Development of Catalytic Isocyanation via Precise Reactivity Control of Ambident Reagent

Isonitrile(R-NC)is a regioisomer of the corresponding nitrile(R-CN), whose C-terminus has carbene like property. Isonitriles have been deeply investigated from the viewpoint of their use. In contrast to the usability, the synthesis of isonitriles themselves are not sufficiently studied. In this manuscript, we describe our findings on catalytic nucleophilic isocyanation using cyanide with precise control of the ambident reactivity. We successfully demonstrated Pd-catalyzed allylic isocyanation. A wide variety of allylic isonitriles were obtained by this method, in high yield with good linear selectivity. Allylic nitriles were not observed at all, which were the possible side products in the reaction. Even though the reaction is the Pd-catalyzed allylic substitution, no π -allyl Pd (II)intermediate is involved in the catalytic cycle. Pd salt, such as Pd (OAc)2 and Pd (CN)2, was just the precursor of catalytic active species. It was reversibly converted into the ate complex,(Me3Si [)Pd-(CN)3], with excess amount of trimethylsilyl cyanide(Me3SiCN). The ate complex plays dual roles: 1)The Me3Si group activates phosphate leaving group on the allylation electrophile. 2)The [Pd (CN)3]- part reacts as the nucleophile with its N-terminus because the strong interaction between Pd center and C-terminus of cyanide suppresses the C-nucleophilicity. Benzylic isocyanation was successfully catalyzed by Ag2O. Both primary and secondary benzylic isonitriles were obtained in high yield. Pd-catalyzed synthesis of α -aryl-α -isocyanoacetamide derivative was also demonstrated. This catalytic procedure was appropriate to the sequential transformation into the trisubstituted oxazole without isolation of the isonitrile intermediate. Mechanistic investigations revealed that the nucleophilic isocyanation proceeded through a SN1-type substitution predominantly. © 2023 Society of Synthetic Organic Chemistry. All rights reserved.