Wolff–Kishner reduction

[1][2] 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.

[4] In general, the reaction mechanism first involves the in situ generation of a hydrazone by condensation of hydrazine with the ketone or aldehyde substrate.

In some cases, formation of the required hydrazone will not occur at sterically hindered carbonyl groups, preventing the reaction.

[4] Kishner found that addition of pre-formed hydrazone to hot potassium hydroxide containing crushed platinized porous plate led to formation of the corresponding hydrocarbon.

A review titled “Disability, Despotism, Deoxygenation—From Exile to Academy Member: Nikolai Matveevich Kizhner” describing the life and work of Kishner was published in 2013.

[5] Wolff later accomplished the same result by heating an ethanol solution of semicarbazones or hydrazones in a sealed tube to 180 °C in the presence of sodium ethoxide.

The method developed by Kishner has the advantage of avoiding the requirement of a sealed tube, but both methodologies suffered from unreliability when applied to many hindered substrates.

[4] A range of mechanistic data suggests that the rate-determining step involves formation of a new carbon–hydrogen bond at the carbon terminal in the delocalized hydrazone anion.

Mildly electron-withdrawing substituents favor carbon-hydrogen bond formation, but highly electron-withdrawing substituents will decrease the negative charge at the terminal nitrogen and in turn favor a bigger and harder solvation shell that will render breaking of the N-H bond more difficult.

In 1946, Huang Minlon reported a modified procedure for the Wolff–Kishner reduction of ketones in which excess hydrazine and water were removed by distillation after hydrazone formation.

Nine years after Huang Minlon’s first modification, Barton developed a method for the reduction of sterically hindered carbonyl groups.

[15] This method features rigorous exclusion of water, higher temperatures, and longer reaction times as well as sodium in diethylene glycol instead of alkoxide base.

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.

[17] 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.

[23] 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.

[24][25] 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.

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.

[30] The authors predicted that diastereoselective transfer of the diazene hydrogen to one face of the prochiral alkene could be enforced during the suprafacial rearrangement.

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.

Cram found that azine formation is favored by rapid addition of preformed hydrazones to potassium tert-butoxide in anhydrous dimethylsulfoxide.

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.

Safety concerns for a large scale Wolff–Kishner reduction were addressed and a highly optimized procedure afforded to product in good yield.