Density Functional Theory Rationalization of the Mechanism, Selectivity, and Role of Substituents in Au(I)-Catalyzed Synthesis of Pyrazolines and Dihydropyridines

J Org Chem. 2024 Dec 20;89(24):18209-18217. doi: 10.1021/acs.joc.4c02087. Epub 2024 Dec 5.

Abstract

A comprehensive theoretical investigation into the gold-catalyzed synthesis of polysubstituted pyrazolines and dihydropyridines from imines and methyl phenylpropiolate was conducted in this study. Three imines with distinct substituents were selected as model reactants. The computational outcomes reveal that four-membered intermediates generated from aza-enyne metathesis significantly affect the reaction selectivity. For nitrogen-centered NHCO2Me substituents (series A), an outward ring opening occurs during the metathesis of the aza-alkyne. This leads to the formation of Z-butadiene intermediates and ultimately to pyrazoline products. Conversely, with an aromatic substituent at the nitrogen site (series B and C), an inward ring opening takes place. This results in E-butadiene intermediates and the synthesis of dihydropyridine derivatives. The dihydropyridine product's configuration is determined by the aromatic ring's substituent. Electron-donating groups tend to directly form 1,4-dihydropyridine through a 6π electrocyclization (series B). In contrast, strong electron-withdrawing substituents initially undergo azayne metathesis, followed by 6π electrocyclization to produce 1,2-dihydropyridine products (series C). Furthermore, the distinctive selectivities were investigated in depth using global reactivity index and distortion/interaction methods. This research may contribute to the design of more effective and selective protocols to access pyrazolines, dihydropyridines, and related compounds.