Dissertations / Theses on the topic 'Pyrazole'

In recent years, the design and synthesis of structures that can potentially mimic the properties of the peptide bond have been of great interest to biological chemists. We are investigating the synthesis of novel pyrazoline-based structures as potential peptide mimetics. The pyrazoline unit is assembled by 1,3-dipolar cycloaddition of nitrile imines, which are generated in situ from hydrazonyl chlorides. We have investigated two routes to afford the hydrazonyl chloride, (1) via a hydrazone and (2) via a hydrazide, both of which have resulted in the successful synthesis of the desired pyrazolines. Subsequent syntheses have been carried out using a variety of different dipoles and dipolarophiles. We have taken approach (1) and used this to synthesize a pyrazole as one major enantiomer. This pyrazole has been subject to peptide couplings to form a complete peptide mimetic. NMR studies have been carried out on the synthesized peptide mimetic to determine the degree of hydrogen bonding and β-turn characteristics.

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

Scorpionates are versatile and flexible ligands with a wide range of applications including catalysis, C-H bond activation, formation of new class of materials, and mimicking enzymatic reactions. This is as a result of its steric and electronic properties, and due to the relative ease with which the 3, and 5-positions of the pyrazole ring can be functionalized. In this work, we report the synthesis of a new class of scorpionate ligands known as cyanoscorpionates which can crosslink various metal centers. Thus, bis (4-cyano-3,5-diphenylpyrazolyl)borate BpPh2,4CN was synthesized and fully characterized by 1H NMR and FT-IR. Coordination of bis (4-cyano-3,5-diphenylpyrazolyl)borate BpPh2,4CN to thallium (I) metal was performed and characterized and we are looking to elucidating its molecular structure by X-ray crystallography in future.

Les structures bicycliques azotées sont parmi les entités les plus utilisées dans le domaine thérapeutique.Les bicycles 5:5 polyazotés sont des structures moins décrites que leurs analogues 6:6 ou6:5. Malgré le potentiel pharmacologique des pyrazolo [3,4-d] thiazoles et des pyrazolo [3,4-c] pyrazoles,deux exemples de ces familles rares, seuls quelques procédés de préparation et de fonctionnalisationdirecte de ces charpentes hétérocycliques sont décrits.De ce fait, l’objectif principal de nos recherches vise à développer de nouvelles voies de synthèse vers cesdeux charpentes bicycliques et ce, à partir de substrats facilement accessibles. Des stratégies efficaces ontété mises au point et s’appuient sur réactions de condensations avec des hydrazines, des N-cyclisationsintramoléculaires, des halogénations chimiosélectives et diverses réactions de couplage-croisé. De surcroît,le motif pyrazolo[3,4-d]thiazole a été fusionné à une structure triazapentalène, afin d’évaluer les propriétésspectroscopiques
Nitrogen-rich fused bicyclic structures are undisputedly one of the most used scaffolds for therapeutic use.The 5:5 polynitrogenated bicycles are moieties considerably less documented then their 6:6 or 6:5analogues. Despite the pharmacological potential of the pyrazolo[3,4-d]thiazoles and of thepyrazolo[3,4-c]pyrazoles, two examples of such rare families, only few methods of preparation and directfunctionalization of these heterocyclic moieties have been described.In this context, the main goal of our research aims at exploring new routes towards these bicyclic systemsfrom readily available and affordable starting materials. Efficient strategies were developed relying onhydrazine condensations, on intramolecular N-cyclizations, on chemo-selective halogenation and variouscross-coupling reactions. Moreover, the pyrazolo[3,4-d]thiazole entity was fused to a triazapentalenestructure in order to assess the spectroscopic properties

The use of metallo-pharmaceuticals, such as the platinum drugs, for cancer treatment illustrates the utility of metal complexes as therapeutic agents. Platinum group metal complexes therefore offer potential as anti-tumour agents to fight cancer. This study was aimed at synthesizing and evaluating the effects of palladium(II) and platinum(II) complexes as anticancer agents.

The present work investigated copper(II)-promoted regioselective synthesis of disubstituted pyrazole scaffolds via cycloaddition reactions between sydnones and alkynes. Cu(OTf)2 has been found to mediate the formation of 1,3-pyrazoles, while Cu(OAc)2·H2O promotes the exclusive formation of the 1,4-regioisomer. Both transformations have been optimised and the scope has been explored for both reactions. A mechanistic proposal is also reported herein that has been derived from both experimental and theoretical investigations, the latter performed in collaboration with colleagues at Universidad del País Vasco (Spain). Furthermore, a catalytic variant of the synthesis of 1,4-disubstituted pyrazoles has been developed using Cu(OAc)2 supported in modified silica gel and, in collaboration with Future Chemistry Holding BV and Radboud University (the Netherlands), this methodology has been implemented under continuous flow. A directed cycloaddition of sydnones and alkynylboranes has also been developed. A range of substrates have been synthesised and subjected to cycloaddition conditions, showing that only pyridine- and quinoline-derived substrates afforded the desired pyrazole products. Mechanistic studies using NMR spectroscopy have also been carried out. Finally, the diastereoselective addition of Grignard reagents to a sydnone sulfinimine derivative has been studied, using this strategy to generate bicyclic pyrazole scaffolds containing stereogenic centres after a functionalisation-cycloaddition tandem process.

Four main series of novel heterocyclic compounds were successfully syniliesised. Two of these series were found to be post-emergence herbicides with the activities of each being based on a different mode of action. The (pyrazole-4-yl)alkanones are inhibitors of protoporphyrinogen oxidase, an enzyme in chlorophyll biosynthesis, whereas alkyl 3-arylsulfonylamino- 3-methyllhio-2-(pyrimidin-2-ylcarbamoyl)acrylates and pyrimidin-2-yl 3-(2- chlorophenyl)sulfonyl-amino-3-methylthio-2-cyanoacrylamides (collectively termed "vinylogous sulfonylureas") are inhibitors of acetohydroxy acid synthase (AHAS). an enzyme in branched-chain amino acid biosynthesis. Both these enzymes are established targets for current commercial herbicides. Studies of the utility of 2-(l-ethoxyalkylidene)-3-oxoaIkanenitriles (acrylonilriles) in heterocycle synthesis were facilitated by the recent development of a convenient route to these starting materials. Acrytonitriles were reacted with different hydrazines to give (pyrazol-4-yl)alkanones and pyrazole-4-carbonitriles in varying proportions depending on the reaction conditions and the substituents on the reactants. Although distinction between alternative 3- and 5-substituted pyrazoles is a perennial problem in pyrazole synthesis, in this case the products of these reactions were successfully characterised and identified using a range of n.m.r. spectroscopy techniques. Once the herbicidal mode of action of the (pyrazol-4-yl)alkanones had been confirmed, synthesis of a series of analogues allowed the structural elements contributing to biological activity to be identified. The reaction of acrylonitriles with bidetate nucleophiles such as thiourea gave novel pyrimidines. but these compounds were not herbicidal. The vinylogous sulfonylureas were synthesised using established procedures to obtain novel compounds structurally related to the commercial herbicide chlorsulfuron. The biological activity of the vinylogous sulfonylureas was found to be sensitive to apparently minor changes in structure, but x-ray crystallographically-generated structures of an active and an inactive member of the series revealed marked differences in conformation. Some of the vinylogous sulfonylureas were used as synthons for pyrazole and pyrazolopyrimidine derivatives. Although these compounds did not exhibit herbicidal activity, this synthesis provided the basis for some interesting chemistry. Unexpected elimination of the arylsulfonylamino group was observed when a vinylogous sulfonyurea was treated with methyl hydrazine. In order to confirm the identity of the 3-methylthiopyrazole product, model compounds were synthesised using alternative routes. The resulting pairs of 3- and 5-substituted pyrazoles were characterised using n.m.r spectroscopy.

