Alkenes, -cycloaddition with ketenes

The limitations of the ketene method for generating cyclobutanoncs is the tendency for ketenes to dimerize as a major competing process. This can be overcome by using excess alkene and by control of reaction temperature in order to minimize dimerization. Another limitation of the ketene route is the inertness of electron-deficient alkcncs to undergo cycloaddition with ketenes. 

For thermally induced [2 + 2] cycloadditions, the concerted mechanism is operative only in particular cases, such as in the reactions between an alkene or alkyne and a ketene. The ketene can be generated directly in the reaction mixture from the appropriate acid chloride with triethylamine. The cycloaddition reaction is stereospecific and occurs exclusively in a cis fashion. Although the intermolecular cycloaddition with ketene itself proceeds in poor yields due to the propensity of the unsubstituted ketene to undergo dimerization, it is quite an efficient reaction with ketenes containing electron-withdrawing substituents. Usually, a-chloro ketenes are employed as reagents formed in situ from the corresponding a-chloro acid chlorides. Typical examples are represented in the preparation of cycloadducts such as 378 and 379 (Scheme 2.127). The latter cycloadduct, prepared in modest yield (ca. 20%),... 

Three classes of [2 -t- 2] cycloadditions do proceed under thermal conditions. Ketenes (R2C=C=0) undergo concerted cycloadditions to alkenes under thermal conditions because the ketene can react antarafacially with an alkene that reacts suprafacially. The two termini of the C=C tt bond of the ketene react from opposite faces of the tt bond, creating positive overlap between the orbitals at both termini of the two tt systems. The antarafacial nature of the ketene does not have any stereochemical consequences, as there is no cis-trans relationship in the ketene to preserve in the product. The alkene component of the [2 -I- 2] cycloaddition with ketenes, however, reacts suprafacially, and its stereochemistry is preserved in the product. 

Other isocyanates undergo [2 + 2] cycloaddition, but only with very electron rich alkenes. Thus phenyl isocyanate gives /3-lactams with ketene acetals and tetramethoxyethylene. With enamines, unstable /3-lactams are formed if the enamine has a /3-H atom, ring opened amides are produced 2 1 adducts are also found. Photochemical addition of cis- and traH5-stilbene to phenyl isocyanate has also been reported (72CC362). 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Ketenes are especially reactive in [2 + 2] cycloadditions and an important reason is that they offer a low degree of steric interaction in the TS. Another reason is the electrophilic character of the ketene LUMO. As discussed in Section 10.4 of Part A, there is a large net charge transfer from the alkene to the ketene, with bond formation at the ketene sp carbon mnning ahead of that at the sp2 carbon. The stereoselectivity of ketene cycloadditions is the result of steric effects in the TS. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis, which is the stereochemistry usually observed in these reactions. 

Scheme 6.8 gives some examples of ketene-alkene cycloadditions. In Entry 1, dimethylketene was generated by pyrolysis of the dimer, 2,2,4,4-tetramethylcyclobutane-l,3-dione and passed into a solution of the alkene maintained at 70° C. Entries 2 and 3 involve generation of chloromethylketene by dehydrohalo-genation of a-chloropropanoyl chloride. Entry 4 involves formation of dichloroketene. Entry 5 is an intramolecular addition, with the ketene being generated from a 2-pyridyl ester. Entries 6, 7, and 8 are other examples of intramolecular ketene additions. 

Cycloadditions give rise to four-membered rings. Thermal concerted [2+2] cycloadditions have to be antarafacial on one component and the geometrical and orbital constraints thus imposed ensure that this process is encountered only in special circumstances. Most thermal [2+2] cycloadditions of alkenes take place by a stepwise pathway involving diradical or zwitterionic intermediates [la]. Considerably fewer studies have been performed regarding the application of microwave irradiation in [2+2] cydoadditions than for other kinds of cydoaddition (vide supra). Such reactions have been commonly used to obtain /1-lactam derivatives by cycloaddition of ketenes with imines [18-20,117,118],... 

Using (-)-lOO [46] as a chiral auxiliary tethered to the enolether, one face of the alkene can be specifically blocked by a n-n interaction of the phenyl rest for the [2 r5+2 r ] cycloaddition with a ketene [47], resulting in the highly diastereoselective formation of the cyclobutanone 102 (Scheme 15). The observed regio- and stereoselectivity is in accord with the stereochemical predictions made on the basis of the Woodward-Hoffmann... 

Cycloadditions of ketenes and alkenes have been shown to have synthetic utility for the preparation of cyclobutanones.101 The stereoselectivity of ketene-alkene cycloaddition can be analyzed in terms of the Woodward-Hoffmann rules.102 To be an allowed process, the [2n + 2n] cycloaddition must be suprafacial in one component and antarafacial in the other. An alternative description of the transition state is a [2ns + (2ns + 2ns)] addition.103 Figure 6.6 illustrates these transition states. The ketene, utilizing its low-lying LUMO, is the antarafacial component and interacts with the HOMO of the alkene. The stereoselectivity of ketene cycloadditions can be rationalized in terms of steric effects in this transition state. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis. This is the... 

