Activated dimethyl sulfoxide can donate the sulfur atom in thiophene ring formation, replacing malodorous P₂S₅, Lawesson’s reagent, or elemental sulfur. It now serves as both solvent and sulfur donor for the heterocycle classes found in drugs and organic electronics. Classical thiophene syntheses carry a sulfur-related environmental cost, and DMSO offers a lower-odor, water-miscible alternative that simplifies aqueous workup.
R2C=O + CH2(CN)2 + (CH3)2SObase, activator (POCl3 / metal cat.)→2-aminothiophene (S from DMSO) + (CH3)2S + H2O
Reaction 1: Gewald-type thiophene synthesis with DMSO as sulfur donor
Where Thiophenes Built from DMSO End Up
The thiophene ring appears in marketed drugs including clopidogrel, pioglitazone, raloxifene, and tienilic acid, and in conjugated polymers and small molecules used for OLEDs and organic field-effect transistors. DMSO-based sulfur delivery reaches the same scaffolds without phosphorus- or elemental-sulfur reagents.
Gewald-type 2-aminothiophenes are assembled from ketones and malononitrile with DMSO as the sulfur component. Benzothiophenes and thiophene-fused indoles such as thieno[2,3-b]indoles, valued as fluorescent and electronic materials, are constructed in the same DMSO-based annulations, and Willgerodt–Kindler thioamide syntheses also exploit it as a sulfur donor.
In these systems the sulfoxide oxygen is removed and the sulfur atom transferred to an organic framework. When DMSO is activated by electrophiles such as POCl₃ or oxalyl chloride, reactive chlorodimethylsulfonium species form; copper, palladium, and iron catalysis also mediates C–S bond formation using DMSO as the sulfur source, enabling benzothiophene construction from aryl alkynes or aryl ketones.
Product Classes vs. Traditional Sulfur Reagents
DMSO doubles as solvent and sulfur donor, which changes how the process is handled versus a dedicated sulfur reagent.
| Feature | Traditional (P₂S₅ / S₈ / Lawesson’s) | DMSO as sulfur source |
|---|---|---|
| Physical form | Solid, often odorous | Low-odor liquid, water-miscible |
| Role | Dedicated sulfur reagent | Solvent plus sulfur donor |
| Workup | Phosphorus / sulfur waste | Aqueous dilution; DMS byproduct |
| Target products | Industrial thiophene APIs | Thiophene drugs, OLED materials |
Table 1: Traditional thiophene sulfur sources vs. DMSO-mediated transfer
Why DMSO Rather Than P₂S₅ or Elemental Sulfur
DMSO is an abundant, inexpensive, water-miscible liquid that doubles as the reaction medium, so switching from S₈ or P₂S₅ removes the characteristic odor and simplifies isolation by direct aqueous quenching. It also opens new disconnections that avoid preloaded thiolation reagents in the first place.
The approach is attractive where odorous or phosphorus-containing waste must be minimized, and it is growing as substrate scope expands. Detailed ³⁴S-DMSO labeling studies have confirmed that the thiophene sulfur originates from the sulfoxide rather than trace elemental sulfur impurities, which is the kind of mechanistic evidence needed before a route can be trusted on scale. For functionalized, complex substrates the reported procedures still use a DMSO excess and generate dimethyl sulfide, so route choice depends on the product’s impurity and waste tolerances.
References
- Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber., 1966, 99(1), 94–100.
- Recent Advances in DMSO-Based Direct Synthesis of Heterocycles (review). Molecules, 2022, 27(23), 8480.