Many of the efforts devoted to improve the Wolff–Kishner reduction have focused on more efficient formation of the hydrazone intermediate by removal of water and a faster rate of hydrazone decomposition by increasing the reaction temperature. The temperature-lowering effect of water that was produced in hydrazone formation usually resulted in long reaction times and harsh reaction conditions even if anhydrous hydrazine was used in the formation of the hydrazone. The modified procedure consists of refluxing the carbonyl compound in 85% hydrazine hydrate with three equivalents of sodium hydroxide followed by distillation of water and excess hydrazine and elevation of the temperature to 200 °C. Significantly reduced reaction times and improved yields can be obtained using this modification. Minlon's original report described the reduction of
β-(
p-phenoxybenzoyl)propionic acid to
γ-(
p-phenoxyphenyl)butyric acid in 95% yield compared to 48% yield obtained by the traditional procedure.
Barton modification Nine years after Huang Minlon’s first modification, Barton developed a method for the reduction of sterically hindered carbonyl groups. This method features rigorous exclusion of water, higher temperatures, and longer reaction times as well as sodium in
diethylene glycol instead of alkoxide base. Under these conditions, some of the problems that normally arise with hindered ketones can be alleviated—for example, the C11-carbonyl group in the steroidal compound shown below was successfully reduced under Barton’s conditions while Huang–Minlon conditions failed to effect this transformation.
Cram modification Slow addition of preformed hydrazones to potassium
tert-butoxide in DMSO as reaction medium instead of glycols allows hydrocarbon formation to be conducted successfully at temperatures as low as 23 °C. Cram attributed the higher reactivity in DMSO as solvent to higher base strength of potassium
tert-butoxide in this medium. This modification has not been exploited to great extent in organic synthesis due to the necessity to isolate preformed hydrazone substrates and to add the hydrazone over several hours to the reaction mixture.
Henbest modification Henbest extended Cram’s procedure by refluxing carbonyl hydrazones and potassium
tert-butoxide in dry toluene. Slow addition of the hydrazone is not necessary and it was found that this procedure is better suited for carbonyl compounds prone to base-induced side reactions than Cram's modification. It has for example been found that double bond migration in
α,β-unsaturated enones and functional group elimination of certain
α-substituted ketones are less likely to occur under Henbest's conditions. The initially reported reaction conditions have been modified and hydride donors such as
sodium cyanoborohydride,
sodium triacetoxyborohydride, or
catecholborane can reduce tosylhydrazones to hydrocarbons. The reaction proceeds under relatively mild conditions and can therefore tolerate a wider array of functional groups than the original procedure. Reductions with sodium cyanoborohydride as reducing agent can be conducted in the presence of esters, amides, cyano-, nitro- and chloro-substituents. Primary bromo- and iodo-substituents are displaced by nucleophilic hydride under these conditions. The reduction pathway is sensitive to the pH, the reducing agent, and the substrate. One possibility, occurring under acidic conditions, includes direct hydride attack of
iminium ion
1 following prior protonation of the tosylhydrazone. The resulting tosylhydrazine derivative
2 subsequently undergoes elimination of
p-toluenesulfinic acid and decomposes via a
diimine intermediate
3 to the corresponding hydrocarbon. A slight variation of this mechanism occurs when
tautomerization to the azohydrazone is facilitated by
inductive effects. The transient azohydrazine
4 can then be reduced to the tosylhydrazine derivative
2 and furnish the decarbonylated product analogously to the first possibility. This mechanism operates when relatively weak hydride donors are used, such as
sodium cyanoborohydride. It is known that these sodium cyanoborohydride is not strong enough to reduce
imines, but can reduce
iminium ions. When stronger hydride donors are used, a different mechanism is operational, which avoids the use of acidic conditions. Hydride delivery occurs to give intermediate
5, followed by elimination of the metal
sulfinate to give azo intermediate
6. This intermediate then decomposes, with loss of
nitrogen gas, to give the reduced compound. When strongly basic hydride donors are used such as
lithium aluminium hydride, then deprotonation of the tosyl hydrazone can occur before hydride delivery. Intermediate anion
7 can undergo hydride attack, eliminating a metal sulfinate to give azo anion
8. This readily decomposes to
carbanion 9, which is protonated to give the reduced product. As with the parent Wolff–Kishner reduction, the decarbonylation reaction can often fail due to unsuccessful formation of the corresponding tosylhydrazone. This is common for sterically hindered ketones, as was the case for the cyclic amino ketone shown below. Alternative methods of reduction can be employed when formation of the hydrazone fail, including
thioketal reduction with
Raney nickel or reaction with
sodium triethylborohydride.
Deoxygenation of α,β-unsaturated carbonyl compounds α,β-Unsaturated carbonyl tosylhydrazones can be converted into the corresponding alkenes with migration of the double bond. The reduction proceeds stereoselectively to furnish the
E geometric isomer. A very mild method uses one equivalent of
catecholborane to reduce
α,β-unsaturated tosylhydrazones. The mechanism of NaBH3CN reduction of
α,β-unsaturated tosylhydrazones has been examined using deuterium-labeling. Alkene formation is initiated by hydride reduction of the iminium ion followed by double bond migration and nitrogen extrusion which occur in a concerted manner. Allylic diazene rearrangement as the final step in the reductive 1,3-transposition of
α,β-unsaturated tosylhydrazones to the reduced alkenes can also be used to establish
sp3-stereocenters from allylic diazenes containing prochiral stereocenters. The influence of the alkoxy stereocenter results in diastereoselective reduction of the
α,β-unsaturated tosylhydrazone. The authors predicted that diastereoselective transfer of the diazene hydrogen to one face of the prochiral alkene could be enforced during the suprafacial rearrangement.
Myers modification In 2004, Myers and coworkers developed a method for the preparation of
N-tert-butyldimethylsilylhydrazones from carbonyl-containing compounds. These products can be used as a superior alternative to hydrazones in the transformation of ketones into alkanes. The advantages of this procedure are considerably milder reaction conditions and higher efficiency as well as operational convenience. The condensation of 1,2-bis(
tert-butyldimethylsilyl)-hydrazine with aldehydes and ketones with Sc(OTf)3 as catalyst is rapid and efficient at ambient temperature. Formation and reduction of
N-tert-butyldimethylsilylhydrazones can be conducted in a one pot procedure in high yield. [This graphic is wrong. It should be TBS-N, not TBSO-N] The newly developed method was compared directly to the standard Huang–Minlon Wolff–Kishner reduction conditions (hydrazine hydrate, potassium hydroxide, diethylene glycol, 195 °C) for the steroidal ketone shown above. The product was obtained in 79% yield compared to 91% obtained from the reduction via an intermediate
N-tert-butyldimethylsilylhydrazone. ==Side reactions==