Mannich N-Indolylmethylation of Amino Acids

Unprotected amino acids and simple peptides (2 examples) with free amino groups are N-indol-3-ylmethylated by a combination of paraformaldehyde or formalin and indole in aqueous ethanol at temperatures from 55–75 °C. Secondary amine incorporating amino acids and primary amine functionalized α-branched amino acids give rise to N-monoalkylation products, whereas unbranched primary amine functionalized amino acids and alanine give N,N-dialkylated products. The modified amino acids are amenable to amide coupling. Other electron-rich (hetero)aromatic cores besides indole (pyrrole, naphthol) are also selectively aminomethylated by amino acids and formaldehyde.