Favorskii rearrangement reaction conditions

Kraus and Shi used condensation reactions for the assembly of precursors to the quasi-Favorskii rearrangement. Reaction of the bromoketoester 83 with ethylamine and formaldehyde gave 84, the result of a double Mannich reaction fScheme 7.22T Under acidic conditions, methyl vinyl ketone combined with 83 to give the annulation product 87. Each of these products, 84 and 87, was a good substrate for the quasi-Favorskii rearrangement. Ketone 84 reacted with the enolate of acetylcyclohexene (85) to produce 86 in 60% yield. Ketone 87,... 

Under similar reaction conditions, some ketones such as (53) gave products via an electrochemically induced Favorskii rearrangement (Eq. 10) [89, 90]. 

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 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)... 

In the presence of base, a-haloketones rearrange to give acid derivatives depending upon the reaction conditions (equation 180). This very versatile reaction, the Favorskii rearrangement, has been the subject of several reviews966-968. The reaction was used in the synthesis of natural products, particularly steroids969-971, and the reader is referred to the reference sources for in-depth information. 

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). 

The Favorskii rearrangement is a base-catalyzed conversion of an a-haloketone into an acid or acid derivative such that the ketone a and a carbons come to share a bond, and the carbonyl carbon of the ketone becomes the carbonyl carbon of the carboxylic acid derivative tScheme 7T). The reaction can be regioselective, and its outcome is dependent not only on structural features of the starting material but on reaction conditions as well. 

Two groups have reported that reaction of 2-bromobicyclo[3,2,l]octan-3-one (557) under Favorskii rearrangement conditions (NaOMe-MeOH) gives mainly the substitution products (558) and (559) and very little of the ring-contraction products, the methyl 2-norbornanecarboxylates (largely exo-isomer). In... 

More recent work on the Favorskii rearrangement has focused on testing the ability of increasingly complex substrates to participate in Favorskii and related rearrangements. Efforts have also been directed at determining how reaction conditions affect the precise mechanism of Favorskii rearrangements. Both of these aspects of the Favorskii rearrangement will be discussed in subsequent sections. 

In specific cases, evidence has been obtained that indicates subtle changes in reaction conditions, such as the identity of the base, can alter the preferred mechanism of product formation, leading to the suggestion that both the Favorskii and semibenzylic mechanisms may be simultaneously operative in some Favorskii rearrangements. ... 

Partial Favorskii rearrangements can sometimes be achieved under mild reaction conditions that prevent rupture of the cyclopropane ring. A series of bicyclic nitroxide spin probes were prepared in this manner. ... 

The purpose of the present chapter is not to present an extensive report concerning all the studies related to the Favorskii rearrangement. It is limited to cyclohexane and constrained polycyclic molecules. However, as an introduction, we will survey rapidly the various processes which have been considered for this reaction. We will then present a general discussion of these mechanisms. The behavior of linear aliphatic a-haloketones will be compared with those of cyclic ones when submitted to basic conditions. We will emphasize the influence of the structure upon the nature of the reaction mechanism involved, as well as on the product distribution. It will be shown that the strain in polycyclic a-haloketones has a decisive influence on the rearrangement mechanism involved. 

Contrary to what is observed in the Favorskii rearrangement, such a substitution product is seldom observed in the Ramberg-Backlund reaction, as cyclic a-halogenated sulfones generally give only the ring-contracted alkene under basic conditions. The sulfone which has a skeleton similar to the diene 37... 

Translation of these results into compound I leads to structure X. Unraveling of the strained zwitterion XI derived from this would yield keto aldehyde XII, a structure that plays a central role in the various possible reaction mechanisms that branch off from the starting material I. Furthermore, under photo-lytic conditions, some alkenes react with carbonyl compounds to form four-membered cyclic ethers, namely, oxetanes, by way of a [2-1-2] cycloaddition reaction known as the Patemo-Buchi process. Such a reaction would be all that is necessary to convert XII into the bicyclic cyclopropanone XIII required for the Favorskii-type rearrangement (see Scheme 42.3). Splitting by methanol attack would directly yield compound II. 

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