Sulfur Versus Nitrogen Chelation in C-H Activation: Cobalt(III)-Catalyzed Unsymmetrical Double Annulation of Thioamides

An unconventional cobalt(III)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o'-C-H bonds of aryl thioamides are involved in this reaction, enabling access to rare 6,6-fused thiopyrano-isoquinoline derivatives. A reverse ‘S’ coordination over more conventional ‘N’ coordination of thioamides to Co-catalyst specifically regulates the formation of four [C-C and C-S at first and then C-N and C-C] bonds in a single operation, a concept which is uncovered for the first time. The power of the N-masked methyl phenyl sulfoximine (MPS) directing group in this annulation sequence is established. The transformation is successfully developed, building a novel chemical space of structural diversity (56 examples). In addition, late-stage annulation of biologically relevant motifs and drug candidates are disclosed (17 examples). Preliminary photophysical properties of thiopyrano-isoquinoline derivatives are discussed. Density functional theory (DFT) studies authenticate the participation of a unique 6p-electrocyclization of a 7-membered S-chelated cobaltacycle in the annulation process.