Wolff-Kishner reduction carbonyl compounds

The disadvantages associated with the Clemmensen reduction of carbonyl compounds (see 3 above), viz., (a) the production of small amounts of carbinols and unsaturated compounds as by-products, (h) the poor results obtained with many compounds of high molecular weight, (c) the non-appUcability to furan and pyrrole compounds (owing to their sensitivity to acids), and (d) the sensitivity to steric hindrance, are absent in the modified Wolff-Kishner reduction. 

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

Redaction of aryl carbonyl compounds.2 This reduction has been conducted traditionally by the Clemmenson or Wolff-Kishner method or by reduction of dithioketals. Actually it can be conducted in high yield with W-7 Raney nickel in 50% aqueous ethanol (2-5 hours). Nitro, halo, and cyano groups are also reduced. Examples ... 

When the carbonyl compound is sensitive to both acids and bases, or for other reasons gives poor yields in both the Clemmensen and Wolff-Kishner reductions, a recourse may be reduction of the corresponding thioacetal or thioketal with hydrogen-saturated Raney nickel (Section 11-2B) ... 

The first report on a successful microwave-assisted one-step reduction of ketones to their respective hydrocarbons via the hydrazones appeared in 20 0 265. This so called Huang-Minlon variant of the Wolff-Kishner reduction was successfully applied to some aromatic and aliphatic aldehydes and ketones, including intermediates in the synthesis of the alkaloid flavopereirine. The reactions were performed by mixing the carbonyl compound with 2 equiv of hydrazine hydrate and an excess of powdered KOH in a commercial microwave oven. The mixtures were irradiated at 150 W for a few minutes before 250-350 W irradiations were applied (Scheme 4.39). The reaction was shown... 

Gadhwal, S., Baruah, M. and Sandhu, J.S., Microwave induced synthesis of hydrazones and Wolff-Kishner reduction of carbonyl compounds, Synlett, 1999, 1573-1574. 

Fig. 17.69. Two-step sequence for the conversion of a ketone into the homologous nitrile ("reductive cyanation of a carbonyl compound"). In the second step of the reaction the diazene anion G is generated and decomposes in a similar way as the diazene anion D in the Wolff-Kishner reduction of Figure 17.67 and the diazene anion G of the semicarbazone reduction in Figure 17.68.

The reduction of carbonyl compounds to hydrocarbons may be achieved under acidic conditions e.g. the Clemmensen reduction with zinc and concentrated hydrochloric acid), basic conditions (e.g. the Wolff-Kishner reduction of a hydrazone with alkali) or neutral conditions (e.g. the catalytic reduction of thioketals with Raney nickel). The carbonyl group may represent the residue from an earlier step in the synthesis of a compound. 

The success of Wolff-Kishner reductions relies on two key processes, namely the reversible reaction of hydrazine with the carbonyl compound, which must be driven toward hydrazone formation, followed by base-induced decomposition of the hydrazone to generate a diimide anion and, subsequently, the hydrocarbon as depicted in Scheme 1. As expected, generation of the required hydrazones is highly dependent on the steric environment flanking the carbonyl and, consequently, much of the efforts devoted to improvements have focused on shifting the equiliMum toward the hydrazone by removal of water and/or the use of high concentrations of hydrazine. Coupled with this is the requirement to provide sufficient rates for the hydrazone decomposition step, which has generally meant modifrcations to provide increased reaction temperatures. 

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). ... 

This type of compound is called a hydrazone, and is the first intermediate in a very important reaction called the Wolff-Kishner reduction. This reaction, along with the Clemmensen reduction (which we will discuss in more detail in the chapter on redox reactions), is one of the principal methods for reducing a carbonyl compound to the corresponding alkane, i.e. R2C=0 to R2CH2. In... 

Wolff-Kishner Reduction. When the hydrazone of a carbonyl compound is heated with strong alkali, nitrogen is evolved, and two hydrogen atoms are introduced into the molecule ... 

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. 

Aldehydes and ketones react with primary amines to form imines and with secondary amines to form enamines. The mechanisms are the same, except for the site from which a proton is lost in the last step of the reaction. Imine and enamine formation are reversible imines and enamines are hydrolyzed under acidic conditions back to the carbonyl compound and amine. A pH-rate profile is a plot of the observed rate constant as a function of the pH of the reaction mixture. Hydroxide ion and heat differentiate the Wolff-Kishner reduction from ordinary hydrazone formation. 

The reduction of C=0 to CH2 may be achieved in three ways Raney nickel desulfurization of thioketals (Section 17-8), Clemmensen reduction (Section. 16-5), and, as described here, WolfF-Kishner reduction. Because there are many ways to make carbonyl compounds, and carbonyl compounds are great places to start for making new carbon-carbon bonds, you will find that carbonyi groups are often present when complex molecules are made from simpler ones. This will be especially evident in Chapters 18-20 and 23. Deoxygenation will be useful if you need to get rid of a carbonyl group that has been used to construct bonds in a large molecule but is not wanted in the final product. The example of Friedel-Crafts alkanoylation followed by deoxygenation is just the first that you will see. 

Similar to the Wolff-Kishner Reduction and Clemmensen Reduction, this reaction is also useful for the conversion of carbonyl compounds into hydrocarbons and olefins. 

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