Title : Regioselective and Atom Economical Metal Free C-5 Chalcogenation of 8-Aminoquinolines under Mild Conditions
A novel and simple transition metal-free protocol for expedient C–H functionalization leading exclusively to the regioselective generation of C-5 chalcogenated 8-aminoquinoline analogues in up to 90% yield at room temperature (25 °C) has been demonstrated. This methodology is a direct and eco-friendly approach to the atom-economical utilization of diaryl/dialkyl chalcogenides for highly efficient access to chalcogenated quinolines and is scalable to the gram scale without significant decrease in the yield of the product. It represents a practical alternative to all other existing metal-catalyzed functionalization of 8-aminoquinoline derivatives with broad functional group tolerance. The successful implementation of this protocol is reflected through the conversion of diversified group of 24 substrates to respective regioselective C-5 chalcogenated products in good to excellent yields. The reaction was found equally efficient in gram scale and no significant reduction in the yield was observed. The controlled experiments based on radical quenching with 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) and butylated hydroxytoluene (BHT) couldn’t reduce the yield of product while no additional compound was determined in the reaction mixture. Furthermore, no difference was detected in the rate of reaction during the study of kinetic isotope effect which reveals that the cleavage of C5-H bond is not involved in rate determining step. Both observations collectively indicates that the reaction possibly proceeds through an ionic SNAr reaction pathway at room temperature.
Furthermore, the potentiality for the functionalization of free amines in chalcogenated-8-aminoquinolines provides an attractive perspective for further elaboration of the amine substituent through chemical manipulations. The applicability of the standardized method has been augmented through late-stage antimalarial drug derivatization of primaquine analogues.