Synthesis of Isoquinolines Through Isochromenylium Intermediates Captured by Nitriles and a CO‐to‐CN Switch

Isochromenylium ions have emerged as versatile intermediates for the rapid construction of molecular complexity through cascade reactions. However, their application in catalytic annulation processes with nitriles to form isoquinolines remains largely unexplored, despite the prevalence of nitrile motifs and isoquinoline frameworks in bioactive molecules and functional materials. Here we report a catalytic cascade strategy for the efficient synthesis of isoquinolines, including enantioenriched variants, from readily available substrates. The reaction includes palladium‐catalyzed cyclization of ortho‐ alkynylaryl aldehydes to generate an isochromenylium palladium species, which is captured by indium‐promoted 1,2‐addition of nitriles. Subsequent water‐assisted ring opening furnishes a Zincke‐type intermediate, followed by intramolecular condensation to deliver the isoquinoline products. This cascade process achieves a net conversion of a carbonyl (CO) unit into a nitrile‐derived carbon‐nitrogen (CN) linkage at an intermediate‐stage in a single operation. Notably, the use of malononitrile‐tethered substrates enables the synthesis of enantioenriched isoquinolines with high enantioselectivity. Mechanistic studies indicate a cooperative role of palladium and indium in promoting the 1,2‐addition of isochromenylium palladium species to the nitrile. The method exhibits excellent atom economy, good functional group tolerance, and scalability, highlighting its potential application for heterocycle synthesis.