Cope rearrangement equilibria

An irreversible consecutive reaction as a driving force to shift an unfavorable Cope rearrangement equilibria in the needed direction can be illustrated by the Cope-Claisen tandem process used for the synthesis of chiral natural compounds243. It was found that thermolysis of fraws-isomeric allyl ethers 484 or 485 at 255 °C leads to an equilibrium mixture of the two isomers in a 55 45 ratio without conversion into any other products (equation 184). Under the same conditions the isomer 487 rearranges to give the Cope-Claisen aldehyde 491 (equation 185). Presumably, the interconversion 484 485 proceeds via intermediate 486 whose structure is not favorable for Claisen rearrangement. In contrast, one of the two cyclodiene intermediates of process 487 488 (viz. 490 rather than 489) has a conformation appropriate for irreversible Claisen rearrangement243. 

The most important sigmatropic rearrangements from the synthetic point of view are the [3,3] processes involving carbon-carbon bonds. The thermal rearrangement of 1,5-dienes by [3,3] sigmatropy is called the Cope rearrangement. The reaction establishes equilibrium between the two 1,5-dienes and proceeds in the thermodynamically favored direction. The conversion of 24 to 25 provides an example ... 

Scheme 6.13 gives some examples of Cope and oxy-Cope rearrangements. Entry 1 shows a reaction that was done to compare the energy of chair and boat TSs. The chiral diastereomer shown can react through a chair TS and has a AG about 8 kcal/mol lower than the meso isomer, which must react through a boat TS. The equilibrium is biased toward product by the fact that the double bonds in the product are more highly substituted, and therefore more stable, than those in the reactant. 

Entry 2 illustrates the reversibility of the Cope rearrangement. In this case, the equilibrium is closely balanced with the reactant benefiting from a more-substituted double bond, whereas the product is stabilized by conjugation. The reaction in Entry 3 involves a cz s-divinylcyclopropane and proceeds at much lower temperature that the previous examples. The reaction was used in the preparation of an intermediate for the synthesis of pseudoguiane-type natural products. 

Thermodynamic and kinetic data for Cope rearrangements leading to allenes have been measured [511]. For preparatively useful yields the equilibrium can be shifted to the allene, for example by the classical use of allylic alcohols leading to carbonyl compounds [512],... 

The first two entries show that, after 1 minute, the 1,2-a is the sole product, but after 1 h the equilibrium is shifted towards the formation of 1,4-y. Evidence is given for the combined effect of retroaldolization and of oxy-Cope rearrangement to the equilibration process. The latter process is estimated to contribute about 20% of final 1,4-y adduct. The thermodynamic most stable regioisomer 1,4-y dominates in refluxing THF, while the... 

A kinetic study of the Cope rearrangement of 2-(trifluoromethyl)oeta-l.5-diene [(Z)-7] showed no rate acceleration in comparison with the rearrangement of unsubsliluled hexa-1,5-diene. Equilibrium was reached after 7 days at 207 C (K = 3.46 favoring the is-isomer). at which stage no intermediate 4-ethylhcxa-l,5-diene 8 was observed.6 In contrast, a trifluoromethyl group at position 2 does accelerate the Claisen rearrangement (sec Section 5.1.5.2.). 

Iminium ions (16) and (17) were shown to be interconverted by a 2-azonia-Cope rearrangement. The position of equilibrium was found to favour (16) strongly, but the... 

H. Quast, M. Seefelder, Angew. Chem. Int. Ed. Engl. 38, 1064 (1999). The Equilibrium between Localized and Delocalized States of Thermochromic Semibullvalenes and Barbaralanes—Direct Observation of Transition States of Degenerate Cope Rearrangements. 

Intramolecular [4+4] cycloaddition of 2-pyrones with furans has been studied by West and coworkers (Sch. 39). Irradiation of 172, with a furan tethered to C6 of the pyrone, leads to a mixture of trans 173 and cis 174 [115]. Interestingly, the Cope rearrangement of the cis isomer 174 yields an equilibrium mixture with cyclobutane 175. The effect of a stereogenic center on the tether was also determined in this study. With the furan tethered to C3 of the triflate-substituted pyrone 176, the trans isomer 177 was formed with good selectivity and isolated in very good yield [116]. 

As is the case with all of these reactions, the process is allowed in both directions, so a mixture of the reactant and product results if the equilibrium constant does not dramatically favor one over the other. Many Cope rearrangements produce such a mixture because the reactant and the product are comparable in stability. 

The major disadvantages in the application of the Cope rearrangement to the synthesis of organic molecules is the equilibrium between starting material and ring enlargement product. The ratio of the two products is not predictable, a priori. 

The Claiscn rearrangement of allyl vinyl ethers is usually an irreversible reaction due to the energetic benefit of forming aC-O double bond. However, in strained bicyclic systems the retro-Claisen rearrangement (3-oxa-Cope rearrangement) of y,<5-unsaturated aldehydes has been observed32. Sometimes equilibrium mixtures of vinyl ether and carbonyl compound were found. For example, the ratio of the valence tautomers, bicyclo[3.1.0]hex-2-ene-6-cWo-methanal to 2-oxabicyclo[3.2.l]octa-3,6-diene, is approximately 7 333. Nevertheless this reaction was used in the preparation of a key intermediate in a prostacyclin synthesis34. 

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