Transformations benzilic acid

Aldoses generally undergo benzilic acid-type rearrangements to produce saccharinic acids, as well as reverse aldol (retro-aldol) reactions with j3-elimination, to afford a-dicarbonyl compounds. The products of these reactions are in considerable evidence at elevated temperatures. The conversions of ketoses and alduronic acids, however, are also of definite interest and will be emphasized as well. Furthermore, aldoses undergo anomerization and aldose-ketose isomerization (the Lobry de Bruyn-Alberda van Ekenstein transformation ) in aqueous base. However, both of these isomerizations are more appropriately studied at room temperature, and will be considered only in the context of other mechanisms. 

The first two reactions of the sequence are similar to reactions that occur in acidic medium. The 1,2- and 2,3-enediols, and the unsaturated elimination-products derived from them, are present both in acidic and basic solutions. In general, however, reactions in basic solution are much faster than in acidic solution, because of the greater catalytic effect of the hydroxyl ion on the transformation reactions Mechanistic differences between the media become operative in steps c and d. In acid, further dehydration, if it is possible, occurs rapidly, before equilibrium of the deoxy-enediol with the dicarbonyl compound has been established,17 and the products are furans. In alkaline solution, the rapid formation of the tautomeric dicarbonyl compound permits the benzilic acid rearrangement42 to proceed. 

Exercise 17-43 Write a mechanism analogous to that for the Cannizzaro reaction for the benzilic acid transformation. What product would you expect to be formed from diphenylethanedione with potassium terf-butoxide in ferf-butyl alcohol Would you expect a benzilic acid-type rearrangement to occur with 2,3-butanedione Give your reasoning. 

Reaction XXXII. Action of Alkalis on certain a-di-ketones. (A., 25, 25 31, 324 B., 14, 326 19, 1868 41, 1644.)—When benzil is fused with potassium hydroxide, or digested with alcoholic potash, or heated for a long time with aqueous potash, a molecular re-arrangement not unlike the pinacoline transformation (p. 79) takes place, and benzilic acid is formed. 

Reaction of a solution of 3a,17p-diacetoxy-ll-hydroxy-5p-androst-9(ll)-en-12-one (71) in aqueous propanol with potassium hydroxide, followed by an acidic work-up, afforded the lactone (75 76%). Three events are involved in this transformation (Scheme 16), namely retro-aldol equilibration to give the cii-fused c-o-ring system (72) - (73), stereoselective benzilic acid rearrangement (73) - (74) to... 

Bromosinomeneine ketone [lxxvi]. can be made to undergo the benzil —> benzilic acid transformation in hot alkali, the product being 1-bromosinomenilic acid [xcm]. This acid is also obtained when the amorphous product of bromination of 1-bromosinomeninone with one equivalent of bromine is treated with alkali, and from sinomenine hydrate and one equivalent of bromine [69]. 

Reviews devoted to various aspects of the transformation have already been published in this Series, and are very informative to the reader who desires more experimental evidence. However, explanation of these transformations and rearrangement reactions proved extremely difficult, and, to the 1,2-enediol, long regarded as the only intermediate, had to be added new enediols and dismutation reactions. Ionization of the enediol was proposed for the sake of clarity and to reach more confident conclusions. Enediol formation and the benzilic acid type of rearrangement, as well as fragmentation and disproportionation of the molecule, are found to occur, and must be regarded as basic reactions in carbohydrate chemistry. Various combinations of these four mechanisms are responsible for the several reaction products found. 

This reaction has general application for preparing benzilic acids and their esters which have important biological activities. The formed benzilic acid can be used as reducing reagent to transform Qf, -unsaturated ketones into saturated ketones.In addition, the benzilic acid rearrangement on cyclic of-diketones will lead to ring contracted products 2ii, 2kk, 2nn... 

In 1966, when the structure of enmein (62) was elucidated, the total synthesis of natural gibberellins had not yet been reported. Hence, Okamoto and co workers attempted the chemical transformation of enmein into a gibberellane derivative (106) and reported the formation of such compound by a benzilic acid rearrangement-like reaction of keto hemi-acetal (128), an oxidation product of acyloin (110). This is shown in Scheme 20. 

Patra et al. described the regiospecific synthesis of benz[a]anthracene-5,6-dione 9 and their efficient conversion to benzo[h]fluorenones 11 through the carboxylic acid 10. The transformation of 9 to 10 has been effected by benzilic acid rearrangement employing the method of Toda et using powdered KOH in dioxane. Several other conditions such as NaOH in water, KOH in a mixture of ethanol and water, KOH in a mixture of dioxane and water and NaOEt in ethanol did not give satisfactory results. 

