Cycloaddition Reactions of Thioketone Derivatives

Thioketones possess a highly polarised carbon–sulfur double bond that renders them exceptionally reactive in cycloaddition processes. These C=S functional groups serve both as potent dipolarophiles in [3+2] cycloadditions, yielding thiadiazoline, thiirane or dithiolane frameworks via thiocarbonyl ylides or stepwise diradical routes, and as super-dienophiles in [4+2] hetero-Diels–Alder reactions, forging thiopyran and related ring systems with high periselectivity. Modulation of substrate architecture, including aromatic or ferrocenyl substitution, imposition of steric hindrance and electronic tuning with fluorinated moieties, directs both chemo- and stereoselectivity. Advances in electrocyclisation strategies further enable stereodefined synthesis of cis-thiiranes from transient thiocarbonyl ylides under mild conditions. Together, these methods have delivered a versatile toolkit for constructing sulfur-rich heterocycles with applications spanning medicinal chemistry, agrochemicals, polymer materials and electronic devices. Ongoing mechanistic studies, underpinned by DFT calculations, continue to elucidate the balance between concerted and stepwise pathways, the influence of heavy-atom stabilisation and the thermodynamic versus kinetic control of product distributions.

Research from Nature Portfolio

Recent studies have established a general stereoselective route to cis-thiiranes via 4π-electrocyclisation of transient thiocarbonyl ylides generated in situ from readily available aldazine N-oxides and thio reagents. This protocol affords a broad range of cis-1,2-diarylthiiranes as essentially single diastereomers in high yields under mild conditions. Mechanistic experiments confirm the intermediacy of trans-thiocarbonyl ylides, while computational analyses provide insight into the stereocontrol and concerted nature of the ring-closure step. The method stands out for its operational simplicity and potential to access sulphur-containing three-membered rings that have proven elusive by conventional routes.

Cycloaddition Reactions of Thioketone Derivatives publication trend

The graph below shows the total number of articles in cycloaddition reactions of thioketone derivatives across all publications each year (not limited to Nature Index journals).

Technical terms

Thioketone: An organic compound featuring a carbon–sulfur double bond (C=S) analogous to a ketone (C=O).

Cycloaddition: A pericyclic reaction in which two or more unsaturated molecules (or parts of the same molecule) join to form a cyclic adduct.

Thiocarbonyl ylide: A 1,3-dipolar intermediate with charge separation between carbon and sulfur used in [3+2] cycloadditions.

Hetero-Diels–Alder reaction: A [4+2] cycloaddition between a conjugated diene and a heteroatom-containing dienophile.

Electrocyclisation: A pericyclic ring-closure process driven by the redistribution of conjugated electrons.

References

1. Synthesis of cis-thiiranes as diastereoselective access to epoxide congeners via 4π-electrocyclization of thiocarbonyl ylides. Nature Communications (2022).
2. Novel Bicyclic P,S-Heterocycles via Stereoselective hetero-Diels–Alder Reactions of Thiochalcones with 1-Phenyl-4H-phosphinin-4-one 1-Oxide †. Molecules (2024).
3. Synthesis of Fluorinated and Fluoroalkylated Heterocycles Containing at Least One Sulfur Atom via Cycloaddition Reactions †. Materials (2022).
4. Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies †. Molecules (2021).
5. Diradical reaction mechanisms in [3 + 2]-cycloadditions of hetaryl thioketones with alkyl- or trimethylsilyl-substituted diazomethanes. Beilstein Journal of Organic Chemistry (2016).
6. Synthesis of ferrocenyl-substituted 1,3-dithiolanes via [3 + 2]-cycloadditions of ferrocenyl hetaryl thioketones with thiocarbonyl S-methanides. Beilstein Journal of Organic Chemistry (2016).