Recyclable Cu-Catalyzed N-Methylation and C5-Methylthiomethylation of Isatins with DMSO

An unprecedented recyclable system of copper-catalyzed C-C/N coupling of isatins and DMSO without any oxidant and acidic/basic additive has been unlocked. The NH-isatins occur tandem N-methylation and C5-methylthiomethylation in order, while N-substituted isatins proceed C5-methylthiomethylation only. DMSO serves as Me and MeSCH₂ sources as well as the solvent. DCE is essential for providing a radical initiator and halogen cation pool. In this protocol, two vital ionic liquids (ILs), reactive methyl(methylene)-sulfonium and inert trimethylsulfonium, are generated in situ to promote homogeneous-to-heterogeneous phase transition. The ILs accumulate in the lower layer to drag the copper catalyst but push the product, enabling separating the catalyst and product through simple decantation. The lower layer can be recycled as a catalyst for at least six cycles. The systematic and comprehensive control experiments, ESI-MS, and DFT calculations indicate that site selectivity is controlled by atomic charge distribution and steric factors; and the interaction between ILs and Cu salts can reduce the reaction energy barrier.