Pyrazoles have been studied for over a century as an important class of heterocyclic compounds and continue to attract considerable interest due to the broad range of biological activities they possess. The incorporation of the essential structural features of pyrazoles with a ferrocene moiety could provide new derivatives with unexpected and/or enhanced biological activities since several ferrocene derivatives have already been shown to be active against a number of tumors. For this reason, we investigated the synthesis of ferrocenyl-substituted pyrazoles, such as 1-alkyl/aryl-5-ferrocenylpyrazoles, by employing the reaction between (2-formyl-1-chlorovinyl)ferrocene and hydrazine derivatives. Although this reaction is known, it was not studied in much detail and the low yields of ferrocenyl pyrazoles were obtained. Thus, we have reinvestigated this reaction and improved the yields of pyrazoles by optimizing the reaction conditions. (2-Formyl-1-chloro vinyl)ferrocene was first reacted with the excess amount (3 equivalents) of hydrazine derivative at 25 0C in dioxane under argon for 2 hours, and the resulting mixture was then heated at 100 0C for 6 hours in the same solvent. Under our optimized conditions, these reactions afforded 1-alkyl/aryl-5-ferrocenylpyrazole derivatives in moderate to good yields as a single or major product of the reaction. In some cases, 1-alkyl/aryl-3-ferrocenylpyrazole derivatives resulted from these reactions as very minor products.

The objectives of this project were to synthesize and characterise pyridine carboxamide ligands and their palladium complexes and investigate their catalytic activity in the polymerization process of phenylactylene.

Ce travail concerne la synthese et la caracterisation des polymeres et copolymeres obtenus par polymerisation de nouveaux monomeres styreniques, vinyliques, maleimiques et methacryliques porteurs des cycles pyridine, pyrazole et bipyrazole. Une discussion sur la copolymerisation de ces monomeres avec d'autres monomeres conduisant a des systemes accepteur-donneur est presentee. En plus, des comparaisons entre la structure et les proprietes, notamment thermiques, sont abordees. Enfin deux applications ont ete etudiees: la premiere concerne les resines acetylantes selectives, la seconde l'obtention de membranes specifiques a la separation des metaux

Ce mémoire est subdivise en deux parties. La première partie concerne la synthèse de pyrazoles présentant un intérêt sur le plan agrochimique. En effet, le noyau pyrazole est présent dans de nombreux composes ayant des activités biologiques diverses et en particulier antifongique. Au cours de ce travail, nous avons développé diverses approches convergentes de pyrazoles diversement substitués au moyen de réactions de couplages croisés pallado-catalyses sélectifs et séquentiels à partir de pyrazoles possédant différents points d’encrages. Dans la deuxième partie, nous nous sommes intéressés à la synthèse de diverses furopyridones en tant qu’analogues de produits naturels possédant une activité antifongique, et notamment le Cladobotryal. Dans ce but, diverses alcynylpyridones ont été synthétisées et mises en jeu dans divers processus de cyclisation pour atteindre de manière divergente une série de furo[3,2-c]pyridin-4-ones, furo[3,2-c]pyridin-6-ones et furo[2,3-b]pyridin-4-ones
This thesis is subdivided into two principal parts. The first part is focussed on the synthesis of pyrazole derivatives of agrochemical relevance. Indeed, the pyrazole nucleus is found in numerous compounds possessing interesting biological properties, and notably antifungal activities. Various convergent approaches to diversely substituted pyrazoles have therefore been developed by means of site-selective palladium-catalyzed cross-coupling reactions conducted sequentially on pyrazole scaffolds. In the second part, we have been involved in the synthesis of furopyridones as simplified analogues of natural compounds possessing antifungal activities such as Cladobotryal. Toward this end, various alkynylpyridones have been synthesizes and involved in diverse cyclization processes to access a series of furo[3,2-c]pyridin-4-ones, furo[3,2-c]pyridin-6-ones, and furo[2,3-b]pyridin-4-ones

The importance of pyrazole and lactam-based molecules in medical and pharmaceutical fields is underlined by the multitude of active ingredients on trade, such as Sildenafil or Apixaban, by Pfizer. In this work, a synthesis of an organic molecule with promising anticancer activity has been developed. This molecular scaffold is characterized by a δ-lactam-fused pyrazolic core, with a well-known biological activity and amenable of further functionalization. The synthetic strategy adopted for the obtainment of the core was based on a 1,3-dipolar cycloaddition of a nitrilimine with an α,β-unsaturated δ-lactam. Secondly, in order to give the final compound an elevated pharmacological activity, a functionalization with a double “side chain”, namely molecular fragment able to improve the interaction with particular biological receptors, was achieved. The target compound was thus obtained, with a highly convergent synthesis, and will be tested for antiproliferative activities towards different cellular lines.

