Functionalization of Indoles with 1,3,5-Triazinanes: Chemistry of Aminomethylation vs the Hofmann–Martius-Type Rearrangement

We have developed efficacious routes toward the selective synthesis of two classes of compounds such as C-3 amino-methylated indoles and 4-indol-3-yl-methylanilines from the same precursors, namely, indoles and 1,3,5-triazinanes. It is reported that the controlled cleavage of 1,3,5-triazinanes can be effected by heat for the generation of aryl imine motifs, and we observed that the presence of Lewis acid influences the course of these transformations toward different products. The reaction toward indol-3-yl-methylanilines proceeds via a nucleophilic attack of indole to the aryl imine generated from the 1,3,5-triazinanes to form an amino-methylated product which undergoes a Lewis acid mediated Hofmann–Martius-type rearrangement. In the absence of a Lewis acid, the reaction between indoles and 1,3,5-triazinane afforded C-3 amino-methylated indoles. Experimentally, we could prove that the amino-methylated product was the intermediate formed during the Lewis acid catalyzed synthesis of 4-indol-3-yl-methylanilines and that the process proceeds in an intermolecular fashion. The selective synthesis of both classes of compounds was found to be general, and a library of molecules was generated.