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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Biomol Chem. Author manuscript; available in PMC 2016 June 28.
Published in final edited form as:
PMCID: PMC4814371

Lewis Acid-Promoted [2+2] Cycloadditions of Alkenes with Arylketenes


A method for the [2+2] cycloaddition of arylketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold found in several natural product families.

Ketene-alkene [2+2] cycloadditions have been established to be important reactions for chemical synthesis.1 These reactions, however, do not function well with poorly reactive and unstable monosubstituted aryl ketenes.2,3 For example, cycloaddition of phenylketene with cyclopentadiene only provides the cycloadduct in 26% yield (Scheme 1).2 Cycloaddition of this type are significant, as the cyclobutanone products generated would represent an important scaffold for chemical synthesis.4 Herein, we provide a solution to this problem through the development of a Lewis acid-promoted [2+2] cycloaddition with monsubstituted aryl ketenes (Scheme 2b). The utility of this method is also demonstrated by the synthesis of a scaffold that is common to several natural product families.

Scheme 1
[2+2] Cycloadditions with Arylketenes
Scheme 2
Lewis Acid-Promoted Ketene-Alkene [2+2] Cycloadditions

As part of a program toward developing new methods for the synthesis of cyclobutanes, we have introduced Lewis acid- promoted ketene-alkene [2+2] cycloadditions.5 In our initial installment, we developed a method for cycloaddition of “stable” disubstituted ketenes (Scheme 2a).5a In these reactions the ketene is fully generated prior to addition of alkene and Lewis acid. To extend the utility of this method towards use of unstable ketenes, like monosubstitued aryl ketenes, a new protocol was developed as pregeneration of the ketene was not possible. This initiative led to the identification of conditions that allow for the in situ generation of a monosubstituted aryl ketene in the presence of a Lewis acid (Scheme 2b).6

Due to efforts towards the total synthesis of gracilioether F (5), a method for cycloaddition with an “unstable” vinyl-ketene (Scheme 3) was developed.5c In this reaction, because mono- substituted ketenes undergo dimerization, the ketene needed to be generated in situ at low concentrations. This was achieved by slow addition of acid chloride 1 to a solution of Lewis acid, i-Pr NEt, and alkene 2.5b

Scheme 3
Summary of Related Work

Due to the known instability of monosubstituted aryl ketenes, the method illustrated in Scheme 3 seemed appropriate for initial reaction development.5c The optimization of the test reaction is outlined in Table 1. We found that the dropwise addition of a solution of acid chloride 6 to a mixture of alkene, base, and Lewis acid at −78 °C then warming to −45 °C was critical to success for formation of cyclobutanone 8. Entries 1-3 show that weaker aluminum Lewis acids provided the highest yield of the cycloadduct 8, which led to our use of Me3Al. Higher equivalents of alkene afforded the cyclobutanone product 8 in excellent yields; however, as low as two equivalents of alkene still provided good yields of the desired product (Table 1, entries 3-4). We propose the success of this method is due to the ephemeral formation of a highly reactive monosubstituted ketene-Lewis acid adduct (e.g., intermediate analogous to 3, Scheme 2b). By maintaining a low concentration of the reactive intermediate and relatively high concentration of the alkene, [2+2] cycloadditions can occur with low rates of ketene dimerization and decomposition. Alternatively, the acid chloride can be used in excess if desired (Table 1, entry 5), albeit with lower yields.

Table 1
Optimization of Reactions Conditionsa

Chart 1 displays the substrate scope of the optimized reaction. All reactions, except where noted, were performed with 20 equivalents of alkene. However, as noted in Table 1, entry 4, fewer equivalents of alkene provided the product in reduced but useful yield. This method has proven successful with both cyclic and acyclic alkenes. The scope of this reaction includes both activated (e.g., diene, allyl silane) and unactivated alkenes (e.g., 1-hexene, cyclopentene). Trisubstituted olefins are also suitable substrates for this reaction (product 13). Aryl acid chlorides of varying steric (vida infra, product 20) and electronic properties (products 15-16) were also found to be viable substrates. Attempted cycloaddition with either acylchloride or butanoyl chloride resulted in low yields of the cycloaddition. This can be attributed to the slower rate of ketene formation with the less acidic acid chloride. Finally, the observed diastereomeric ratios are likely, in part, due to equilibration under the reaction or workup conditions. This is due to the known configurationally instability of the aryl substituted stereocenter.7,8 Furthermore, equilibrium diastereomeric ratios for bicyclic systems such as 8 are known to be near 1:1 dr.7

Chart 1
Substrate Scopea

Reaction with chiral allylsilane 17 led to formation of cyclobutanone 18 with excellent levels of diastereoselectivity (Scheme 4).9 In this example, the precious alkene component was used as the limiting reagent.

