Theoretical investigation of gold(I)-catalyzed intramolecular SEAr in isoxazole derivatives: Mechanisms, origin of regioselectivity, and role of hydrogen acceptor

Abstract

A detailed theoretical study on the mechanism and regioselectivity of the Au(I)-catalyzed intramolecular electrophilic aromatic substitution (SEAr) in 4-substituted isoxazole derivatives is reported, using two model substrates, 4-(1-methylpropargyloxy)isoxazole (Series A) and 4-(1-methyl propargylamino)isoxazole (Series B). The obtained theoretical data reveal similar energy profiles in both series for the 6-endo-dig heteroatom-assisted SEAr to form an alkenyl Au(I) intermediate. Then, in the series A, the 1,3-H-shift assisted by the 4-propargyloxyisoxazole leads to a final product and the catalyst regeneration. In contrast, in the series B, the elimination of proton by N-phenylbenzaldimine additive results in an iminium cation and dihydropyridine. In the next step, a hydride from dihydropyridine is accepted by the iminium cation to furnish pyridinium and N-benzylidenebenzenaminium species. Subsequently, protodeauration leads to a final product and N-phenylbenzylamine along with the catalyst regeneration. In the absence of N-phenylbenzaldimine additive, 4-(1-methylpropargylamino)isoxazole accepts the hydride instead of N-phenylbenzylamine and causes the consumption of the reactants, thus accounting for a low product yield. Furthermore, the regioselectivity and its origin as well as the rationalization of the deuterium labeling experiments are also examined and discussed in detail.