Dimethylketene 2+2 cycloaddition reactions

A new and completely different methodology involving a cycloaddition reaction has been described. The reaction between diphenylketene, ferf-butylcyanoketene or dimethylketene with 2,4,6-trimethylbenzonitrile A-oxide gave the corresponding 5(4//)-oxazolones 107 in moderate yields (Scheme 7.30). 

In contrast with the photochemical cycloaddition reaction of two alkenes, the [2+2] cycloaddition of a ketene and an alkene occurs under thermal conditions. The ketene is formed typically from an acid chloride and a mild base such as EtsN, or from an a-halo-acid chloride and zinc. Cycloaddition with an alkene occurs stereospecifically, such that the geometry of the alkene is maintained in the cyclobutanone product. The regioselectivity is governed by the polarization of the alkene, with the more electron-rich end of the alkene forming a bond to the electron-deficient central carbon atom of the ketene. Thus, the product from cycloaddition of dimethylketene with the enol ether Z-171 is the cyclobutanone m-172, whereas with -171, the isomer trans-lll is formed (3.116). ... 

Unlike non-strained acyclic allenes, cyclonona-1,2-dienes undergo cycloaddition reactions with halogenated ketenes, e.g. 1-methylcyclonona-l,2-diene reacts with chloromethylketen to give a mixture of adducts with (168) predominating. The cycloaddition of dimethylketen to optically active bicyclo[7,l,0]deca-4,5-diene gave U -(169).2° ... 

A suggestion has been made that asymmetric induction is possible in cycloaddition reactions leading to azetidinones. The reaction of dimethylketene methyl-trimethylsilylacetal with the Schifl s bases of chiral a-aminoesters in the presence of titanium tetrachloride gave rise to the corresponding /3-lactams with extremely high stereoselectivity. The authors propose the formation of a template (183) between titanium and the Schiff s base leading to stereocontrol (Scheme 24). 

Across carbon multiple bonds Ketenes are very reactive in [2+2] cycloaddition reactions to numerous double-bonded substrates. They form four-membered ring cycloadducts, even with regular olefins. In the reaction of ketenes with acetylene derivatives sometimes also four-membered ring [2+2] cycloadducts are obtained. The isolation of ethoxycy-clobutenones in the thermolysis of ethoxyacetylenes was interpreted by Nieuwenhuis and Arens to occur via a [2+2] cycloaddition reaction of the generated ketene with the starting material. This type of reaction is also observed when dimethylketene is reacted with ethoxyacetylene to give a 83 % yield of the cyclobutenone . The ketene also reacts with ethoxyacetylene to give the cyclobutenone derivative 95. ... 

The [2+2] cycloaddition reaction of ketenes with olefins was already observed by Staudinger and his coworkers, who postulated the four-membered ring structure for the cycloadducts. The rate of reaction of ketenes with olefins is as follows diphenylketene > dimethylketene > butylethylketene > ketene. Because of its slow rate of dimerization butylethylketene is an especially useful reagent and its cycloaddition to slow reacting olefins can be forced by using elevated temperatures. 

The [2+2] cycloaddition reaction of ketenes with vinyl ethers and thioethers also occurs very readily. Even allyl ethers undergo this reaction. The reaction of diphenylketene with vinyl ethers is stereospecific, indicating a concerted one-step process . Also, dimethylketene and -MeOCH=CHMe affords a cycloadduct in which the alkene stereochemistry is maintained In contrast, the [2+2] cycloadduct obtained fl om t-butylcyanoketene and CH2=CHOEt or CH2=CHOAc did not give a 100% stereoselectivity and linear products are often also obtained, indicating the formation of a switter ionic intermediate. The latter are detected in the reaction of bis(trifluoromethyl)ketene with ethyl vinyl ether (see the General Introduction ). The initial reaction occurs across the C=0 bond of the ketene, which rearranges via switter ionic intermediates to form the cyclobutanone reaction product . 

The last [2 + 2] cycloaddition performed onto methylenecyclopropane itself consists of the use of ketene derivatives, particularly of dimethylketene 508 (Table 40, entry 1) [133]. The result is an almost equimolar mixture of the two possible regioisomers 511, albeit no yield has been reported. Anyway, the particular reactivity of methylenecyclopropane was confirmed, since it was found to be around 15 times more reactive than isobutene [133]. The scarce regioselectivity of this cycloaddition was confirmed by the reactions of the same ketene 508 with 2,2-disubstituted methylenecyclopropanes (entries 2 and 3) [134], BCP has also been shown to be reactive towards chloro-substituted ketenes 509 and 510, affording the expected cycloadducts 514 and 515 in mild conditions (entries 4 and 5) [13b],... 

Allene ketene cycloadditions are of greater synthetic utility than cither mixed allene dimerization or mixed ketene dimerization. In this class of reaction the ketene is the more reactive species and homodimerization of ketene can be minimized by use of excess allene. Such cycloadditions always result in 2-alkylidenecyclobutanones with the sp carbons of both moieties forming the initial bond. In substituted allenes and ketenes, mixtures of stereoisomers of 2-alkylidenecyclobutanones are obtained with very little stereoselectivity, the stereoisomers arise from cisUrcins isomerism in the cyclobutane ring and EjZ isomerism of the exocyclic double bond. In unsymmetrically substituted allenes some regiochemical preference for ketene cycloaddition is observed. Examples of dimethylketene allene cycloadditions are summarized in Table 1,2... 

Since 1,3-disubstituted allcnes can exist in two enantiomeric forms, the use of partially resolved allenes in these cycloadditions led to some early reports of chiral cyclobutanones. For example, reaction of dimethylketene with partially resolved (/ )-l,3-dimethylallene (4, R = Me) or (/ )-1.3-di-/er -butylallcnc (4, R = r-Bu) gave the corresponding 2-alkylidenecyclobutanones 5 and 6 with the R configuration at the newly created stereogenic center.3... 

