Aldehydes Eschenmoser fragmentations

A cyclopentane aldehyde (297) is obtained when verbenone epoxide (298) is treated with zinc bromide. The presence of pinene in the products is difficult to explain, and the difference in products obtained with aluminium chloride (Vol. 1, p. 45) is remarkable. When the toluene-p-sulphonylhydrazone of the epoxide (298) is treated with potassium t-butoxide, both isomers of the cyclobutyl-acetylene (299) are obtained in an Eschenmoser fragmentation. ... 

Hydrazones can be readily prepared by the addition of a hydrazine to an aldehyde or ketone. Treatment of tosyl hydrazones (or other arylsulfonyl hydrazones) with a base has been used for the preparation of alkenes. In the Bamford-Stevens reaction, a mild base, such as NaOMe or KH, is employed and promotes deprotonation of the acidic N—H proton (compare with the Eschenmoser fragmentation. Scheme 2.33). 

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). 

This modification resulted in a yield improvement for the pentacyclization process from 47 % to 66 %. Treatment of the amino ether 192 with diisobutylaluminum hydride in refluxing toluene accomplished Eschenmoser-Grob fragmentation and reduction of the initially formed immonium ion, to give the unsaturated amino alcohol 193 in 86% yield. It was gratifying to find that 193 was the only product formed in this reaction. In the tetrahydropyran derivative, reduction of 192 to 193 is accompanied by about 15 % simple elimination. Displacement of the tosyl group in 196 gives sulfide 197, which is oxidized to sulfone 198. This material is metallated and coupled with enantiomerically pure aldehyde to secure the codaphniphylline skelton [74]. 

Eelix, D., Wintner, C., Eschenmoser, A. Eragmentation of a,P-epoxyketones to acetylenic aldehydes and ketones preparation of 2,3-epoxycyclohexanone and its fragmentation to 5-hexynal. Org. Synth. 1976, 55, 52-56. 

The most dramatic of all these reactions is the Eschenmoser fragmentation30 - a general route to alkynyl aldehydes 189 and ketones. The tosylhydrazone 186 of an epoxyketone 185 gives an anion on treatment with base that fragments once 187 to give an alkene and again 188 in the reverse direction 188 to give the alkyne. 

The synthesis of three fragments 278, 282, and 285 for the C21-C42 bottom segment is summarized in Scheme 41. The Eschenmoser-Claisen rearrangement of amido acetal of 276, which was prepared via 2-bromocyclohexenone by Corey s asymmetric reduction, afforded amide 277. Functional group manipulation including chain elongation provided Evans-type amide 278. The Evans aldol reaction of boron enolate of 279 with aldehyde 280 stereoselectively afforded 281, which was converted into aldehyde 282 through a sequence of seven steps... 

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. 

Eschenmoser has published an extensive account of the fragmentation of ttjff-epoxy-ketones to alkynones numerous examples illustrate the course of thermolysis of hydrazones derived from ajS-epoxy-ketones and substituted aminoaziridines (Scheme 111). This preparatively useful method is also applicable to the preparation of acetylenic aldehydes. 

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