complexes NHC-avec chiralité axiale ont été conçus et synthétisés par des méthodologies de synthèse décrites dans la littérature. Les complexes chiraux de palladium possédants un NHC de symétrie C2 ont été d’abord préparés puis les diastéréoisomères ont été purifiés par chromatographie sur colonne de gel de silice pour éliminer les composés méso. Par la suite, les complexes hétérochiraux ont été résolus par HPLC chirale à l’échelle préparative pour les obtenir sous forme énantiomériquement pure. Enfin, la réactivité catalytique et l’induction énantiomérique que permet d’atteindre ces catalyseurs Pd-NHC-chiraux ont été évaluées dans une réaction modèle : l’α-amide arylation d’amides. De très bonnes inductions chirales ont été atteintes.Dans le troisième chapitre, de nouvelles transformations catalysées par le palladium ont été conçues et étudiées avec les nouveaux complexes chiraux-NHC précédemment établis en laboratoire. Après une étape d’optimisation des conditions de réaction et le criblage de plusieurs catalyseurs, nous avons constaté que ces nouveaux catalyseurs permettent d’obtenir une bonne induction chirale dans l’α-arylation de cétones. Nous avons également essayé l’hydrogénation catalysée par des complexes Pd-NHC cependant cette réaction n’a pas conduit à des résultats notables. Les réactions de couplage de Kumada ont également été étudiées pour synthétiser des métacyclophanes possédant une chiralité planaire. Divers métacyclophanes chiraux ont été préparés et leurs stabilités de configuration ont été étudiées. Des conditions de réaction optimales ont été identifiées afin de réaliser cette réaction asymétrique avec de bons résultats en termes de réactivité et d’énantiosélectivité
The performances of palladium-based catalysts in various cross-coupling reactions have attracted an ever-growing attention since the seventies and the development of enantioselective versions was the subject of intensive research. In this field, monodentate auxiliary N-heterocyclic carbene (NHCs) ligands possessing robust σ-donating and adaptable π-accepting properties confer to the metal excellent reactivities. NHCs ligands are referred as smart ligands, because their electronic and steric properties can be finely tuned to specific catalytic transformations. Therefore, chiral NHC-Pd complexes are a class of chiral catalysts that have developed rapidly in the recent decades. Nevertheless, new catalysts with enhanced reactivity and enantioselectivities are required as only few applications are actually developed in the industry. The goal of my Ph.D. was the investigated of a new design of chiral NHC-Pd complexes and their application to explore new catalytic transformations. The first chapter is focused on carbene chemistry as ligands of transition metals with main achievements reported in the literature. Chemical properties of NHCs have been also reviewed. In this chapter, the different designs of chiral NHC ligands for palladium-based catalysis reported in the literature as well as their applications in enantioselective catalysis have been also surveyed. Finally, previous studies on chiral NHC-palladium complexes in our laboratory are presented in order to define the objectives and issues of my Ph.D. work. In the second chapter of this manuscript, we analyze the advantages and disadvantages of the catalysts developed in our group, with the goal of simplifying the synthesis steps and improving the catalytic activity. As a result, some novel NHC-Pd complexes with axial chirality were designed and synthesized by known synthetic methods. The synthesized C2-symmetric NHC-Pd complexes were first attempted to separate diastereomers by silica gel column chromatography to remove meso compounds. Subsequently, heterochiral complexes were resolved in enantiomerically pure form by preparative-scale chiral HPLC. Finally, the catalytic reactivity and enantiomeric inductions of these highly enantiomerically pure chiral NHC-Pd catalysts were evaluated in the benchmark reaction: α-amide arylation of amides. Up to good chiral inductions were reached.In the third chapter, novel palladium-catalyzed transformations were investigated and developed with the new chiral Pd-NHC complexes previously established in the laboratory. After the optimization of reaction conditions and the screening of several catalysts, we found that these new catalysts can achieve good chiral induction in the α-arylation of ketones. We also tried NHC-Pd catalyzed hydrogenation, although the reaction did not lead to noticeable results. Kumada coupling reactions were also studied to synthesize planar-chiral metacyclophanes. Various chiral metacyclophanes have been prepared and their configurational stabilities have been investigated. Finally, optimal reaction conditions have been identified allowing to carry this asymmetric reaction with good results in terms of both reactivity and enantioselectivity

