One-Pot Mechanochemical Synthesis of Mono- and Bis-Indolylquinones via Solvent-Free Multiple Bond-Forming Processes

Bis-indolylquinones are fungal natural products endowed with interesting pharmacological properties. Most of the previously described methodologies in solution for the construction of the bis-indolylquinone framework show disadvantages associated with long reaction times and difficult, waste-generating purifications. A one-pot mechanochemical methodology for the synthesis of indolylquinones was developed, starting from indoles and dihaloquinones in the presence of FeCl₃ or p-TsOH as catalysts and Fetizon's reagent as an oxidant. In contrast to solution chemistry, mechanochemical activation allowed the double addition of indole to a quinone substrate in one pot, leading to symmetrical or non-symmetrical bis-indolylquinones via a domino processes comprising up to six steps. In terms of sustainability, the method has several advantages over the solution protocol, including much shorter reaction times, no external heating, one-pot operation, and the absence of chromatography, leading to a drastically better performance in green metrics and demonstrating the application of several principles of green chemistry, in particular principles 2, 3, and 5.