published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Dans le cadre de nos travaux, nous avons développés des voies de synthèses permettant d'accéder à deux familles d'hétérocycles aromatiques: les phosphonylpyrazoles, et les fluoropyridazines. La synthèse des pyrazoles phosphonylés a été réalisée en utilisant un couplage croisé pallado-catalysé de type Hirao, et nous avons démontré qu'un système catalytique unique à base de Pd(OAc)2/XantPhos pouvait catalyser le couplage entre une large gamme d'halogénopyrazoles et de H-phosphonyles. Bien que souffrant de certaines limites dans son champ d'application, notamment au niveau du motif de substitution de l'halogénopyrazole, cette méthode consiste probablement à l'heure actuelle la voie d'accès la plus modulable pour accéder aux pyrazoles phosphonylés.Les 5-fluoropyridazines ont été synthétisées par réactions de cycloadditions séquentielles [2+1]/[3+2] entres des alcynes, le difluorocarbène :CF2, et des diazoacétates d'alkyles. Nous avons démontré que cette séquence réactionnelle était compatible avec un grand nombre d'alcynes diversement substitués, et que les 5-fluoropyridazines ainsi obtenues pouvaient être aisément fonctionnalisées. / The work presented in this manuscript concerns the development of synthetic routes to two families of heterocycles, namely phosphonylpyrazoles and fluoropyridazines. Phosphonylpyrazoles were synthesized using a Hirao-type cross-coupling, and it was demonstrated during this study that a single catalytic system based on Pd(OAc)2/XantPhos could perform the cross-coupling between a wide range of halopyrazoles and H-phosphonyls. Significant limits have been met in the scope of this method, especially regarding the substitution pattern of the halopyrazole. Nevertheless, at this time, this method is arguably one of the most flexible ways to synthesize phosphonylpyrazoles. Fluoropyridazines were synthesized using a [2+1]/[3+2] cycloaddition sequence between alkynes, the difluorocarbene :CF2, and alkyl diazoacetates. It was demonstrated during this study that a wide range of alkynes could be involved in this sequence, and that the corresponding 5-fluoropyridazines could be easily diversified.

No description available.

none

Les hétérocycles aromatiques sont des motifs structuraux rencontrés dans un grand nombre de substances d'intérêts biologiques ou pharmacologiques. Plus particulièrement, les pyridazines substituées font l'objet d'un intérêt grandissant pour leurs propriétés pharmaceutiques (antibactériens, anti-inflammatoires, médicaments cardiovasculaires…). De plus, les structures comportant des pyridazines peuvent également être utilisées en tant qu'agents chélatants de cations métalliques et s'ordonner en édifices utilisés en chimie supramoléculaire.Nous nous sommes donc intéressés à l'élaboration d'éléments de base comportant des cycles pyridaziniques de type aryl ou hétéroarylpyridazines. La mise au point de méthodes impliquant des espèces organométalliques a été l'un de nos objectifs primordial. L'élaboration de ces composés a été réalisée par formation de liaisons C-C. Une approche électrochimique d'hétérocouplage associé à une catalyse au nickel a été utilisée. Quelques limites à cette méthode ont cependant été observées dans le cas des couplages mettant en jeu des 3,6-dihalogénopyridazines. Une étude par électrochimie analytique a permis d'en comprendre les raisons. La seconde partie de notre travail a consisté en l'étude de la réactivité d'arylzinciques ou de triarylbismuths vis-à-vis de 3,6-dihalogénopyridazines / Heteroaromatic rings are present in various biological and pharmacological active molecules. Substituted aryl-pyridazines have given rise to considerable interest because of their diverse pharmacological properties (antibacterial, anti-inflammatory, cardiovascular drugs…). Moreover, structures which contain pyridazines are used in supramolecular chemistry for their applications through self-assembly processes in the presence of metal ions.In order to elaborate building blocks containing pyridazine rings such as aryl or heteroaryl-pyridazines, we turned our intention on the development of complementary methods involving organometallic reagents. Transition metal-catalyzed cross-coupling reaction of organometallic compounds with organic halides is one of the most powerful methods for the generation of C-C bonds.We chose to develop the most straightforward method involves heterocoupling reaction of aryl/heteroaryl compounds under electrochemical conditions (sacrificial anode process) associated to a nickel catalysis. However some limitations have been pointed out when 3,6-dihalogenopyridazines are involved in the cross-coupling reaction. An electrochemical study was investigated in order to propose some mechanistic considerations. A second part of this work consisted in the study of arylzinc and triarylbismuths reagents toward 3,6-dihalogenopyridazines

