Hydrazine epoxy ketones

Conversion of a-haloketones to olefins using hydrazine (via enedlitnides C-C-N NH). Also reduction of o,3-epoxy ketones to allyl alcohols. 

Pyrazoles were synthesized in the authors laboratory by Le Blanc et al. from the epoxy-ketone as already stated in Sect. 3.1.1a, Scheme 35 [80]. The synthetic strategy employed by Le Blanc et al. [80] was based upon that the strategy published by Bhat et al. [81] who also described the synthesis of pyrazoles but did not report cytotoxic evaluation on the synthesized compounds. Scheme 48 shows the synthesis of the most active compound (178). Dissolution of the epoxide (179) with a xylenes followed by treatment with p-toluenesulfonic acid and hydrazine hydrate produced the pure nitro-pyrazole 180 in good yield (60%). Catalytic hydrogenation with palladium on activated carbon allowed the amino-pyrazole (178) to be obtained in a pure form. This synthesis allowed relatively large numbers of compounds to be produced as the crude product was sufficiently pure. Yield, reaction time, and purification compared to reported approaches were improved [50, 61, and 81]. Cytotoxicity of these pyrazole analogs was disappointing. The planarity of these compounds may account for this, as CA-4, 7 is a twisted molecule. 

Reduction of a,(3-epoxy ketones by hydrazine to allylic alcohols. 

A useful reduction reaction takes place with hydrazine in the presence of a strong base. In the Wolff-Kishner reduction a carbonyl group is reduced to a methylene. If the hydrazone is formed from an epoxy ketone, the decomposition takes place easily with the formation of an allylic alcohol. 

This transformation has found extensive use in converting cyclopentenone and cyclohexenone ring systems to the rearranged allylic alcohols during the course of the total syntheses of natural products. In the preparation of ( )-quadrone (Scheme 12), the tricyclic enone was epoxidized and the resulting a,P-epoxy ketone treated with hydrazine to afford the allylic alcohol. The cyclopropane-directed epoxidation shown in Scheme 13 gives an allylic alcohol that is taken on to (-)- and (+)-carenones. In the total syn-... 

There are a few applications of the Wharton reaction in acyclic systems. For example, treating an acyclic a, -epoxy ketone (Scheme 19) with hydrazine hydrate at 0 °C affords the expected product, but as a l l-( ) ( mixture. However, the major product (60%) in this particular case is the bicyclic alcohol that arises via cyclization of the intermediate vinyl radical (or anion) on the endocyclic carbon-carbon double bond. 

Stork, G., Williard, P. G. Five- and six-membered-ring formation from olefinic a,P-epoxy ketones and hydrazine. J. Am. Chem. Soc. 1977, 99, 7067-7068. 

A novel reaction discovered by Wharton is the reduction of a,j8-epoxy ketones by hydrazine to allylic alcohols. When a suspension of the steroid (1) in excess 64% CHj CH,... 

Treatment of this epoxy-ketone with tosyl hydrazine gives a compound with the spectra shown below. What is its structure ... 

The Wharton reaction is the transformation of a,(3-epoxy ketones 1 by hydrazine to allylic alcohols 2. It is also known as the Wharton transposition, Wharton rearrangement, and Wharton reduction. 

The mechanism of the Wharton reaction is analogous to that of the Wolff-Kishner reduction. Addition of hydrazine to a, 3-epoxy ketone 1 gives rise to hydroxyl-hydrazine 6, which dehydrates to afford the intermediate, hydrazone 7. Tautomerization of hydrazone 7 then leads to diazene 8, a common intermediate as the Wolff-Kishner reduction. But different... 

Eschenmoser a,p-epoxy ketone cleavage (2,419-422 3,293). In the synthesis of a prostanoid, Corey and Sachdev encountered a case where the Eschenmoser cleavage reaction with p-toluenesulfonylhydrazine gave a very complex mixture from which none of the desired acetylenic aldehyde could be isolated. They then found that cleavage could be effected with 2,4-dinitrobenzenesulfonyl-hydrazine in CH2CI2 or THF at 0-25°. Pyridine, sodium carbonate, or sodium bicarbonate can be used as catalysts. The yield can sometimes be improved by addition of ethyl isocyanate to scavenge the sulfinic acid formed in the fragmentation. This modified procedure was shown to be effective in five cases. 

Stork and Williard have noted that when certain olefinic a,/8-epoxy-ketones are treated with hydrazine in methanol, conditions normally resulting in the Wharton reaction, anomalous behaviour resulting in cyclization is observed.Thus the epoxy-ketone (185) was converted into the bicyclic alcohol (186) in 85% yield. 

Two papers have appeared discussing cycloadditions of hydrazine derivatives (e.g. 294) to olefins,and one in which tosyl hydrazine reacted with a-epoxy-ketones to afford functionalized pyrazolines (295) and (296) or pyrazolidines. ... 

The Wharton reaction converts an epoxy ketone to an allylic alcohol by reaction with hydrazine. Propose a mechanism. (Hint Review the Wolff-Kishner reaction in Section 19.9.)... 

Wharton, P. S. Bohlen, D. H. Hydrazine Reduction of Epoxy Ketones to Allylic Alcohols /. Or. Chem. 1961, 26, 3615-3616. For a mechanistic study see Stork, G. Williard, P. G. Five- and Six-Membered-Ring Formation from Olefinic a,j8-Epoxy Ketones and Hydrazine /. Am. Chem. Soe. 1977, 99, 7067-7068. For a recent appUcation of the Wharton rearrangement see Liu, J. Hsung, R. P. Peters, S. D. Total Syntheses of (+)-Cylindricines C-E and (-)-Lepadiformine through a Common Intermediate Derived from an z -Prins Cyclization and Wharton s Rearrangement Oi. Lett. 2004, 6, 3989-3992. 

Certain a,/8-epoxy-ketones (the requirements for a successful reaction are not clear) cyclize on reaction with hydrazine to form cyclopentene carbinols [equation (22)]. "... 

Next, a three-step sequence was employed to convert diastereomeric spirocycles 415 to epoxy ketone 416. This intermediate was subjected to a Wharton rearrangement using 5.0 equiv hydrazine and 0.5 equiv HO Ac to yield the desired transposed allyl alcohol 417-trans in 66% yield as an inseparable diastereomeric mixture. While we observed this tra/w-allyl alcohol in most trials, we found the c/r-allyl alcohol 417-c/r in 42% yield when using 10 equiv HOAc. 

This elegant and versatile synthesis of acetylenic ketones and aldehydes through fragmentation of a,/3-epoxy-ketones with p-toluenesulfonyl hydrazine was developed by ). Shreiber, D. Felix, A. Eschenmoser, M. Winter, F. Gautschi, K. H. Shulte-Elte, E. Sundt, G. Ohioff, J. Kalvoda, H. Kaufmann, P. Wieland and G. Anner, Helv. Chim. Acta, 50, 2101 (1967). 

Cyclic a,(5-epoxy ketones have been fragmented upon treatment with hydrazine to give alkynic aldehydes... 

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