Palladium-Catalyzed Cascade Heck/C–H Activation for Divergent Synthesis of Functionalized Pyrrolo[2,1- a ]isoquinolinones via Alkyne or Aryne Insertion

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Isoquinoline-containing polycyclic skeletons are ubiquitous in bioactive compounds. Introduced in this paper is Pd-catalyzed cascade Heck/C–H activation/cyclative insertion reactions to construct fused pyrroloisoquinolinones. Intramolecular Heck reaction of alkene- and aryl halide-tethered pyrrolidines affords C–H activated palladacycles which undergo [4 + 2] insertion with alkyne or aryne to afford the title products. Pd(PPh3)4/Cs2CO3 was employed for ethyl arylpropiolate insertion, and Pd(OAc)2/PPh3/CsF for insertion of arynes generated in situ from silyl aryl triflates. This cascade protocol has a broad substrate scope and can be performed on a gram scale. Control reactions demonstrate that electron-rich alkynes favor insertion into palladacycles. Naphthalene-derived substrates undergo exclusive premature reductive elimination, preventing the seven-membered ring formation.