Favorskii reaction mechanisms

Bromo-6,6-diinethylcyclohexanone gives 2,2-dimethylcyclopentane-carboxylic acid on treatment with aqueous NaOH followed by acidification, a process called the Favorskii reaction. Propose a mechanism. 

A reaction related to the pure carbanion rearrangement, but one that eventually involves an external displacing agent as well, is the Favorskii reaction. It has been shown with the aid of isotopic tracers that the mechanism is 429... 

Although experimental evidence makes it unlikely that the latter has any general relevance to Favorskii reactions, it is included for consideration here because it appears as a likely mechanism in the special case of 5a,7a-dibromocholestan-6-one (31) [3iy]. This compound undergoes a ring contraction on treatment with pyridine to give the unsaturated carboxylic... 

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. 

This work was part of a thorough investigation into the mechanism of the Favorskii reaction by F. G. Bordweii and group, J. Am. Chem. Soc., 1970, 92, 2172. 

The Favorskii reaction involve. treatment of an a-bromo ketone with base to yield a ring-contracted product. For example, reaction of 2-bromocyclohexanone with aqueous NaOH yields cyclepentnnecarboxylic acid. Propose a mechanism. 

In order to distinguish between a mechanism proceeding via a symmetrical cyclopropanone intermediate (Favorskii reaction) and a mechanism closely related to the benzilic acid rearrangement and called semibenzilic (or quasi-Favorskii) rearrangement, the ring contraction of 2-bromocyclobutanone was studied in deuterium oxide using sodium carbonate as base (50 C) or in boiling deuterium oxide only. 

Concerning the mechanism of the Favorskii reaction, it is suggested that loss of the nucleofuge oecurs, resulting in a 2-oxyallyl cation, but that disrotatory ring closure is facile and the only products observed result from nucleophilic trapping of the cyclopropanone intermediate to provide cyclopropanols in fair to good yield. 

A carboxylic acid is formed when an a-haloketone reacts with hydroxide ion. This reaction is called a Favorskii reaction. Propose a mechanism for the following Favorskii reaction. Hint In the first step, HO removes a proton from the a-carbon that is not bonded to Br a three-membered ring is formed in the second step and HO is a nucleophile in the third step.)... 

Reaction of the a-bromoketone (401) with primary amines gives good yields of amides resulting from a Favorskii type mechanism the amides in turn are a useful source of substituted tryptamines (Equation (114)) <90JHC1601>. 

An elegant study by Warnhoff et al. systematically analyzed mechanism as a function of structure in bridged bicyclic ketones related to 21. Treatment of 21 with NaOD in refluxing Et0D/D20 afforded the corresponding acid 24 in 95% yield with no incorporation of deuterium f Scheme 7.8. Eq. 1). Had this been a normal Favorskii reaction, one deuterium should have been incorporated. Similarly, when 25 was treated under the same conditions, the ring contraction product 26 contained no deuterium tScheme 7.R. Eq. 2). However, with 27, essentially a completely monodeuterated compound was obtained, indicative of a normal Favorskii reaction tScheme 7.8. Eq. 3). 

The quasi-Favorskii rearrangement has been used often in the synthesis of unnatural, conplex, polycyclic structures. Indeed, this method is uniquely suited for such targets. However, undesired side reactions can occur. An exanple, discussed here within its mechanistic context, is based on a report by Ueda and coworkers. They treated the polycyclic dibrominated diketone 37 with potassium hydroxide in the expectation of obtaining cubane-l,3-dicarboiq lic acid 38. Given what was known about quasi-Favorskii reactions at the time (vide supra), the plan made perfect sense. However, exposure of 37 to 5% KOH for 15 min at 80 °C afforded not 38 but the cyclopropyl lactone 43 fScheme 7.12). A proposed mechanism for the process began with a Haller-Bauer cleavage, always a potential risk in quasi-Favorskii... 

An early study on Favorskii reaction gives a plain explanation how radioactive tracers are used in elucidation of reaction mechanisms (Loftfield 1950). The reaction is the rearrangement of an a-haloketone in alkaline medium. Two mechanisms (1 and 2) had been proposed for the reaction. 

Although the Favorskii reaction is pretty well known, studies concerning its mechanism are still in progress, especially in view of the current interest in reaction intermediates such as zwitterion, carbanion, and cyclopropanones. 

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. 

Malonate anions react at low temperatures (0—25 C) with cyclic a-haloketones via a Favorskii-type mechanism leading to jS-keto-esters (153) in reasonable yields (Scheme 17). " Reactions at higher temperatures result in simple 5n2 substitution. Specific Dieckmann cyclizations of alkyl pimelates can be effected by attaching one end of the substrate to a polymer support. ... 

The mechanism of the novel transformation of a-nitro- to a-hydroxy-ketones has been probed. The reaction, which proceeds under basic aqueous conditions, requires that the Q -nitro substrate be CH-acidic in the a -position, and that it be readily depro-tonated under the conditions employed. NO2 -OH exchange occurs with retention of configuration, with the hydroxyl oxygen being predominantly derived from the solvent. A mechanism involving neighbouring-group participation, via a Favorskii-like cyclopropanone intermediate, is proposed. 

For a discussion of the mechanism of the Favorskii addition reaction, see Kondrat cva Potapova Grigina Glazunova Nikitin J. Org. Chem. USSR 1976, 12, 948. 

---