Scheme 4Scheme 4
Reaction with Chiral Alkene

To demonstrate the utility of the method, a scaffold that is prevalent in several natural product families was prepared. The synthesis commences with [2+2] cycloaddition of o- bromoaryl substituted ketene derived from acid chloride 19. Cyclobutanone 20 was accessed in 80% yield on gram scale. Subsequent deprotonation with KHMDS and alkylation with methyl iodide afforded a single diastereomer of product. Baeyer-Villiger oxidation provided lactone 21 in good yield over two steps.5c Upon addition of t-butyllithium, lithium-halogen exchange occurred followed by an intramolecular acyl substitution to generate 22. Structures related to 22 are common to several natural products such as 25,10 24,11 and 23.12


In summary, we have developed a method for the cycloaddition of arylketenes and alkenes. This process shows broad scope, includes highly diastereoselective variants, and has enabled the synthesis of a scaffold that is common to several natural product families.

Supplementary Material

ESI - 1

ESI - 2


Indiana University and the National Institutes of Health (R01GM110131) are also acknowledged for generous financial support.


Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x

Notes and references

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(2) (a) Rey M, Roberts S, Dieffenbacher A, Dreiding AS. Helv. Chim. Acta. 1970;53:417–432.(b) Brady WT, Hoff EF., Jr. J. Org. Chem. 1970;35:3733–3737.(c) Hassner A, Dillon J, Onan KD. J. Org. Chem. 1986;51:3315–3319.
(3) Falmagne JB, Escudero J, Taleb-Sahraoui S, Ghosez L. Cycloadditions with aryl-substituted ketene iminium salts and alkenes are known. Angew. Chem. Int. Ed. 1981;20:879.
(4) (a) Lee-Ruff E, Mladenova G. Chem. Rev. 2003;103:1449–1484. [PubMed](b) Namyslo JC, Kaufmann DE. Chem. Rev. 2003;103:1485–1538. [PubMed]
(5) (a) Rasik CM, Brown MK. J. Am. Chem. Soc. 2013;135:1673. [PubMed](b) Rasik CM, Brown MK. Synlett. 2014;25:760.(c) Rasik CM, Brown MK. Angew. Chem. Int. Ed. 2014;53:14522–14526. [PubMed](d) Wang Y, Wei D, Li Z, Zhu Y, Tang M. J. Phys. Chem. A. 2014;118,:4288. For a DFT studies regarding the mechanism of Lewis acid-promoted ketene-alkene [2+2] [PubMed](e) Rasik CM, Hong YJ, Tantillo DJ, Brown MK. Org. Lett. 2014;16:5168. [PubMed]
(6) a) Yoon TP, Dong VM, MacMillan DWC. J. Am. Chem. Soc. 1999;121:9726. For examples of ketene generation in the presence of a Lewis acid.b) Nelson SG, Wan Z. Org. Lett. 2000;2:1883. [PubMed]C) Paull DH, Abraham CJ, Scerba MT, Alden-Danforth E, Lectka T. Acc. Chem. Res. 2008;41:655–663. [PubMed]D) Abraham CJ, Paull DH, Bekele T, Scerba MT, Dudding T, Lectka T. J. Am. Chem. Soc. 2008;130:17085–17094. [PubMed]
(7) Rey M, Roberts SM, Dreiding AS, Roussel A, Vanlierde H, Toppet S, Ghosez L. Helv. Chim. Acta. 1982;65:703.
(8) See the Supporting Information for details.
(9) a) Knölker HJ, Baum G, Graf R. Angew. Chem. Int. Ed. 1994;33:1612–1615. For examples of Lewis acid promoted [2+2] cycloadditions with allyl silanes.b) Knölker HJ, Jones PG, Wanzl G. Synlett. 1998:613.c) Knölker HJ, Baum E, Schmitt O. Tetrahedron Lett. 1998;39:7705.d) Knölker H-J, Schmitt O, Wanzl G, Baum G. Chem. Commun. 1999:1737–1738.
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