Ring 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. 

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. 

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... 

Reaction (b) is a normal Favorskii reaction going to the right in the diagram. The only point of interest is the way in which the three-membered ring breaks up. The more stable carbanion is the doubly benzylic one so the right product is formed. 

You may wonder how the presence of excess MeO stops this from happening. It doesn t. 7 t oxyallyl cation and the cyclopropanone are in equilibrium and excess MeO captures jh cyclopropanone and drives the normal Favorskii reaction onwards. If there is no excess MeC the oxyallyl cation lasts long enough for the five-membered ring to be the main product. 

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. 

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. 

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.)... 

There is a ring contraction via a Favorskii reaction, through the following steps ... 

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). 

An intramolecular (4+3)-cycloaddition illustrates the potential of the quasi-Favorskii approach in the preparation of complex ring systerns.Reaction of readily available alcohol 80 with triflic anhydride afforded the cycloadduct 81 stereoselectively in 65% yield (Scheme 7.21 V Treatment of this compound with lithium aluminum hydride (LAH) afforded an essentially quantitative yield of alcohol 82 from a sequence of reduction, quasi-Favorskii rearrangement, and further reduction. 

As part of our program exploring the (4+3)-cycloaddition/quasi-Favorskii reaction sequence, we undertook a formal total synthesis of spatol fFigure 7.9T an interesting natural product possessing a unique diepoxide, a 5-4-5 ring-fused carbocyclic core, and antitumor... 

Aryl bromocycloalkyl ketones react with lithium amides in a homogeneous medium by quasi-Favorskii reactions. The quasi-Favorskii reaction is preferred over direct substitution by hindered bases or when electron-donating groups are present in the aryl ring. For example, 1-bromocyclohept-l-yl phenyl ketone gave the rearranged amide (329) when treated with lithium 2-methylanilide. ... 

When cyclic a-haloketones are submitted to the Favorskii reaction conditions, a ring contraction can be observed. This efllcient procedure has been applied to constrained substrates. The most spectacular example is probably the cubane synthesis achieved in 1964 by Eaton and Cole ... 

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