# Dithiane
**Dithiane** is the name for saturated six-membered heterocycles containing two sulfur atoms and four carbon atoms; the most important member is **1,3-dithiane** (C₄H₈S₂, CAS 505-23-7), a cyclic thioacetal of formaldehyde that serves in organic synthesis as a masked carbonyl group and, after deprotonation, as an acyl anion equivalent[1](https://webbook.nist.gov/cgi/cbook.cgi?ID=505-23-7). Three positional isomers exist, 1,2-, 1,3-, and 1,4-dithiane, but the 1,3-isomer and its derivatives, called 1,3-dithianes, dominate the chemistry because of their role in polarity-inverted (umpolung) carbonyl synthesis[2](https://chem.libretexts.org/Ancillary_Materials/Reference/Organic_Chemistry_Glossary/Dithiane).
| Key fact | Detail |
|---|---|
| Formula / mass | C₄H₈S₂, molecular weight 120.236; CAS Registry Number 505-23-7[1](https://webbook.nist.gov/cgi/cbook.cgi?ID=505-23-7) |
| Other names | m-Dithiane; 1,3-dithiacyclohexane; dithiane-1,3[1](https://webbook.nist.gov/cgi/cbook.cgi?ID=505-23-7) |
| Synthetic role | Cyclic thioacetal of formaldehyde; the 2-position can be deprotonated to give a 2-lithio-1,3-dithiane, an acyl anion equivalent[3](https://www.uwindsor.ca/people/jgreen/sites/uwindsor.ca.people.jgreen/files/tet-2003-59-6147-yus.pdf) |
| Origin of the method | Corey and Seebach described the use of dithianes to access acyl anion equivalents from aldehydes in the 1960s[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC8518712/) |
| Chiral variant | trans-1,3-Dithiane-1,3-dioxide acts as a chiral acyl anion equivalent for enantioselective synthesis of α-hydroxy acid derivatives[5](https://pubs.rsc.org/en/content/articlelanding/1994/c3/c39940001653) |
## Structure and properties
1,3-Dithiane is a six-membered ring in which sulfur atoms occupy the 1 and 3 positions. The NIST Chemistry WebBook lists the formula C₄H₈S₂, molecular weight 120.236, and the InChIKey WQADWIOXOXRPLN-UHFFFAOYSA-N; condensed-phase thermochemistry, phase change, ion energetics, IR, mass, UV/visible, and gas chromatography data are available for the compound[1](https://webbook.nist.gov/cgi/cbook.cgi?ID=505-23-7). As a thioacetal it is stable to many conditions that would destroy a free aldehyde or ketone, which is the basis of its double use as a protecting group and as a reactivity-inverting reagent[6](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/thioacetal).
## The umpolung principle
A carbonyl carbon is electrophilic: the electronegativity of oxygen leaves the carbon partially positive, so it is normally attacked by nucleophiles. Umpolung, a term introduced by Corey and Seebach and popularized by Seebach, temporarily reverses this polarity so that the carbonyl carbon behaves as a nucleophile[7](https://www.sciencedirect.com/science/article/abs/pii/S0040402003009554) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC8518712/). Converting an aldehyde to its 1,3-dithiane achieves this: the two sulfur atoms stabilize a carbanion at the carbon between them, and deprotonation with a strong base such as n-butyllithium gives 2-lithio-1,3-dithiane, which reacts with electrophiles and, after hydrolysis of the thioacetal, delivers a carbonyl compound with a new carbon-carbon bond[3](https://www.uwindsor.ca/people/jgreen/sites/uwindsor.ca.people.jgreen/files/tet-2003-59-6147-yus.pdf). The sulfur atoms are essential here; the oxygen analog is not viable because it does not stabilize the anion comparably[8](https://www.quimicaorganica.org/en/sulfur%2C-phosphorus%2C-and-silicon/1831-synthesis-of-1%2C3-dithianes-umpolung-reactions.html).
The anions of cyclic dithianes are more stable than those of noncyclic thioacetals, an advantage credited to Corey and Seebach[6](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/thioacetal). A second deprotonation and alkylation sequence on a monosubstituted dithiane extends the method to formaldehyde or methylene dianion equivalents, giving products that can be hydrolyzed or reduced further[3](https://www.uwindsor.ca/people/jgreen/sites/uwindsor.ca.people.jgreen/files/tet-2003-59-6147-yus.pdf).
