Copper-Catalyzed Site-Selective Oxidative C-C Bond Cleavage of Simple Ketones for the Synthesis of Anilides and Paracetamol

Abstract

A copper-catalyzed approach for the N-acylation of anilines with acetone and acetophenones via C-C bond cleavage is described. Under the developed conditions both CHCl3 and CH2Cl2 were identified as potential C1-source to promote the transformation. The reaction features a site selective C-C bond cleavage to install the amide moieties with high functional-group compatibility and wide substrate scope. The developed method avoids the use of sensitive and narcotic agents. The method also represents an excellent complement to the previous protocols with lower E-factor (13.91 mg/1 mg) than current industrially used method (E-factor 17.54 mg/1 mg). The developed approach has also been extended for the effective preparation of pyridine derivatives and paracetamol in gram scale. The course of the reaction was monitored by H-1 NMR as a preliminary investigation of the reaction mechanism.