Ce travail de thèse a eu pour but la synthèse de nouveaux composés hétérocycliques (rhodanines et pyrazoles) potentiellement actifs sur des protéines kinases, des lignées cellulaires tumorales, les influx SOCE (Store Operated Calcium Entry) et a ciblé principalement comme pathologies la malaria, la leishmaniose et le cancer. La première partie de cette étude a permis la synthèse d'une nouvelle famille de dérivés 5-arylidène rhodanines dissymétriques comportant un bras espaceur diaminé et ce par l'intermédiaire de la technologie micro-onde. Sur les 7 protéines kinases testées avec ces composés, CK1δ/ε et CDK5/p25 ont été inhibées spécifiquement avec des CI50 comprises entre 1,1 et 10 µM. L'activité anticancéreuse enregistrée est moyenne avec des CI50 variant de 8 à 23 µM. Les travaux réalisés au cours de la seconde partie de cette étude se sont appuyés sur le SKF-96365 comme modèle structural et ont permis d'accéder à 3 librairies inédites d'analogues comportant les plateformes pyrazole et rhodanine. L'activité pharmacologique visée ici était une modulation des influx SOCE et diverses variations structurales ont été effectuées en vue de réaliser une étude Relation Structure-Activité (RSA). Plusieurs analogues "pyrazoles" ont montré une activité supérieure à celle du SKF-96365 et de la GSK-7975A sur les influx SOCE de la lignée HEK-293. Les 2 composés montrant la meilleure activité (30f et 30h), sont également plus actifs que la Synta 66 aux faibles concentrations. Ces analogues ont également une activité sélective des canaux SOCE concernés car totalement inactifs sur l'ensemble des protéines kinases testées. Les CI50 les plus significatives pour l'activité anticancéreuse varient entre 3 et 8 µM
This thesis work has been aimed the synthesis of new heterocyclic compounds (rhodanines and pyrazoles) potentially active on kinase proteins, tumor cell lines, SOCE impulses (Store Operated Calcium Entry) and has mainly targeted pathologies such as malaria, leishmaniasis and cancer. The first part of this study allowed the synthesis of a new family of 5-arylidene rhodanine derivatives asymmetric having a diamino spacer arm and via microwave technology. Of the 7 protein kinases tested with these compounds, CK1δ/ε and CDK5/p25 have been specifically inhibited with IC50 between 1.1 and 10 µM. The recorded anticancer activity is average with IC50 ranging from 8 to 23 µM. The work carried out during the second part of this study was based on SKF-96365 as structural model and provided access to 3 unpublished libraries of analogs containing pyrazole and rhodanine platforms. The desired pharmacological activity was SOCE modulating and various structural changes were made to undertake a study Structure-Activity Relationship (SAR). Several "pyrazole" analogs have shown a higher activity than SKF-96365 and GSK-7975A on SOCE of HEK-293 line. The two compounds showing the best activity (30f and 30h) are also more active than Synta 66 at low concentrations. These analogs are completely inactive on all protein kinases tested, indicating selectivity for SOCE channels concerned. The most significant IC50 for the anticancer activity vary between 3 and 8 µM

Le travail décrit dans cette thèse concerne la synthèse et l’étude de la réactivité d’acides et d’esters boroniques en série pyrazole. La première partie est consacrée à l’étude bibliographique des différentes méthodes de synthèse d’acides et d’esters boroniques notamment en série hétérocyclique azotée ainsi qu’à l’étude de la synthèse et de la réactivité du pyrazole. La seconde partie expose les travaux personnels concernant les méthodes de synthèse d’acides et d’esters pyrazolylboroniques via une réaction de lithiation. L’expérience acquise dans ce domaine a été mise à profit dans la synthèse de 3(5)-halogéno-1H-pyrazoles. L’étude de la réactivité des dérivés pyrazolylboroniques, notamment dans des couplages métallo-catalysés, nous a conduits à préparer des diarylpyrazoles et de nouvelles pyrazoloisoindolones. Enfin les premiers résultats concernant les synthèses de dérivés organoborés en séries triazoles et tétrazole sont présentés. La partie expérimentale de ce document décrit les modes opératoires et les caractéristiques physicochimiques des composés présentés. Enfin, plus de 200 références bibliographiques replacent cette étude dans son contexte chimique et pharmacologique
The work described in this thesis relates to the study of the synthesis and the reactivity of boronic acids and esters in pyrazole series. The first part is devoted to the bibliographical study of the various synthetic methods of organoboron compounds and particularly in nitrogen containing heterocyclic series and the study of the synthesis and the reactivity of pyrazole. The second part details personnal work concerning the synthetic methods of pyrazolylboronic acids and esters via lithiation reaction. The experience gained in this field was made profitable in the synthesis of 3(5)-halogeno-1H-pyrazoles. The study of the reactivity of pyrazolylboronic compounds, in particular in cross-coupling reaction, led us to prepare diarylpyrazoles and new pyrazoloisoindolones. Finally our first results concerning the syntheses of organoboron compounds in triazoles and tetrazole series are presented. The experimental part of this document describes the procedures and the physicochemical characteristics of the compounds presented. Finally more than 200 bibliographical references replace this study in its chemical and biological context

Estrogen stimulation of the medial amygdala (MEA) of the brain promotes male rat mating behavior. However, selective stimulation of either of the estrogen receptor subtypes found in the MEA (ERα or ERβ) does not support mating behavior. We tested the hypothesis that dual stimulation of ERα and ERβ is required to activate estrogen-dependant neural circuits in the MEA responsible for mating by local treatment of MEA with a combination of selective estrogenic agonists: propyl pyrazole triol (PPT, an ERα agonist ) and diarylpropionitrile (DPN, an ERβ agonist) administered to castrated, DHT maintained male rats. Estradiol (E2) or cholesterol (Chol) MEA implants served as positive and negative controls respectively. The animals receiving a mixture of PPT and DPN into the MEA displayed higher levels of mating behavior than the Chol treated animals but lower levels of mating behavior than the E2 treated animals.

Le diabète est l'affection endocrinienne de loin la plus fréquente. Il touche environ deux millions de personnes en France et se caractérise par une élévation de la concentration plasmatique en glucose et triglycérides. Cette hyperglycémie chronique contribue à l'apparition de complications spécifiques. Dans le cadre d'une recherche de nouveaux agents antidiabétiques, nous avons préparé à partir d'un synthon commun, le 3-hydroxy-1H-pyrazole-4-carboxylate d'éthyle, des composés diversement fonctionnalisés notamment en position 1 et 3 via des réactions de O et N-alkylations régiospécifiques, et en position 5 via des réactions de couplage catalysées au palladium (0). Par la suite, la mise au point des réactions de type ± Eenie-Meenie α à partir du (3-méthoxy-1-méthyl-1H-pyrazol-4-yl)-méthanol a permis la synthèse de 4-benzylpyrazoles. Les tests pharmacologiques, effectués par la société Merck-Santé, ont montré que certains composés synthétisés présentent une bonne activité hypoglycémiante.

La synthese de ceramiques oxydes conductrices, par reaction a l'etat solide, necessite des traitements a haute temperature. Une autre methode est d'utiliser des composes de coordination precurseurs pour la preparation de materiaux oxydes hautement disperses. Nous avons utilise l'acide 3,5-pyrazole dicarboxylique (dcph#3) qui se decompose a 300c ; ce diacide est potentiellement tetrachelatant. Nous avons obtenu des complexes stables avec une grande variete d'elements (cu, bi, vo, ba, pb, ni, co) ; ceux ci ont ete caracterises par a. T. G et par diffraction x a haute temperature. La structure cristalline du ligand (sous forme anhydre et hydratee) a ete determinee, l'etude structurale d'un complexe de nickel montre que dcph#3 se comporte comme un bidentate. Nous avons utilise la coprecipitation pour preparer des materiaux oxydes conducteurs en une seule etape par un traitement thermique approprie. Une synthese a ete aussi mise au point pour les oxydes conducteurs type bimevox recemment decouverts, tout comme les oxydes supraconducteurs yba#2cu#3o#7#-# ou (bi,pb)#2sr#2ca#2cu#3o#x. Une nouvelle famille d'oxydes mixtes a ete obtenue et caracterisee. La serie ba#2#-#xsr#xbio#4#+# adopte une structure type double perovskite, ou le bi presente un degre d'oxydation mixte (+iii, +v) et les cations alcalino terreux sont repartis dans les sites a et b du modele perovskite. La conductivite est majoritairement de type electronique.

