Metal-catalyzed synthesis and functionalization of 2-methoxy-6H-benzo[b]indeno[1,2-d]thiophen-6-one tetracyclic scaffold

2-Methoxy-6H-benzo[b]indeno[1,2-d]thiophene-6-one 1 has been shown to be a potent inhibitor of DYRK1A and related kinases, for which it represents a promising scaffold for the development of chemical/fluorescent probes. To increase its potential for functionalization, we investigated the regioselective modification of positions 1, 9, and 10 of the tetracyclic core. At position 1, the halogenation conditions allowed us to obtain brominated and iodinated derivatives, which were successfully used in Sonogashira cross-coupling reactions with different types of alkyne-bearing linkers, albeit in low yields. For positions 9 and 10, a palladium-catalyzed cascade reaction allowed for the direct introduction of alkene-bearing linkers’ reactive precursors, after the cyclization process. Moreover, additional studies were conducted on oxygen- and nitrogen-based precursors, adequate for further functionalization. Overall, these strategies enabled the introduction of reactive functions that could be exploited for the attachment of linkers, thereby opening new synthetic pathways for the design of chemical/fluorescent probes.