Wharton reaction

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

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 285, Springer International Publishing Switzerland 2014 

(a) Wharton, P. S. Bohlen, D. H. J. Org. Chem. 1961, 26, 3615-3616. (b) Wharton, P. S. J. Org. Chem. 1961, 26, 4781-4782. Peter S. Wharton earned his Ph.D. at Yale University under the tutelage of Harry H. Wasserman and began his independent aea-demia eareer at University of Wisconsin at Madison. This was his first paper out of graduate sehool  

Wharton Reaction. In Name Reactions for Functional Group Transformations, Li, J. J., Ed. Wiley Hoboken, NJ, 2007, pp 152-158. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 266, Springer-Verlag Berlin Heidelberg 2009 

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Ring opening by intramolecular attack by an electron source located on a /3-carbon is represented by the Wharton reaction (Scheme 62) (8UCS(P1)2363) and the Eschenmoser fragmentation (Scheme 63) (81S276). 

Wharton reaction (1, 439 8, 245). This reaction can also be conducted under free-radical conditions of reduction of thiocarbonylimidazolide derivatives of a,/l-epoxy alcohols with tri-n-butyltin hydride.17 In some cases, inverse addition is necessary to prevent further rearrangement of the allylic alcohol initially formed. Yields are around 50-60%. The modification is not useful in the carbohydrate field, where very complex product mixtures are formed. 

While it is not clear from these applications whether the Wharton reaction necessarily proceeds via trans diaxial epoxide opening, Ziegler et al in synthetic studies towards quassinoids, have found that there is no such stereoelectronic requirement in a rigid fraws-decalin ring system (Scheme 16). 

The Wharton reaction has also been applied to the conversion of exocyclic a,p-epoxy ketones to the corresponding exocyclic hydroxy methylene products (Scheme 17). Similar conditions transform exocyclic methyl ketones into the exocyclic ethylidene derivative (Scheme 18). Not unexpectedly, the (Z)-alkene is isolated in only slightly higher yields than the ( )-isomer. 

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. 

Verbanone and its derivatives are normally made by oxidation of a-pinene [usually (+ )-116] when Takayanagi and Nishino required (— )-trans-verbanone (822), they used a synthetic procedure starting from (+ )-apoverbenone [(+ )-823] accessible from the ( —)-p-pinene series. The Wharton reaction (hydrazine hydrate) with the (trons)-epoxide of 823 yields 824, which can be oxidized to (— )-apoverbenone [( —)-823], from which 822 was obtained by reaction with lithium dimethyl cuprate. [This work was actually to prepare verbanyl acetates, the (l/ ,2/ ,5/ )-series of which notably ( + )-825 is active as pheromone mimics in the cockroach Periplaneta americana, while the (15,2S,5S)-series from 822 are inactive. 

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... 

No sooner than Wharton s landmark publications did Dodson of G. D. Searle discover a side reaction of the Wharton reaction.7 Treatment of 16a,17-epoxypregnenolone (9) with hydrazine hydrate resulted in not only the expected allylic alcohol 10 (ca. 25% yield), but also a small amount of pyrazole 11 (ca. 10% yield) as well. It was speculated that the mechanism involved an intramolecular Sn2 displacement of the epoxide by the diazene (the anchimeric process) followed by dehydration.8... 

Another deviation from the normal course of the Wharton reaction was recorded by OhlofF and Uhde of Firmenich in 1970.9 When olefinic epoxyketone 12 was treated with hydrazine hydrate, not only was the expected allylic alcohol 13 obtained, a bicyclic product 14 was also isolated. The authors proposed that both products went through a common intermediate, vinyl anion 17. 

An apparent failure of the Wharton reaction of a sterically hindered epoxyketone 19 was recorded.11 Instead of the expected allylic alcohol, its isomer, allylic alcohol 20, and allylic ether 21 were isolated. The Wharton allylic alcohol could be otherwise synthesized... 

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