# Ketene cycloaddition

Ketene cycloaddition is the class of pericyclic and stepwise reactions in which a ketene, a compound of general structure \( \mathrm{R_2C=C=O} \) in which a carbonyl group is connected by a double bond to an alkylidene group, combines with an unsaturated partner such as an alkene, carbonyl, imine, or alkyne to form a ring, most often a four-membered one.<sup>[1](https://goldbook.iupac.org/terms/view/K03378)</sup> Ketenes are among the few synthetic building blocks that undergo facile thermal [2 + 2] and [4 + 2] cycloadditions, yielding cyclobutanones, β-lactones, β-lactams, dioxins, pyranones, and other carbo- and heterocycles.<sup>[2](https://onlinelibrary.wiley.com/doi/10.1002/0471264180.or082.02)</sup>

| Key fact | Detail |
|---|---|
| Defining reaction | A ketene reacts with an unsaturated compound to give a cyclic product by formation of two bonds between the reactants.<sup>[3](https://www.organicreactions.org/pubchapter/ketene-cycloadditions/)</sup> |
| With alkenes | Thermal [2 + 2] cycloaddition gives cyclobutanones, described by Woodward and Hoffmann as a thermally allowed [\(_{\pi}2_{s}\) + \(_{\pi}2_{a}\)] process with an orthogonal approach.<sup>[4](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)</sup> |
| With imines | The Staudinger ketene–imine [2 + 2] cycloaddition, first reported in 1907, remains one of the most reliable methods for β-lactam synthesis.<sup>[5](https://pubs.acs.org/achre4/article/41/8/925/1296759/The-Mechanism-of-the-Ketene-Imine-Staudinger)</sup><sup> • </sup><sup>[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)</sup> |
| With carbonyls | Ketenes add to carbonyl compounds to give 2-oxetanones (β-lactones), which decarboxylate when heated.<sup>[4](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)</sup> |
| Mechanism | For most real systems the ketene–imine reaction is stepwise, via a zwitterionic intermediate, rather than fully concerted.<sup>[5](https://pubs.acs.org/achre4/article/41/8/925/1296759/The-Mechanism-of-the-Ketene-Imine-Staudinger)</sup> |
| Catalysis | Cinchona alkaloids dominate Lewis base-catalyzed asymmetric variants; Al(III), Fe(II), Ti(IV), and Cu(II) complexes dominate Lewis acid-catalyzed ones.<sup>[2](https://onlinelibrary.wiley.com/doi/10.1002/0471264180.or082.02)</sup> |
| Lewis acid effect | Lewis acid promotion raises yields and selectivity and can reverse the diastereoselectivity of aryl/alkyl ketene–alkene cycloadditions relative to thermal conditions.<sup>[7](https://www.orgsyn.org/demo.aspx?prep=v93p0401)</sup> |

## Historical background

In 1908, researchers in two countries reported ketene dimerization at nearly the same time: Chick and Wilsmore did so in England, while Staudinger and Klever announced it in Germany; the German team granted Wilsmore credit for the first discovery.<sup>[3](https://www.organicreactions.org/pubchapter/ketene-cycloadditions/)</sup> Ketene cycloaddition was an early example of a process that formed carbon–carbon bonds with ease, often without solvent, catalyst, or high heat. Interest revived in the 1960s for three reasons: haloketenes were found to be highly reactive and their halogens easily removed after reaction; NMR spectroscopy revealed the reaction's stereochemical features; and the new theory of orbital symmetry conservation provided a framework for these puzzling "no mechanism" reactions.<sup>[3](https://www.organicreactions.org/pubchapter/ketene-cycloadditions/)</sup>

The ketene–imine variant predates the dimerization work. In 1907, before the antibacterial activity of penicillin was known, [Hermann Staudinger](https://www.edgepedia.org/hermann-staudinger) reported the first synthesis of a β-lactam, 1,3,3,4-tetraphenylazetidin-2-one, from diphenylketene and a [Schiff base](https://www.edgepedia.org/schiff-base) derived from aniline and benzaldehyde.<sup>[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)</sup> In 1950, Sheehan and co-workers used the [2 + 2] cycloaddition of an in situ generated ketene with an imine to make a penicillin analog, confirming Woodward's structural assignment.<sup>[8](https://www.sciencedirect.com/science/article/pii/S0040402008014907)</sup>

