Cyclopropanone Favorskii rearrangement

The currently accepted mechanism for the Favorskii rearrangement of dihalo ketones involves a cyclopropanone intermediate formed by loss of HX. This is followed by attack of alkoxide synchronous with cyclopropanone fragmentation and departure of halide ion to form the unsaturated ester... 

Quantum mechanical/molecular mechanical study on the Favorskii rearrangement in aqueous media has been carried out.39 The results obtained by QM/MM methods show that, of the two accepted mechanisms for Favorskii rearrangement, the semibenzilic acid mechanism (a) is favored over the cyclopropanone mechanism (b) for the a-chlorocyclobutanone system (Scheme 6.2). However, the study of the ring-size effects reveals that the cyclopropanone mechanism is the energetically preferred reactive channel for the a-chlorocyclohexanone ring, probably due to the straining effects on bicycle cyclopropanone, an intermediate that does not appear on the semibenzilic acid pathway. These results provide new information on the key factors responsible for the behavior of reactant systems embedded in aqueous media. 

As usual, the key to this problem is numbering correctly. The main question is whether the ester C in the product is C3 or C4. Because a ring contraction from 6- to 5-membered is likely to proceed by a Favorskii rearrangement, where the last step is cleavage of a cyclopropanone, it makes sense to label the... 

Semiempirical calculations on the Favorskii rearrangement of a-chlorocyclobutan-one to cyclopropenecarboxylic acid suggest that it proceeds via a stepwise semibenzilic acid pathway, both in solution and in vacuo, rather than by a cyclopropanone... 

A common intermediate is required in this Favorskii rearrangement to set the same product. Removal of an aH by OH- is followed by an SN2 displacement of Cl- to give a cyclopropanone ring. Ring opening occurs to give the more stable benzylic carbanion. 

In order to activate the 21 position to halogenation, it is hrst converted to an oxalate. Condensation of the triketone with ethyl oxalate in the presence of alkoxide proceeds preferentially at the 21 position to give (12-2) due to the well-known enhanced reactivity of methyl ketones. Reaction of the crude sodium enolate with bromine leads to the dibromide (12-3), the oxalate moiety being cleaved under the reaction conditions. The Favorskii rearrangement is then used to, in effect, oxidize the 17 position so as to provide a site for the future hydroxyl group. Thus, treatment of (12-3) with an excess of sodium methoxide hrst provides an anion at the 17 position (12-4). This then cyclizes to the transient cyclopropanone (12-5)... 

The quasi-Favorskii rearrangement obviously cannot take place by the cyclopropanone mechanism. The mechanism that is generally accepted (called the semibenzilic mechanisml57)... 

Cyclopropanones deserve special comment, not because of their practical importance (they have no commercial value at this time), but because of their novel behavior and reactivity. No unambiguous synthesis of cyclopropanones was known prior to 1965, and the older textbooks usually contained statements such as cyclopropanones apparently cannot exist. However, they had been postulated as intermediates in various reactions (see, for example, the Favorskii rearrangement, Section 17-2C and Exercise 17-15), but until recently had defied isolation and identification. The problem is that the three-ring ketone is remarkably reactive, especially towards nucleophiles. Because of the associated relief of angle strain, nucleophiles readily add to the carbonyl group without the aid of a catalyst and give good yields of adducts from which the cyclopropanone is not easily recovered ... 

Another useful route to cyclopentanes is the ring contraction of 2-bromo-cyclohexanones by a Favorskii rearrangement to give cyclopentanecarboxylic acids. If a,fi-dibromoketones are used, ring opening of the intermediate cyclopropanone leads selectively to /J,y-unsaturated carboxylic acids (S.A. Achmad, 1963, 1965 J. Wolinsky, 1965). 

The acid hydrolysis of cyclopropanone ethylene ketals to the corresponding esters appears to be a facile, high yield reaction (75—90%) which may be of synthetic importance. Thus, as shown in Scheme 29, a ring contraction similar to a Favorskii rearrangement may be achieved under mildly acidic conditions.107)... 