Stroke is the 3rd leading cause of death in the United States. For this reason, it has become our goal to find a drug that is capable of reestablishing intracellular and extracellular Ca+2 flux upon direct binding to the sigma receptor, which can be delivered easily and efficiently. Our active research focuses the development of guanidine analogues that can serve as therapeutic drugs which target sigma 1 and sigma 2 receptors having a direct effect on Ca+2 levels on the cell. The use of symmetrical guanidine analogues such as N,N'-di-o-tolyl guanidine (o-DTG) as therapeutic drugs for ischemic stroke, is promising due to the fact that neuronal cells can restore the proper blood flow and block Ca+2 flux into the cell. Our main objective is to be able to develop a cost efficient, mild reaction methodology that affords access to guanidine analogues. The synthetic design of the guanidine analogues has been accomplished using copper-catalyzed cross-coupling diarylation reaction. This methodology employs a non-expensive guanidine salt and substituted aryl iodides along with N,N'-diethylsalicylamides as the key ligand in this strategy. Similar methodology was employed for the synthesis of monoarylated amidines employing ligand-free conditions for the copper-catalyzed cross-coupling reaction. Moreover, efforts to find alternative methodologies to access other sigma receptor ligands were accomplished. A new method to create N,N'-disubstituted carbamides employed HATU as a peptide coupling agent allowing for the formation of carbamides using the inexpensive guanidine nitrate and carboxylic acids as starting materials. Studies on the sigma response of the cortical neuron cell were conducted upon completion of the analogue design. Moreover, it was discovered that N,N'-di-p-bromophenyl guanidine (p-BrDPhG) gave a higher Ca+2 inhibition than N,N'-di-o-tolyl guanidine (o-DTG). Experimental studies, such as the middle cerebral occlusion were conducted on rats and subsequent injections of the p-BrDPhG at 24, 48, and 72 hours' time marks. When compared to o-DTG, it was found that p-BrDPhG is better at reducing the ischemic volume on the brain size

A ce jour, l’un des défis dans le développement des couplages directs catalytiques de type [C-H / C-CO2H] et [C-H / C-H] est de fonctionnaliser des briques moléculaires à haute valeur ajoutée synthétique possédant un haut potentiel d’aménagement dans le but d’accroître la diversité structurelle et fonctionnelle. Les éthers d’énols font partis de cette classe de motif structuraux ; cependant un déficit de méthodes de fonctionnalisation économiques en termes d’étapes, faciles à mettre en oeuvre et permettant de contrôler la régiosélectivité (α/β) et la stéréochimie (E/Z) de ces derniers est clairement observé. Ce travail de thèse s’inscrit dans ce contexte et a pour objectif de développer de nouvelles méthodes d’(hétéro)arylations régio- et stéréosélectives des α-carboxyvinyl éthers par couplages directs déshydrogénants [C-H / C-H] et décarboxylants [C-H / C-CO2H] impliquant deux partenaires de couplage inédits, les acides α-alkoxycinnamiques et les α-étheroxyacrylates d’éthyle. Ainsi, un premier chapitre a porté sur le développement d’une première méthodologie de préparation d’éthers d’énol gem-hétéroarylés basée sur l’engagement d’acides cinnamiques α-alkoxylés dans le couplage direct de type [C–CO2H / C–H] sous catalyse coopérative Pd(0) / Cu(I). Cette méthodologie a ensuite permis d’accéder aux 2-cétohétéroarènes α-énolisables après modulation de la fonction éther d’énol, et ces derniers ont ensuite été valorisés pour conduire aux systèmes 2,4’-bis-azoliques présents dans les polypeptides naturels. Les deux autres chapitres, deux et trois, ont été consacrés à l’étude de la fonctionnalisation de la position β d’éthers d’énol par couplages direct régio- et stéréosélectif pallado-catalysés des α-étheroxyacrylates d’éthyle selon deux stratégies : (1) Le couplage de Heck oxydatif décarboxylants de Myers de type [C-H / C-CO2H] avec les dérivés d’acides benzoïques et (2) le couplage oxydatif de Fujiwara-Moritani de type [C-H / C-H]