Among the most commonly applied chiral moiety for nitrones (2) is the N-a-methylbenzyl substituent (Scheme 12.6) (18-25). The nitrones 8 with this substituent are available from 1 -phenethylamine, and the substituent has the advantage that it can be removed from the resulting isoxazolidine products 9 by hydrogeno-lysis. This type of 1,3-dipole has been applied in numerous 1,3-dipolar cycloadditions with alkenes such as styrenes (21,23), allyl alcohol (24), vinyl acetate (20), crotonates (22,25), and in a recent report with ketene acetals (26) for the synthesis of natural products. Reviewing these reactions shows that the a-methylbenzyl group... 

One of the most reactive electrophilic alkenes is l,l-dicyano-2,2-bis(trifluoromethyl)ethene which undergoes cycloadditions with enol ethers, thioenol ethers, ketene acetals and thioacetals even at temperatures as low as — 78 °C. The cyclobutancs are formed as the sole products of the reaction.37-38 The reactions arc regiospecific and highly stereoselective even though evidence for zwitterionic intermediates have been obtained. 

Ketene acetals and thioacetals can be used as ketene equivalents in cyclobutanone synthesis in situations where ketene to alkene cycloadditions are inefficient such as in the case of electron-deficient alkenes.14 Although thermal cycloadditions of ketene acetals and thioacetals with electron-deficient alkenes have been observed (see Section 1,3.2.1.), such cycloadditions proceed more efficiently and under milder conditions with metal catalysts. Efficient cycloadditions between ketene dimethyl acetal and alkenes substituted by a single electron-withdrawing group have been reported.15... 

Steroids represent rigid chiral systems which are convenient substrates for mechanistic studies of geometric details. Early studies on the difacial selectivity of ketene to steroidal alkene cycloadditions led to the preparation of optically pure cyclobutanones. The addition of dichloroketene to 2- or 3-methyl-5a-cholcst-2-ene (1) generates the cyclobutanones 2 and 3 with regio- and stereoselectivity. The cycloadditions proceed to give the adducts resulting from ketene approach to the a-face.4... 

The application of chiral auxiliary groups which can be removed after the cycloaddition has met with limited success. The chiral auxiliary can be attached to either the ketene or alkene moiety. In a study of dichloroketene cycloadditions with a series of enol ethers 18, to which a chiral alkoxy group is attached, diastereoselectivities ranged from 55 to 90%,n with the choice of chiral auxiliary being crucial to obtaining the desired diastereoselectivity. 

The stereochemistry of ketene to alkcne cycloadditions is such that retention of the alkene configuration is observed. Furthermore, in cycloadditions with unsymmetrically substituted ketenes the larger of the two ketene substituents ends up as with respect to the adjacent alkene substituent (or eiulo in cycloalkene cycloadditions). This stereochemical outcome was originally attributed to the concerted [ff2a + n2a] nature of kctcnc to alkene cycloadditions,21 although more recent experimental and theoretical evidence indicate that these reactions are asynchronous and in some cases in which polarized double bonds are involved actual zwittcrions may be intermediates.9 1195 Also in certain cases the endo product in ketene to alkene cycloadditions may be the thermodynamic product from equilibration studies.22,23 Nevertheless, stereochemical control can be achieved in most such reactions as shown by the examples of 12,24 13,29 14,25 15,26 16,27 and 17.28... 

With vinylketene adducts (2-vinylcyclobutanones) possessing an enolizable hydrogen, the presence of triethylamine used for generating the ketene will occasionally cause double-bond isomerization resulting in alkylidenecyclobutanones 22.138,139 These derivatives are not readily prepared by alkylideneketene to alkene cycloadditions because of the extreme reactivity towards dimerization of these ketenes. 

Reactions of ketenes with electron-rich alkenes proceed more readily than with nonactivated alkenes and in the case of enol ethers, enol sulfides and ketene acetals, the cycloaddition is regiospecific (see Table 6). With tetraalkoxyethene, cycloaddition with the relatively inert ketene can be carried out 124 however, with less activated alkenes the use of metal catalysts such as zinc(ll) chloride is required for cycloaddition of the parent ketene.115... 

Unlike ketcnc cycloadditions, very few mechanistic studies have been carried out with ketene iminium salt cycloadditions. Differences in regiochemistry in the latter examples suggest that these reactions are not concerted and that a carbcne-type addition to the alkene leading to an intermediate such as 6 is responsible for these reactions.8... 

In addition to the alkylations discussed above, some special reactions have been reported that enable the solid-phase synthesis of cycloalkanes. These include the intramolecular ene reaction and the cyclopropanation of alkenes (Figure 5.5 see also [44]). Cyclobutanes have been prepared by the reaction of polystyrene-bound carbanions with epichlorohydrin, and by [2 + 2] cycloadditions of ketenes to resin-bound alkenes. 

Ketenes also can be used for the synthesis of cyclobutane derivatives through [2 + 2] cycloadditions with suitably active alkenes (Section 13-3D) ... 

So special reactions are often used to make cyclobutanes. In the next chapter we shall see that thermal cycloadditions of alkenes with ketenes give four-membered rings, but the commonest method is photochemical cycloaddition. You are already aware that Diels-Alder reactions (chapter 17) occur easily when a diene 6 and a dienophile 7 are heated together and six-membered rings 8 are formed. Have you ever wondered why four-membered rings 9 are not formed instead Orbital symmetry allows cycloadditions involving six Ti-electrons but not those involving four 7r-electrons.2... 

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