Selective N-Alkylation of Indoles with α,β-Unsaturated Compounds Catalyzed by a Monomeric Phosphate

Catalytic N-alkylation of indoles is challenging because the N1 nitrogen atoms are inert toward electrophilic reagents. Herein, an organic-solvent-soluble alkylammonium salt of a simple monomeric phosphate ion, [PO4](3-), with a high charge density acts as an efficient homogeneous catalyst for selective N-alkylation of indoles with alpha,beta-unsaturated compounds. For the reaction of indole with ethyl acrylate, the turnover number reached up to 36 and the turnover frequency was 216 h(-1); these values are the highest among those reported for base-mediated systems so far. In the presence of [PO4](3-) ions, various combinations of nitrogen nucleophiles (ten examples) and alpha,beta-unsaturated compounds (four examples) were efficiently converted to the desired N-alkylated products in high yields. NMR and IR spectroscopies showed formation of the indolyl anion through the activation of indole by the [PO4](3-) ion, which plays an important role in the present N-alkylation.