The benzilic acid rearrangement

Oestrone lacks one of progesterone s methyl groups, probably removed in the body as CO2 after oxidation. In 1946, Carl Djerassi, a man whose work led directly to the invention of the contraceptive pill, showed that another derivative of cholesterol could be rearranged to the oestrone analogue 1-methyloestradiol—notice how the methyl group has this time migrated to an adjacent carbon atom. At the same time, the dienone has become a phenol. 

Carl Djerassi, an American bom in Vienna in 1923, worked chiefly eft CIBA, Syntax in Mexico, and at Stanford, He developed syntheses of human steroids from compounds in plants, was a pioneer of mass spectrometry, and is a colourful campaigner for peace and disarmament. 

The reaction is driven from dienone to phenol because the product cation can rapidly undergo elimination of Hf to become aromatic. 

In 1838, Justus von Liebig found that treating benzil (l,2-diphenylethan-l,2-dione) with hydroxide gave, after acid quench, 2-hydroxy-2,2-diphenylacetic acid, which he called benzilic acid . 

You may find it helpful to think of the benzilic acid rearrangement as a semipinacol rearrangement in which we have a breaking C=0 n bond instead of a leaving group. 

Afali discussion bfthib poinirequireS Balckvin s ruiesi, which appear in Chapter 41, 

Aliphatic diketones rearrange similarly. Thus, 1,2-cyclohexanedione is converted to 1-hydroxy-l-cyclopentanecarboxylic acid (Equation 9.70). 

Problem 9.19. Write a pathway, involving curved arrows, to account for the transformation depicted in Equation 9.70. 

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This reaction applies to many i,2 diketones, and is termed the Benzilic Acid Rearrangement. It provides a ready method for the preparation of disubstituted a4iydroxy-carboxylic acids. When applied to a cyclic 1,2-diketone, the ring system is necessarily reduced by one carbon atom for example, cyclohexan-i,2 ... 

The benzilic acid rearrangement of steroid a-diketones is often the preferred method for ring contraction. Yields are generally excellent, and in several instances the reaction has been shown to be stereospecific. Preparation of the starting a-diketones is discussed below and illustrated with several excellent experimental procedures. 

Hirschmann and co-workers have reported the synthesis of another A-nor analog of cortisone obtained from the benzilic acid rearrangement of a 2,3-diketo-A -steroid. 17a,20 20,21-Bismethylenedioxypregna-L4-diene-... 

Finally a proton transfer leads to formation of carboxylate anion 3. Of particular interest is the benzilic acid rearrangement of cyclic diketones such as 4, since it... 

Substrates can be 1,2-diketones with aryl groups as well as some aliphatic substituents, cyclic and heterocyclic diketones. However the benzilic acid rearrangement is of limited preparative importance. 

Mechanistically closely related is the benzilic acid rearrangement, where an alkyl or aryl group migrates instead of the hydrogen. 

The following reaction, called the benzilic acid rearrangement, tajkes place by typical carbonyl-group reactions. Propose a mechanism fPh = phenyl). 

Benzil (and other a-diketones Ar—CO—CO—Ar) upon refluxing with aqueous-alcoholic potassium hydroxide undergo the benzilic acid rearrangement. Thus benzil is converted into a salt of benzilic acid ... 

We have already discussed a large group of reactions in which carbanions add to the C=0 group (cf. pp. 221-234), including examples of intramolecular carbanion addition, e.g. an aldol reaction (p. 226), Dieckmann reaction (p. 230), and the benzilic acid rearrangement (p. 232), and also to the C=C—C=O system, the Michael reaction... 

Water and the Benzil Acid Rearrangement. J. Amer. chem. Soc. 60, 880 (1938). 

The benzilic acid rearrangement, though catalyzed by hydroxide ion, probably belongs in the same category as carbonium ion rearrangements. Kinetic and isotopic exchange experiments show that there is a rapid reversible addition of hydroxide ion.841 242... 

The most important reaction of benzil and related compounds is the benzilic acid rearrangement discovered by J. von Liebig. 

By a similar reaction phenanthraquinone yields biphenylene-glycollic acid. (The equation should be written.) The benzilic acid rearrangement also plays a part in many other reactions (croconic acid, purpurogallin). 

Under the influence of the catalyst (PC15, concentrated H2S04) a compound rich in energy is converted into its stable isomeride the change which occurs is similar to that which was discussed on pp. 186, 187 in connexion with the relationship between hydrazobenzene and benzidine. A comparison with the benzilic acid rearrangement also suggests itself. 

Fragmentation and recombination reactions predominate in nearneutral, alkaline solutions. Fragments from the cleavage of the carbohydrate, and from its dehydration products, undergo further dehydration, condensation, and intermolecular, Cannizarro-type reactions. The benzilic acid rearrangement, an intramolecular Cannizarro reaction, seems to be inoperative. 

Komoto detected lactic acid in the mixture from reaction of D-glucose with ammonia,4 and presumed that it was produced from pyruvaldehyde formed by decomposition of D-glucose. Lactic acid has, indeed, been found as a product of the action of alkali (lime-water) on substituted D-glucose and substituted D-fructose,81,83,96 and the mechanism of its formation involves the reversible aldol reaction, followed by formation of pyruvaldehyde, and the benzilic acid rearrangement already described for saccharinic acid this is illustrated83,96 in Scheme 11. 

An analogous reaction occurs with diphenylethanedione, which results in carbon-skeleton rearrangement. This is one of the few carbon-skeleton rearrangements brought about by basic reagents, and is known as the benzilic acid rearrangement. ... 

Figure 8-42. The benzilic acid rearrangement of l,10-phenanthroline-5,6-quinone gives an intermediate which decarboxylates to a diazafluorenone.

Figure 8-43. In the case of complexes of 2,2 -pyridil, the benzilic acid rearrangement may be followed and complexes of the intermediate may be isolated.

The oxidation of the metal complexes of l,10-phenanthroline-5,6-quinone is thought to proceed in a similar manner, with the first step being a benzilic acid rearrangement. Rearrangements of this type may also be followed directly in nickel(u) and cobalt(m) complexes of 2,2 -pyridil. The first step of the reaction involves nucleophilic attack on an O-bonded carbonyl group to form a hydrate, followed by a benzilic acid rearrangement. In this case, the benzilic acid rearrangement products may be isolated as metal complexes (Fig. 8-43). 

With alkoxides, the benzilic acid rearrangement can lead directly to esters by the same sort Ph of mechanism. 

That intermediate is a three-membered cyclic ketone, a cyclopropanone the alkoxide acts not as a nucleophile (its role in the benzilic acid rearrangement) but as a base, enolizing the ketone. The eno-late can alkylate itself intramolecularly in a reaction that looks bizarre but that many chemists think is not unreasonable. The product is the same cyclopropanone in each case. 

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