Sulfur-Enhanced Synthesis of Thioamides and Heterocycles

The integration of elemental sulfur into organic synthesis has transformed the preparation of thioamides and diverse heterocycles. Thioamides, where the amide oxygen is replaced by sulfur, exhibit distinctive electronic and steric properties that enhance their stability and bioactivity. Advances in mild thioacylation strategies now allow direct conversion of amines to thioamides under ambient conditions, obviating harsh reagents and elevated temperatures. Meanwhile, novel annulation protocols have enabled one-pot construction of thiazoles, benzothiazoles and related frameworks via multicomponent reactions of amines, carbonyl compounds and sulfur. Such methodologies leverage radical or ionic pathways to forge C–S and C–N bonds sequentially, often with high regio- and chemoselectivity. These developments have broadened the synthetic toolkit for pharmaceuticals, materials science and agrochemicals, underscoring the global significance of sustainable sulfur chemistry.

Research from Nature Portfolio

Recent studies have demonstrated a direct thioacylation of nitroalkanes with amines in the presence of elemental sulfur and a sulfide source to deliver a wide spectrum of thioamides in high yield and with complete retention of stereochemical integrity. This approach has proven effective for late-stage functionalisation of peptides and complex bioactive molecules, enabling site-specific installation of thioamide bonds without epimerisation. Separately, a transition-metal-free strategy has been devised to generate α-ketothioester reagents from α-hydroxy ketones, sulfur and alkyl halides. These reagents act as versatile 1,2-dicarbonyl forming agents, facilitating mild dicarbonylation of amines and cross-coupling with boronate esters to construct multifunctional targets, including natural products and therapeutic agents.

Sulfur-Enhanced Synthesis of Thioamides and Heterocycles publication trend

The graph below shows the total number of articles in sulfur-enhanced synthesis of thioamides and heterocycles across all publications each year (not limited to Nature Index journals).

Technical terms

Thioamide: An amide in which the carbonyl oxygen is replaced by a sulfur atom, altering electronic and steric properties.

Thionation: A chemical transformation that introduces sulfur into an organic molecule, often replacing oxygen atoms.

Heterocycle: A cyclic organic compound containing atoms of at least two different elements, typically carbon and sulfur or nitrogen.

Elemental sulfur: The most stable allotrope of sulfur, used as a sustainable sulfur source in synthesis.

Thioacylation: The process of converting an amine into a thioamide via introduction of a thioacyl functional group.

References

1. Nitroalkanes as thioacyl equivalents to access thioamides and thiopeptides. Nature Communications (2023).
2. Design and application of α-ketothioesters as 1,2-dicarbonyl-forming reagents. Nature Communications (2019).
3. Towards Symmetric Thioamides: Microwave-Aided Synthesis of Terephthalic Acid Derivatives. Pharmaceuticals (2023).
4. Towards More Practical Methods for the Chemical Synthesis of Thioamides Using Sulfuration Agents: A Decade Update. Molecules (2023).
5. An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides. Beilstein Journal of Organic Chemistry (2023).