In this study, the synthesis of 5-ferrocenyl/aryl-4-(phenylselenyl)-1H-pyrazole derivatives was investigated since the integration of ferrocenyl and selenium moieties into pyrazole derivatives may increase their current biological activities. Initially, the starting propargyl aldehydes were synthesized from corresponding acetylenes. Subsequently, propargyl aldehydes were reacted with hydrazines to yield corresponding hydrazones. Then the in situ synthesized hydrazones were subjected to electrophilic cyclization with phenylselenyl chloride, which afforded 5-ferrocenyl/aryl-4-(phenylselenyl)-1H-pyrazoles in one-pot manner. Subsequently, reaction conditions were optimized in terms of electrophile, base, temperature and solvent. Best results were obtained with phenylselenyl chloride and NaHCO3 at room temperature in DCM for ferrocenyl substituted pyrazoles and DCE for aryl substituted pyrazoles. In summary, by employing the electrophilic cyclizations of in situ synthesized acetylenic hydrazones, a variety of 5-ferrocenyl/aryl-4-(phenylselenyl)-1H-pyrazole derivatives were synthesized in one-pot way in moderate to good yields.

This work presents a crystal chemistry study of seven compounds grouped into three classes: isoxazoles, pyrazoles and pyrazolines here called IPISOX, PRISOX, 4D, OCISOX, C90, B07 e 13B, in order to identify novel acetylcholinesterase inhibitors. The structures of the listed compounds were determined by X-ray diffraction method using monocrystalline samples of the aforementioned substances. The disagreement rates seen between the model and the model defined by the diffraction pattern were: 0.0708; 0.0399; 0.0513; 0.0562; 0.0726; 0.0519; 0.0457 to IPISOX, PRISOX, OCISOX, 4D, B07, 13B e C90, respectively. A appendix refers to several methods involved in the process of recrystallization was attached to work, since it received 13 of the 16 substances to study were improperly to be subjected to the technique of Xray diffraction. To obtain factors responsible for the stability of the lens system were carried Closed Layer Interactions Analysis (ICF). The average values of delocalized electron energies determined in kcal.mol-1 were: 19.00 (IPISOX) ; 23.00 (PRISOX) ; 12.00 (OCISOX and B07) ; 9.00 (4D) ; 6,00 (13B) and 5.00 (C90) . Such relocations are from electronic transitions of the type n * (donor receiver). Other electronic relocation of C-N *O-H and C-H *O-H were also observed for some compounds. However, the first mentioned are relevant to the stability of the electron lens packaging.
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Este trabalho apresenta um estudo cristaloquímico de sete compostos agrupados em três classes: isoxazóis, pirazóis e pirazolinas aqui denominados de IPISOX, PRISOX, 4D, OCISOX, C90, B07 e 13B, no intuito de identificar novos inibidores da Acetilcolinesterase. As estruturas dos compostos mencionados foram determinadas por método de difração de Raios X usando amostras monocristalinas das substâncias mencionadas anteriormente. Os índices de discordância verificado entre o modelo proposto e o modelo definido pelo padrão de difração foram: 0,0708; 0,0399; 0,0513; 0,0562; 0,0726; 0,0519; 0,0457 para IPISOX, PRISOX, OCISOX, 4D, B07, 13B e C90, respectivamente. Um apêndice referente aos diversos métodos envolvidos no processo de recristalização foi anexado ao trabalho, uma vez que 13 das 16 substâncias recebidas para estudo estavam em forma inadequada para serem submetidas à técnica de difração de raios X. Visando obter fatores responsáveis pela estabilidade do sistema cristalino foram realizadas Análises de Interações de Camada Fechada (ICF). Os valores médios das energias de deslocalização eletrônica determinados, em kcal.mol-1, foram: 19,00 kcal.mol-1 (IPISOX); 23,00 (PRISOX); 12,00 (OCISOX E B07); 9,00 (4D); 6,00 (13B) E 5,00 (C90). Tais deslocalizações são oriundas de transições eletrônicas do tipo n * (doador receptor). Outras deslocalizações eletrônicas do tipo C-N *O-H e C-H *O-H também foram observadas para alguns compostos. No entanto, as primeiras mencionadas são relevantes para a estabilidade eletrônica do empacotamento cristalino.

