Isocyanides have been utilized in several synthetic routes as reactive building blocks. Classical Passerini/Ugi multicomponent reactions provided the useful strategy for the construction of functionalized amides, and further transformations widen the utility of those reactions. In addition, introduction of transition-metal catalysis in isocyanide chemistry has led enormous development of isocyanide-based syntheses. Combination of Pd-based catalytic system with isocyanide insertion chemistry could produce various types of imine-related products, and direct binding of metal catalyst toward the terminal carbon of isocyanide further enhances the electrophilicity, so that facile addition of various nucleophiles was possible. Despite the well-defined activation strategies for isocyanide, there have been only limited examples for the use of relatively inert coupling partners, such as unactivated proton sources or unsaturated systems, because of the weak nucleophilicity (basicity) of the isocyanide itself.<br/><br/>To widen the scope of utility of isocyanide, we proposed a nucleophilic activation strategy to further enhance the reactivity of isocyanide. Especially, we focused on the utilization of N-heterocyclic carbene (NHC), which has been widely applied in nucleophilic organocatalysis. Based on the previous literatures on the interaction between NHC and isocyanide, we designed the involvement of an imidoyl intermediate, which can act as an activated form of isocyanide. With this strategy, we successfully synthesized enaminones directly from isocyanides and ketones in high efficiency. Various types of ketones and aryl isocyanides were able to participate in the developed reaction, affording di-/tri-substituted enaminones. Control experiments clearly suggested involvement of carbene in catalytic cycle, and proton-transfer reaction is necessary to generate activated species for further transformations.

Organocatalytic activation of isocyanides: N-heterocyclic carbene-catalyzed enaminone synthesis

253rd National Meeting (2017)

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