Les cancers représentent un problème majeur de santé public d'où la nécessité de rechercher de nouvelles classes de médicaments. Parmi les pistes pour développer de nouveaux traitements, deux ont retenu notre attention et celle de nos collaborateurs : la modulation de l’épissage par des composés comme le NVS-SM2, et l’inhibition de l’oncogène KRAS par des dérivés de produits naturels, les flavaglines. Dans ce contexte, nous avons développé la première synthèse robuste du NVS-SM2, qui peut satisfaire la demande globale de cet agent pour examiner en détail son potentiel thérapeutique dans différents types d’affection. En outre, la stratégie de synthèse rapportée ici pourrait être étendue à de nouveaux analogues de ce composé. D’autre part, nous avons synthétisé de nouvelles flavaglines qui sont en cours d'étude pour leurs effets sur l’inhibition de KRAS. Au cours de cette étude, nous avons découvert de nouvelles réactions, notamment une inversion de configuration d’amines induite par du chlorure de diméthylcarbamoyle. / Cancers represent a major public health problem hence the need to use new classes of medicines. Among the opportunities for developing new treatments, two have caught our attention and that of our collaborators: the modulation of splicing by compounds such as NVS-SM2, and the inhibition of the oncogene KRAS by derivatives of natural products, the flavaglines.In this context, we have developed the first robust synthesis of NVS-SM2, which can satisfy the global demand of this agent to examine in detail its therapeutic potential in different types of disorders. In addition, the synthetic strategy reported here could be extended to new analogues of this compound. Furthermore, we have synthesized new flavaglines that have been examined for their effects on KRAS inhibition. During this study, we discovered new reactions, including a dimethylcarbamoyl chloride-induced amine inversion of configuration.

Transition metal mediated [2 + 2 + 2] cyclizations have been well researched over the past several years. As a well-developed methodology, [2 + 2 + 2] chemistry has been employed as a major pathway to various carbo- and heterocyclic synthetic targets. Numerous transition metals have been applied as catalysts for these cyclizations. Previous work in our group developed cobalt(I) catalyzed inter- and intramolecular [2 + 2 + 2] cyclizations of two alkynes and a nitrile, leading to the preparation of tetrahydro-naphthyridines. Pyridazines could be generated if the cyclization could be accomplished with two nitriles and an alkyne, which would be a novel way to synthesize 1,2-diazines through the formation of the N-N bond. To this end, metal-catalyzed intramolecular [2 + 2 + 2] cyclizations between an alkyne and two nitriles were investigated. The intramolecular nature of the reaction provided the entropic advantage to successfully assist the formation of the critical N-N bond. Optimal conditions were achieved with cobalt(I) catalysts under microwave irradiation in chlorobenzene, producing the desired pyridazines in moderate to good yields. This success led to the preparation of a series of annulated pyridazines. The use of two tethering nitrogens in the preparation of the cyclization precursors incorporated points for further diversification, the next step in the development of this chemistry. This ring closure through N,N-bond formation allowed the construction of annulated pyridazine scaffolds that were utilized further in a small molecule library synthesis. Using this methodology, sixteen new annulated pyridazines were prepared. Inverse electron demand Diels-Alder (IEDDA) reactions of arynes and 1,2,4-triazines were also investigated for the generation of isoquinoline core structures. The results showed that only triazines with electron withdrawing groups participated in the IEDDA reactions with benzyne as a partner after screening of several different arynes, which limited the scope of the reaction. Liebeskind–Srogl reactions of 3-methylthiotriazines and boronic acids were investigated during the diversification of triazines, and microwave irradiation with palladium and copper catalysts were found to be the optimal conditions for the coupling. The chemistry allowed for further triazine diversification.

