Mixed Bases Mediated Synthesis Of Thioamides In Water

Thioamides are important sulfur-containing compounds,serving as significant intermediates in the construction of sulfur-containing heterocyclic compounds?such as thiazoles,thiazolines,thiazolones,and etc.?in organic synthetic chemistry.Thioamide motifs are also widely present in a large variety of biologically active compounds for pharmaceutical and agrochemical use.For instance,ethionamide?ETH?and prothionamide?PTH?are generally used as second-line drugs in tuberculosis treatment.Elesclomol has been proved to show anticancer activity by elevating oxidative stress and reactive oxygen species.Meanwhile,extensive researches have been made to apply thioamides as ligands in organic chemistry and fluorescence quenching probes in material chemistry.There are three traditional methods for synthesizing thioamide derivatives:?1?using amides and sulfur reagents?such as Lawesson's reagent or P₂S₅?,but Lawesson's reagent and P₂S₅ are sensitive to moisture and have obvious defects;?2?Willgerodt-Kindler reaction of thioamide derivatives with aldehyde?or ketone?,elemental sulfur and amine compounds as raw materials;?3?Friedel-Crafts thioacylation of aromatics and isothiocyanates.Most of those protocols require using organic solvents with high boiling points,resulting in great pollution and high cost.Therefore,exploring a green and sustainable method to synthesize thioamides has significant industrial value.This dissertation provides a novel method to synthesize thioamide derivatives involving mixed bases in water.We evaluated reaction parameters including substrate ratio,solvent,bases,reaction atmosphere,temperature,et al.Finally,the optimal reaction conditions for the synthesis of thioamide derivatives were determined.With aldehydes and N-substituted amides as the reaction substrate,elemental sulfur as the sulfur source,and water as the solvent,excellent reaction yields were reached by using mixed bases consisting of sodium carbonate and triethylamine.Twenty-nine different thioamide compounds were synthesized and characterized by melting point,¹H NMR,¹³C NMR,and low-resolution or high-resolution mass spectrometry.Through investigation of related literature,a possible reaction mechanism was proposed.Conclusively,a simple,efficient,and environmentally friendly method for the synthesis of thioamides has been developed.The product yield could reach as high as97%in gram-scale test,implying great potential in industrial application.