Ynamide-Mediated Thioamide and Primary Thioamide Syntheses

Environmentally friendly ynamide-mediated thioamidation of monothiocarboxylic acids with amines or ammoniumhydroxide for the syntheses of thioamides and primary thioamides is described. Simple and mild reaction conditions enable thereaction to tolerate a wide variety of functional groups such as hydroxyl group, ester, tertiary amine, ketone, and amide moieties.Readily available NaSH served as the sulfur source, avoiding the use of toxic, expensive, and malodorous organic sulfur reagents andmaking this strategy environmentally friendly and practical. Importantly, the stereochemical integrity of alpha-chiral monothiocarboxylicacids was maintained during the activation step and subsequent aminolysis process, thus offering a racemization-free strategy forpeptide C-terminal modification. Furthermore, a number of thioamide-modified drugs were prepared in good yields by using thisprotocol and the synthesized primary thioamides were transformed into backbone thiazolyl modified peptides.

Automated summary

This study describes an environmentally friendly synthesis of thioamides and primary thioamides using a simple and mild reaction conditions and readily available NaSH as the sulfur source. The reaction can tolerate a wide range of functional groups and maintains the stereochemical integrity of alpha-chiral monothiocarboxylic acids, offering a racemization-free strategy for peptide C-terminal modification. Additionally, this method can be used to prepare thioamide-modified drugs and backbone thiazolyl modified peptides.