Insertion of Isocyanides into N-Si Bonds: Multicomponent Reactions with Azines Leading to Potent Antiparasitic Compounds.
Kishore, Kranti G;
Ghashghaei, Ouldouz;
Estarellas, Carolina;
Mestre, M Mar;
Monturiol, Cristina;
Kielland, Nicola;
Kelly, John M;
Francisco, Amanda Fortes;
Jayawardhana, Shiromani;
Muñoz-Torrero, Diego;
+4 more...Pérez, Belén;
Luque, F Javier;
Gámez-Montaño, Rocío;
Lavilla, Rodolfo;
(2016)
Insertion of Isocyanides into N-Si Bonds: Multicomponent Reactions with Azines Leading to Potent Antiparasitic Compounds.
Angewandte Chemie (International ed in English), 55 (31).
pp. 8994-8998.
ISSN 1433-7851
DOI: https://doi.org/10.1002/anie.201604109
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Trimethylsilyl chloride is an efficient activating agent for azines in isocyanide-based reactions, which then proceed through a key insertion of the isocyanide into a N-Si bond. The reaction is initiated by N activation of the azine, followed by nucleophilic attack of an isocyanide in a Reissert-type process. Finally, a second equivalent of the same or a different isocyanide inserts into the N-Si bond leading to the final adduct. The use of distinct nucleophiles leads to a variety of α-substituted dihydroazines after a selective cascade process. Based on computational studies, a mechanistic hypothesis for the course of these reactions was proposed. The resulting products exhibit significant activity against Trypanosoma brucei and T. cruzi, featuring favorable drug-like properties and safety profiles.