Se han sintetizado dos nuevos complejos mononucleares de Ru, con formula [RuCl2(Hbpp)(dmso)2], a partir de la reacción entre [RuCl2(dmso)4] y Hbpp (3,5-bis(2-piridil)pirazola). El hecho que sólo tres de los seis posibles estereoisómeros se obtengan a partir de esta reacción, se ha racionalizado en base a factores estructurales y electrónicos. Estos complejos se han caracterizado de forma estructural, espectroscópica y electroquímica. En acetonitrilo en medio básico, el isómero trans,cis-[RuCl2(Hbpp)(dmso)2] da lugar a procesos de isomerización de enlace de un ligando dmso cuando el Ru(II) se oxida a Ru(III). Las constantes termodinámicas y cinéticas para el proceso se han determinado por voltametria cíclica. La irradiación de trans,cis-[RuCl2(Hbpp)(dmso)2] y cis(out),cis-[RuCl2(Hbpp)(dmso)2] con luz UV o solar da lugar a reacciones de fotosustitución de un ligando dmso por una molécula de acetonitrilo para dar un nuevo compuesto el cual ha sido caracterizado en solución por técnicas espectroscópicas y electroquímicas. Ambos complejos resultan catalizadores útiles en la transferencia de hidrógeno de isopropanol a acetofenona, obteniéndose 1-feniletanol como único producto y un 42.1% de conversión (36.1 ciclos metálicos) a 80ºC con el isómero trans,cis-[RuCl2(Hbpp)(dmso)2], que resulta significativamente más eficaz que el complejo cis(out),cis-[RuCl2(Hbpp)(dmso)2].
La reacción de cis(out),cis-[RuCl2(Hbpp)(dmso)2] con trpy (2,2':6',2"-terpiridina) da lugar a los dos isómeros geométricos del complejo [Ru(Hbpp)(trpy)(Cl)]+, el in y el out. Estos complejos se han aislado y caracterizado por técnicas estructurales, espectroscópicas y electroquímicas. Estos cloro complejos han sido utilizados como precursores para la síntesis de los complejos análogos con ligandos aqua (in,out-[Ru(Hbpp)(trpy)(H2O)]2+) y piridina (in,out-[Ru(Hbpp)(trpy)(py)]2+), los cuales también han sido aislados y caracterizados. Las propiedades ácido-base de los aqua complejos, y del complejo out-py se han estudiado detalladamente por voltametria cíclica y mediante valoraciones espectrofotométricas ácido-base. El tratamiento matemático de los datos así obtenidos nos ha permitido determinar los valores de pKa para los distintos equilibrios de protonación de los complejos en los estados de oxidación II y III. El complejo out-aqua ha demostrado ser un buen catalizador para la oxidación electroquímica del alcohol benzílico, presumiblemente a benzaldehido. La constante de velocidad de segundo orden para el proceso ha sido determinada como 17.1 M-1 s-1, por simulación matemática.
El dímero con un puente cloro, [Ru2Cl(bpp)(trpy)2]2+ ha sido preparado por dos rutas sintéticas diferentes. El dímero análogo con un puente acetato se ha obtenido por reacción del cloro dímero con un exceso de acetato sódico. El dímero con dos ligandos aqua [Ru2(bpp)(trpy)2(OH2)2]3+ puede obtenerse por hidrólisis ácida del complejo con un acetato puente o por hidrólisis básica del complejo con un puente cloro. Estos complejos han sido caracterizados por técnicas estructurales, espectroscópicas y electroquímicas. Las soluciones del dímero con dos ligandos aqua en medio ácido resultan inestables a la coordinación de aniones de la solución con el tiempo. Las propiedades ácido-base del dímero con dos aguas coordinadas han sido estudiadas por voltametria cíclica y mediante experimentos de electrólisis a potencial controlado. El pKa para la desprotonación de uno de los ligandos aqua ha sido determinado mediante una valoración espectrofotométrica ácido-base como 6.7. Este valor tan bajo de pKa se atribuye a la formación de la entidad {Ru2O2H3}, favorable termodinámicamente. Los espectros UV-vis para los distintos estados de oxidación del aqua dímero, de RuIIRuII a RuIIIRuIV, han sido obtenidos por oxidación química y electroquímica del complejo. Se han llevado a cabo estudios cinéticos de la oxidación, paso a paso, de RuII,II a RuIV,IV , y se han determinado las constantes de oxidación de segundo orden para los distintos procesos de oxidación. La capacidad del aqua dímero en la oxidación del agua a oxígeno molecular ha sido investigada en solución homogénea utilizando CeIV como oxidante. La evolución de oxígeno se ha demostrado por cromatografia de gases. Se ha obtenido una eficiencia del 73% y 18.6 ciclos catalíticos, cuando 1.83 x 10-6 moles de dímero se han mezclado con un exceso de 100 equivalentes de cerio. El dímero con dos aguas cataliza también la oxidación del agua de forma heterogénea, con el complejo adsorbido sobre una membrana de nafion, aunque la eficiencia es menor. Se ha propuesto un mecanismo intramolecular para la reacción de oxidación del agua. Consiste en la oxidación a 4 electrones del dímero, de RuII,II a RuIV,IV, el cual reacciona con el agua para formar oxígeno y revierte nuevamente al estado de oxidación II,II. Este modelo es consistente con estudios catalíticos de la evolución de oxígeno en función de las concentraciones de cerio y catalizador, llevados a cabo en solución ácida homogénea, que demuestran que la oxidación a 4 electrones del agua se encuentra catalizada por una sola molécula de complejo bajo concentraciones elevadas de cerio. La constante de pseudo-primer-orden para la evolución de oxígeno tiene un valor de 1.4 x 10-2 s-1, que es uno de los valores de constante más elevados obtenidos hasta la fecha. Desafortunadamente, el aqua dímero se desactiva durante el proceso de catálisis dando lugar a una especie naranja, la cual estamos actualmente tratando de caracterizar.
Two new mononuclear Ru complexes with formula [RuCl2(Hbpp)(dmso)2], 2a and 2b, have been prepared from [RuCl2(dmso)4] and Hbpp (3,5-bis(2-pyridyl)pyrazole). The fact that only three (2a and the pair of enantiomers 2b) from the six possible stereoisomers are obtained from this reaction, has been rationalized in terms of structural and electronic factors, particularly the intramolecular hydrogen bond between the inner dmso and the aminic proton of Hbpp. 2a and 2b have been structurally, spectroscopically and electrochemically characterized. In acetonitrile basic media, 2a has proven to undergo linkage isomerization reactions of one dmso ligand when going from RuII to RuIII. The kinetic and thermodynamic constants for this process have been determined by means of cyclic voltammetry. Irradiation of either 2a or 2b with UV or sunlight provokes the replacement of one dmso by an acetonitrile molecule so that a new compound is formed, which has been characterized in solution by spectroscopic and electrochemical techniques. The fact that only one of the two dmso ligands is substituted, compared to related systems where two successive substitutions of dmso for MeCN take place, suggests that the inner dmso is much more stable due to the hydrogen bond with the aminic proton of Hbpp. 2a and 2b have proven to be active catalysts in the hydrogen transfer from 2-propanol to acetophenone, yielding 2-phenylethyl alcohol as the only product and 42.1% conversion (36.1 metal cycles) at 80 ºC for 2a, which is markedly more efficient than 2b.
Two geometrical chloro isomers with formula out and in-[Ru(Hbpp)(trpy)(Cl)]+, 2a (out) and 2b (in), are obtained from the reaction of cis(out),cis-[RuCl2(Hbpp)(dmso)2] and trpy (2,2':6',2"-terpyridine). Better yields of these complexes can be obtained by a different route which uses [RuCl3(trpy)] and bpp-BOC as starting materials. These compounds have been isolated and characterized by means of structural, spectroscopic and electrochemical techniques. 2a and 2b have been used as starting materials for the synthesis of the analogous aqua (out and in-[Ru(Hbpp)(trpy)(H2O)]2+; 3a and 3b) and pyridine (out and in-[Ru(Hbpp)(trpy)(py)]2+; 4a and 4b) complexes, which have also been isolated and characterized. The acid-base properties of the aqua complexes, 3a and 3b, and the pyridyne complex 4a have been thoroughly investigated by cyclic voltammetry (Pourbaix diagram) and acid-base spectrophotometric titrations. Mathematical treatment of the experimental data thus obtained has allowed us to determine the pKa values for the different protonation equilibria of the complexes in oxidation states II and III. 3a has been shown to be a good catalyst in the electrochemical oxidation of benzyl alcohol, presumably to benzaldehyde. The second-order rate constant for the process has been determined as 17.1 M-1 s-1 by mathematical simulation. Two different synthetic routes have been used to prepare the chloro-bridge dimer [Ru2(Cl)(bpp)(trpy)2]2+, 1, in good yield. The acetato-bridge dimer [Ru2(O2CCH3)(bpp)(trpy)2]2+, 2, has been obtained from 1 and excess sodium acetate. The diaqua complex [Ru2(bpp)(trpy)2(OH2)2]3+, 3, has been prepared from either basic hydrolysis of 1 or acid hydrolysis of 2. These complexes have been characterized by means of structural, spectroscopic and electrochemical techniques. Long-standing solutions of the diaqua dimer 3 in acidic media have proven to be unstable to coordination of anions from the solution. Crystals of the trifluoroacetato-bridge dimer 4 have been obtained in acidic CF3COOH media after some days. The acid-base properties of the diaqua dimer 3 have been thoroughly investigated by cyclic voltammetric and bulk electrolysis experiments, and the corresponding Pourbaix diagram obtained. The pKa for the one-proton deprotonation of one aqua ligand has been determined by acid-base spectrophotometric titration as 6.7. This low pKa value is attributed to the formation of the highly stable (Ru2O2H3) entity. The UV-vis spectra for the different oxidation states of 3, from RuIIRuII to RuIIIRuIV, have been obtained by either chemical or electrochemical oxidation of the complex. UV-vis kinetic studies on the stepwise oxidation from RuII,II to RuIV,IV have been performed, and the individual second-order rate constants for the different oxidation processes determined. The capability of 3 in water oxidation to molecular dioxygen has been investigated in homogeneous solution using CeIV as oxidant. Oxygen evolution has been clearly demonstrated by gas chromatography. An efficiency of 73% and 18.6 metal cycles were obtained using 1.83 x 10-6 mols of dimer and 100-fold molar excess of cerium. This complex has also been shown to catalyze water oxidation in a heterogenous Nafion membrane, but the yields of O2 evolution are lower. An intramolecular pathway for the water oxidation process has been proposed. It involves the four-electron oxidation of the RuII,II dimer to the RuIV,IV complex that reverts to the RuII,II oxidation state upon releasing of molecular dioxygen. This model is consistent with kinetic studies on the evolution of oxygen as a function of catalyst and cerium concentrations, performed in homogeneous acidic solution, which show that the four-electron oxidation of water is catalyzed by one molecule of complex under large excesses of cerium. The pseudo-first-order rate constant for oxygen evolution has been calculated as 1.4 x 10-2 s-1, which is among the highest values reported up to date. Unfortunately, the diaqua dimer 3 is deactivated during the catalysis to yield an orange species which we are currently trying to characterize.

