Zorba Leandros P, Stylianakis Ioannis, Tsoureas Nikolaos, Kolocouris Antonios, Vougioukalakis Georgios C
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis, 15771 Athens, Greece.
Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, 15771 Athens, Greece.
J Org Chem. 2024 Jun 7;89(11):7727-7740. doi: 10.1021/acs.joc.4c00394. Epub 2024 May 9.
The synthesis of thiazolines, thiazolidines, and thiazolidinones has been extensively studied, due to their biological activity related to neurodegenerative diseases, such as Parkinson's and Alzheimer's, as well as their antiparasitic and antihypertensive properties. The closely related thiazolidin-2-imines have been studied less, and efficient strategies for synthesizing them, mainly based on the reaction of propargylamines with isothiocyanates, have been explored less. The use of one-pot approaches, providing modular, straightforward, and sustainable access to these compounds, has also received very little attention. Herein, we report a novel, one-pot, multicomponent, copper-catalyzed reaction among primary amines, ketones, terminal alkynes, and isothiocyanates, toward thiazolidin-2-imines bearing quaternary carbon centers on the five-membered ring, in good to excellent yields. Density functional theory calculations, combined with experimental mechanistic findings, suggest that the copper(I)-catalyzed reaction between the -formed propargylamines and isothiocyanates proceeds with a lower energy barrier in the pathway leading to the S-cyclized product, compared to that of the N-cyclized one, toward the chemo- and regioselective formation of 5-exo-dig S-cyclized thiazolidin-2-imines.
由于噻唑啉、噻唑烷和噻唑烷酮与神经退行性疾病（如帕金森病和阿尔茨海默病）相关的生物活性，以及它们的抗寄生虫和抗高血压特性，对其合成进行了广泛研究。与之密切相关的噻唑烷-2-亚胺研究较少，且主要基于炔丙胺与异硫氰酸酯反应来合成它们的有效策略也探索较少。使用一锅法途径为这些化合物提供模块化、直接且可持续的合成方法也很少受到关注。在此，我们报道了一种新颖的、一锅多组分、铜催化的伯胺、酮、端炔和异硫氰酸酯之间的反应，用于合成在五元环上带有季碳中心的噻唑烷-2-亚胺，产率良好至优异。密度泛函理论计算与实验机理研究结果相结合表明，与N-环化产物相比，在导致S-环化产物的途径中，所形成的炔丙胺与异硫氰酸酯之间的铜（I）催化反应具有较低的能垒，从而实现5-外向-环化S-环化噻唑烷-2-亚胺的化学和区域选择性形成。