Cyclopropanone cleavage with elimination 72 can also lead to ring contraction as in the synthesis of the trans acid 74 from natural pulegone13 70. Bromination gives the unstable dibromide 71 that is immediately treated with ethoxide to initiate the Favorskii rearrangement. The product is a mixture of cis and trans isomers of the ester 73 but hydrolysis under vigorous conditions (reflux in aqueous ethanol) epimerises the ester centre and gives exclusively the trans acid 74. 

So how can the cycloaddition be promoted at the expense of the Favorskii rearrangement Nothing can be done about the equilibrium between the oxyallyl anion and the cyclopropanone— that s a fact of life. The answer is to reduce the nucleophilicity of the alcohol by using trifluoro-ethanol instead of ethanol. Under these conditions the major product is the cycloadduct, which can be isolated in 73% yield. 

The reverse reaction of this general class—an allyl cation giving a cyclopropyl cation—is found in Favorskii rearrangements. The diastereoisomeric Q-chloro enolates 6.334 and 6.337 give the cyclopropanones 6.335 and 6.338, respectively. Thus the reaction is stereospecific, at least in a nonpolar solvent. Evidently the allyl cation is not formed, otherwise the two chlorides... 

The generally accepted mechanism for the Favorskii rearrangement involves the formation of reactive cyclopropanone intermediate C. Base abstracts the a-hydrogen from A to give the carbanion B, which undergoes intramolecular Sn2 displacement of the halide ion. The resulting cyclopropanone intermediate C is opened under the reaction conditions to give the more stable carbanion D, which takes proton from solvent to furnish the final product, an ester E (Scheme 2.25). 

Sterically crowded a-haloketones and a-haloketimines cyclize to cyclopropanones and ketiinines, respectively, upon treatment with bases. The reaction of a series of a-haloketones with dialkyl sodiomalonate has been found to give the adducts of the malonate anion to incipient cyclopropanones, i.e. (l-hydroxycyclopropyl)malonic esters, instead of the products of the Favorskii rearrangement . Cyclopropanone aminals and l-alkoxycyclopropylamines have been obtained in the reactions of cyclic a-chloroketones (equation 16) with secondary amines and of a-chloroketimines with... 

Cyclopropanone is a generally accepted intermediate in the Favorskii rearrangement, as shown in equation 9. BordwelF has suggested that the second step of the Favorskii... 

Other symmetrical intermediates originally identified by radioactive labelling include the cyclopropanone in the Favorskii rearrangement in Chapter 37, p. 000, and a spirocyclic intermediate in electrophilic substitution on an indole in Chapter 43,... 

Favorskii rearrangement Skeletal rearrangement of a-halo ketones via a cyclopropanone intermediate to give carboxylic acids or carboxylic acid derivatives. 164... 

Rappe, C., Knutsson, L. Cyclopropanones and the Favorskii rearrangement. An unexpectedly large secondary isotope effect. A/ geiv. Chem., Int. Ed. Engl. 1972,11, 329-330. 

When the Favorskii rearrangement is carried out on a substrate which contains an internal nucleophile, this can attack the cyclopropanone intermediate to yield cyclic products. The reaction shown in Scheme 13 provides a route to polysubstituted "y-butyrolactones by this kind of mechanism. 

The whole process comprising the conversion of an a-halo ketone into a cyclopropanone, the adduct formation, and subsequent ring opening into carboxylic acid derivatives (carboxylic esters, carboxylic acids or carboxylic amides by using alkoxides in alcohols, hydroxides in water or amines in various solvents, respectively) is known as the Favorskii rearrangement. 

The Favorskii rearrangement will not be treated in detail here because, in general, it does not lead to isolable cyclopropanones. Additions to cyclopropanones are treated amongst the reactions of cyclopropanes, while the Favorskii rearrangement has been reviewed extensively in the literature. ... 

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