Ce manuscrit de thèse concerne le développement d'une stratégie de synthèse multi-étapes de nouveaux composés comportant plusieurs plateformes hétérocycliques (rhodanine, benzimidazole, pyrazole et imidazole) à visée thérapeutique multiple contre la malaria, la leishmaniose, le cancer et les maladies neurodégénératives. Les pharmacomodulations de ces composés ont été élaborées sur la base du modèle de la pentamidine 35 comportant 2 motifs benzamidines (parties « Ouest » et « Est »). En effet, la substitution de sa partie « Ouest » par une plateforme rhodanine ou benzimidazole et de sa partie « Est » par un système aromatique plan ou système azole (pyrazole, imidazole) a permis d’accéder respectivement aux 5-arylidènes rhodanines (50, 58), aux dérivés ''aza'' (99,100) et aux dérivés ''aza azoles'' 174 qui sont des analogues de la pentamidine. Les rendements de ces composés sont respectivement compris entre 26 et 98%, 10 et 93% et 10 et 97%. L’ensemble des composés synthétisés dans les chapitres II, III et IV de ces travaux ont été l'objet d'évaluations pour leur activité antiproliférative sur les lignées cellulaires et pour leur activité inhibitrice sur les protéines kinases
This thesis manuscript is focused on the development of multi-steps synthesis strategy of new compounds bearing several heterocyclic platforms (rhodanine, benzimidazole, pyrazole and imidazole) for multiple therapeutic use to fight malaria, leishmaniasis, cancer et neurodegenarative diseases. The pharmacomodulations of these compounds were developped from the design of pentamidine 35 which containins 2 fragments benzamidine (parts ''West'' and ''East''). Indeed, the substitution of its part ''West'' by a platform rhodanine or benzimidazole and its part ''East'' by an "azole" aromatic ring system (pyrazole, imidazole) lead respectively to 5-arylidene rhodanines (50, 58), to derivatives ''aza'' (99,100) and to derivatives ''aza azoles'' 174 which are pentamidine analogs. The chemical yields of these compounds are ranging respectively from 26 to 98%, 10 to 93% and 10 to 97%. All the compounds synthesized in the chapters II, III and IV of this research work were evaluated for their antiproliferative activity on tumoral cell lines and for their inhibitory activity on protein kinases

This thesis focuses on development of new regents which are suitable for recovering nickel, cobalt and copper from laterite leach solutions, specifically focusing on reagent requirements for novel base metal flowsheets developed by Anglo American. The work aims to design reagents which can extract nickel(II), cobalt(II) and copper(II) from a highly acidic aqueous sulfate solutions whilst showing selectivity over iron(II) and iron(III). Chapter 1 reviews current extractive metallurgy processes for separating and concentrating metals in laterite ores and describes new flowsheets proposed by Anglo American. Chapter 2 considers whether single reagent molecules with sets of tridentate donor atoms can generate sufficiently stable nickel(II) complexes to allow selective extraction of nickel from an aqueous sulfate solution. The salicylaldimines, 3-X-4-alkyl-6-(quinolin-8-imino)phenol, 3-X-4-alkyl-6-(2- methoxyphenylimino)phenol and 3-X-4-alkyl-6-(2-thiomethoxyphenylimino)phenol (alkyl = tert-butyl or tert-octyl; X = H, Br or NO2), were selected for study. The synthesis and characterisation of these proligands and their nickel(II) complexes are reported. XRD structures of Br-substituted salicylaldimines and their nickel(II) complexes are compared and discussed. The 4-tert-octylsalicylaldimines were used to extract nickel(II) from an aqueous sulfate solution with a pH > 2.8 and 3- nitro-4-tert-octyl-6-(quinolin-8-imino)phenol was found to be the strongest extractant in the series with a pH0.5 of 3.5. Computational studies of an analogous series of salicylaldimine proligands in the gas phase calculated the formation energies of their nickel(II) complexes and the predicted trend follows the experimentally determined solvent extraction results. Chapter 3 investigates modifications to phenolic pyrazoles, which are known copper(II) extractants. A series of 6-X-4-methyl-2-(5-alkyl-1H-pyrazol-3-yl)-phenols (X = H, OMe, Br and NO2) was synthesised and characterised. Varying the 6-X-substituent of the phenolic pyrazole altered the strength of copper extraction and 6-nitro-4-methyl-2-(5-(1,3,5-tri-methyl-pentyl)-1H-pyrazol-3-yl)-phenol was found to be the strongest extractant in the series. Analysis of XRD structures of related phenolic pyrazoles and their copper(II) complexes showed evidence of inter- and intra-molecular hydrogen bonding. Computational DFT studies in the gas phase were carried out to calculate the formation energies of analogous phenolic pyrazole copper complexes. The predicted order of these energies followed the same trend shown by experimental solvent extraction studies. The double deprotonation of 4-tert-butyl-(pyrazol-3-yl)-phenol at high pH forms a polynuclear complex in the organic phase with a copper(II) to ligand ratio of 1:1, thereby increasing the mass transport efficiency of copper by the reagent. The synthesis and characterisation of the [Cu16(4-tert-butyl-(pyrazol-3-yl)- phenolate)16(EtOH)4(H2O)2] wheel complex was carried out to demonstrate how such polynuclear copper(II) complexes could be formed under solvent extraction conditions. Chapter 4 explores the solvent extraction of nickel(II) and cobalt(II) by novel combinations of neutral nitrogen-donor heterocyclic ligands with organic acids, such as dinonylnaphthelenesulfonic acid (DNNSAH). The synthesis and characterisation of 2,6-bis(5-alkyl-1H-pyrazol-3-yl)-pyridine, 2-(5- alkyl-1H-pyrazol-3-yl)-pyridine and 5,5'-alkyl-3,3'-bi-1H-pyrazole (alkyl = tert-butyl or nonyl) and their nickel(II) complexes were reported. Also reported are synthesis and 6-N-alkyl-2-(2-pyridinyl)- benzothiazole (alkyl = n-butyl or n-decyl) and 2-(1-Isopropyl-benzimidazol-2-yl)-pyridine. The extraction of nickel(II) from highly acidic mixed metal aqueous sulfate solutions by some of these ligands was studied. These synergistic mixtures demonstrated remarkable strength and selectivity for nickel(II), and cobalt(II) over iron(II). XRD structures of nickel(II) complexes of 2,6-bis(5-tert-butyl- 1H-pyrazol-3-yl)-pyridine, 2-(5-tert-butyl-1H-pyrazol-3-yl)-pyridine and 5,5'-tert-butyl-3,3'-bi-1Hpyrazole with sulfonates or perchlorates as ion-pairs have intermolecular hydrogen bonding interactions between the inner-sphere ligands and the counterions.