To date, one of the challenges in the development of catalytic direct couplings of [CH / C-CO2H] and [CH / CH] type is the functionalization of molecules, with high synthetic value, having a high potential of development in the goal of increasing structural and functional diversity. Enol ethers are part of this class of structural motifs; however, till now, no economical and selective functionalization method have been developed. In this context, the aim of this work was to develop a selective (hetero)arylation strategy of α-carboxyvinyl ether by direct dehydrogenative CH/ CH or decarboxylative C-H / C-CO2H cross coupling using α-alkoxy cinnamics acid and α-etheroxyacrylates as coupling partners. The first chapter has been focused on the development of the first methodology for the preparation of gem-heteroaryl enol ethers based on the engagement of α-alkoxylated cinnamic acids in the direct coupling of [C-CO2H / C-H] type under cooperative Pd(0) / Cu(I) catalysis. This methodology gave access to the α-enolizable 2-ketoheteroarenes after modulation of the enol ether function, and these were then valorized to give the 2,4'-bis-azole systems that are present in the natural polypeptides. The second and third chapters have focused on the study of β-functionalization of enol ethers by direct and selective Pd-catalyzed coupling of ethyl α-etheroxyacrylates according to two strategies: (1) Myers’s type decarboxylative Heck coupling [C-H / C-CO2H] with benzoic acid derivative and (2) Fujiwara-Moritani’s type [C-H / C-H] oxidative coupling

L'objectif principal de cette thèse est de parvenir, au moyen des méthodes de la chimie computationelle, à une meilleure compréhension des processus de couplages catalysés par le palladium. Une attention toute particulière a été apportée à l'étude de l'influence électronique des ligands du palladium (phosphine ou carbène N-hétérocyclique) sur les profils énergétiques des trois principales transformations: addition oxydante, transmetallation et élimination réductrice. Pour quantifier cette influence électronique, deux méthodes d'analyse différentes ont été utilisées : NBO et NOCV. La méthode NBO est classique alors que la méthode NOCV est plus récente. Il convenait pour cette dernière de tester sa pertinence pour le problème étudié.De plus, en collaboration avec différents groupes d'expérimentateurs, le mécanisme de deux réactions catalysées au Pd ont été étudiés:hydrophosphonylation du styrène et arylation directe de dérivés aromatiques fluorés. Dans chacun des cas, l'objectif principal était d'identifier les facteurs à l'origine des régiosélectivités observées
The main objective of the present thesis is to get a better understanding of the Pd-catalyzed cross-coupling reactions, using the tools of computational chemistry. In particular, a detailed mechanistic study of all the possible reaction paths was carried out with different supporting ligands at palladium (phosphines and N-heterocyclic carbenes) in order to understand the elctronic influence of the latter on the three main steps : oxidative addition, transmetalation and reductive elimination. To probe the electronic influence of the ligands, the well-known Natural Bond orbital (NBO) analysis and the innovative Charge Displacement via Natural Orbital for Chemical Valence (NOCV) were used. In addition, two computational studies of Pd-catalyzed transformations were carried out in collaboration with some experimental groups : hydrophosphonylation of alkenes and direct arylation of fluorinated substrated aromatic rings. The main purpose of these studies was to identify the factors at the origin of the regioselectivity observed

L’accès à de nouveaux composés hétérocycliques originaux biologiquement actifs nécessite la mise au point de nouvelles méthodes de synthèse rapides et efficaces. Dans ce contexte, nous nous sommes intéressés à la réactivité des indazoles. Dans la première partie, nous avons étudié la sélectivité des couplages de type Suzuki, pour fonctionnaliser la position 3 d’indazoles possédant la fonction NH libre. Par la suite, un nouveau procédé d’(hétéro)arylation direct pallado-catalysé régiosélectif a été mis à profit pour synthétiser des indazoles fonctionnalisés tant sur la position 3 que sur le sommet 7. Nous avons ensuite montré la possibilité d’accéder à des entités disubstituées indazoliques en une seule étape, via une procédure "one-pot". Afin d’accroître la diversité autour du noyau indazole, nous avons mis au point une réaction d’alcénylation oxydative pallado-catalysée, des (2H)- et (1H)-indazoles sur les sommets C-3 et C-7. Pour exemplifier cette méthodologie, nous avons développé une synthèse en trois étapes du Gamendazole, composé actuellement en phase clinique pour la contraception masculine et ce, en utilisant l’alcénylation directe en C3 d’(1H)-indazoles convenablement fonctionnalisés. Le dernier volet de ce mémoire a été consacré à la préparation de composés à structure indazolique contenant une fonction sulfonamide afin de générer des librairies de dérivés substitués par un tel motif, dans le but de les tester biologiquement dans le domaine des anticancéreux
