Carboxylic acids Favorskii rearrangement

Another useful route to cyciopentanes is the ring contraction of 2-bromo-cydohexanones by a Favorskii rearrangement to give csrdopcntanecarboxylic acids. If a 0 dibromoketones are used, ring opening of the intermediate cydopropanone leads selectively to, y-unsaturated carboxylic acids (S.A, Achmad, 1963, 1965 J. Wolinsky, 1965). 

The methyl ester (100, R = CH3), derived from this A-nor acid by treatment with diazomethane, is different from the ester (102) obtained either by Favorskii rearrangement of 2a-bromo-5a-cholestan-3-one (101) or by the action of cyanogen azide on 3-methoxy-5a-cholest-2-ene (103) followed by hydrolysis on alumina. The ketene intermediate involved in photolysis of (99) is expected to be hydrated from the less hindered a-side of the molecule to give the 2j -carboxylic acid. The reactions which afford (102) would be expected to afford the 2a-epimer. These configurational assignments are confirmed by deuteriochloroform-benzene solvent shifts in the NMR spectra of esters (100) and (102). ... 

An interesting analog of the Favorskii rearrangement treats a ketone such as 4-/ r/-butylcyclohexanone, without an oc-halogen with T1(N03)3 to give 3-tert-butylcyclopentane-1 -carboxylic acid. ... 

The subjects of this section are two reactions that do not actually involve carbo-cation intermediates. They do, however, result in carbon to carbon rearrangements that are structurally similar to the pinacol rearrangement. In both reactions cyclic intermediates are formed, at least under some circumstances. In the Favorskii rearrangement, an a-halo ketone rearranges to a carboxylic acid or ester. In the Ramberg-Backlund reaction, an a-halo sulfone gives an alkene. 

Favorskii rearrangement org chem A reaction In which a-halogenated ketones undergo rearrangement in the presence of bases, with loss of the halogen and formation of carboxylic acids or their derivatives with the same number of carbon atoms. fa vor-ske, re-3 ran -m3nt)... 

The reaction of a-haloketones (chloro, bromo or iodo) with alkoxide ions to give rearranged esters is called Favorskii rearrangement. For example, 2-chlorocyclohexanone is converted to the methyl ester of cyclopentane carboxylic acid by treatment with sodium methoxide in ether. 

The methyl ester has also been obtained by esterification of cyclopentanecarboxylic acid.8 The acid, in turn, has been prepared by the Favorskii rearrangement,6 7 9-11 by the reaction of cyclopentyl Grignard reagent with carbon dioxide,12 by the carbonylation of cyclopentyl alcohol with nickel carbonyl13 or with formic acid in the presence of sulfuric acid,14 and by the hydrogenation of cyclopentene-1-carboxylic acid prepared from ethyl cyclopentanone-2-carboxylate 15 or from cyclopentanone cyanohydrin.16... 

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)... 

Favorskii rearrangement of cyclic 2-bromoketones leads to ring contraction and this has become one of the most fruitful uses of the rearrangement in synthesis. Bromination of cyclohexanone is a simple reaction (Chapter 21) and treatment with methoxide gives the methyl ester of cyclopentane carboxylic acid in good yield. 

This means that it can be used to build up heavily branched esters and carboxylic acids—the sort that are hard to make by alkylation because of the problems of hindered enolates and unreactive secondary alkyl halides. Heavily substituted acids, where CO2H is attached to a tertiary carbon atom, would be hard to make by any other method. And the Favorskii rearrangement is a key step in this synthesis of the powerful painkiller Pethidine. 

The base-catalyzed rearrangement of a-haloketones (chloro and bromo) to carboxylic acid derivatives is called Favorskii rearrangement. 

A typical Favorskii rearrangement involves reaction of an a-halo ketone with a base to give an ester or carboxylic acid, as in the following example ... 

E. Lee and co-workers demonstrated that the chlorohydrin derived from (+)-carvone undergoes a stereoselective Favorskii rearrangement to afford a highly substituted cyclopentane carboxylic acid derivative. This intermediate was then converted to (+)-dihydronepetalactone. When the THP-protected chlorohydrin was treated with sodium methoxide in methanol at room temperature, the rearrangement took place with excellent stereoselectivity (10 1) and high yield. Interestingly, the major product was the thermodynamically less stable cyclopentanecarboxylate. 

Favorskii rearrangement Skeletal rearrangement of a-halo ketones via a cyclopropanone intermediate to give carboxylic acids or carboxylic acid derivatives. 164... 

This reaction is called the Favorskii rearrangement. Again, there are many variations for example, instead of an alkoxide anion, a hydroxide anion or even an amine may be used, in which case the salt of the carboxylic acid or the amide will be formed, respectively. This reaction may also be used so as to result in a ring contraction. Write down the mechanism for the reaction between an alkoxide anion and 2-chlorocyclohexanone. 

In the benzil-benzilic acid rearrangement, an a-diketone is treated with a base to give the sodium salt of an a-hydroxy carboxylic acid. In the Favorskii rearrangement, an a-halogenoketone is treated with an alkoxide anion to give the a-alkyl ester. This reaction may also be used to effect a ring contraction. 

The whole process comprising the conversion of an a-halo ketone into a cyclopropanone, the adduct formation, and subsequent ring opening into carboxylic acid derivatives (carboxylic esters, carboxylic acids or carboxylic amides by using alkoxides in alcohols, hydroxides in water or amines in various solvents, respectively) is known as the Favorskii rearrangement. 

The Favorskii rearrangement also occurs with di-, tri- and tetrahalo ketones and gives rise to (halogenated) unsaturated carboxylic acid derivatives. 

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