Monodentate transient directing group promoted Pd-catalyzed direct ortho-C‒H arylation and chlorination of α-ketoesters for three-step synthesis of Cloidogrel racemate

• Published in: Tetrahedron Vol. 123; p. 132980
• Main Authors: Wang, Jian, Wu, Yongdi, Xu, Wengang, Lu, Xuelian, Wang, Yunfang, Liu, Guangyuan, Sun, Bing, Zhou, Yirong, Zhang, Fang-Lin
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 24.09.2022
• Subjects: C–H activation; Palladium; Transient directing group; α-Ketoester; C–H activation; Palladium; α-Ketoester; Transient directing group
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2022.132980

An unprecedented direct ortho C–H arylation and chlorination of α-ketoesters were successfully accomplished by using a combination of monodentate transient directing group strategy and palladium catalysis. The in situ formed imine changed the bidentate coordination model of α-ketoesters to monodentate, so as to fulfill the ortho C–H activation. Importantly, the key binuclear cyclopalladium intermediate bridged by acetate anion was unambiguously characterized by X-ray diffraction, which solidly supports the proposed mechanism. The practical utility was further depicted as facile access to oral antiplatelet agent Clopidogrel racemate via subsequent two-step derivatization. [Display omitted]