Cyclobutanone1

[1191-95-3]  · C4H6O  · Cyclobutanone  · (MW 70.09)

(strained cyclic ketone capable of undergoing ring-expansion, ring-contraction and ring-opening reactions to give functionalized cyclopentanones,2 tetrahydrofurans,3 cyclopropanes, and terminally functionalized butyric acid derivatives1d)

Physical Data: mp -51.1 to -52.5 °C; bp 97-100 °C; d 0.931 g cm-3; nD20 1.421.

Solubility: slightly sol H2O; sol most organic solvents.

Form Supplied in: colorless liquid, >99% pure, limited availability; relatively expensive.

Preparative Methods: over 30 preparative methods have been reported. The most convenient methods include the ketene-diazomethane condensation4 and the selective di-Grignard reaction using 1,3-dibromopropane with carbon dioxide.5

Purification: distillation by spinning band column or preparative GC.

Handling, Storage, and Precautions: flammable liquid (flash point 27 °C). Contact with skin and eyes should be avoided.

Introduction.

The strain associated with the cyclobutanone ring system permits ring-expansion reactions to occur more readily than with larger cycloalkanones.

Ring Expansion to Cyclopentanones.

The one-carbon ring expansion of cyclobutanone and its derivatives represents a convenient method for the preparation of cyclopentanones. The general scheme is represented by eq 1, in which a one-carbon nucleophile bearing a potential leaving group is added to the carbonyl function, followed by an a-carbon migration. The one-carbon homologation of cyclobutanone with Diazomethane gives cyclopentanone as the major product (58%), along with small amounts of cycloheptanone (17%) and cyclooctanone (25%).6 a-Functionalized cyclopentanones are readily prepared by alkylation of cyclobutanone with dithio- or trithiomethide ions followed by rearrangement of the intermediate cyclobutanols. The yields of the cyclopentanones are satisfactory for this two-step sequence (eqs 2 and 3).2,7 a-(Phenylthio)cyclopentanone may also be obtained by addition of LiCHIS(O)Ph (88%), followed by reductive rearrangement of the b-hydroxy sulfoxide adduct with TiCl4 and Zn (62%).8

The electrochemical condensation of Ethyl Trichloroacetate with cyclobutanone gives the five-carbon a-chloro-b-keto ester (eq 4).9

1-Alkenylcyclobutanols, which are readily prepared by metal alkenyl additions to cyclobutanone, undergo Lewis acid-catalyzed ring expansion to cyclopentanones. For example, the spirocyclic cyclopentanone is readily prepared in high yields from the acid-catalyzed rearrangement of the 5-lithio-2,3-dihydrofuran condensation product (eq 5).10

In similar fashion, 2-chloromethyl-2-methylcyclopentanone can be prepared from 1-isopropenylcyclobutanol (eq 6); this rearrangement may involve a radical mechanism.11 Acid-catalyzed rearrangement of this cyclobutanol in a sulfuric acid-ethanol mixture gives 2,2-dimethylcyclopentanone, isolated as the DNP in 51% yield.

2-Methylcyclopent-2-enones are readily prepared from the PdII-assisted rearrangement of 1-vinylcyclobutanols (eq 7). However, this scheme has not been applied to the unsubstituted cyclobutyl ring.12

The pinacol rearrangement of the reductive coupling product of cyclobutanone gives the spirooctanone (eq 8).13 More recently, the same pinacol has been obtained in higher yields with cerium(II) iodide.14 The same spirooctanone is obtained by the thermal rearrangement of dicyclobutylidene epoxide (eq 9).15 Dicyclobutylidene may be obtained by thiadiazoline elimination or, in lower yield, by a direct Wittig reaction with cyclobutylphosphonium ylide.

Ring Expansions to Cyclohexenones and Cyclohexanones.

a-Alkylidene- and a,a-dialkylidenecyclobutanones, obtained from cross-aldol condensations of cyclobutanone, rearrange readily with Polyphosphoric Acid (PPA) at elevated temperatures to the corresponding cyclohexenones (eq 10).16

Cyclohexanones can also be readily prepared by the base-catalyzed 1,3-sigmatropic rearrangement of 1-alkenyl-2-thiophenoxycyclobutanols which are accessible from 2-phenylthiocyclobutanone (eqs 11 and 12).17 The latter can be obtained from nucleophilic substitution of thiophenoxy ion on 2-bromocyclobutanone,18 the major bromination product (95%) of cyclobutanone.19 This substituted cyclobutanone can be used as a cyclobutanone equivalent since the phenylthio group can be reductively cleaved with Lithium 1-(Dimethylamino)naphthalenide.17

Ring Expansions to Five-Membered Heterocycles.

