Atualmente, o núcleo imidazo[1,2-a]piridina vem atraindo considerável interesse pois está presente em uma série de moléculas que apresentam potencial para aplicações farmacêuticas. Entre suas características importantes, cabe ressaltar o isosterismo com o indol, um sistema heterocíclico encontrado em muitos alcaloides. Assim, o principal objetivo deste trabalho foi investigar o desenvolvimento de metodologias versáteis que permitissem a rápida preparação de imidazo[1,2-a]piridinas funcionalizadas e que possam ser aplicadas na síntese de moléculas bioativas. No Capítulo 1 deste trabalho, são apresentados e discutidos os resultados obtidos nos estudos sobre a reatividade de bases organometálicas, dentre as quais os novos reagentes mistos de magnésio e de lítio, frente às imidazo[1,2-a]pyridinas. De acordo com as condições reacionais estabelecidas, as bases LiHMDS e TMPMgCl.LiCl demonstraram melhores resultados nos estudos de metalação dirigida, proporcionando a preparação regiosseletiva de novos reagentes organometálicos a partir destes substratos. Além disso, após as reações do intermediários organometálicos com eletrófilos, várias imidazo[1,2-a]piridinas substituídas com diferentes grupos funcionais puderam ser isoladas e caracterizadas. Com o objetivo de demonstrar a importância sintética da metodologia de funcionalização de imidazo[1,2-a]piridinas mediada por LiHDMS, investigou-se sua aplicação em uma nova rota de síntese do alpidem, um importante ansiolítico. Finalmente, no Capitulo 2 deste trabalho, são apresentados e discutidos os resultados de um estudo de Ressonância Magnética Nuclear Dinâmica do 4-formil-aminoantipirina (4-FAA), um dos principais metabólitos da dipirona (metamizol). / Nowadays, the imidazo[1,2-a]pyridine core has attracted considerable interest considering it is present in a series of molecules which have potential for pharmaceutical applications. Among its important properties, it is worth noting the isosterism with indole, a heterocyclic system found in many alkaloids. Thus, the main goal of this work was to investigate the development of versatile methodologies that allow the quickly preparation of functionalized imidazo[1,2-a]pyridines for further applications in the synthesis of bioactive molecules. In Chapter 1 of this work, the results obtained in the studies about the reactivity of organometallic bases against imidazo[1,2-a] pyridines, including new mixed reagents magnesium and lithium, are presented and discussed. According to the established reaction conditions, LiHMDS and TMPMgCl.LiCl bases showed better results in the studies of directed metalation, providing regioselective preparation of new organometallic reagents from these substrates. Moreover, after the reactions of the organometallic intermediate with electrophiles, many imidazo[1,2-a]pyridines substituted with different functional groups were isolated and characterized. In order to demonstrate the synthetic importance of methodology of functionalization imidazo[1,2-a]pyridines mediated by LiHDMS, it application in a new route of synthesis of anxiolytic alpidem was investigated. Finally, in Chapter 2 of this work the results of a study of Nuclear Magnetic Resonance Dynamics of 4-formyl-aminoantipyrine (4-FAA), one of the main metabolites of dipyrone (metamizol), are presented and discussed.

Les motifs imidazo[1,2-a]pyridines et imidazo[1,2-b]pyridazines sont des noyaux très étudiés par la communauté scientifique, notamment dans le domaine thérapeutique. Ceci s’explique en partie par les progrès récents réalisés dans le domaine de la métallocatalyse qui ont permis une fonctionnalisation plus simple de ces molécules. Cependant, les dérivés tricycliques de ces structures sont restés assez peu étudiés malgré le fait que certains de leurs isostères présentent des propriétés biologiques intéressantes. Les travaux de cette thèse ont porté sur deux projets distincts : -La synthèse d’imidazo[1,2-b]pyridazines présentant un troisième cycle diazoté entre les positions 7 et 8, dans le cadre d’un contrat conclu avec la société Sanofi-Aventis. Ces composés, totalement originaux, représentent un véritable défi chimique et leur synthèse a nécessité d’importants travaux de mise au point. Nous avons ainsi employé différentes méthodes de couplages métallocatalysés. -La synthèse d’imidazo[1,2-a]pyridines un troisième cycle pyridinique entre les positions 2 et 3. Ces molécules, peu décrites dans la littérature, n’ont fait l’objet d’aucune évaluation biologique. Dans le but de synthétiser efficacement une chimiothèque intéressante pour ces structures, j’ai développé une méthode d’hétérocyclisation qui nous permet d’obtenir en deux étapes, gràce à des produits de départ très accessible, une importante variété de tricycles. / The imidazo[1,2-a]pyridines and imidazo[1,2-b]pyridazines moeities are very studied by scientific community, specially in therapeutic field. This is mostly due to recent progress in metallocatalyzed couplings which allow easier functionnalization of these structures. However, the tricyclic derivatives of these compounds remained not very studied despite important biological properties of some of there isosters. This thesis is divided in two parts : -The synthesis of imidazo[1,2-b]pyridazines with a dinitrogenated third cycle between the positions 7 and 8 in collaboration with Sanofi-Aventis. These new compounds were a real chemical challenge and their synthesis required important works of development. We used various metallocatalyzed couplings methods. -The synthesis of imidazo[1,2-a]pyridines with a pyridinic cycle between the positions 2 and 3. These molecules, poorly described in the literature, have never been subject to biological study. In order to effectively synthesize an interesting range of these structures, I have developed a new heterocyclization method which allows us to obtain in two steps, starting from commercialy available starting materials, some original tricyclics compounds.

Les préparations de composés comportant un noyau imidazo[1,2-a]pyridinique constituent un thème de recherche important en synthèse organique, compte tenu des nombreuses activités biologiques qu’ils peuvent présenter. Dans la première partie, nous nous sommes concentrés sur le développement de nouvelles stratégies rapides et efficaces basées sur l’utilisation de cuivre et de fer pour fonctionnaliser la position 6 du cycle imidazo[1,2-a]pyridine avec diverses amines et divers thiols. Ensuite, nous avons appliqué avec succès cette procédure pour la préparation de thioéthers symétriques et dissymétriques en utilisant le 2-mercaptobenzooxasole, réactif économique qui ne présente aucun risque chimique. Dans le dernier volet de ce travail, nous nous sommes intéressés au développement de nouvelles réactions multicomposants en vue de synthétiser divers pyrrolo[3',2':4,5]imidazo[1,2-a]pyridines et 5-aminopyrido[2’,1’:2,3]imidazo[4,5-c]isoquinoléines. / The preparations of imidazo[1,2-a]pyridine is one of important research topic in organic synthesis, This entitie present some interesting biological activities. First, we devoleped a new rapid and efficient strategies to functionalize position 6 of the imidazo[1,2-a]pyridine with various amines and thiols catalysed by copper and iron. Then we applied this procedure to the preparation of symmetric and asymmetric thioethers using 2 mercaptobenzooxasole, which is an economical reagent and which presents no chemical risk. The last part of this work concerns the development of new multicomponent reactions for the synthesis of various pyrrolo[3',2':4,5]imidazo[1,2-a]pyridine and 5-amino pyrido[2’,1’:2,3] imidazo [4,5-c]isoquinoléines.