Meerwein-Eschenmoser amide acetal

Sigmatropic rearrangement of A, 0-ketene acetals to yield Y,5-unsaturated amides. Since Eschenmoser was inspired by Meerwein s observations on the interchange of amide, the Eschenmoser-Claisen rearrangement is sometimes known as the Meerwein-Eschenmoser-Claisen rearrangement. 

In 1964, Eschenmoser [5] discovered that the exchange between amide acetals and allylic alcohols observed by Meerwein [6] afforded after rearrangement of y,d-unsaturated amides (Scheme 6.1). 

The Meerwein-Eschenmoser-Claisen rearrangement is one of the most useful pericyclic reactions. In its basic form, it involves the conversion of an allylic alcohol 1 to a ketene N, 0-acetal 2, which undergoes rapid [3,3]-sigmatropic rearrangement to yield a y,d-unsaturated amide 3 (Scheme 7.1). In accordance with the general electronic effects observed in Claisen rearrangements, the presence of an electron-donating amino substituent on the ketene acetal intermediate substantially increases the rate of the pericydic step. 

The most convenient and common way to carry out a Meerwein-Eschenmoser-Claisen rearrangement is by heating an aUylic alcohol with a ketene acetal or amide acetal (Schemes 7.3 and 7.4). In this chapter, these conditions are referred to as the Eschenmoser-CIaisen rearrangement per se. 

The Meerwein-Eschenmoser-Claisen rearrangement, in particular the Eschen-moser amide acetal version, has been extensively applied toward the synthesis of natural products and other complex target molecules. The literature is replete with cases where the reaction provided the only way to place a substituent in a sterically hindered environment. The following paragraphs provide selected examples of its use and also serve to highlight the further synthetic transformation of the unsaturated N,N-dimethylamides normally obtained. Perhaps the only drawback of the Eschenmoser-Claisen rearrangement is the stabiUty of these amides, whose hydrolysis and reduction requires relatively harsh conditions. However, electrophilic activation via the y,(5-double bond can be used to manipulate this functionality. 

Shortly after Meerwein s and Eschenmoser s original reports, Ficini disclosed the use of ynamines as suitable precursors of aUyhc ketene N,0-acetals (Scheme 7.8) [10, 17]. AUyhc alcohols add to ynamines (15) either in the presence of catalytic amounts of a Lewis acid, for instance BFj-OEtj, or at elevated temperatures. This addition presumably proceeds through the intermediacy of a keteniminium ion 16. The resulting ketene N,0-acetals then undergo the sigmatropic rearrangement to yield the corresponding amides. 

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