Favorski rearrangement

The Favorski rearrangement is widely applicable. In the aliphatic series it leads to branched-chain carboxylic acids and in the cycloalkane series to ring contraction. The latter feature has been made use of in conversion of a six-membered into a five-membered steroid ring d and in the synthesis of cubane. 

The reaction is effected by potassium hydroxide in ethanol, by an alkoxide in the corresponding alcohol, or often in two phases by sodium methoxide and diethyl ether. It usually occurs at room temperature. 

4-Chloro-3-heptanone (200 g) is stirred with a suspension of sodium methoxide (73.5 g) in anhydrous ether (400 ml) for 75 min, the temperature being kept below 10°. Thereafter the mixture is boiled for 40 min and then treated with water. Methyl 2-ethylvalerate (147 g, 77%) is obtained from the ethereal layer.169 

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An interesting variation of this theme starts with the a-chlorination of dicyclohexylketone (58). Treatment of the halo-genated intermediate with base leads to the acid, 60, by the Favorski rearrangement. Esterification of the acid with 2(1-pyrolidino)ethanol yields dihexyrevine (61). Both this agent and its earlier congener are recommended for use in GI spasms. 

A similar situation should prevail in the quasi-Favorski rearrangement. Indeed, it has been observed (65) that refluxing compounds 184 and 187 in xylene in the presence of sodium hydroxide gave the isomeric carboxylic acid derivatives 256 and J89 respectively. Thus, there is a neat inversion of configuration of the carbon atom which was initially bearing the halogen atom (cf. 185 and 188). 

The Favorski rearrangement normally goes with inversion at the terminus, as in 86 (semi-ezo-S) rather than 87 (semi-17). Reusch and Mattison (1967) have verified this for the pulegone oxides of which only one of the optically active forms is given in (181). It is of interest that the cyclopropanone intermediate opens abnormally, that is with retention. These authors note that their conditions are similar to those for electrophilic substitution with retention, namely frontside proton transfer from a polar aggregate (Cram, 1965). 

Knutsson, L. Favorsky rearrangements. XVII. Studies on the mechanism of the rearrangement of 1,1,3-tribromoacetone using carbon-13-NMR spectroscx)py. Large intramolecular secondary deuterium isotope effect. Chem. Scr. 1972, 2, 227-229. 

Baudry, D., Begue, J. P., Charpentier-Morize, M. Stereochemistry and mechanism of the dehalogenation of a-bromo ketones without a -hydrogen atoms under quasi-Favorsky rearrangement conditions. Bull. Soc. Chim. Fr. 1971,1416-1424. 

A postulated intermediate in the Favorsky rearrangement is the product of dehydrochlorination. For rearrangement of 2-chlorocyclohexanone Goheen and Vaughan stirred a suspension of commercial sodium methoxide in 330 ml. of ether, added the... 

Breslow and co-workers used triethylamine to effect Favorski rearrangement of a.a -dibromodibenzyl ketone (1) to (2) and dehydrohalogenation of this intermediate to produce diphenylcyclopropenone (3). 

Favorski rearrangement, 1092, 1202 Fehling solution, 390 Fenton s reagent, see Hydrogen peroxide, with salt or oxide catalysts Ferric chloride, 297, 390-392, 702, 814 anhydrous, 392 Ferrocene, 181, 392 Ferrous chloride, 392 Ferrous sulfate, 393 Fieser reagent, 145 Fieser s solution, 222, 393, 737 Filter aid, see Celite Fischer indole synthesis, 899 Fischer reagent, see Karl Fischer reagent Fisetin, 64... 

An alternate synthesis was developed by E. Smissman and G. Hite2, using a modified Favorski rearrangement. Iso-nicotinic acid was methylated, reduced to 1-methyl-U-piperi-dinecarboxylic acid hydrochloride, and converted to the acid chloride hydrochloride. This was then condensed with benzene, chlorinated, treated with alkali, esterfied, and converted to the hydrochloride (See Figure 8). 

Steroidal spirocyclobutanones. The reaction of 17-halo-20-ketosteroids such as (1) with a 2.4-fold excess of dimethyloxosulfonium methylide results in formation of the cyclobutanones (3) and (4), formed presumably by way of a spiro-cyclopropanone (2) (Favorsky rearrangement).3... 

From in situ generated N -(3,3-dibromoacryloyl)hydrazinecarboxylic acid ethyl ester. The previously unreported 5-bromopyrazol-3-one 274 was prepared on a multigram scale by adaptation of standard literature procedures (04SL795) (Scheme 60). Thus, l,l,3,3-tetrabromopropan-2-one 268 underwent a Favorski rearrangement to 3,3-dibromopropanoic... 

Benzopyrans have been synthesised from benzoxepine derivatives by way of the Favorsky rearrangement. The bromo compound shown, when added in methanol to a methanolic solution of zinc chloride at 115 C and then reacted with stirring for 17 hours afforded methyl 4-methyl-7-methoxychroman-4 -carboxylate in 61% yield (ref. 161). 

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