Wolff–Kishner reduction

The Wolff–Kishner reduction is a reaction used in organic chemistry to convert carbonyl functionalities into methylene groups. In the context of complex molecule synthesis, it is most frequently employed to remove a carbonyl group after it has served its synthetic purpose of activating an intermediate in a preceding step. As such, there is no obvious retron for this reaction. The reaction was reported by Nikolai Kischner in 1911 and Ludwig Wolff in 1912.

class=skin-invert-image|center|420px|Scheme 1. Wolff-Kishner Reduction

In general, the reaction mechanism first involves the in situ generation of a hydrazone by condensation of hydrazine with the ketone or aldehyde substrate. Sometimes it is however advantageous to use a pre-formed hydrazone as substrate (see modifications). The rate determining step of the reaction is de-protonation of the hydrazone by an alkoxide base to form a diimide anion by a concerted, solvent mediated protonation/de-protonation step. Collapse of this alkyldiimide with loss of N2 These initial modifications were followed by many other improvements as described below.

Mechanism

The mechanism of the Wolff–Kishner reduction has been studied by Szmant and coworkers. According to Szmant's research, the first step in this reaction is the formation of a hydrazone anion 1 by deprotonation of the terminal nitrogen by MOH. If semicarbazones are used as substrates, initial conversion into the corresponding hydrazone is followed by deprotonation. Several molecules of solvent have to be involved in this process in order to allow for a concerted process. A detailed Hammett analysis The overall driving force of the reaction is the evolution of nitrogen gas from the reaction mixture.

class=skin-invert-image|center|620px|Scheme 4. Mechanism of the Wolff-Kishner reduction

Modifications

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.

class=skin-invert-image|center|650px|Scheme 5. Huang Minlon modification

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.

class=skin-invert-image|center|600px|Scheme 6. Barton modification

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.

class=skin-invert-image|center|350px|Scheme 7. Cram modification

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.

class=skin-invert-image|center|580px|Scheme 8. Caglioti modification

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.class=skin-invert-image|center|680px|Scheme 9. Mechanistic proposal for the Caglioti reaction 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.

class=skin-invert-image|center|700px|Scheme 10. Alternative mechanistic proposal for the Caglioti reactionWhen 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.

class=skin-invert-image|center|602x602px|Scheme XX. Caglioti Reaction|alt=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.

class=skin-invert-image|center|400px|Scheme 11. Unsuccessful substrate in Caglioti reaction

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.

class=skin-invert-image|center|620px|Scheme 12-1. Deoxygenation of an α,β-unsaturated carbonyl compound

A very mild method uses one equivalent of catecholborane to reduce α,β-unsaturated tosylhydrazones.

class=skin-invert-image|center|320px|Scheme 12-2. Deoxygenation of an α,β-unsaturated carbonyl compound

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.

class=skin-invert-image|center|460px|Scheme 13. Mechanism of allylic diazene 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.

class=skin-invert-image|center|700px|Scheme 14. Myers modification

[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

The Wolff–Kishner reduction is not suitable for base–sensitive substrates and can under certain conditions be hampered by steric hindrance surrounding the carbonyl group. Some of the more common side-reactions are listed below.

Azine formation

A commonly encountered side-reaction in Wolff–Kishner reductions involves azine formation by reaction of hydrazone with the carbonyl compound. Formation of the ketone can be suppressed by vigorous exclusion of water during the reaction. Several of the presented procedures require isolation of the hydrazone compound prior to reduction. This can be complicated by further transformation of the product hydrazone to the corresponding hydrazine during product purification. Cram found that azine formation is favored by rapid addition of preformed hydrazones to potassium tert-butoxide in anhydrous dimethylsulfoxide. In general, alcohol formation may be repressed by exclusion of water or by addition of excess hydrazine.

Kishner–Leonard elimination

Kishner noted during his initial investigations that in some instances, α-substitution of a carbonyl group can lead to elimination affording unsaturated hydrocarbons under typical reaction conditions. Leonard later further developed this reaction and investigated the influence of different α-substituents on the reaction outcome. He found that the amount of elimination increases with increasing steric bulk of the leaving group. Furthermore, α-dialkylamino-substituted ketones generally gave a mixture of reduction and elimination product whereas less basic leaving groups resulted in exclusive formation of the alkene product.

class=skin-invert-image|center|300px|Scheme 16. Kishner-Leonard elimination

The fragmentation of α,β-epoxy ketones to allylic alcohols has been extended to a synthetically useful process and is known as the Wharton reaction.

Cleavage or rearrangement of strained rings adjacent to the carbonyl group

Grob rearrangement of strained rings adjacent to the carbonyl group has been observed by Erman and coworkers. During an attempted Wolff–Kishner reduction of trans-π-bromocamphor under Cram’s conditions, limonene was isolated as the only product.

Similarly, cleavage of strained rings adjacent to the carbonyl group can occur. When 9β,19-cyclo-5α-pregnane-3,11,20-trione 3,20-diethylene ketal was subjected to Huang–Minlon conditions, ring-enlargement was observed instead of formation of the 11-deoxo-compound.

class=skin-invert-image|center|450px|Scheme 17. Ring cleavage during Wolff-Kishner reduction

Applications in total synthesis

The Wolff–Kishner reduction has been applied to the total synthesis of scopadulcic acid B, aspidospermidine and dysidiolide.

The Huang Minlon modification of the Wolff–Kishner reduction is one of the final steps in their synthesis of (±)-aspidospermidine. The carbonyl group that was reduced in the Wolff–Kishner reduction was essential for preceding steps in the synthesis. The tertiary amide was stable to the reaction conditions and reduced subsequently by lithium aluminum hydride. The authors explain this observation with the stereoelectronic bias of the substrate which prevents “anti–Bredt” iminium ion formation and therefore favors ejection of alcohol and hydrazone formation. The amide functionality in this strained substrate can be considered as isolated amine and ketone functionalities as resonance stabilization is prevented due to torsional restrictions. The product was obtained in 68% overall yield in a two step procedure.

class=skin-invert-image|center|640px|Scheme 19. Reduction of a twisted amide

A tricyclic carbonyl compound was reduced using the Huang Minlon modification of the Wolff–Kishner reduction. Several attempts towards decarbonylation of tricyclic allylic acetate containing ketone failed and the acetate functionality had to be removed to allow Wolff–Kishner reduction. Finally, the allylic alcohol was installed via oxyplumbation.

class=skin-invert-image|center|650px|Scheme 20. Synthesis of sec-credenol

The Wolff–Kishner reduction has also been used on kilogram scale for the synthesis of a functionalized imidazole substrate. Several alternative reduction methods were investigated, but all of the tested conditions remained unsuccessful. Safety concerns for a large scale Wolff–Kishner reduction were addressed and a highly optimized procedure afforded to product in good yield.

class=skin-invert-image|center|530px|Scheme 21. Large-scale application

An allylic diazene rearrangement was used in the synthesis of the C21–C34 fragment of antascomicin B. The hydrazone was reduced selectively with catecholborane and excess reducing agent decomposed with sodium thiosulfate. The crude reaction product was then treated with sodium acetate and to give the 1,4-syn isomer.

class=skin-invert-image|center|700px|Scheme 22. Allylic diazene rearrangement