Benzilic acid preparation

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. 

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. 

A mixture containing 8 g (0.06 mol) of N-methyl-3-chloro-piperidine and 13.6 g (0.06 mol) of benzilic acid in 50 cc of anhydrous isopropyl alcohol was refluxed for 3 days the isopropyl alcohol was removed by distillation in vacuo, the residue treated with dilute aqueous hydrochloric acid and the aqueous acid mixture extracted repeatedly with ether. The aqueous phase was separated, made strongly alkaline with 20% aqueous sodium hydroxide and extracted with ether. The ether extracts were dried with potassium carbonate and distilled the product was collected at 175° to 176°C (0.03 mm), yield 11.5 g (59%). The ester base thus prepared was then dissolved in 75 cc of isopropyl alcohol and 3.4 g (0.037 mol) methyl bromide added. The reaction mixture was allowed to stand at 30°C for 2 days and the product isolated by filtration, yield, 13 g (87%), MP 228° to 229°C dec. 

N-ethyl-3-chloropiperidine was prepared according to the method of Fuson and Zirkle described in Volume 70, J. Am. them. Soc., p 2760. 12.0 g (0.0B1 mol) of N-ethyl-3-chloropiperidine was mixed with 1B.6 g (0.0B1 mol) of benzilic acid and 80 cc of anhydrous isopropyl alcohol as a solvent. The mixture was refluxed for 72 hours. The solution was then filtered and concentrated at 30 mm of mercury. The concentrate was dissolved in water, acidified with hydrochloric acid and extracted with ether to remove the unreacted benzilic acid. 

RecrystaUise 5 0 g. from about 40 ml. of hot rectified (or methylated) spirit upon cooling, 4-5 g. of pure benzoin (a white, crystalline solid, m.p. 137°) separate. Reserve the remainder of the preparation for benzil and benzilic acid (Sections IV,126 and IV,127 respectively). 

Due to excellent yields, mild reaction conditions, and a fast reaction rate, the azolide method is well suited to the synthesis of isotopically labeled esters, even ones with very short half-lives, just as it is always useful for the esterification of sensitive carboxylic acids, alcohols, and phenols under mild conditions. An example is provided by the synthesis of [nC]-quinuclidinyl benzilate prepared from benzilic acid, CDI, and nC-labeled quinuclidinol.[147]... 

In the preparation of certain benzilic acid derivatives froir substituted benzils, it has been found that simply dissolving the substituted benzil in alcoholic alkali is sufficient to complete the conversion and no heating is required. With unsubstituted benzil, however, a much poorer yield of benzilic acid is obtained if the reaction mixture is not heated. Longer heating than that given in the directions is likely to decompose some of the product to benzoic acid. 

Beckmann rearrangement of oximes, 572 Benzidine rearrangement, 682 Benzilic acid rearrangement, 435 Benzils, see a-Diketones Benzofurans, preparation, by dehydro-cyclization, 842... 

Dienone-phenol rearrangements are mechanistically diverse. They may involve 1,2-shifts of the Wag-ner-Meerwein type, or of the benzil-benzilic acid kind 1,3-shifts by a Claisen-Cope mechanism 1,5-sigmatropic shifts Favorskii-like reactions and other types. They may also be induced photochemically. A number of reviews are available, which discuss mechanistic aspects in detail. In this chapter emphasis is put on preparative aspects of these reactions and the examples are organized on a structural basis, stressing the new bond(s) formed. 

By ESR studies, the benzilic acid rearrangement in solution has been proven to proceed via a radical intermediate [14], For the benzilic acid reanangement in the solid state, a radical intermediate was also detected. For example, a freshly prepared mixture of finely powdered 35e and KOH showed a strong ESR signal (g=2.0049), and this signal declined as the reaction proceeded. 

In the benzil analog (107) a benzilic acid rearrangement leading to the acid (108) can be done and the acid isolated either as a salt or as the methyl ester prepared with diazomethane at a low temperature. The surprise lies in the fact that the acid (108) is unexpectedly unstable in the free state what... 

Preparation. Staudinger prepared diphenylketene for the first time by the action of zinc turnings in ether on a-chlorodiphenylacetyl chloride, an intermediate now readily available by the action of phosphorus pentachloride on benzilic acid (1), but evidently the yield was poor. He then tried dehydrohalogenation of... 

Disubstituted hydantoins and 2-thiohydantoins, especially their 5,5-diaryl derivatives, have been prepared by means of a condensation that involves a rearrangement similar to that in which benzilic acid is formed from benzil.1,3 Examples include the synthesis of fluorinated hydantoins,35 spirofluorene-,36 and spiroacenaphthylenehydantoins,37 2-thiohydantoins,30 38 39 and 5,5-diphenylhydantoin-2,4,5-13C3.40... 

Interest in the structure-activity relationships of the gibberellins has led to the partial synthesis of the four stereoisomers about positions 5 and 6 of the hexa-hydrofluorene (57). The unsaturated acid anhydride (56) was prepared by the benzilic acid ring-contraction of the 6,7-diketones obtained from oxidation of desisopropyl dehydroabietic acid, and converted into the saturated acids by reduction and base-catalysed epimerisation. 

It is curious that Jowett and Pyman did not prepare benziloyltropeine, since benzilic acid contains the groups, phenyl and alcoholic hydroxyl, which they had found to confer high activity on esters of tropine this ester was studied by Benda and Kraupp (17a) who found that its hydrochloride was as active as atropine sulphate on the cat eye and had, if anything, a slightly more prolonged effect. Kreitmair s results (14) with benziloyl- -tropine have already been mentioned, and several mydriatic benzilic esters of alkamines simpler than tropine will be mentioned later. 

It is prepared by the eondensation of two moleeules of benzaldehyde with sodium cyanide to get benzoin, which on treatment with nitric acid or cupric sulphate forms benzil. In the presence of sodium ethoxide, benzil in hot condition yields benzilic acid ester, (a) The latter on condensation with urea in the presence of sodium ethoxide give rise to phenytoin the enol-form of which on neutralization with sodium hydroxide ultimately results into the formation of phenytoin sodium. 

It may be prepared by treating benzilic acid with diethylamne ethanol resulting the official compound with the elimination of a molecule of water. 

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