Pyrazoles have been intensely studied in the design and synthesis of biologically active agents because they display considerable medicinal activities. Recent studies have shown that integration of a ferrocenyl unit with structural features of pyrazoles can result in the formation of the new products with enhanced or/and unexpected biological activity since several ferrocene derivatives have already been illustrated to be active against a number of tumors. Therefore, we have investigated the electrophilic cyclizations of the hydrazones to afford 5-ferrocenyl-4-((4-nitrophenyl)sulfenyl)-substituted pyrazole derivatives. First, the requisite hydrazone derivatives were synthesized by the reactions of ferrocenyl propargyl aldehydes or ketones with a series of hydrazines. Then electrophilic cyclizations of these hydrazones were investigated by treating with 4-(nitrophenyl)sulfenyl chloride as electrophile. By employing these electrophilic cyclizations, a series of 5-ferrocenyl-4-((4-nitrophenyl)sulfenyl)-1H-pyrazoles, 5-ferrocenyl-4-((4-nitrophenyl) sulfenyl)-3-methyl-1H-pyrazoles and 5-ferrocenyl-4-((4-nitrophenyl)sulfenyl)-3-phenyl-1H-pyrazoles have been synthesized in moderate to good yields.

Die vorliegende Arbeit thematisiert Eisen(II)-Komplexe mit Spinübergangseigenschaften. Dafür wurden neue hexadentate Liganden auf Basis von N,N'-Bis(2,2'-bipyridin-6-ylmethyl)-2,2'-biphenylendiamin entwickelt. Die in Kapitel 3.1 vorgestellten Systeme variieren dabei in den jeweiligen Substituenten der 6,6‘-Positionen der Biphenyleinheit. Es wird der Einfluss dieser Gruppen auf die magnetischen Eigenschaften der resultierenden Komplexe gezeigt. Im darauffolgenden Kapitel 3.2 wird ein variiertes Ligandensystem vorgestellt, in welchem anstelle einfacher Substituenten Donorfunktionen eingeführt wurden, sodass ein symmetrischer dinuklearer Eisen(II)-Komplex zugänglich war. In diesem sind die beiden Spin Crossover (SCO) Zentren erstmalig durch eine Biphenyleinheit verbrückt. Die durchgeführten Untersuchungen geben Hinweise auf eine allostere Wechselwirkung. Weiterhin wurde der Ligand durch N-Methylierung in ein tertiäres Amin überführt und die entsprechenden Komplexe mit Fe(II), Co(II) und Zn(II) synthetisiert (Kapitel 3.3). Diese wurden strukturell und elektrochemisch untersucht und hinsichtlich ihrer Redoxeigenschaften und Magnetismus mit den Komplexen der sekundären Amine verglichen. Ebenfalls wurde das Grundgerüst des auf sekundären Aminen basierenden Liganden so variiert, dass der terminale Donor durch stickstoffhaltige Fünfringheterocyclen – anstelle von Pyridin – verkörpert wurde (Kapitel 3.4). So konnten Eisen(II)-SCO Komplexe erhalten werden, welche eine wesentlich niedrigere Übergangstemperatur aufwiesen und somit magnetische Untersuchungen im Festkörper sowie des Photomagnetismus ermöglichten. Schließlich wurden neue tridentate Amine (2-(6-R-Pyridin-2-yl)-1,10-phenanthrolin) und deren Eisen(II)-Komplexe synthetisiert (Kapitel 3.5). Für einige dieser Komplexe konnte bereits das Spin Crossover Verhalten in Lösung untersucht werden
The present thesis addresses iron(II) complexes with spin transition properties. For this purpose new hexadentate ligands were developed on the basis of N,N’-bis(2,2’-bipyridine-6-ylmethyl)-2,2’-biphenylenediamine. The systems introduced in chapter 3.1 vary in respect to the substituents in the 6,6’-positions of the biphenyl unit. The influence of these varying moieties on the magnetic behavior of the resulting complexes is shown. In the following chapter 3.2 a tuned ligand system is introduced, in which the substituents are donor functions so that a symmetrical dinuclear iron(II) complex was feasible. In this the two Spin Crossover (SCO) centers are for the first time connected by a biphenyl core. The executed experiments give hints to an allosteric interaction in this dinuclear compound. Moreover the ligand was reacted by N-methylation yielding a tertiary amine and the corresponding complexes with Fe(II), Co(II) and Zn(II) were synthesized (chapter 3.3). Those were investigated structurally and electrochemically and were then compared with the complexes with secondary amines in respect to their redox and magnetic properties. The ligand motif based on secondary amines was also modified in a way that the terminal donor was represented by nitrogen based five-ring heterocycles instead of pyridine (chapter 3.4). So iron(II) SCO complexes were available which showed much lower thermal transition temperatures and thus magnetic investigations in the solid state as well as investigations on the photomagnetic properties became possible. Ultimately, novel tridentate amines (2-(6-R-pyridine-2-yl)-1,10-phenanthroline) and the corresponding iron(II) complexes were synthesized (chapter 3.5). For some of those complexes the spin transition could already be monitored in solution

