Ko Hoon Kim

Construction of a Tetracyclic Butterfly‐Like Scaffold: Palladium‐Catalyzed Heck/Arylation Cascade

Palladium-catalyzed domino reactions coupled with carefully designed substrates allow for rapid establishment of complex molecules. In particular, tandem carbon carbon bond formations through a palladium-catalyzed Heck/arylation cascade are important in that complex molecules can be directly constructed in a single operation. Interor intra-Heck reactions are the origin of a variety of domino reactions in which the key common feature is the formation, after the carbopalladation step, of a s-alkylpalladium(II) intermediate lacking a suitable b-hydrogen syn with respect to the palladium center. The s-alkylpalladium(II) intermediate undergoes various cascade processes such as another Heck reaction, alkyl C H activation, and aryl C H activation. As an example of intramolecular Heck/arylation cascade, Grigg and co-workers reported that an aryl halide bearing a carbon carbon multiple bond and an additional aryl group undergoes a bis-cyclization when treated with a palladium(0) catalyst. Although tremendous efforts have been invested in the Pd-catalyzed domino reactions, there remains limited overlap between two key transformations, intramolecular Heck reaction and arylation. Recently, we reported the synthesis of g-hydroxybutenolides from g-hydroxy ester which was prepared from the Baylis–Hillman adducts via an indium-mediated Barbier reaction. We established that this g-hydroxy ester could be used as an excellent substrate for the construction of indeno ACHTUNGTRENNUNG[2,1-a]indane scaffold when the aryl moiety has an ortho-Br substituent via the Pd-catalyzed Heck (carbopalladation)/aryl C H activation cascade (Scheme 1). We also imagined that the conformation of indeno ACHTUNGTRENNUNG[2,1-a]indane scaffold would resemble the butterfly-like conformation which is essential to many NNRTIs (Non-Nucleosides Reverse Transcriptase Inhibitors) including nevirapine; derivatives of this class could be developed as a new candidate for the treatment of HIV-1 (Scheme 1).