A palladium-catalyzed three-component cascade process for the synthesis of isoindolone and phthalazone derivatives is reported. The cascade process involves carbonylation of an aryl iodide/Michael acceptor to give an acylpalladium species which is intercepted by a hydrazine nucleophile. Intramolecular Michael addition follows to give either N-aminoisoindolones or mono- N- and di-N,N'-phthalazones depending on whether a monosubstituted or 1,2-disubstituted hydrazine nucleophile is used.
The use of Pd(DPEPhos)Cl (P26) as a catalyst for the formation of benzonitriles and their heterocyclic analogues provides excellent complementarity to existing catalysts, allowing highly electron-deficient heterocyclic aryl halides to be efficiently converted to the corresponding nitriles using K[Fe(CN)]) as cyanide source. This catalyst significantly enhances the scope of this reaction to include a number of substrates that are highly relevant for pharmaceutical and agrochemical applications. Importantly, not only does this cyanation method employ a nontoxic cyanide source, simple semiquantitative testing suggests that, unlike many other methods, no free cyanide is present in the reaction mixture or during a variety of potential workups, thus improving the safety aspects of this method from initial setup through to product isolation. Finally, developing and testing a series of convenient cyanation kits has allowed facile application and broader adoption of this method in our laboratories.
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