Mechanism and Origins of Product Selectivity of Au‐Catalyzed Coupling Benzisoxazoles with Ynamides: A Computational Study

Abstract

Au(I)-catalyzed coupling of benzisoxazoles and ynamides was recently reported to synthesize challenging indoloquinoline core structures. In this report, we employed DFT methods to elucidate the mechanistic details of this reaction. The results reveal that the catalytic cycle involves initial coupling of ynamide with benzisoxazole, simultaneous ring opening of the isoxazole unit and attack of the dimethoxybenzene (DMOB) unit to gold carbenoid, proton transfer from the DMOB group to hydroxyl group, thioether migration, ring closure, and proton transfer. The experimentally observed ligand-controlled product selectivity is reproduced well by the calculations. The product selectivity-determining step is the ring opening of the isoxazole unit. The flexible P(t-Bu) 2 (o-biphenyl) ligand facilitates the approach of the DMOB group to gold carbenoid, which brings about significant CÀ H/π interactions in the transition state for ring opening, and thus leads to the indoloquinoline product. The rigid 1,3-bis(diisopropylphenyl)imidazol-2-ylidene ligand prefers keeping the DMOB group away from the gold carbenoid, which can cause strong orbital interaction in the transition state for ring opening, and thus results in indole product.

Transition Metal‐Mediated Functionalization of Isoxazoles: A Review

“…Ramana and co‐workers utilized 1,2‐benzo[d]isoxazoles for effective trapping of α‐oxo gold carbenes (generated from 2‐alkynylnitrobenzenes) with a Au(I) catalyst leading to the formation of functionalized quinazoline 1‐oxide [113b] . In 2021, Li and co‐workers studied mechanism and origin of product selectivity of Au‐catalyzed coupling benzisoxazoles with ynamides by carrying out detailed DFT studies and they observed ligand controlled product selectivity by the calculations [114a] …”