## Reaction partners and products

**Alkenes.** The cycloaddition of a ketene with an olefin yields a cyclobutanone, and this [2 + 2] process occurs even with conjugated dienes.<sup>[4](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)</sup> It is one of the few general methods for constructing four-membered rings, and the intramolecular version gives fused bicyclo[n.2.0]cyclobutanones.<sup>[9](https://sites.google.com/brandeis.edu/barrysnider/research/intramolecular-ketene-alkene-cycloadditions)</sup> When an unsymmetrical ketene reacts with an unsymmetrical alkene, the product with bulky substituents cis to each other predominates.<sup>[10](https://www.sciencedirect.com/topics/chemistry/dichloroacetyl-chloride)</sup> In intramolecular reactions, the regiochemistry is set by the alkene substitution pattern: substrates with the more substituted internal alkene carbon give bicyclo[n.2.0]alkanones, while those with the more substituted terminal carbon give bicyclo[n.1.1]alkanones.<sup>[11](https://www.sciencedirect.com/science/article/abs/pii/S0166128006003885)</sup>

**Carbonyl compounds.** Ketenes add to aldehydes and ketones to give 2-oxetanones, the β-lactones, which are susceptible to decarboxylation on heating.<sup>[4](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)</sup> The Wynberg β-lactone synthesis, in which quinidine and quinine catalyze the formal [2 + 2] cycloaddition of ketene with chloral, was one of the first practical catalytic asymmetric reactions; toluene as solvent, which precipitates the hydrochloride salt of Hünig's base and generates the nucleophilic free-base catalyst, was crucial to its success.<sup>[12](https://www.sciencedirect.com/topics/chemistry/beta-lactone)</sup>

**Imines.** The Staudinger reaction is regarded as one of the most reliable routes to β-lactams because of its broad substrate scope and simple procedure.<sup>[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)</sup> Stereochemical control remains a major concern: non-polar solvents favor cis-β-lactams while polar solvents favor trans, because a polar medium stabilizes the zwitterionic intermediate long enough for isomerization before ring closure.<sup>[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)</sup> Cyclic imines usually give trans products, but cycloaddition with an acyclic imine followed by ring closure can deliver the cis product, an approach used in the enantioselective synthesis of a carbacephalosporin analog.<sup>[8](https://www.sciencedirect.com/science/article/pii/S0040402008014907)</sup>

**Alkynes.** [Ab initio](https://www.edgepedia.org/ab-initio) and DFT studies of monosubstituted acetylenes adding to ketene show that addition to the ketene C=C bond, giving cyclobutenones, is preferred for less electron-rich acetylenes, but for the most electron-rich ones (X = NH\(_2\) and NMe\(_2\)) addition to the C=O bond, giving oxetes, becomes competitive, with activation barriers as low as about 45 kJ mol\(^{-1}\).<sup>[13](https://pubs.rsc.org/en/content/articlelanding/2004/ob/b309549e)</sup>

**Ketenes themselves.** Aldoketenes generally undergo thermal dimerization to 2-oxetanones, while ketoketenes dimerize to 1,3-cyclobutanediones; halogenated ketenes do not homodimerize but are highly prone to polymerization.<sup>[4](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)</sup>

## Mechanism

Two mechanisms are commonly accepted for the ketene–alkene [2 + 2] cycloaddition: a stepwise sequence of nucleophilic additions through a zwitterionic intermediate, and a concerted thermally allowed antarafacial (bond formation on opposite faces of a pi system) process that frontier molecular orbital theory predicts can be highly asynchronous.<sup>[11](https://www.sciencedirect.com/science/article/abs/pii/S0166128006003885)</sup> The Woodward–Hoffmann description requires an orthogonal approach in which the ketene π system acts antarafacially and the olefin π system suprafacially.<sup>[4](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)</sup> The observation that ketene cycloadditions give predominantly the more hindered product was long adduced as evidence for concerted antarafacial addition, but least-motion stepwise pathways also account for these cis products if rotation in the intermediates is not much faster than cyclization.<sup>[14](https://onlinelibrary.wiley.com/doi/10.1002/qua.560490104)</sup>

For the ketene–imine reaction, computational and experimental work has established a stepwise pathway: nucleophilic addition of the imine nitrogen to the sp-hybridized central carbon of the ketene forms a zwitterionic intermediate, which then closes by a four-electron conrotatory electrocyclization subject to torquoelectronic effects.<sup>[5](https://pubs.acs.org/achre4/article/41/8/925/1296759/The-Mechanism-of-the-Ketene-Imine-Staudinger)</sup> Zwitterionic intermediates of this type have been isolated and characterized in reactions of stabilized ketenes with imidazoles and pyridine.<sup>[15](https://www.sciencedirect.com/topics/chemistry/staudinger-reaction)</sup>

