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

Abstract

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 FeCl 3 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.

Ball-Milling-Enabled Zn(OTf)2-Catalyzed Friedel–Crafts Hydroxyalkylation of Imidazo[1,2-a]pyridines and Indoles

“…The organic layer was separated and dried over an anhydrous Na 2 SO 4 , and finally concentrated under reduced pressure to get the crude. The resulting crude was washed with a mixture of diethyl ether and n-pentane and dried under vacuum to afford 2- (2-(4-chlorophenyl) (12). Washing by diethyl ether and n-pentane; off white solid; 16 mg (73%); mp = 170−172 °C; FT-IR v max (neat)/cm −1 : 3394, 1712, 1620, 1489, 1404, 1087, 985, 825, 756; 3, 143.6, 133.6, 132.8, 132.4, 131.8, 130.6, 129.2, 128.8, 126.8, 124.6, 119.7, 118.4, 64.7 Experimental Procedure H: Intermolecular Kinetic Isotope Effect (KIE).…”

“…11 The Meneńdez group developed a mechanochemical method for the synthesis of indolylquinones from indoles and dihaloquinones using FeCl 3 or p-TsOH as a catalyst and Fetizon's reagent as an oxidant. 12 high-speed ball-milling conditions. 13 Very recently, the Bolm group developed a mechanochemical iron(III)-catalyzed intramolecular amidation reaction for the synthesis of 3,4-dihydro-2(1H)-quinolinones from readily available dioxazolones.…”

Green metrics in Mechanochemistry

“…Menéndez et al proposed an original synthesis of mono-indolylquinones or bis-symmetrical and unsymmetrical indolylquinones by mechanochemistry. 142 Mono-indolylquinones 138 were prepared, by grinding indole 136 (1 equiv. ), 2,5-chloro-or 2,5-dibromoquinone 137 (1 equiv.…”

Exploring the In Situ Formation Mechanism of Polymeric Aluminum Chloride–Silica Gel Composites under Mechanical Grinding Conditions: As a High-Performance Nanocatalyst for the Synthesis of Xanthene and Pyrimidinone Compounds

“…Many research groups have contributed to the greening of both processes and achieved good results. − The mechanochemical synthesis of organic molecules offers the advantages of a simple operating technique, low energy consumption, decreased waste treatment, and ease of large-scale manufacturing. − Because mechanochemistry does not require the use of solvents in the reaction process, it has been hailed as one of the most promising technologies for green synthesis and catalysis. − While mechanochemistry often brings unexpected surprises to researchers in terms of results, the mechanism of catalysis in the process is still like a “black box” full of uncertainties. For this reason, it is important to investigate the reaction process in detail and to reveal the reaction mechanism. − …”