Understanding the reaction mechanism of gold-catalyzed reactions of 2,1-benzisoxazoles with propiolates and ynamides

Abstract

The detailed reaction mechanisms of gold-catalyzed reactions of 2,1-benzisoxazoles with propiolates and ynamides have been investigated with the aid of density functional theory calculations. Our investigation focused on the different selectivities observed for the reactions of the two different classes of substituted alkynes. Through our systematic calculations, we found that the catalytic reactions start with a nucleophilic nitrogen atom attacking one coordinated alkyne carbon. Then, an N–O bond cleavage takes place to give two different gold carbenoid intermediates, from which four possible pathways lead to different products (7-acylindolyl derivatives and quinolone oxides). In the reaction of 2,1-benzisoxazole (anthranil) with the propiolate PhCCCOOMe, the relevant N–O bond cleavage leading to the 7-acylindolyl product is only slightly less favorable than that leading to the quinolone oxide product. The steps following the N–O bond cleavage are all very facile. Therefore, the N–O bond cleavage step is responsible for the selective outcome observed experimentally. In the reaction of 2,1-benzisoxazole (anthranil) with the ynamide PhCCNMeMs, the N–O bond cleavages leading to the 7-acylindolyl product and the quinolone oxide have comparable barriers. However, the C–N coupling that followed has a very high barrier, making the pathway leading to the quinolone oxide product unfavorable. As a result, only the 7-acylindolyl product is experimentally observed.