Cu(i)-catalyzed dearomatizing cascade of thiazoles using two molecules of an α-aryl-α-diazoester: a novel approach for the synthesis of densely substituted 4-thiazolines

Abstract

A novel copper(I)-catalyzed cascade reaction has been devised for the functionalization of thiazoles, which employs two molar equivalents of an α-aryl-α-diazoester. This synthetic strategy, which utilizes CuPF₆(MeCN)₄ as the catalyst, facilitates the efficient conversion of thiazoles into highly functionalized 4-thiazolines under benign conditions. The generality of the reaction has been extensively probed, revealing its utility in transforming various thiazoles and α-aryl-α-diazoesters into their corresponding 4-thiazolines. An analytical platform centered on high-performance liquid chromatography has been established to elucidate the kinetics of this reaction. The kinetic data obtained suggest that the two-step functionalization process proceeds without the generation of isolable intermediates. Furthermore, the kinetic isotope effect measured at the C2 position of benzothiazole implies a β-secondary isotope effect. The proposed mechanism involves the formation of an N-heteroaromatic ylide, followed by a [1,2]-Stevens rearrangement and subsequent isomerization to a 4-thiazoline, which are posited as essential steps in the cascade reaction. This study offers a comprehensive insight into the copper(I)-catalyzed functionalization cascade of thiazoles, providing an efficient route for the preparation of densely functionalized 4-thiazolines from thiazoles directly.