Cascade C─H‐Alkenylation‐Intramolecular Aminative Cyclization of Benzylsulfonamides for Synthesis of Isoindoline Cores

One-step isoindoline synthesis from benzylamines with (SO₂(3-Npy)) as a directing group was achieved using Pd(OAc)₂ as a catalyst, Ag(I) as an additive, and Cu(II)-salt as an oxidant. Pd-assisted as well as alternative Pd-─Ag bimetallic catalytic pathways were investigated through DFT studies to provide mechanistic insights.

Abstract

Several isoindoline-core-bearing compounds are pharmaceutically relevant due to their activity against a myriad of diseases. Traditionally, the isoindoline core is synthesized from benzylamines by two-step synthesis involving ortho-C─H alkenylation followed by acid- or metal-catalyzed cyclization. In this study, we execute a direct synthesis of the isoindoline core by a one-step procedure involving the ortho-C─H alkenylation-oxidative followed by intramolecular aminative cyclization of pyridinesulfonamide derivatives of benzylamines with different acrylates and vinyl sulfones using Pd(II)-salt as catalyst, Ag(I)-salt as additive, and Cu(II)-salt as oxidant. The reactions are tolerant of several functional groups on the benzylamine as well as different alkyl groups on the acrylates, providing the isoindoline products with moderate to excellent yields. Control experiments and computational studies revealed the importance of the pyridine-3-sulfonamide for the reaction since it provides a key intramolecular site for stabilizing an intermediate species which favors the C─H activation and oxidative amination-based cyclization process.

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