Access to new biologically active compounds requires the development of new rapid and efficient methods for the synthesis of original heterocyclic scaffolds. In this context, we decided to focus particularly on the reactivity of indazoles. First, we studied the selectivity of Suzuki cross-coupling reaction to functionalize position 3 of the indazole with the free NH function. Indeed, we have described the first example of the direct and regioselective palladium-catalyzed (hetero)arylation of indazoles, the reaction may be induced to occur at either in position 3 and 7. We then showed the possibility of "one-pot" synthesis of disubstituted indazolic entities. Moreover, in order to increase diversity around the indazole scaffold, we developed a direct and regioselective alkenylation of (2H)- and (1H)-indazoles by oxidative palladium catalyzed at the C-3 and C-7, then we envisaged a three staps synthesis of Gamendazole, molecule currently in clinical phase for male contraception, by using the direct alkenylation at C3 of the suitably functionalized (1H)-indazoles. The last part of this report was dedicated to the preparation of indazoles containing a sulphonamide function, with the aim of biological testing them as potentially anti-cancer candidates

Depuis de nombreuses années, des notions telles que « l'économie d'atome » ou encore la nécessité de développer des méthodes de valorisation rapide des hydrocarbures, ont pris une place importante en chimie organique. Dans ce contexte, la fonctionnalisation de liaisons carbonehydrogène (C–H) s'avère être un outil puissant de la chimie moderne, thématique fort présente au sein du laboratoire depuis de nombreuses années. En 2010, le développement de la réaction de β- arylation d'esters a initié au sein du laboratoire de nouvelles perspectives. L'extension de cette réaction fait l'objet des travaux de recherches réalisés dans ce manuscrit, pour la fonctionnalisation de liaisons C(sp3)–H en position α, β et γ d'amines. Ces structures sont présentes au sein de nombreuses molécules naturelles de la famille des alcaloides, ou molécules d'intérêt pharmacologique, ce qui en fait des motifs d'intérêt majeur. Les travaux réalisés dans le cadre de ce projet de thèse s'articulent autour de la réaction de couplage de Negishi (co-lauréat du prix Nobel de Chimie 2010), qui est un outil de synthèse puissant pour la formation de liaisons carbone-carbone. Son application aux couplages migratoires est au coeur des développements présentés dans ce manuscrit, selon trois grands axes de recherche. Le premier s'intéresse à la réalisation de couplages palladocatalysés sélectifs en positions β de N-Boc-pipéridines. Il y est développé l'importance de la flexibilité des ligands biarylphosphines dans le contrôle de la sélectivité α/β. Le second étudie l'extension de ces premiers travaux pour l'α– et β–fonctionnalisation sélective de N-Boc-amines acycliques, qui a nécessité de nouvelles avancées pour la lithiation dirigée d'amines acycliques, et le développement de nouvelles biarylphosphines plus flexibles, et plus sélectives. L'étude des étapes de lithiation, et de transmétallation, a été réalisée par analyse IR in-situ, ainsi que l'influence d'aryles aux propriétés électroniques variées lors de l'α-arylation. Un dernier axe d'étude pour la γ- fonctionnalisation d'allylamines, permet d'étendre le champ d'application du couplage de Negishi pour la fonctionnalisation C–H d'alkylamines, pour la formation de γ–arylamines et β–aryles aldéhydes
Since several years, the emergence of terms such as atom- and step-economy, or the need for the development of rapid and efficient synthetic methods have taken an important place in chemistry. In this context, the transition-metal-catalyzed functionalization of unactivated carbonhydrogen bonds has emerged as a powerful tool and an important field of research. In 2010, the development of the β arylation of esters has initiated a new perspective in our laboratory, and has been at the origin of the research described in this manuscript on the selective C(sp3)–H functionalization of amines at α, β and γ positions. The work performed during this Ph.D. project is related to the Negishi cross-coupling reaction (co-laureate of Chemistry Nobel prize in 2010), an important method for the formation of carbon-carbon bonds. Three different aspects are explored in this manuscript. The first one deals with the development of the palladium-catalyzed β -arylation of N-Boc-piperidines, which highlights the importance of ligand flexibility to control the α- vs. β- arylation selectivity. The second part focuses on the selective α - and β -functionalization of acyclic N-Boc-amines, which required to reinvestigate the directed lithiation of acyclic amines and to synthesize new biarylphosphines possessing greater flexibility. A kinetic analysis of each individual step from the lithiation to the α -arylation was performed by in situ IR spectroscopy, and proved an efficient method to gain further mechanistic insights. Finally, we have developed a selective γ - arylation reaction of allylamines, which represents a new extension of the Negishi cross-coupling for the C–H functionalization of alkylamines, and allows a direct access to valuable γ -arylamines and β - arylaldehydes

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.