Baeyer-Villiger oxidation of cyclobutanone to g-butyrolactone is best accomplished with Hydrogen Peroxide in trifluoroethanol (eq 13).20,21 Some regioselectivity is observed with a-substituted cyclobutanones.1b The photochemical ring expansion of cyclobutanones to give 2-alkoxytetrahydrofurans is a general reaction (eq 14); however, for the parent cyclobutanone, the yield is only 8%.22

One example of the ring expansion of a cyclobutanol derivative to a pyrrolidine has been reported in the total synthesis of nor-nicotine. This rearrangement is effected by treatment of the cyclobutanol with Hydrazoic Acid (eq 15).23

Ring Contraction to Cyclopropanes.

The nucleophile-assisted Favorskii rearrangement of a-halocyclobutanones gives cyclopropylcarbonyl derivatives (eq 16).1a

Nucleophilic substitution may accompany the rearrangement with soft nucleophiles. This transformation is best accomplished with 2-bromocyclobutanone and hard nucleophiles, although 2-chlorocyclobutanone, obtained from the Sulfuryl Chloride chlorination of cyclobutanone,24 or 2-tosyloxycyclobutanone can be used (eq 17).

Whereas 2,2-dibromocyclobutanone undergoes ring-opening reactions (see section on ring-opening reactions), 2,4-dibromocyclobutanone, an overbromination product of cyclobutanone, gives ring-contracted products (eq 18).24 The stereochemistry of the starting 2,4-dibromocyclobutanone and the ring-contracted products have not been assigned. An interesting thermal reaction of the ethylene acetal derivative of 2-bromocyclobutanone has been reported (eq 19).25 The pyrolysis of cyclobutanone tosylhydrazone gives methylenecyclopropane (eq 20).26

Condensation and Annulation Reactions.

The carbonyl group in cyclobutanone is more reactive than that of larger ring ketones towards nucleophilic additions and condensations. For example, Wittig-type reactions occur readily with cyclobutanone (see eq 9).15 Other examples are illustrated in eq 21. Reactions with cyclopentadiene (pyrrolidine, MeOH),26 PhSO2CHLiCH2TMS followed by MeSO2Cl,27 2-pentylcyclopropyllithium,28 2-lithio-2-trimethylsilyl-1,3-dithiane,29 and CNCHLiPO3Et230 afforded the addition or alkenation products shown.

1-Cyclobutenyl ketones and 1-cyclobutenecarbaldehyde are accessible from cyclobutanone in three steps, as shown in eqs 22 and 23.31,32 The starting a-sulfonylvinyl isocyanide and a-chloro sulfoxide were prepared in one step using p-Tolylsulfonylmethyl Isocyanide and LiCHClS(O)Ph (93%), respectively.

The ring annulation of cyclobutanes is achieved in a Diels-Alder reaction using cyclobutenes as dienophiles or 1-alkenylcyclobutenes as dienes. The piperidine enamine of cyclobutanone readily cycloadds to conjugated ketones to give cyclobutapyrones (eq 24).33

1-Vinylcyclobutene, available by vinyl Grignard addition (66%) and I2-induced elimination (72%), undergoes a [4 + 2] cycloaddition with 1,2-cyclobutenedicarboxylic acid dimethyl ester to give a key intermediate in the synthesis of the biscyclobutabenzene (eq 25).34 The addition of methyl propiolate to 1-vinylcyclobutene gives a mixture of regioisomers in about equal amounts.35

Ring-Opening Reactions.

The strain associated with cyclobutanones allows ring-opening reactions to occur with ease. Cyclobutenes and cyclobutenol derivatives are readily available from cyclobutanone, and their thermolytic ring-opening reactions give synthetically useful 1,3-butadienes.36,37 Two examples are given (eqs 26 and 27).

Although 2-halocyclobutanones give ring-contracted products upon treatment with nucleophiles, 2,2-dihalocyclobutanones undergo ring-opening reactions. This is the result of the stabilization of the anion brought about by gem-dihalogen substitution (eq 28).24

a-Alkylations of Cyclobutanone.

a-Alkylation of cyclobutanone via its enolate anion is not an efficient method for monoalkylation. The reaction usually results in polyalkylations, accompanied by resin formation.38 Although the trimethylsilyl enol ether39 and the pyrolidine enamine40 are known, alkylations of these intermediates cannot be achieved because of the acid and thermal labilities of these intermediates. Monoalkylated cyclobutanones can be prepared from base-assisted alkylation of the cyclobutanone equivalent, 2-phenylthiocyclobutanone, and subsequent reductive cleavage of the thiophenoxy group with lithium 1-dimethylaminonaphthalenide.17

Related Reagents.

1,2-Bis(trimethylsilyloxy)cyclobutene; Cyclopropanone; Dichloro(ethoxy)oxovanadium(V); 1,2-Dicyanocyclobutene; 1-Ethoxycyclopropanol; 2-Methoxy-3-phenylthio-1,3-butadiene; Methylenecyclobutane; Squaric Acid; 1-(Tetrahydropyranyloxy)cyclopropanecarbaldehyde; p-Tolylsulfonylmethyl Isocyanide; Tricarbonyl(cyclobutadiene)iron.


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Edward Lee-Ruff

York University, Toronto, Ontario, Canada



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