Wolff-Kishner reduction side reactions

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. ... 

Method A. Huang-Minlon modification of the Wolff-Kishner reduction. Place 36.0 g (0.3 mol) of redistilled acetophenone, b.p. 201 °C, 300 ml of diethylene glycol, 30ml of 90 per cent hydrazine hydrate (CAUTION) and 40g of potassium hydroxide pellets in a 500-ml two-necked round-bottomed flask fitted with a reflux condenser insert a thermometer supported in a screw-capped adapter in the side-neck so that the bulb dips into the reaction mixture. Warm the mixture on a boiling water bath until most of the potassium hydroxide has dissolved and then heat under reflux for 1 hour either by means of a free flame or by using a heating mantle. Remove the reflux condenser and fit a still-head and condenser for downward distillation. Distil until the temperature of the liquid rises to 175 °C (1). Separate the upper hydrocarbon layer from the distillate and extract the aqueous layer twice with 20 ml portions of ether. Dry the combined upper layer and ethereal extracts with magnesium sulphate, remove the ether on a water bath and distil the residue. Collect ethylbenzene at 135-136 °C the yield is 20 g (62.5%). 

A number of side reactions have been reported to occur during Wolff-Kishner reductions in addition to those discussed above. In particular, cleavage of strained rings located adjacent to the carbonyl may accompany reduction to afford saturated and/or alkene products. For example, the pentacyclic diketone (41) afforded the unsaturated tetracyclic compound (42) and saturated derivative (43) in addition to the normal Wolff-Kishner product (44 equation 13). Likewise, the cyclopropyl ring in alkaloid (45) suffered cleavage during reduction to give the alkene (46 65% equation 14). ... 

We decided to use glycol as a solvent for several reasons. First, the results of Pew and Withrow (1) indicate that the properties of glycol and KOH are such that more drastic conditions could be expected to result in improved extract yields. In addition, it is possible to obtain higher reaction temperature with gylcols without using an autoclave, and cleavage of C-C bonds has occurred as a side reaction in Wolff-Kishner reductions (10). Finally, alkaline hydrolysis at high temperatures 200 C) will cleave ethers (11, 12) and carbonyls (12). 

The most important side-chain conversion involves reduction of ketones either by amalgamated zinc and HCl (Clemmensen reduction) or by hydrazine and strong base Wolff-Kishner reduction). This method is important because the necessary ketones are readily available through a modification of the Friedel-Crafts reaction that involves acid chlorides (see Sec. 19.6). Unlike alkylation by the Friedel-Crafts reaction, this method does not involve rearrangement. 

There are two side reactions, namely, formation of an azine and reduction of the carbonyl compound to the alcohol, that may, under certain circumstances, interfere with the decomposition of the hydrazone in Wolff-Kishner reduction. Both side reactions are favored by any water present. Part of the hydrazone can be cleaved by water to the carbonyl compound and hydrazine which then interact to yield the azine. Also the carbonyl compound liberated by hydrolysis of the hydrazone or semicarbazone can be reduced to the alcohol by the alkoxide anions present in the reaction medium, oxidation states being interchanged. Both side reactions can be suppressed by preventing hydrolysis of the hydrazone or semicarbazone, which can be effected either by using an excess of hydrazine or by removing the water liberated during formation of the hydrazone. 

In the original procedure described by Fieser and Rajagopalan (51) for the preparation of chenodeoxycholic acid, methyl esters were used throughout the sequence of reactions. Since methyl esters form hydrazides with hydrazine used in the Wolff-Kishner reduction, this side reaction is avoided by hydrolysis of the methyl ester (XXVII) to the free acid (XXVIII) before Wolff-Kishner reduction is attempted. 

A side-reaction occurring in the Wolff-Kishner reduction of certain acetylenic aldehydes [(213) (214)] is believed to be the result of two successive... 

As mentioned previously, DMSO as the reaction medium provides significant enhancement of Wolff-Kishner reaction rates and this allows the use of much lower temperatures to effect reductions. In 1962 Cram et al. introduced the use of r-butoxide in dry DMSO for the successful reduction of preformed hydrazones at room temperature. Using this process, benzophenone hydrazone (15) afforded an 88% yield of diphenylmethane (16), along with 11% of benzophenone azine (17) as side product (equation 5). However, maximum success requires very slow addition (i.e. over 8 h) of the hydrazone to the reaction solution, otherwise yields of reduced products are decreased and azine formation augmented. Thus, addition of (15) over 0.5 h in the above reaction lowered the yield of (16) to 72%, while the yield of (17) was increased to 22%. - Other successful reductions reported - include hydrazones of benzaldehyde (67%), camphor (64%) and cyclohexanone (80%). 

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