## Preparation and removal
1,3-Dithianes are made by treating a carbonyl compound with 1,3-propanedithiol under [Lewis acid catalysis](https://www.edgepedia.org/lewis-acid-catalysis), for example with [boron trifluoride etherate](https://www.edgepedia.org/boron-trifluoride-etherate), to form the dithioacetal[9](https://www.epfl.ch/labs/lcso/wp-content/uploads/2018/06/StructureandReactivity-2010.pdf).
## Applications in synthesis
The most important use of 1,3-dithianes stems from their ability to function as acyl anion equivalents: metallation, alkylation of the anion, and cleavage of the dithiane group produces a carbonyl compound[10](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/dithiane). Beyond simple alkylation, β-keto 1,3-dithianes serve as masked 1,3-dicarbonyl systems that can be converted into functionalized oxygen-containing heterocycles for natural product synthesis[11](https://pubs.rsc.org/en/content/articlehtml/2003/ob/b208982c).
**Complex natural products.** Since the late 1970s, dithianes have featured prominently in the natural product synthesis program of [Amos B. Smith](https://www.edgepedia.org/amos-b-smith-iii), III, at the Monell Chemical Senses Center and the University of Pennsylvania, both for union of advanced fragments and for multicomponent linchpin couplings; Smith and Christopher M. Adams reviewed this evolution in *Accounts of Chemical Research* in 2004[12](https://pubs.acs.org/achre4/article/37/6/365/3453470/Evolution-of-Dithiane-Based-Strategies-for-the). A 2003 review in *Tetrahedron* surveyed total syntheses involving dithiane chemistry from 1990 onward, earlier reviews having covered the literature to 1990[7](https://www.sciencedirect.com/science/article/abs/pii/S0040402003009554).
**Chiral dithiane dioxides.** Oxidation opens an asymmetric variant. trans-1,3-Dithiane-1,3-dioxide, reported by [Varinder K. Aggarwal](https://www.edgepedia.org/varinder-kumar-aggarwal) and coworkers at Oxford in 1994, reacts with high diastereoselectivity with aromatic aldehydes, and a Pummerer reaction converts the dithiane dioxide moiety to a thiolester without racemization; the thiolester is readily transformed into acids, esters, amides, ketones, and aldehydes[5](https://pubs.rsc.org/en/content/articlelanding/1994/c3/c39940001653). In the fuller 1997 study, (R,R)-(+)-1,3-dithiane-1,3-dioxide gave single diastereomers with benzaldehyde and 3,4-dimethoxybenzaldehyde in 84 and 76 percent purified yields, and the adducts became protected S-ethyl α-hydroxythioesters in 95 to 100 percent ee; the approach furnished the dimethyl ether of (R)-(−)-3,4-dihydroxymandelic acid in its naturally occurring form[13](https://www.sciencedirect.com/science/article/pii/S0040402097010107).
**Related heterocycles.** The five-membered analogs, 1,3-dithiolanes, are familiar [carbonyl protecting groups](https://www.edgepedia.org/carbonyl-protecting-groups) but fragment at relatively low reaction temperatures, which limits their synthetic application to alkylation with highly reactive electrophiles[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC9907017/). A nitrogen-containing analog of 1,3-dithiane, 4,5-dihydro-5-methyl-1,3,5-dithiazine, provides a formaldehyde anion equivalent[10](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/dithiane). 1,3,5-Trithiane, the cyclic trimer of thioformaldehyde, is a second sulfur-based umpolung reagent that serves as a precursor to nucleophilic carbon species alongside 1,3-dithiane, though the two differ in their primary applications[15](https://pdf.benchchem.com/122/1_3_5_Trithiane_vs_1_3_Dithiane_A_Comparative_Guide_to_Umpolung_Chemistry.pdf).
