Enolate accelerated Cope

Wender and cowoikers reported the first example of an enolate-accelerated Cope rearrangement in 1985. Exposure of the trienone (51 Scheme 4) to potassium hydride in THF at room temperature for 17 h led to the formation of a 1.2 1 mixture of (55) and (54) each rearranged trienone was produced as a mixture of alkene isomers. The facility with which the rearrangement of the ketone enolates takes place is underscored by the observation that the corresponding silyl enol ethers remain unchanged under identical conditions, and require temperatures in excess of 100 °C for efficient rearrangement. 

Majetich and Hull also showed that the presence of an enolate moiety in conjunction with the diene can facilitate the Cope rearrangement. This variation was called an enolate accelerated Cope rearrangement. 23 When 564 was heated to 180°C, 566 was formed in 45% yield via bond migration from the initial Cope product, 565. When 564 was treated with fluoride, however, enolate 567 was formed and Cope rearrangement to 568 occurred at 25°C (92% yield). Hydrolysis gave 566. 

The novelty of these annulations prompted us to investigate the reaction mechanism. Although the scope of this manuscript precludes a detailed discussion of the mechanistic pathway, we believe that this annulation occurs via a novel tandem Michael addition / enolate-accelerated Cope pathway (Eq. 23). ... 

Takeda and Yoshii also developed a remarkable annulation using a,l -unsaturated ketone enolates for addition to y silylacryloyl silane 78. The reaction was stereospecific, with ( )-78 providing 79 in good yield, but (Z)-78 leading to the /ran -product diastereomer 80 in a sluggish, lower-yielding reaction. The proposed mechanism involved an anion-accelerated Cope rearrangement of a 1,2-divinylcyclopropanediolate intermediate. ... 

This reaction, called the oxy-Cope rearrangement has proved highly useful in synthesis." The oxy-Cope rearrangement is greatly accelerated (by factors of 10 -10 ) if the alkoxide is used rather than the alcohol.In this case the direct product is the enolate ion, which is hydrolyzed to the ketone. 

The 2-azonia analog of the Cope rearrangement is estimated to be accelerated by 106, relative to the unsubstituted system.270 The product of the rearrangement is an isomeric iminium ion, which is a mild electrophile. In synthetic applications, the reaction is often designed to generate this electrophilic site in a position that can lead to a cyclization by reaction with a nucleophilic site. For example, the presence of a 4-hydroxy substituent generates an enol that can react with the iminiun ion intermediate to form a five-membered ring.271... 

Enol formation provides the necessary 1,5-diene for the Cope-like rearrangement. If one provides an enolate anion, the ionic nature of the reaction provides the expected acceleration of rate. 

The oxyanion of the enolate (or a silyloxy group) appears to speed up this reaction relative to an unadorned Claisen system, but an even more dramatic acceleration is seen when Cope systems have an oxyanion substituent on the tetrahedral carbon, as in the reaction 5.59 —> 5.61, which takes place at a... 

A donor substituent at position 4 or 6 will favor the reaction and an attractor similarly placed will hinder it. Conversely, an attractor (donor) at position 1 stabilizes (destabilizes) the enolate fragment. As atoms 2 and 5 bear no charge, the electronic character of the substituent has little consequence. By analogy with the Cope reaction, we expect that a substituent at these positions also accelerates the Claisen reaction. 

A correlation between rate acceleration and the electron-donating ability of the MO group of enolates 2 shows the potassium enolatc to be superior to the lithium, sodium or trimethylsilyl derivative84. The rate enhancement, in this case, lias been attributed to a vinylogous weakening effect of the oxyanion on the 0-3 C-4, oxygen-carbon bond, similar to effects that have been encountered in anionic oxy-Cope rearrangements119. 

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