The Wolff-Kishner Reduction

The method of choice for the reduction of keto groups to methylenes remains the WolfT-Kishner reaction (2) or its modification discovered by Huang-Minlon (5). Originally, the hydrazone formation was carried out in a separate step, followed by 

The carbonyl compound to be reduced (0.1 mole) is placed in a 250-ml round-bottom flask with 13.5 g of potassium hydroxide, 10 ml of 85% hydrazine hydrate, and 1(X) ml of diethylene glycol. A reflux condenser is attached and the mixture is heated to reflux for I hour (mantle). After refluxing 1 hour, the condenser is removed and a thermometer is immersed in the reaction mixture while slow boiling is continued to remove water. When the pot temperature has reached 200°, the condenser is replaced and refluxing is continued for an additional 3 hours. The mixture is then cooled, acidified with concentrated hydrochloric acid, and extracted with benzene. The benzene solution is dried, and the benzene is evaporated to afford the crude product, which is purified by recrystallization or distillation. 

/rflrt 10-Methyl-2-decalone (Chapter 3, Section III) gives /rfl j-9-methyldecalin, bp 90-91 °/20 mm, 1.4764 (4). 

This reaction is usually called the Wolff-Kishner reduction.14 In early procedures, sodium ethoxide was the base commonly employed and the reaction was carried out at about 180° in a sealed tube. A simplified technique, however, has been developed for carrying out the reaction in diethylene glycol solution with sodium o potassium hydroxide Little i lmown concerning the mechanism of the reaction, but two possibilities 14(16 are shown on p. 275. 

14 For a review of the Wolff-Kishner reaction, see Todd in Adams, Organic Reac-tions, Vol. IV, p. 378, John Wiley and Sons, New York, 1948. 

Although.thc conversion of hydrazones (XII) to substituted diimines (XIII) does not seem to have been realized, the reverse reaction, which probably involves the same intermediates, is well known.17 Benzene 

17 See (a) Taylor and Baker in Sidgwick s Organic Chemistry of Nitrogen, pp. 432- 434, Oxford University Press, Oxford, England, 1937, and (b) Todd, J. Am. Chem. Soc., 71, 1356 (1949). 

With N-substituted hydrazones it is not possible to write the ionic mechanism shown above for the last step. 

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Both the Clemmensen and the Wolff-Kishner reductions are designed to carry out a specific functional group transformation the reduction of an aldehyde or ketone carbonyl to a methylene group Neither one will reduce the carbonyl group of a carboxylic acid nor... 

Two methods for converting carbonyl groups to methylene units are the Clem mensen reduction (zinc amalgam and con centrated hydrochloric acid) and the Wolff-Kishner reduction (heat with hydra zine and potassium hydroxide in a high boiling alcohol)... 

Both the Wolff-Kishner and Clemmensen reductions of a, -unsaturated ketones give olefins. There has been considerable confusion concerning the exact product composition in the case of A -3-ketones. Wolff-Kishner reduction gives A" -, 5a-A - and 5 -A -olefins, and, depending on the substrate reaction conditions and work-up, any one or more of these may be isolated. (See ref. 287 for a recent review of the Wolff-Kishner reduction.)... 

The tritylone ether is used to protect primary hydroxyl groups in the presence of secondary hydroxyl groups. It is prepared by the reaction of an alcohol with 9-phenyl-9-hydroxyanthrone under acid catalysis (cat. TsOH, benzene, reflux, 55-95% yield). It can be cleaved under the harsh conditions of the Wolff-Kishner reduction (H2NNH2, NaOH, 200°, 88% yield) and by electrolytic reduction (—1.4 V, LiBr, MeOH, 80-85% yield)". It is stable to 10% HCl, 55 h. ... 

Whereas halogens in the a-positions are removed in the Wolff-Kishner reduction, this is not the case with /3-positioned bromine. ... 

The Huang-Minlon modification of the Wolff-Kishner reduction has been used innumerable times for the reduction of thiophenealde-hydes and thienyl Besides the few... 

Another important synthetic method for the reduction of ketones and aldehydes to the corresponding methylene compounds is the Woljf-Kishner reduction. This reaction is carried out under basic conditions, and therefore can be applied for the reduction of acid-sensitive substrates it can thus be regarded as a complementary method. The experimental procedure for the Clemmensen reduction is simpler however for starting materials of high molecular weight the Wolff-Kishner reduction is more successful. 

An aldehyde or ketone 1 can react with hydrazine to give a hydrazone 2. The latter can be converted to a hydrocarbon—the methylene derivative 3—by loss of Na upon heating in the presence of base. This deoxygenation method is called the Wolff-Kishner reduction. ... 

