Direct Synthesis of Annulated Indoles through Palladium-Catalyzed Double Alkylations

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Yadong Gao, Jianhua Li, Songlin Bai, Daoquan Tu, Zhiwen Ye, Bingcheng Hu, Xiangbing Qi,* and Chao Jiang*

          A facile, one-step synthesis of annulated indoles from (N-H) indoles and dibromoalkanes was developed through a palladium-catalyzed double alkylations process. The reaction undergoes a palladium-catalyzed norbornene-mediated C2-alkylation of indoles and subsequent regioselective cyclization. The reaction is compatible with various indole substituents, as well as a range of simple and functionalized dibromoalkyl reagents. The detailed reaction mechanism was investigated by key intermediate experiments, NMR spectroscopic analyses, and DFT calculations. The results of a preliminary mechanistic study show a catalytic cycle consists of initial C2-alkylation of indoles that is followed by N-alkylation or palladium promoted intramolecular C3-nucleophilic substitution to yield, respectively, [a]- or [b]-annulated indoles.