B. Luque, F. J. Gámez-Montaño, Rocío Lavilla
2019
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Abstract
Trimethylsilyl chloride is an efficient activating agent for azines in isocyanide-based reactions, involving a key insertion of the isocyanide into an N-Si bond. The reaction proceeds through Nactivation of the azine, followed by concomitant 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 nucleophilies leads to a variety of α-substituted dihydroazines after a selective cascade process. Computational studies and a unified mechanistic hypothesis account for the course of these reactions. The resulting products exhibit significant activity against Trypanosoma brucei and T. cruzi, featuring favourable drug-like and safety profiles. Isocyanides hold a central role in several chemistry-related fields. Their formal divalent character makes them ideal partners for multicomponent reactions (MCRs). However, their mild nucleophilicity, together with their affinity to metals, complicate the activation of many MCRs, often requiring harsh conditions. Transition metal-catalyzed isocyanide processes are synthetically useful, although complex, in part due to the metal coordination. In this context, the search for new facilitated MCR transformations is actively pursued, particularly those involving heterocycles, due to their relevance in biological/medicinal chemistry. As a testing ground for developing new activation modes, we selected isocyanide variants of the Reissert MCR. In this way, the interaction of isoquinoline with chloroformates or similar reagents, and isocyanides gives the MCR-adduct 2, following the typical mechanism of N-activation and isocyanide attack at its α-position (Scheme 1A). However, interaction with trifluoroacetic anhydride, a stronger electrophilic agent, gives rise to mesoionic acid fluorides 3 (Scheme 1B). Interestingly, strong Brønsted acid activation (TfOH, pTosOH) of isoquinoline, allowed an ABB’ reaction with isocyanides (Scheme 1C), leading to isoquinoline-fused imidazolium salts. The latter reactions were productive, but mechanistic and selectivity issues remain unsolved. Furthermore, the drastic conditions required in these MCRs prevent applications to sensitive substrates.