Direct Path to Bioactive Benzo[e]isoindoles

The isoindole structure (a benzene ring fused with pyrrole) is often found in natural products or pharmaceuticals, and isoindoles can have diverse biological activities. Specifically, benzo[e]isoindole-1,3,5-trione derivatives can inhibit glycogen synthase kinase 3β (GSK-3β), an enzyme that plays a role, e.g, in the treatment of bipolar disorder. New efficient methods for the synthesis of benzo[e]isoindole-1,3,5-triones could, thus, be useful in drug development. Sulfoxonium ylides can be valuable tools in these reactions, acting as both coupling partners and traceless directing groups to ensure site selectivity.

Dattatraya H. Dethe, Indian Institute of Technology Kanpur, India, and colleagues have developed a reaction that provides straightforward access to benzo[e]isoindole-1,3,5-trione derivatives via a ruthenium-catalyzed, sulfoxonium ylide-directed C–H activation/[4+2] annulation cascade with maleimides (example product structure pictured). Maleimide units are also common in biologically active compounds. The team used [RuCl₂(p-cymene)]₂ as the catalyst together with AgSbF₆ in the presence of acetic acid, with trifluoroethanol as the solvent. The reactions were performed at 50 °C.

Under these conditions, the researchers prepared a range of benzo[e]isoindole-1,3,5-triones in high yields and with high selectivity for the [4+2]-annulated product. The team proposes a reaction mechanism in which the ruthenium complex and the silver salt form an active ruthenium complex and AgCl, followed by coordination to the sulfoxonium ylide and C–H activation. The resulting five-membered ruthenacycle reacts with the maleimide, forming a seven-membered ruthenacycle. An internal oxidation process, which eliminates the former sulfoxonium unit in the form of dimethylsulfoxide (DMSO), and a reductive elimination then give the desired carbon skeleton. Finally, a protodemetalation step releases the product. Overall, the reaction proceeds under mild conditions, is atom- and step-economical, and provides a direct route to useful benzo[e]isoindole-1,3,5-triones.