Multiple Roles of Isocyanides in Palladium‐Catalyzed Imidoylative Couplings: A Mechanistic Study

Abstract

Kinetic, spectroscopic and computational studies examining a palladium-catalyzed imidoylative coupling highlight the dual role of isocyanides as both substrates and ligands for this class of transformations. The synthesis of secondary amides from aryl halides and water is presented as a case study. The kinetics of the oxidative addition of ArI with RNC-ligated Pd species have been studied and the resulting imidoyl complex [(ArC=NR)Pd(CNR) I] (Ar=4-F-C H , R=tBu) has been isolated and characterized by X-ray diffraction. The unprecedented ability of this RNC-ligated imidoyl-Pd complex to undergo reductive elimination at room temperature to give the amide in the presence of water and an F /HF buffer is demonstrated. Its behavior in solution has also been characterized, revealing an unexpected strong tendency to give cationic complexes, and notably [(ArC=NR)Pd(CNR) ] with excess isocyanide and [(ArC=NR)Pd(PP^ )(CNR)] with bidentate phosphines (PP^ ). These species may be responsible for catalyst deactivation and side-reactions. Ab initio calculations performed at the DFT level allowed us to rationalize the multiple roles of RNC in the different steps of the catalytic cycle.

Silver Nitrate-Catalyzed Isocyanide Insertion/Lactamization Sequence to Imidazolones and Quinazolin-4-ones: Development and Application in Natural Product Synthesis

“…Metal-catalyzed isocyanide insertion reactions have attracted much recent attention, and a variety of heterocycles are now readily accessible by careful engineering of the substrate structure. − As part of our research program aimed at exploiting the diverse reactivities of the isocyano group, we recently reported metal triflate-catalyzed domino processes initiated by the insertion of isocyanide into the N–H bond of amines . We document herein the synthesis of 3,5,5-trisubstituted imidazolones 1 and quinazolin-4-ones 2 by silver nitrate-catalyzed reactions of primary amines with methyl α-isocyanoacetates and 2-isocyanobenzoates, respectively (eq 2, Scheme ).…”

Cooperative Pd/Cu Catalysis: Multicomponent Synthesis of Tetrasubstituted Imidazolones from Methyl α-Isocyanoacetates, Primary Amines, and Aryl(vinyl) Iodides

“…Metal-catalyzed domino processes initiated by isocyanide insertion reaction has recently been developed into a powerful tool for the rapid construction of heterocycles. − In connection with our research program aimed at exploiting the diverse reactivities of the isocyano group, we reported a silver nitrate-catalyzed synthesis of the 3,5,5-trisubstituted imidazolones 1 from methyl α-isocyanoacetates 3 and primary amines 4 . As a continuation of this research topic, we describe herein a three-component synthesis of 2,3,5,5-tetrasubstituted imidazolones 2 by a Pd/Cu-catalyzed reaction of methyl α,α-disubstituted α-isocyanoacetates 3 with primary amines 4 and aryl­(vinyl) halides 5 (Scheme c).…”

Recent Advances in Palladium-Catalyzed Isocyanide Insertions

“…Recent studies in the field of isocyanide insertions are directed towards further development of these imidoylative Buchwald-Hartwig type cross-couplings. To facilitate this, over the past couple of years there have been multiple reports on the mechanistic aspects of these reactions, allowing chemists to easier predict catalytic behavior and develop more effective catalysts [40][41][42].…”