Insertion of Isocyanides into N-Si Bonds: Multicomponent Reactions with Azines Leading to Potent Antiparasitic Compounds

23 Jul 2016
Kishore KG, Ghashghaei O, Estarellas C, Mestre MM, Monturiol C, Kielland N, Kelly JM, Francisco AF, Jayawardhana S, Muñoz-Torrero D, Pérez B, Luque FJ, Gámez-Montaño R, Lavilla R.

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.

azines; isocyanides; multicomponent reactions; silicon; trypanosomiasis