Guirado et al reported a one-pot preparative process involving a benzilic acid rearrangement step followed by a spontaneous epoxidation of the intermediates. Treatment of diketone 32 with sodium hydroxide at room temperature gave 2,5,5-trichloro-l,2-epoxycyclopentane-l-carboxylic acid 35 as a single product in quantitative yield. This transformation has been explained by sequential participation of intermediates 33 and 34. 

Chloro-3-ethylbenzoxazolium salts (565) are remarkably versatile reagents the fluoroborate converts a-hydroxy-carboxylic acids into ketones, e.g. benzilic acid into benzophenone, methyl thiocarbamates RNHCSOMe into isocyanates RNCO, ° and alkyl- and aryl-formamides into isocyanides the chloride transforms alcohols into alkyl chlorides. 

Oxidation of chalcones with TTN has been studied in detail (95, 96), and it has been shown that the products obtained depend on the amount of reagent and the solvent employed. Oxidation with 1 equivalent of TTN in methanol, methanol-chloroform, or methanol-boron trifluoride leads to acetals of the type (XXXIV) (see also Scheme 21) in yields of 20-80%. When 3 equivalents of TTN are employed, however, and aqueous glyme containing a little perchloric acid used as solvent, the products are benzils. This remarkable transformation, which proceeds in yields varying from moderate to good (40-80%), involves three distinct oxidations by TTN, and these are outlined in Scheme 22. Each individual step in this reaction sequence has been investigated in detail, with the result that useful procedures have been developed for the oxidation of both deoxybenzoins and benzoins to benzils with TTN (96). 

The diketo acids were transformed to their methyl esters under the action of diazomethane (5), SOCl2/CH3OH (102), or methanolic hydrogen chloride (117). Like other benzils, JV-methyloxohydrasteine (109) when... 

Symmetrical and unsymmetrical benzoins have been rapidly oxidized to benzils in high yields using solid reagent systems, copper(II) sulfate-alumina [105] or Oxone-wet alumina [105, 106] under the influence of microwaves (Scheme 6.32). Conventionally, the oxidative transformation of a-hydroxy ketones to 1,2-diketones is accomplished by reagents such as nitric acid, Fehling s solution, thallium(III) nitrate (TTN), ytterbium(III) nitrate, ammonium chlorochromate-alumina and dayfen. In addition to the extended reaction time, most of these processes suffer from drawbacks such as the use of corrosive acids and toxic metals that generate undesirable waste products. 

Pyrido[l,2-7][l,2,4]triazinium salts 113 can be obtained from 112 with benzil in the presence of either base <2001CPH77> or sulfuric acid (Scheme 73) <2003ARK(xiv)155>. In an analogous reaction, 1,2-diaminopyridines 114 are transformed into 2,3,6-trioxopyridotriazines 115 by treatment with oxalyl chloride in the presence of triethylamine (Scheme 74) <1998SC3331, CHEC-III(12.03.2A4)237>. 

Although 1,2-dicarbonyl substrates (especially unsymmetrical benzils) are often difficult to make, there are a number of approaches which may be appropriate. Propane-1,3-dithiol reacts with aldehydes to give cyclic thioacetals (in 52-91% yields) which form stable dithiane anions when treated with butyllithium. Subsequent quenching with an acid chloride followed by mercury(ll) chloride treatment gives a 1,2-dicarbonyl species. Alternatively, substitution of an aldehyde for the acid chloride gives rise eventually to an a-hydroxycarbonyl derivative (Scheme 5.1.2) [16j. An alternative approach to a-ketoaldehydes (82-86% yields) reacts an a-ketonitrate ester with sodium acetate in DMSO [17]. Aryl a-diketones can be made from a-ketoanils, which are in turn made by cyanide ion-catalysed transformation of aromatic aldimines [18], and the range of unsymmetrical benzils has been increased by... 

The scheme was verified usii chronopotentiometric and potentio-static methods (Alberts and Shain, 1963). A similar scheme was considered for the reduction of o- and p-nitrophenols and nitroanilines but the theoretical treatment is more involved owing to the irreversibility of the first four-electron reduction step. Similarly also a chemical reaction is interposed between the first and second electrode process in the reductions of a-substituted ketones of the type RCO.CHg—X (for X=NR2, NR, SR, SRf, OR, PRJ and halogen) and in the reductions of a,)9-unsaturated ketones. In both these systems enolate is a primary electro-inactive reduction product that must be first transformed into the electro-active keto-form. The rate of this transformation, which is acid-base catalysed, limits the wave-height of the more negative wave of the saturated ketone. Similarly it was explained why the more negative wave observed on curves of benzil is smaller than expected for the given concentration of benzoin. 

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