## Place among umpolung methods
Dithianes are one of three widely used approaches to acyl anion species from carbonyl compounds, alongside the cyanide-catalyzed benzoin reaction, known since 1832, and [N-heterocyclic carbene](https://www.edgepedia.org/n-heterocyclic-carbene) (NHC) catalysis[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC8518712/). A practical limitation of dithiane umpolung reagents is that the molecule cannot carry acidic hydrogen atoms elsewhere, since these would be deprotonated along with the dithiane carbon; as the umpolung center is moved farther from the carbonyl, preparation of the requisite reagents also becomes more difficult[16](https://www.sciencedirect.com/topics/chemistry/umpolung). Within these limits, the general synthetic accessibility and reactivity of 1,3-dithianes have led to widespread application in fragment coupling and multicomponent linchpin strategies for architecturally complex targets[12](https://pubs.acs.org/achre4/article/37/6/365/3453470/Evolution-of-Dithiane-Based-Strategies-for-the).
## References
1. [1,3-Dithiane, NIST Chemistry WebBook, SRD 69](https://webbook.nist.gov/cgi/cbook.cgi?ID=505-23-7)
2. [Dithiane, Chemistry LibreTexts Organic Chemistry Glossary](https://chem.libretexts.org/Ancillary_Materials/Reference/Organic_Chemistry_Glossary/Dithiane)
3. [M. Yus, The role of 1,3-dithianes in natural product synthesis, Tetrahedron 59 (2003) 6147 (full text, University of Windsor)](https://www.uwindsor.ca/people/jgreen/sites/uwindsor.ca.people.jgreen/files/tet-2003-59-6147-yus.pdf)
4. [S. Wang, B. König, Catalytic Generation of Carbanions through Carbonyl Umpolung, Angew. Chem. Int. Ed. 2021, 60, 21624](https://pmc.ncbi.nlm.nih.gov/articles/PMC8518712/)
5. [V. K. Aggarwal, A. Thomas, R. J. Franklin, trans-1,3-Dithiane-1,3-dioxide, a new chiral acyl anion equivalent, J. Chem. Soc., Chem. Commun., 1994, 1653](https://pubs.rsc.org/en/content/articlelanding/1994/c3/c39940001653)
6. [Thioacetal, ScienceDirect Topics overview](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/thioacetal)
7. [The role of 1,3-dithianes in natural product synthesis, Tetrahedron (ScienceDirect abstract)](https://www.sciencedirect.com/science/article/abs/pii/S0040402003009554)
8. [Synthesis of 1,3-dithianes. Umpolung reactions, quimicaorganica.org](https://www.quimicaorganica.org/en/sulfur%2C-phosphorus%2C-and-silicon/1831-synthesis-of-1%2C3-dithianes-umpolung-reactions.html)
9. [Structure and Reactivity course notes, EPFL LCSO](https://www.epfl.ch/labs/lcso/wp-content/uploads/2018/06/StructureandReactivity-2010.pdf)
10. [Dithiane, ScienceDirect Topics overview (Comprehensive Heterocyclic Chemistry chapter)](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/dithiane)
11. [Development of β-keto 1,3-dithianes as versatile intermediates for organic synthesis, Org. Biomol. Chem., 2003](https://pubs.rsc.org/en/content/articlehtml/2003/ob/b208982c)
12. [A. B. Smith, III, C. M. Adams, Evolution of Dithiane-Based Strategies for the Construction of Architecturally Complex Natural Products, Acc. Chem. Res. 2004, 37, 365–377](https://pubs.acs.org/achre4/article/37/6/365/3453470/Evolution-of-Dithiane-Based-Strategies-for-the)
13. [trans-1,3-dithiane-1,3-dioxide; a chiral acyl anion equivalent, Tetrahedron 53 (1997) 16213](https://www.sciencedirect.com/science/article/pii/S0040402097010107)
14. [1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9907017/)
15. [1,3,5-Trithiane vs. 1,3-Dithiane: A Comparative Guide to Umpolung Chemistry, BenchChem](https://pdf.benchchem.com/122/1_3_5_Trithiane_vs_1_3_Dithiane_A_Comparative_Guide_to_Umpolung_Chemistry.pdf)
16. [Umpolung, ScienceDirect Topics overview](https://www.sciencedirect.com/topics/chemistry/umpolung)
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