Thio-Mannich-Type Reactions for C-H Thioalkylation of Carbon Nucleophiles

<jats:p>Multicomponent condensation reactions provide fundamental driving force for both laboratory and industrial synthesis. Classical example such as Mannich reaction has significantly promoted the advances of modern organic synthesis toward numerous valuable target molecules and the designation of valuable new multicomponent reactions (MCRs). Yet, the condensation using a thiol nucleophile to replace the amine in Mannich reaction to react with aldehyde and conventional carbon nucleophiles such as methyl ketone or enone etc has not yet been achieved. The absence of such thio-Mannich-type reaction retards the synthesis and discovery of functional alkylthiolated molecules. Herein, by employing rongalite as the aldehyde source, the thio-Mannich-type reaction tolerating a plethora of typical carbon nucleophiles has been accomplished, enabling both diversity- and target-oriented synthesis of alkylthiolated compounds, including thioglycosides, biologically relevant lead compounds and alkylthio-functionalized natural products. Comprehensive studies on reaction mechanism have revealed that the key factor for the success of the titled reactions is the inhibition of rongalite to the oxidation of thiols to unreactive disulfides or decomposing disulfides to reactive thiols. The work represents fundamental breakthrough in MCRs development and will significantly facilitate the synthesis as well as application of organosulfur scaffolds.</jats:p>