The Favorskii reaction

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

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. 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

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... 

The Favorskii reaction has been used to effect ring contraction in the synthesis of strained ring compounds. Entry 4 in Scheme 10.3 illustrates this application of the reaction. With 7,7 -dihalo ketones, the rearrangement is accompanied by dehydrohalo-genation to yield an a,/ -unsaturated ester, as illustrated by entry 3 in Scheme 10.3. 

The method is simple, and has the additional virtue of great versatility. The requisite ally lie alcohol can be prepared via the Favorskii reaction of a 20-ketopregnane, or via ethoxyacetylene addition to a 17-ketoandrostane. Additional functional groups may be present prior to these reactions or introduced into the A17(20)-compound later. An aromatic A-ring, A-ring unsaturated ketones and the 11 /1-hydroxyl group are all stable to the oxidative attack on the A17(20)-olefln, and the 21-acetate is not hydrolyzed during the reaction. 

The classic labeling studies of Loftfield 49a> have demonstrated that cyclopropanones are intermediates in the Favorskii reaction 49b) — the base-induced rearrangement of a-haloketones (Scheme 8). The related reaction of a,a -dibromoketones has, in fact, become a convenient preparative route for cyclopropenones, e.g., 48 ->- 49 via 50.50>... 

In the Favorskii reaction a haloketone reacts with alkali to give a carboxylic acid with simultaneous skeletal rearrangement thus 2-chlorocyclohexanone (XXX) gives cyclopentanecarboxylic acid (XXXI)... 

But is the same cyclopropanone an intermediate in the Favorskii reaction If the bromoketone is treated with methoxide in methanol, it gives the Favorskii product but, if it is treated with a much more hindered base, such as the potassium phenoxide shown, it gives the same cyclopropanone with the same stereochemistry. 

Other, less stable cyclopropanones, such as the 2,2-dimethyl compound, can be made by carbene addition (Chapter 40) to ketenes. This compound did the Favorskii reaction with methoxide in methanol the only product came from the expected loss of the less unstable carbanion. This will, of course, be general-acid-catalysed by methanol as no free carbanion can be released into an alcoholic solvent. 

The formation of hydrazodicarbonamide by the reaction of chlorobiuret sodium salt with ammonia is through the Favorskii reaction illustrated in Eq. 2 ... 

Classic work by Loftfield on the Favorskii reaction showed that cyclopropanones are intermediates in the base-induced rearrangement of a-haloketones (l heme 4). Isolation of such an intermediate was accomplished in the reaction of the sterically hindered a-bromodineopentyl ketone (9) with potassium p-chlorophenyldimethylcarbinolate. The identity of the product (10), rrans-2,3-di-t-butylcyclopropanone, was established by independent synthesis of 1,3-di-t-butylallene oxide (11) which underwent valence isomerization to (10) ... 

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. 

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. 

There is an obvious difficulty if the cyclopropane ring is unsymmetrically substituted and our best guideline here is the last stage of the Favorskii reaction,8 e.g. 27 to 31, where a cyclopropoxide ion is protonated 30 at the carbon atom giving the better anion, usually at the less substituted carbon. 

With two more electrons, and rather more complicated structures, the Nazarov-like reactions of the carbamates 6.536 and 6.538 are conrotatory, with the torquoselectivity determined, as in the Favorskii reactions, by which side of the conjugated system the nucleofugal group departs from, clockwise as drawn for the carbamate 6.536 and anticlockwise for its diastereoisomer 6.538.964 The topological sense of the event in the left-hand ally lie system corresponds to an anti Sn2 reaction in both cases. 

In the view of the present authors the involvement of an a-lactam intermediate114 116 (126) in a process reminiscent of the Favorskii reaction must at least be considered. 

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