Activated dimethyl sulfoxide can donate a methylene, methyl, carbonyl, or methylthio unit into a new bond, replacing formaldehyde, carbon monoxide, or toxic methylating agents in modern synthesis. It is now a practical C1 building block for heterocycle and specialty chemical manufacture. Because DMSO is inexpensive, abundant, and of relatively low toxicity, this approach offers a greener alternative to more hazardous one-carbon reagents.
2-H2N–C6H4–CONH2 + (CH3)2SOactivator (PIFA / I2 / Cu), heat→quinazolin-4(3H)-one + (CH3)2S + H2O
Reaction 1: DMSO as C1 source — C-2 carbon incorporation into quinazolinone ring
Where DMSO Is Used as a C1 Reagent
The Corey–Chaykovsky sulfoxonium route uses a DMSO-derived salt to transfer a methylene onto aldehydes and ketones, producing epoxides and glycidyl ethers used in epoxy and pharmaceutical intermediates. The same ylide adds methylene across α,β-unsaturated carbonyls to form cyclopropanes.
In N-heterocycle synthesis, activated DMSO supplies the C-2 carbon of quinazolin-4(3H)-ones and a ring carbon of quinolines, classes that feed oncology and antibacterial APIs. It also serves as the methyl donor in C–H methylation and as the source of the methylthio (–SCH₃) group in thioethers and methylthiomethyl (MTM) esters and ethers.
The transfer proceeds by activation of DMSO at sulfur, generating an electrophilic sulfonium or sulfoxonium intermediate. Reported activation routes use hypervalent iodine reagents such as PIFA or PIDA, copper and oxidant systems, strong oxidants, or Brønsted and Lewis acids. Either the substrate attacks this activated species, or a single-electron-transfer event generates a methyl radical that adds to the substrate; in both cases the S–C bond is cleaved and the carbon fragment is incorporated into the product while sulfur exits as dimethyl sulfide or a related byproduct.
Product Classes and Transferable Units
Each transferable unit from activated DMSO maps to a recognizable product family rather than an isolated laboratory transformation.
| C1 Unit Donated | Product Class Built | Representative End Use |
|---|---|---|
| Methylene (CH₂) | Epoxides, cyclopropanes | Glycidyl ethers, steroid epoxides |
| Methyl (CH₃) | Quinolines, quinazolinones | Antibacterial / oncology intermediates |
| Carbonyl (C=O) | Carbonylated rings | Formaldehyde / CO surrogate routes |
| Methylthio (–SCH₃) | Thioethers, MTM derivatives | Specialty and protected intermediates |
Table 1: Product classes that draw a C1 unit from activated DMSO
Why Choose DMSO Over Traditional C1 Sources
DMSO is an abundant, low-toxicity liquid produced on a large scale, and it doubles as the reaction solvent, cutting auxiliary solvent use. Replacing stoichiometric formaldehyde, pressurized carbon monoxide, or diazomethane with DMSO simplifies handling and reduces noxious-reagent inventory on plant sites.
Deuterated DMSO (DMSO-d₆) additionally serves as a deuterated methyl source for isotope-labeled compounds used in metabolic and ADME studies. The same molecule that dissolves a substrate can become the carbon atom in the product, which is what makes it attractive versus dedicated, often more hazardous C1 reagents.
References
- Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc., 1965, 87(6), 1353–1364.
- Recent Advances in DMSO-Based Direct Synthesis of Heterocycles (review). Molecules, 2022, 27(23), 8480.