Fragmentation reactions Eschenmoser

A simple, high yielding (65-90%) procedure has been described for the preparation of medium ring and macrocyclic acetylenic lactones which is mechanistically related to the well known Eschenmoser fragmentation reaction, and the following example is representative. Bromination of the tosylhydrazone of 1 was carried out with NBS at -10°C in a water/t-butanol/acetone mixture. The reaction mixture was then treated with aqueous NaHSC>3 solution and the resulting mixture heated at 50-60°C for one hour, which gave the acetylenic lactone 2. 

There is much current interest in the design and development of the "double functional group transformation" concept, an excellent illustration of which is the now well known and widely exploited Eschenmoser fragmentation reaction. A recent example of the "double functional group transformation" is the one-flask conversion of 1-nitrocycloalkenes into terminally unsaturated nitriles by treatment first with trimethylsilylmethylmagnesium chloride (1.8 eq.) in THF at -20°C and then, in situ, with PCI3 (2.5 eq.) at 67°C. 2-Nitrobicyclo[2.2.1]hept-2-ene, for example, gave cis-1 -cyano-3-vinylcyclopentane in 33% yield, and similar yields of ene-nitriles were obtained from a variety of monocyclic and bicyclic 1-nitrocycloalkenes. 

Mesitylene-2-sulfonylhydrazone is found to be particularly effective in the Eschenmoser fragmentation reaction. For example, reaction of the epoxy ketone of type (97) gives rise to the corresponding cy-cloalkynone in reasonable yield (equation 51). The same reaction with tosylhydrazone failed, however. 

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). 

The Eschenmoser fragmentation does not have to be a ring expansion, and it is a useful synthetic method for making keto-alkynes. The following reaction, which we will use to discuss the fragmentation s mechanism, was used to make an intermediate in the synthesis of an insect pheromone, exo-brevicoinin. 

A special reaction type involves the a,p-epoxy ketone to alkynone fragmentation, often cited as the Eschenmoser fragmentation . First published by Eschenmoser, and a little later and independently by Tanabe, the utility of this fragmentation for the synthesis of open-chained or cyclic alkynones (Scheme 3) is obvious. 

Unsaturated macrolides such as (115) or (117) (Scheme 38) have been synthesized by Eschenmoser using a fragmentation reaction as a key step. The tricyclic ketal carboxylate (114) can be cleaved as an amidinium salt to give (115) in excellent yield simply on heating. Similarly, the macrolide (117) with ( , )-configuration is obtained from (116). This decarboxylative double fragmentation represents a nine-center Grob type. 

Occasionally, the fragmentation is unexpected and unwanted. For the synthesis of sesquicarene (152), Coates heated the sodium salt of tosylhydrazone (150). However, the main reaction was the carbon analog of the Eschenmoser fragmentation leading to the alkyne (151 Scheme SO). 

Eschenmoser, A., Eelix, D., Ohioff, G. New fragmentation reaction of a,P-unsaturated carbonyls. Synthesis of exaltone and rac-muscone from cyclododecanone. Helv. Chim. Acta 1967, 50, 708-713. 

Eschenmoser fragmentation (2, 419-422). This hydrazine can be more effective than tosylhydrazine for this fragmentation.2 Thus reaction of 1 with the oc-keto epoxide 2 results in formation of l-cyclononyn-5-one (3) in about 43% yield. Another example is the preparation of 2,2-dimethyl-5-hexynal (5) from 4. These reactions proceed in about 15-20% yield with tosylhydrazine. 

Eschenmoser et al. used the reverse thermal fragmentation reaction of cyclobutane 113 to generate captodative alkene 114 [61]. 

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. 

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). 

---