The classical procedure for the Wolff-Kishner reduction—i.e. the decomposition of the hydrazone in an autoclave at 200 °C—has been replaced almost completely by the modified procedure after Huang-Minlon The isolation of the intermediate is not necessary with this variant instead the aldehyde or ketone is heated with excess hydrazine hydrate in diethyleneglycol as solvent and in the presence of alkali hydroxide for several hours under reflux. A further improvement of the reaction conditions is the use of potassium tcrt-butoxide as base and dimethyl sulfoxide (DMSO) as solvent the reaction can then proceed already at room temperature. ... 

The Wolff-Kishner reduction is an important alternative method to the Clem-mensen reduction, and is especially useful for the reduction of acid-labile or high-molecular substrates. Yields are often below 70%, due to various side-reactions such as elimination or isomerization reactions. ... 

To 1,400 ml of an approximately 50% water/triglycol solution of the potassium salt of cheno-deoxycholic acid, obtained by the Wolff-Kishner reduction (using hydrazine hydrate and potassium hydroxide) from 50 g of 7-acetyl-12-ketochenodeoxycholic acid, 220 ml of dilute hydrochloric acid is added to bring the pH to 2. The solution is stirred and the crude cheno-deoxycholic acid precipitates. The precipitate is recovered and dried to constant weight at about 60°C. About 36 g of the crude chenodeoxycholic acid, melting in the range of 126°-129°C, is obtained. 

Note that the Wolff-Kishner reduction accomplishes the same overall trans-fonnation as the catalytic hydrogenation of an acylbenzene to yield an alkyl-benzene (Section 16.10). The Wolff-Kishner reduction is more general and more useful than catalytic hydrogenation, however, because it works well with both alkyl and atyl ketones. 

Figure 19.11 MECHANISM Mechanism of the Wolff-Kishner reduction of an aldehyde or ketone to yield an alkane.

The procedure outlined is much quicker and simpler than previous methods Starting materials are readily available, and the preparation can be run on any scale in the length of a day. Because exclusion of a basic catalyst eliminates the Wolff-Kishner reduction of the cinnamalhydrazone, separation of the 5-phenylpyrazoline from cinnamalhydrazone, or of phenylcyclopropane from propenylbenzene, does not have to be effected. The present procedure can also be used to convert other ring-substituted cinnamaldehydes to the corresponding arylcyclo-propanes... 

The present method of making docosanedioic acid has been described by Hiinig and Liicke. The Wolff-Kishner reduction of the diketonic intermediate is am application of the modification of Gardner, Rand, and Haynes. ... 

Not much is known about the mechanism of the Clemmensen reduction. Several mechanisms have been proposed, " including one going through a zinc-carbene intermediate. " One thing reasonably certain is that the corresponding alcohol is not an intermediate, since alcohols prepared in other ways fail to give the reaction. Note that the alcohol is not an intermediate in the Wolff-Kishner reduction either. 

The deoxygenation of aldehydes and ketones to the corresponding hydrocarbons via the hydrazones is known as the Wolff-Kishner reduction.28 Various modifications of the original protocols have been suggested. One of the most useful is the Huang-Minlon modification, which substituted hydrazine hydrate as a safer and less expensive replacement of anhydrous hydrazine. In addition, diethylene glycol together with sodium hydroxide was used to increase the reaction... 

Propanes in the Wolff-Kishner Reduction of a,/S-unsaturated Carbonyl Compounds. J. chem. Soc. [London] 1952, 4686. 

Mesylation of alcohol 14 and hydrolysis of the acetal with oxalic acid leads to the key decalone 16 which cyclises in the presence of NaH in dioxane to afford twistanone 17 in quantitative yields. The elimination of the carbonyl group was carried out by an alternative method to the Wolff-Kishner reduction, which involves the thioacetalisation of the twistanone (18) with ethane-1,2-dithiol and removal of the resulting thioacetal by Raney nickel in boiling ethanol (62% yield). 

In work which remains unpublished, Wenkert has succeeded in cleverly transforming 2-methylcyclopentanone into isocomene The key elements of his strategy (Scheme LXXXIII) are the acid-catalyzed ring expansion of methoxycyclopropane 747 to 748 and the regiospecific homologation of the cyclobutanone to 749. Unfortunately, the Wolff-Kishner reduction of this penultimate intermediate affords both 731 and its epimer. 

A common alternative to the Wolff-Kishner reduction of cyclobutanones to the parent cyclobutane (see Section S.2.4.2.), is formation of thiocetals (see Section 5.2.4.7.1.) followed by hydrogenolyses using Raney nickel.64,146-149 For example, l,4,4-trimethyl-6,6-(propane-l,3-diyldithia)bicyclo[3.2.0]heptan-3-one gave 15 using this method. It was found that the W-2 quality of Raney nickel works well.64"148... 

The reaction is usually done at high temperatures in ethylene glycol, a high-boiling polar solvent, and is called the Wolff-Kishner reduction reflux in... 

The reduction of xanthone to xanthene has been achieved by using the Huang-Minlon modification of the Wolff-Kishner reduction (52JCS3741) by LAH (55JA5121) and by diphenyl-silane (61JOC4817). 

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