Nouvelles réactions multicomposants et ouverture de cycles contraints pour la synthèse d’hétérocycles

Abstract : Multicomponent reactions (MCR) are a response to two big challenges faced by pharmaceutical chemistry : the discovery of new bioactive molecules and their production with reduced costs in a environmentally acceptable way. Indeed, by combining several reactants in one pot, MCR allow the synthesis of a wide diversity of complex molecules by simple and quick procedures, with good yields, and with limited amounts of reaction waste. In the framework of this thesis, we have developed new isocyanide-based multicomponent reactions, these compounds having an exceptionnaly rich reactivity.First, we were interested in the use of strong acids in the Ugi reaction. The first trials were made with sulfinic, sulfonic, phosphinic and phosphonic acids, and they failed. Nevertheless, thanks to the introduction of nitric acid as the acid component in the Ugi reaction, we described a one-pot synthesis of highly functionalized nitramines starting from an aldehyde, an isocyanide and an ammonium nitrate. This transformation is the first multicomponent reaction leading to a N-N bond formation.We also proposed a new variant for the Passerini reaction, involving thiocarbonyl derivatives. These compounds generally being quite unstable, we imagined a strategy in order to generate a thiocarbenium in situ from a 3-sulfanyl phthtalide, in the presence of titanium chloride. The coupling of this thiocarbenium with an isocyanide and a carboxylic acid leads to a divergent synthesis of two types of sulfur-containing heterocycles : thiophthalides and 3-amino-4-sulfanyl isocoumarines. This study represents the first formal approach of a Thio-Passerini reaction.Finally, as part of our continuing interest in in sulfur-containing derivatives, we described a new synthesis of thiovinylethers. These compounds, synthetically equivalent to thiocarbonyl derivatives, were obtained by the palladium-catalyzed ring opening of thiocyclopropanes.While the use of transition metals for constrained ring opening is well known for oxygen or nitrogen derivatives, this is the first reaction of this type for sulfur derivatives.Overall, we developed three original methodologies that give access to different types of functionalized compounds, potentially useful in pharmacy and agrochemistry. This work relies on the unique reactivity of isocyanides and adds on this especially rich chemistry.
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Aude Nyadanu. Nouvelles réactions multicomposants et ouverture de cycles contraints pour la synthèse d’hétérocycles. Chimie organique. Université Paris-Saclay, 2018. Français. ⟨NNT : 2018SACLX065⟩. ⟨tel-02012060⟩

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