## Catalytic asymmetric variants

Because two chiral centers can be generated in one preparative step, the [Staudinger reaction](https://www.edgepedia.org/staudinger-reaction) is a mainstay of asymmetric β-lactam synthesis, using combinations of chiral imines with achiral ketenes, chiral ketenes with achiral imines, or both chiral.<sup>[5](https://pubs.acs.org/achre4/article/41/8/925/1296759/The-Mechanism-of-the-Ketene-Imine-Staudinger)</sup><sup> • </sup><sup>[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)</sup> Catalytic control is also well developed. Cinchona alkaloids play the leading role in Lewis base-catalyzed asymmetric carbonyl and imine cycloadditions, while Al(III)-, Fe(II)-, Ti(IV)-, and Cu(II)-complexes carry the Lewis acid-catalyzed transformations, and [N-heterocyclic carbene](https://www.edgepedia.org/n-heterocyclic-carbene) catalysts are significant for both ketene–carbonyl and ketene–imine cycloadditions.<sup>[2](https://onlinelibrary.wiley.com/doi/10.1002/0471264180.or082.02)</sup>

**Ketene dimerization.** Building on Calter's alkaloid-catalyzed ketene homodimerization, Kerrigan and co-workers at [Oakland University](https://www.edgepedia.org/oakland-university) developed a catalytic asymmetric heterodimerization of two different ketenes to give ketene heterodimer β-lactones. The optimal catalysts were cinchona alkaloid derivatives (TMS-quinine or Me-quinidine); the key was slow addition of the more reactive donor ketene precursor to a solution of the less reactive acceptor ketene, which ensured complete regioselectivity, with only one heterodimer regioisomer observed in all cases. Products were obtained in yields up to 90% with enantioselectivity of at least 90% ee for 33 examples and Z-olefin selectivity of at least 90:10 for 20 examples.<sup>[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC5012991/)</sup> Adding 1–2 equivalents of lithium perchlorate switched the olefin selectivity toward the E-isomer, giving 10 examples with E-selectivity from 74:25 to 97:3 and 84–98% ee; the lithium salt is proposed to stabilize a longer-lived enolate intermediate that equilibrates before lactonization.<sup>[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC5012991/)</sup>

## Lewis acid promotion

Ketene–alkene [2 + 2] cycloadditions were historically carried out exclusively under thermal conditions, which limited scope and stereoselectivity.<sup>[17](https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0033-1340626?device=mobile&id=&innerWidth=412&lang=en&offsetWidth=412)</sup> [M. Kevin Brown](https://www.edgepedia.org/m-kevin-brown)'s group at [Indiana University](https://www.edgepedia.org/indiana-university) developed Lewis acid-promoted variants in which the ketene is generated in situ in the presence of a Lewis acid, addressing several of these problems.<sup>[17](https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0033-1340626?device=mobile&id=&innerWidth=412&lang=en&offsetWidth=412)</sup> In a representative [Organic Syntheses](https://www.edgepedia.org/organic-syntheses) procedure, diphenylacetyl chloride and cyclopentene with ethylaluminum dichloride gave 7,7-diphenylbicyclo[3.2.0]heptan-6-one in 64% yield; compared with thermal conditions, the Lewis acid variant gave higher yields for unactivated alkenes (84% versus 5% for one substrate), better diastereoselectivity (18:1 versus 2:1 for another), and, for aryl/alkyl ketenes, a reversal of diastereoselectivity, with the thermal reaction delivering the opposite diastereomer as the major product.<sup>[7](https://www.orgsyn.org/demo.aspx?prep=v93p0401)</sup> A drawback is the need for a stoichiometric amount of Lewis acid because of severe product inhibition, which has prevented catalytic enantioselective variants of this particular reaction.<sup>[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC11041672/)</sup>

## Applications

Cyclobutanones from ketene–alkene cycloadditions are versatile synthetic intermediates, and the Lewis acid-promoted reaction has been used to prepare the marine natural product gracilioether F, in which a stereoselective [2 + 2] cycloaddition of an alkenyl ketene with cyclopentene built a tricyclic core bearing five contiguous stereogenic centers, two of them quaternary, followed by regioselective Baeyer–[Villiger oxidation](https://www.edgepedia.org/villiger-oxidation).<sup>[18](https://pmc.ncbi.nlm.nih.gov/articles/PMC11041672/)</sup> β-Lactams from the Staudinger reaction underpin the penicillin, cephalosporin, carbapenem, and carbacephem antibiotic classes and serve as chiral synthons for non-protein amino acids, peptidomimetics, and other medicinally active compounds.<sup>[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)</sup> Asymmetric synthesis by [2 + 2] cycloadditions of ketenes to form β-lactams and β-lactones has been achieved with high yields and high stereoselectivities.<sup>[19](https://onlinelibrary.wiley.com/doi/10.1002/ejoc.200500452)</sup>