Plastics or polymers are thought to behave oppositely from metals. Ideally, polymers behave as insulators while metals conduct electricity. Shirakawa and coworkers discovered conductive polymers in 1977.1 These conductor polymers have been extensively studied, discovering that charge transfer oxidative doping of polyacteylene could increase its conductivity by 12 orders of magnitude. Polyacetylene, although showing promise as an organic conductor, because it is highly air-sensitive and oxidizes when exposed to molecular oxygen, therefore making this an unattractive use for commercial products. Attention has been focused on heterocylic aromatic polymers such as polythiophene and polypyrrole, in efforts to produce conductive polymers that are air-stable, tractable, and have a low band gap. The lone-pair electrons of the sulfur and nitrogen atoms tend to stabilize the positive charges of the p-doped polymers through resonance. 2 By using Shirakawas’ idea of using polypyrrole as the focus point of our research and expanding upon that by the addition of a rhenium metal to an organic compound, (1,2-C5H3(CNR)2) and this should offer some new and interesting chemical properties. These new properties are; new optical properties, new electronic properties, improved physical properties, and a reversible electrochemical shift. This research will help in the field of organometallic semiconductors in applications such as OLED’s, and electrochromic windows.3-6

Heterocyclic organic and organometallic compounds (i.e. polypyrrole), and their derivatives, have been of great interest for conductive polymers due to their novel properties and environmental stability as compared to their non-aromatic analogs (i.e. polyacetylene). Our current interest focus upon the potential role of metal ligand bound pyridazines as the next generation of electronic devices that utilize the metal ligands bound to organics as the semiconducting material. Pyridazine is a 6-membered aromatic ring with two adjacent nitrogen atoms. These are promising candidates for a variety of materials and commercial applications; but they are difficult to get a metal ligand to fuse to the aromatic ring. Our recent efforts focused in attaching Rhenium and Manganese ligands/substituents (process in which is called doping) that would cause oxidation to occur to our polymer making it a p-type polymer. Since p-type polymers charge carriers leave a vacancy that does not delocalize completely. This vacancy (known as a hole) or a radical cation that only partially delocalizes over several monomeric units causing them to be structurally deformed. This deformed structure is at a higher energy than that of an undoped polymer. Typical carriers in organic semiconductors are holes and electrons in a π-orbital. So when these molecules of π-conjugated systems have a π-bond overlap (or π- stacking), electrons can move via these π-electron clouds overlapping thus causing an electrical current. Our worked focused on the synthesis of pyridazines and their organometallic rhenium complexes and polymer research. Several aryl-substituted 5,6-fused pyridazines have been synthesized but none have been documented until this study. The main goal of the research was to fully characterize the general synthesis of furan containing organometallic complexes, [M(CO)3{η5-1,2-C5H3(CC4H3ON)(CC4H3ON)}] (M = Re or Mn) (4B). We successfully characterized the ability to attach a metal organic ligand to pyridazine though IR and NMR. However, when attempts were made to recrystallize our product, we yielded an orange-brown, block like crystal of 1,2- C5H3(CC4H3ONH)(CC4H3ON) (5) in which our metal ligand group fell off and we were left with pyridazine and inorganics. Though, we successfully got an X-ray characterization and electronic studies of compound 5 which are reported herein.

No / The reactions of ionised pyridazine, aminopyrazine and aminopyridine and the corresponding ¿-distonic ions are examined by a combination of tandem mass spectrometric techniques, including analysis of metastable ion (MI), collision induced dissociation and neutralisation¿reionisation mass spectra (NRMS). Further insight into the relative stability and energy barriers towards tautomerism of each ionised heterocycle with its ¿-distonic isomer is obtained by computational methods. In all these systems, both the conventional radical-cation and the ¿-distonic tautomer are stable species which exist in discrete energy wells, with a significant barrier towards their interconversion. Although each ¿-distonic ion is sufficiently stable to survive neutralisation¿reionisation, the conventional ionised heterocycle is more stable in each case. The possibility of investigating proton-transport catalysis in the tautomerism of these ionic systems is discussed.