Some of the earlier studies using partially resolved allenes (1,3-dimethylallene and l,3-di-/ert-butylailene) in cycloadditions with dimethylketene and terf-butylcyanoketene reported some asymmetric induction in the resulting 2-alkylidenecyclobutanones,2 3 however, no optical purity measurements were reported. Furthermore, these reactions arc of limited value due to partial racemization accompanying the intermediacy of zwitterionic intermediates (see Section 1.3.3.). 

The third type of cycloaddition results from the reaction of cyclopropanones with activated olefins. For example, dimethylketene adds to methyl substituted cyclopropanones affording the spiro lactones 153 a—c. 96,n8,i22b) Similarly the ortho ester 154 is formed from 1,1-dimethoxy-ethylene and 2,2-dimethylcyclopropanone 154 dimerizes to 155 upon standing. ng>... 

The ratio of spirohexan-4-one/spirohexan-5-one was close to 1 1 which can be rationalized by assuming a diradical mechanism as proposed for the cycloaddition of dimethylketene to methylenecyclopropane. Dichloroketene also underwent nonregioselective addition to methylenecyclopropane (49% yield) however, 4,4-dichlorospiro[2.3]hexan-5-one was formed as the main product. When methylenecyclopropane was reacted with chloro(2,2,2-tri-chloroethyl)ketene, generated by elimination of chlorine from 2,2,4,4,4-pentachlorobutanoyl chloride with zinc and phosphoryl chloride, 4-chloro-4-(2,2,2-trichloroethyl)spiro[2.3]hexan-5-one (10) was isolated in 31% yield. The isolation of a single isomer instead of mixtures as described above is possibly due to the different reaction conditions which do not guarantee an uncatalyzed cycloaddition. 

Besides the addition of classical reagents to cyclopropanones vide supra), there are some reactions of cyclopropanones which lead to functionalized cyclopropanes via such reactions as cycloadditions with various reagents. Cycloadditions of the 2 + 2 - 4 type with the carbonyl moiety of 2,2-dimethylcyclopropanone (1) and dimethylketene and 1,1-dimethoxyethene give spiro compounds 2 and 3, respectively. ... 

Bicyclo[3,2,0]heptanes.—It might have been thought that filifolone (207) could be prepared by cycloaddition of dimethylketen to methylcyclopentadiene (205), but it has been shown that this reaction gives mainly two isomers (206a) and (206b), with small amounts of unidentified byproducts. For the conversion of the pinene skeleton to filifolone, see below. 

Also the dimerisation of dimethylketene is quite sensitive to solvents. Table 17(f), in a measure unknown with Diels-Alder reactions and 1,3-cycloadditions. However, for the reaction of diphenylketene with styrene the rate is slightly decreased with increasing dielectric constant of the medium. Table 17(e). 

Comparing cis and trans isomers of propenyl propyl ether in their reactivity towards diphenylketene, a ratio kcislknans of about 180 has been found (in PhCN, 40°C) , confirmed by the value of 172 20 from experiments without solvent with dimethylketene the ratio is 60 10 . The opposite phenomenon has been observed in Diels-Alder reactions of fumarate/maleate and other 1,2-disubstituted ethylenes (Section 4.1.3). The fact that cis isomers are thermodynamically less stable than trans isomers seems to prevail in determining relative reactivities of these 1,2-cycloadditions. 

Stereochemistry, substituent effects and activation parameters of most ketene reactions are consistent with a one-step cycloaddition polar effects of substituents and solvents, as well as the isotope effect, often require, however, that a fair amount of charge separation (that is, unequal bond formation) characterises the transition state. It has been kinetically proved that cycloadditions of enamines to ketenes can also proceed through a dipolar intermediate this is so for the reaction between dimethylketene and N-isobutenylpyrrolidine . In the latter case, the rate coefficient for the formation of the intermediate strongly depends on solvent polarity itacetonuriie/ cyclohexane = 560. Use of the Same criteria used for ketenes (as far as experimental data allow it) in the case of the 1,2-cycloadditions of fluorinated olefins results, instead, in the conclusion that a two-step biradical mechanism is operating. Results for 1,2-cycloaddition of sulfonyl isocyanates to olefins, cases (g) and (h) in Table 17, give indications of dipolar intermediates during the course of these reactions. 

Cyclobutanones.— These are frequently prepared by the cycloaddition of a keten or its formal derivative to an olefin. The secondary detuerium isotope effect, for the reaction of [a- H]styrene with dimethylketen is 0.8, indicating that the reaction is concerted, by analogy with other concerted cycloadditions which exhibit inverse isotope effects. ... 

The confusion was compounded when Isaacs and Hatcher [54] reported an inverse isotope effect (fcn/A D 0.8) at Ci of styrene in its cycloaddition to dimethylketene and cited it as further evidence for a concerted reaction. Finally, Holder et al [55] measured the isotope effect for the reaction of DPK with 5,5-dimethylcyclopentadiene. 

Mixed ketene dimers are also obtained by generating haloketenes in the presence of dimethylketene, by mixing of solutions of two different ketenes, and by cogeneration of two different ketenes from the carboxylic acid precursors Bis(trifluoromethyl)ketene does not dimerize thermally, but it reacts with Me2C=C=0 to form cyclobutanone and /3-propiolactone-type dimers ". The cycloaddition always proceeds across the C=C bond in the dimethylketene. In the reaction with ketene and methylketene, only the jS-propiolactone-type mixed dimers are formed. 

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