Control over the Chemoselectivity of Pd‐Catalyzed Cyclization Reactions of (2‐Iodoanilino)carbonyl Compounds

Abstract

The factors that control the chemoselectivity of palladium-catalyzed cyclization reactions of (2-iodoanilino)carbonyl compounds have been explored by an extensive experimental computational (DFT) study. It was found that the selectivity of the process, that is, the formation of fused six- versus five-membered rings, can be controlled by the proper selection of the initial reactant, reaction conditions, and additives. Thus, esters or amides produce ketones by a nucleophilic addition process, whereas the addition of PhO(-) ions leads to the formation of indolines by an α-arylation reaction. In contrast, the corresponding ketone reactants yield a mixture of both reaction products, the ratio of which depends on the base used, in the presence of phenol. The outcome of the processes can be explained by the formation of a common four-membered palladacycle intermediate from which the competitive nucleophilic addition and α-arylation reactions occur. The remarkable effect of phenol in the process, which makes the α-arylation reaction easier, favored the formation of enol complexes, which are stabilized by an intramolecular hydrogen bond between the hydroxy group of the enol moiety and the oxygen atom of the phenoxy ligand. Moreover, the chemoselectivy of the process can be also controlled by the addition of bidendate ligands that lead to the almost exclusive formation of indoles at expenses of the corresponding alcohols.

Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups

“…Very extensive investigations with a variety of o -haloaniline derivatives as precursors have been reported by the group of Solé, Bonjoch and Fernández [ 22 – 23 ]. They also analyzed this reaction and the competing enolate arylation by computational studies [ 24 – 25 ] (for a review, see [ 26 ]). Singular contributions employing different systems were contributed by other groups [ 27 – 29 ].…”

Recent Progress in the Chemistry of Daphniphyllum Alkaloids

“…138 A 2012 paper reported a detailed mechanistic study of the Pd-catalyzed enolate arylation reaction. 139 A face-selective Luche reduction of the ketone functionality of 278 afforded borane complex 279. It was postulated that formation of the borane complex was necessary to create more steric crowding on the top face, thus favoring reduction of the exomethylene from the bottom face.…”