C-H Activation: A Versatile Tool for the Synthesis of Niclosamide and Its Derivatives

A novel strategy has been developed for the direct and regioselective ortho -acetoxylation of N -(2-benzoylphenyl)benzamides through C-H activation using a catalytic amount of Pd(OAc)(2) (5 mol%) and a stoichiometric amount of PhI(OAc)(2) in a mixture of acetic anhydride and acetic acid. By using this protocol, a new series of niclosamide derivatives was produced in good yields. This is the first report on the synthesis of niclosamide and its derivatives by means of C-H functionalization. This newly developed method offers several advantages such as high regioselectivity, operational simplicity, and good to excellent yields. It provides a short three-step process for the synthesis of niclosamide involving acid-amine coupling, ortho -acetoxylation through C-H activation, and deacylation.