Gold versus Palladium: A Regioselective Cycloisomerization of Aromatic Enynes

International audienceAromatic enynes can be transformed into arylnaphthalenes or benzofulvenes depending on the reaction conditions. Under gold(I) catalysis, exclusive or major 6-endo-dig cyclization took place leading to arylnaphthalenes. However, a catalytic system based on palladium iodide/1,3-Bis(diphenylphosphino)propane, in the presence of cesium carbonate as a base was necessary to furnish exclusively 5-exo-dig cyclization pattern, regardless to the electronic effects of the substituents. In the latter transformation, a mechanistic study (Kinetic Isotopic Effect, Density Functional Theory) involving a C-H activation is suggested for the exclusive benzofulvenes formation

N-Tosylhydrazones : towards the synthesis of isocombretastatin A-4 analogues

Les travaux rapportés dans ce mémoire concernent le développement de la réactivité de N-tosylhydrazones dans la création de liaisons carbone-carbone et carbone-azote ainsi que leurs applications à la synthèse des analogues de l’isocombrétastatine A-4 (isoCA-4), aux propriétés antivasculaires.Au cours de ce travail, des molécules de type 1,1-diaryléthylène furent synthétisées par un couplage pallado-catalysé entre des N-tosylhydrazones et des aryles halogénés. Ainsi, des oléfines polysubstituées avec un motif alcoxyle, analogues de l’isoCA-4, ont présenté des activités biologiques intéressantes. De même, les N-tosylhydrazones constituent des intermédiaires pour la synthèse de 1,5-énynes aromatiques. La cyclisation de ces derniers a pu être contrôlée selon la nature du catalyseur utilisé. En effet, en présence de l’or comme catalyseur, une cyclisation 6-endo-dig majoritaire est obtenue alors qu’en présence du palladium, une cyclisation 5-exo-dig exclusive est observée. Cette méthode permettrait de synthétiser des analogues contraints de l’isoCA-4. Le couplage réducteur, catalysé au cuivre, entre des N-tosylhydrazones et des amines et conduisant à des motifs arylalkylamines fut développé. Enfin, un processus cascade entre des 2’-halogéno-biaryl- N-tosylhydrazones et des amines fournit des dérivés du fluorène par la création d’une liaison CN et d’une liaison CC sur le même atome carbénique.This manuscript reports the development of new metal-catalyzed reactions using N-tosylhydrazones as coupling partners for the creation of carbon-carbon and carbon-nitrogen bonds. These reactions are applied in the synthesis of analogues of isocombretastatine A-4 (isoCA-4), a vascular disrupting agent.First, a palladium-catalyzed cross-coupling reaction between N-tosylhydrazones and aryl halides was developed. By this means, polysubstituted olefins with an alkoxy motif were synthesized and presented good biological activities. Then, aromatic 1,5-enynes were synthesized by a multi-step approach using N-tosylhydrazones as intermediates. The regioselectivity of the cyclisation of these enynes was controlled depending on the reaction conditions. Under gold catalysis, a major 6-endo-dig cyclisation pattern leads to naphthalene derivatives while under palladium catalysis; an exclusive 5-exo-dig cyclisation furnishes benzofulvène derivatives. Conformationnally restricted isoCA-4 analogues could be synthesized by applying this method. A copper-catalyzed reductive coupling between N-tosylhydrazones and amines leading to -branched amine derivatives was also developed. Finally, a cascade reaction between 2’-halo-biaryl-N-tosylhydrazones and amines furnished fluoren scaffold by the formation of CC and CN bonds on the same carbenic atom

Direct Alkynylation of 3<i>H</i>‑Imidazo[4,5‑<i>b</i>]pyridines Using <i>gem</i>-Dibromoalkenes as Alkynes Source

C2 direct alkynylation of 3<i>H</i>-imidazo­[4,5-<i>b</i>]­pyridine derivatives is explored for the first time. Stable and readily available 1,1-dibromo-1-alkenes, electrophilic alkyne precursors, are used as coupling partners. The simple reaction conditions include an inexpensive copper catalyst (CuBr·SMe₂ or Cu­(OAc)₂), a phosphine ligand (DPEphos) and a base (LiO<i>t</i>Bu) in 1,4-dioxane at 120 °C. This C–H alkynylation method revealed to be compatible with a variety of substitutions on both coupling partners: heteroarenes and <i>gem</i>-dibromoalkenes. This protocol allows the straightforward synthesis of various 2-alkynyl-3<i>H</i>-imidazo­[4,5-<i>b</i>]­pyridines, a valuable scaffold in drug design

Copper-Catalyzed Coupling of N-Tosylhydrazones with Amines: Synthesis of Fluorene Derivatives

International audienceAn original formation of one C-N bond and one C-C bond on the same carbenic center has been developed. This approach involves a copper-catalyzed cross-coupling reaction between 2’-bromo-biaryl-N-tosylhydrazones and different amines leading to 9H-fluoren-9-amine derivatives. This reaction proceeds under mild conditions in glycerol, an inexpensive and environmentally friendly solvent without adding any external ligand

Design, synthesis, biological evaluation and cellular imaging of imidazo[4,5-b]pyridine derivatives as potent and selective TAM inhibitors

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Synthesis, biological evaluation, and structure–activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors

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