A Novel High-Yield Synthesis of Substituted Isoindolequinones

The high-yield, general, one-pot synthesis of substituted isoindolequinones, a group of important radiosensitizers which sensitize hypoxic cells to the lethal effect of radiation in cancer radiotherapy, is described. Primary amines react with 2,3-bis[2-(trimethylsilyl)ethynyl]-5,6-dimethylhydroquinone (2) in methanol at room temperature under an inert atmosphere to give substituted isoindolequinones 2-alkyl-1,3,5,6-tetramethylisoindole-4,7-quinone (4) in almost quantitative yields. Moderate yields of 4 are also obtained using 2,3-diethynyl-5,6-dimethylhydroquinone (3) and amines as reactant and solvent under the similar conditions. Tris(2-aminoethyl)amine (TREN) reacts with 2 in MeOH/THF on reflux to produce the isoindolequinone derivative of TREN. Water with 2 on reflux in MeOH forms an isobenzofuranquinone. This indicates that the formation of similar heterocycles from small molecules (e.g., Group VA and VIA hydrides) and 2 is likely. Readily synthesizable starting materials, ease of chromatographic isolation of the product, reaction generality, use of no catalyst, and cost-effective environmentally benign solvents such as MeOH/EtOH make this novel reaction simple and convenient.