Les bicycles imidazo-imidazoles constituent une classe de composés hétérocycliques intéressants tant sur le plan chimique que pharmaceutique. Ils jouent un rôle très important dans la synthèse et la fonctionnalisation des composés à visé thérapeutique. Dans le cadre de la recherche de nouveaux candidats inhibiteurs de kinases, nous avons développé une voie de synthèse des imidazo[1,2-a]imidazoles mono- et bifonctionnalisés. Par la suite, nous avons mis au point une stratégie de synthèse rapide et efficace de bicycles imidazo[1,5-a]imidazolin-2-one et imidazo[1,5-a]imidazole. En outre, nous avons développé deux stratégies de fonctionnalisation via des réactions de couplage pallado-catalysées. Finalement nous avons synthétisé le motif imidazo[1,5-a]imidazole via la réaction de Groebke-Blackburn-Bienaymé (GBB). La potentialité de cette réaction a été exploitée dans des réactions decyclisation intramoléculaire! afin de préparer une nouvelle chimiothèque de composés polyhétérocycliques azotés
The imidazo-imidazoles bicycles have received special attention among other nitrogen cycles due to their biologically interesting properties exploited in the medicine manufacturing. The imidazo-imidazole scaffold is one of the most representative nitrogen containing heterocycle, as it plays a significant role and possesses a major interest in drug synthesis and functionalization. In this work we report firstly a synthetic pathway to novel imidazo[1,2-a]imidazoles candidates for CKD inhibitors. Secondly we develop two strategies to prepareimidazo[1,5-a]imidazoles and their reactivity via pallado-catalyzed reactions. Finally, we disclose a fast and an efficient access to imidazo[1,5-a]imidazoles by using the Groebke-Blackburn-Bienaymé reaction (GBB), followed by a palladium catalysed intramolecular cyclization, affording thus new tetracyclic products with an elevated degree of molecular diversity

Aryl amines have received significant interest because these compounds widely exist in the structural backbones of ligands, pharmaceuticals, agrochemicals, natural products, and functional materials. In N-arylation reactions, several types of organic electrophile coupling partners such as (pseudo)halides (Ullmann-type and Buchwald–Hartwig couplings) and boronic acids (Chan–Lam coupling) are popular. The main synthetic methods for the preparation of these compounds involving N-arylation utilize aryl halides. Progress has been made with the coupling of arylating reagents which are less expensive than aryl halides, providing both a cost-effective and more efficient reaction route. For example, the process of C–H bond activation/functionalization, a step-efficient and atom-economical transformation, has emerged as a powerful strategy in C–N bond-forming reactions. Moreover, a transition-metal-free method for the N-arylation of amines using an aryne intermediate has been developed. This chapter focuses on recent advances in chemo- and regioselective N-arylation (either on one N-center or on the exocyclic N-site of the ring) or the selective arylation of amino alcohols without additional protection/deprotection using arylating reagents. This chapter provides an overview of arylating reagents for N-arylation reactions found in both basic and applied chemical research. The substrate scope, limitations, reaction mechanism, and chemoselectivity, as well as related control strategies of these reactions, are discussed. To the best of our knowledge, there has been no book about introducing arylating reagents to develop more efficient and environmentally friendly cross-coupling methods for the N-arylation of amines. We believe this critical review will provide necessary background information on the N-arylation of amines.