Nucleophiles Favorskii rearrangement

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). ... 

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 ... 

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 2-methyl-4/3,5/3-epoxy-3-ketone (244) reacts with methoxide ion to give the three products (245)—(247).208 A Favorskii-type rearrangement is clearly responsible for producing the A-nor-lactone (245), and is considered also to account for the other two products. The 2-methoxy-2-methyl-4-en-3-one (246), however, could possibly result from direct attack of methoxide ion on the A2-enol derivative of the epoxy-ketone (cine substitution), followed by elimination of a 5/3-hydroxy-group to give the a/3-unsaturated ketone. The occurrence of Favorskii rearrangement in the 2-methylated compound (244) contrasts with a simple nucleophilic opening of the unsubstituted 4/3,5/3-epoxy-3-ketone this is one of several recent examples in which an a-substituent favours Favorskii rather than alternative reactions.208... 

The key step in the stereocontrolled total synthesis of the tricyclic (+)-kelsoene by M. Koreeda et al. was a base-catalyzed homo-Favorskii rearrangement of a y-keto tosylate to elaborate the 4-5 fused ring portion of the target molecule. The bicyclic 5-6 fused y-keto tosylate was treated with excess potassium fert-butoxide, which effected the desired rearrangement in less than 2 minutes at room temperature. The nucleophilic solvent was too bulky to effect the opening of the cyclobutanone intermediates, making their isolation possible. The mixture of isomeric cyclobutanones was converted to a separable 1 1 mixture of cyclobutanones with p-TsOH, and the ketone functionality was then removed via the corresponding tosylhydrazone. 

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. 

Cyclopropylideneamines were trapped in an intramolecular manner during the Favorskii rearrangement of suitably functionalized a-chloro ketimines 44 bearing a protected nucleophile in the molecule. Base-induced 1,3-dehydrochlorination generates the three-membered ring intermediate 45 which undergoes intramolecular nucleophilic addition of the deprotected nucleophile to form adducts 46. 

The details of the Favorskii rearrangement continue to attract attention and cyclopropanone intermediates in the peracid epoxidation of allenes have been noted. The fluoride-ion-promoted elimination of chlorotrimethylsilane from (375) leads to the allene oxide (376) which undergoes regiospecific ring-opening with nucleophiles. However, rearrangement of (376) to cyclopropanone (377) only occurs prior to nucleophilic capture when C-1 carries an aryl substituent (Scheme 45). ... 

A Stereoselective Synthesis volume of the Science of Synthesis series has reviewed the alkylation and allylation of carbonyl and imino groups, as well as the enantio-selective addition of metal alkynylides to imino and carbonyl compounds. Recent advances in Favorskii rearrangement, Sonogashira reactions, and catalytic enantio-selective allylic substitutions with carbon nucleophiles have been highlighted. 

When a-haloketones are treated with a nucleophilic base in protic or ethereal solvents, a transformation known as the Favorskii rearrangement occurs to yield carboxylic acid derivatives. Depending on the identity of the incorporated base the final product will be a carboxylic acid, ester, or amide. Cyclic a-haloketones undergo a ring contraction during the course of the rearrangement. 

The canonical formulation of the mechanism of the Favorskii rearrangement involves initial deprotonation of the a-carbon to generate an enolate, intramolecular displacement of the leaving group on the a -carbon by the enolate to generate a cyclopropanone, addition of a nucleophile to the cyclopropanone ketone followed by elimination to generate the more stable of two possible carbanions, and protonation to yield the rearranged carboxylic acid derivative. 

The Favorskii rearrangement is a base-mediated carbon skeletal rearrangement that occurs when a nucleophile adds to an a -halo ketone possessing an a-hydrogen. This transformation converts an a-halo ketone 1 to a carboxylic acid derivative 2. There is also an intramolecular variant of this transformation in which the resulting ring size contracts by one-carbon atom. 

Stevens and coworkers reported on the quasi-Favorskii rearrangement of a norborane derivative. The exo-2-bromo-e /o-2-benzoyl norborane 52 tmdergoes a rearrangement with lithium anilide as the nucleophile to form 53. The concerted semi-benzylic mechanism of this reaction produces only one of the possible isomeric products. A trace amount of the bromo-displaced product 54 was also observed. The rearranged product was... 

Crown ether has been used for nucleophilic displacement of chloride by cyanide at hindered position. At room temperature the reaction of 2-chloro-2-methyl cyclohexanone with potassium cyanide in acetonitrile in presence of 18-crown-6 affords the cyanide in excellent yield, but when the reaction is conducted at reflux temperature Favorskii rearrangement occurs to yield five membered compound in high yield (Scheme 36). 

In some cases an alternative mechanism is involved in what has been called a pseudo-Favorskii rearrangement (Eq. 11.61). The reaction involves nucleophilic addition to the carbonyl, followed by breakdown of the tetrahedral intermediate with concomitant migration... 

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