The main objective of this project is to synthesize the first family of polynuclear chromium pyrazolate complexes. Complexity in analysis of the experimental magnetic data of multinuclear complexes arises from their (2S +1)N microstates, where S is the spin of each metal center and N is the number of metal centers. For example, high-spin (HS)-FeIII3 has 216 microstates and HS-FeIII8 ≈ 1.7x106 microstates (S= 5/2). However, complexes with chromium(III) S = 3/2 will have a noticeable reduction of microstates. Mononuclear complexes with formula [mer-CrCl3(pzH*)3] (pz*H = pyrazole, 3-Me-pzH, 4-Me-pzH, 4-Cl-pzH, 4-I-pzH, 4-Br-pzH) and [trans-CrCl2(pzH*)4]Cl (pzH* = pyrazole and 3-Me-pzH) were synthesized and thoroughly characterized. Polynuclear iron pyrazolate complexes are prepared by the addition of base to [mer-FeCl3(pzH*)3] and [trans-FeCl2(pzH*)4]Cl complexes; the path is not paralleled by mononuclear chromium(III) pyrazole complexes. There is a challenging situation with these reactions, caused by the attainment of equilibrium, where the stable mononuclear complexes and traces of dinuclear species coexist in solution. Microwave assisted reaction of Cr(NO3)3·9H2O and pyrazole ligand in dimethylformamide (DMF) solution afforded redox inactive trinuclear formate-pyrazolate mixed-ligand complexes with formula [Cr3(μ3-O)(μ-O2CH)3(μ-4-R-pz)3(DMF)3]+ (pz = pyrazolate anion; R= H, Me, Cl). Thermally assisted synthesis with non-hydrolysable solvent yielded an electrochemically active all-pyrazolate complex. Complex with formula (Ph4P)2[Cr3(μ3-O)(μ-4-Cl-pz)6Cl3] and (Ph4P)2[Cr3(μ3-O)(μ-4-Cl-pz)6Br3] have an oxidation process at 0.502 V at 0.332 V, respectively. The latter has a second accessed oxidation process at 0.584 V. These systems are the first example of electrochemically amendable trinuclear pyrazolate complex with {Cr3O} core. The all-ferric complexes [Fe3(μ3-O)(μ-4-NO2-pz)6(L)3]2- (L = NCO-, N3) were synthesized from reaction of [Fe3(μ3-O)(μ-4-NO2-pz)6Cl3]2- with NaNCO and NaN3. Expected reversible reduction processes were observed for both complexes at more negative potential, -0.70 V, compared to the thiocyanate complex (-0.36 V). The 57Fe Mössbauer of the reduced [Fe3(μ3-O)(μ-4-NO2-pz)6(N3)3]3- is suggestive of a HS-to-LS electronic reorganization, as seen for the [Fe3(μ3-O)(μ-4-NO2-pz)6(SCN)3]3- complex. Furthermore, compound [Fe3(μ3-O)(μ-4-NO2-pz)6(N3)3]2-, shows a unique reversible oxidation process at 0.82 V (vs. Fc+/Fc) to a mixed-valent, formally Fe3+2/Fe4+ species.

Le Diabète est une affection due à une déficience des mécanismes de régulation de la glycémie, dont la fréquence a augmentée de façon régulière et significative au sein des pays riches occidentaux durant les trente dernières années. Les hypoglycémiants de synthèse sont employés dans le cadre du traitement du Diabète non insulino-dépendant. Afin de synthétiser de nouvelles molécules hypoglycémiantes, des méthodologies de fonctionnalisation du 1H-pyrazole-4-carboxylate d'éthyle ont été développées à partir des 3 et 5 aminopyrazole-4-carboxylate d'éthyle. Dans un premier temps les positions 3 et 5 ont été halogénées par diazotation ou substitution électrophile. Les halogénopyrazoles obtenus ont permit d'accéder à divers pyrazoles tétrasubstitués par métallation, couplage ou SNar. Dans un deuxième temps des pontages N1-C5, C3-C4, C4-C5 ont conduit à de nouveaux hétérocycles polycondensés tel que les thiéno[2,3c]pyrazoles ou les 4-thia-1,8a-diaza-azulènes obtenus par métathèse.

Pyrazoles have been focus of a large number of investigations in the design and synthesis of novel biologically active agents that show remarkable medicinal activities. Although pyrazoles have been studied for over a century as an important class of heterocyclic compounds, they still continue to attract considerable attention due to the wide range of medicinal activities they possess. Recent studies have shown that combination of a ferrocenyl unit with structural features of pyrazoles can lead to products with enhanced or/and unexpected biological activity since several ferrocene derivatives have already been shown to be active against a number of tumors. As a result, we have investigated the reaction of 3-ferrocenylpropynal with hydrazinium salts. As anticipated, these reactions afforded two kinds of pyrazoles, namely 1-alkyl/aryl-5-ferrocenylpyrazoles (1,5-isomer) and 1-alkyl/aryl-3- ferrocenylpyrazoles (1,3-isomer). In most cases, 1,5-pyrazole isomers have resulted from these reactions as the single or the major product of the reactions. The structures of 1-benzyl-5-ferrocenylpyrazole, 1-phenyl-5-ferrocenyl-pyrazole and 1- (2-hydroxy-ethyl)-3-ferrocenylpyrazole were identified by X-ray single crystal analysis. The analogous reactions between 3-phenylpropynal and hydrazinium salts were also studied, which afforded 1-alkyl/aryl-5-phenylpyrazoles (1,5-isomer) and/or v 1-alkyl/aryl-3-phenylpyrazoles (1,3-isomer). The regioselectivity of the reactions is mainly governed by the nature of the substituents in hydrazine derivative.

Pyrazoles constitute one of the most important classes of heterocyclic compounds due to their interesting chemical and biochemical features. Researchers have studied many pyrazole containing structures for almost over a century in order to investigate the various biological activities possessed by these molecules. A new and important trend in these studies is to produce ferrocenyl substituted pyrazoles since ferrocene attracts considerable interest in the research field of organometallic and bioorganometallic chemistry because of its valuable chemical characteristics like high stability, low toxicity and enhanced redox properties. Moreover, the results of the studies focusing on ferrocenyl compounds have been quite promising. Therefore, the scope of this project involves the combination of the essential structural features of pyrazoles with a ferrocene moiety, which could provide new derivatives with enhanced biological activities. In the course of the project the synthesis of new pyrazole derivatives was performed through Sonogashira and Suzuki-Miyaura cross-coupling reactions of 5-ferrocenyl-4-iodo-1-phenyl-1H-pyrazole with terminal alkynes and boronic acids respectively in the presence of a catalytic amount of PdCl2(PPh3)2. Although Sonogashira and Suzuki-Miyaura coupling reactions are well known in literature, they were not studied in much detail with multi-substituted pyrazoles. This also revealed the requirement of the reinvestigation of the reactions and improvement of the yields of pyrazoles by optimizing the reaction conditions.