## References

1. [IUPAC Gold Book: ketenes](https://goldbook.iupac.org/terms/view/K03378)
2. [G. Nelson, Catalytic Asymmetric Ketene [2 + 2] and [4 + 2] Cycloadditions, Organic Reactions / Wiley](https://onlinelibrary.wiley.com/doi/10.1002/0471264180.or082.02)
3. [J. A. Hyatt and P. W. Raynolds, Ketene Cycloadditions, Organic Reactions Vol. 45 (1994)](https://www.organicreactions.org/pubchapter/ketene-cycloadditions/)
4. [R. A. Owens, Trimethylsilylbromoketene and Reactions of α-Haloacid Halides with Diisopropylcarbodiimide, North Texas State University dissertation (1977)](https://digital.library.unt.edu/ark:/67531/metadc332482/m2/1/high_res_d/1002783976-Owens.pdf)
5. [F. P. Cossío, A. Arrieta, M. A. Sierra, The Mechanism of the Ketene–Imine (Staudinger) Reaction in Its Centennial, Acc. Chem. Res. 2008, 41, 925](https://pubs.acs.org/achre4/article/41/8/925/1296759/The-Mechanism-of-the-Ketene-Imine-Staudinger)
6. [Advances in the chemistry of β-lactam and its medicinal applications, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3525065/)
7. [C. M. Rasik, E. M. Salyers, M. K. Brown, Synthesis of Cyclobutanes by Lewis Acid-Promoted Ketene-Alkene [2+2] Cycloadditions, Org. Synth. 2016, 93, 401](https://www.orgsyn.org/demo.aspx?prep=v93p0401)
8. [Preparation of β-lactams by [2+2] cycloaddition of ketenes and imines, Tetrahedron (ScienceDirect)](https://www.sciencedirect.com/science/article/pii/S0040402008014907)
9. [Snider group, Intramolecular Ketene Alkene Cycloadditions, Brandeis University](https://sites.google.com/brandeis.edu/barrysnider/research/intramolecular-ketene-alkene-cycloadditions)
10. [Dichloroacetyl Chloride, ScienceDirect Topics](https://www.sciencedirect.com/topics/chemistry/dichloroacetyl-chloride)
11. [Intramolecular competition between alkenes in ketene–alkene [2+2] cycloaddition. A theoretical study, ScienceDirect](https://www.sciencedirect.com/science/article/abs/pii/S0166128006003885)
12. [Beta-Lactone, ScienceDirect Topics](https://www.sciencedirect.com/topics/chemistry/beta-lactone)
13. [Ketene–acetylene [2 + 2] cycloadditions: cyclobutenone and/or oxete formation? Org. Biomol. Chem. (RSC)](https://pubs.rsc.org/en/content/articlelanding/2004/ob/b309549e)
14. [R. A. Firestone, Least-motion stepwise [2 + 2] ketene cycloaddition pathways predict the more hindered cis-cycloadducts, Int. J. Quantum Chem. (1994)](https://onlinelibrary.wiley.com/doi/10.1002/qua.560490104)
15. [Staudinger Reaction, ScienceDirect Topics](https://www.sciencedirect.com/topics/chemistry/staudinger-reaction)
16. [S. Chen et al., Catalytic Asymmetric Synthesis of Ketene Heterodimer β-Lactones: Scope and Limitations, J. Org. Chem. 2016, 81, 7824](https://pmc.ncbi.nlm.nih.gov/articles/PMC5012991/)
17. [C. M. Rasik, M. K. Brown, Intermolecular Ketene–Alkene [2+2] Cycloadditions: The Significance of Lewis Acid Promoted Variants, Synlett 2014, 25, 760](https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0033-1340626?device=mobile&id=&innerWidth=412&lang=en&offsetWidth=412)
18. [Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11041672/)
19. [T. T. Tidwell, Ketene Chemistry after 100 Years: Ready for a New Century, Eur. J. Org. Chem. 2006](https://onlinelibrary.wiley.com/doi/10.1002/ejoc.200500452)

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*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Organic substances › Organic reactions, structure and reference › Organic reactions and synthetic methods › Pericyclic and cycloaddition reactions › [2+2] and photochemical cycloadditions*

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