A Novel Cu(II)-Iodine Catalyzed Hantzsch Type Synthesis of 2-Aminothiazole Derivatives

Abstract

Heterocycles having nitrogen and sulphur atoms attract chief attention due to their importance in diverse fields, especially in medicinal chemistry and pharmaceutical industry. Among those, 2-aminothiazole, one of the most flexible and pervasive heterocyclic scaffolds found in many natural and synthetic products, exhibits a wide variety of biological activities. A one-pot method for the synthesis of 2-aminothiazoles through Cu(II)-iodine-catalyzed Hantzsch condensation has been achieved for the first time. This novel green methodology facilitates the formation of a broad range of 2-aminothiazole derivatives utilizing catalytic quantities of Cu(II) salts and iodine, incorporating various methyl aryl ketones and thiourea as substrates. This novel strategy involves a Hantzsch-type condensation between thiourea and in situ generated α-iodoketones, formed from the reaction of methyl aryl ketones and iodine. The present protocol reveals PEG-400 as the best solvent, which furnishes moderate to good yields of the desired 2-aminothiazole derivatives. The addition of a catalytic quantity of copper acetate ensures the continuous availability of iodine for several catalytic cycles, as copper(II) allows the oxidation of iodide to iodine. The feasibility of this novel route is studied with electron-withdrawing, electron-donating, and halo-substituted derivatives of methyl aryl ketones with thiourea to confirm the functional group compatibility of the reaction. Moreover, this efficient strategy evades the direct use of noxious and lachrymatory α–halocarbonyls as reaction substrates and strong oxidants. Using a catalytic quantity of iodine in the reaction makes the separation of the desired products much easier by reducing the amount of unwanted side-products than utilizing a stoichiometric amount of iodine.