The Cope Rearrangements

The Cope rearrangement is perhaps the premier example of [3,3]-sigmatropic rear- 

15 shown in Reaction 4.5. Though first discovered in the 1940s, the mechanism of this reaction remained controversial into the 1990s.  

A good substrate for the Cope rearrangement is a m-l,2-divinylcyclopropane, since ring-opening of the strained three-membered ring occurs on rearrangement. 

In addition to the oxy-Cope and anionic oxy-Cope rearrangements, an important variant is the aza-Cope rearrangement of A -butenyl-iminium ions (3.175). This rearrangement occurs under mild conditions, but suffers as a synthetic method because of its reversibility. However, with a hydroxy group attached to the butenyl chain (R=OH), the reaction is driven in the forward direction by capture of the rearranged iminium ion in an intramolecular Mannich reaction, to provide an excellent synthesis of substituted pyrrolidines.  

The required iminium ion can be obtained readily by the condensation of an aldehyde with a butenylamine. For example, heating the butenylamine 276 with pyridine-3-carboxaldehyde and an acid catalyst (camphorsulfonic acid, CSA), gave the acetyl nicotine derivative 277 (3.176). The initial iminium ion 278 rearranges to the new iminium ion 279, which is irreversibly trapped in an intramolecular Mannich reaction to give the pyrrohdine 277. 

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. 

Attempts have been made to find reaction sequences which allow the introduction of more than four atoms into a ring by a Cope rearrangement. Two of these methods should be mentioned, both quite different. The first method uses an enlarged Cope system , which forms bigger rings than the normal Cope system. In the second method the product of one Cope rearrangement can be easily transformed into the starting material for a second Cope shift sequence. 

A method of repetitive ring expansion of cyclic ketones was published based on the use of (phenylseleno)acetaldehyde on the siloxy-Cope rearrangement [29a], The authors were able to transform cyclododecanone into cycloeicosadec-5-en-l-one in 23 % yield. 

2) (Phenylseleno)acetaldehyde was recommended as an alternative synthetic equivalent to the vinyl carbocation for a-vinylation of ketones [30], 

Interest in the mechanism and stereochemistry of the Cope rearrangement, which attracted considerable attention twenty-odd years ago [13], has recently been rekindled after several years of comparative neglect, and is presently the subject of a considerable amount of critical discussion, with particular emphasis on the synchronicity of the bond-breaking and bond-forming processes [17]. 

The experimental evidence indicates that in both the Cope rearrangement [18] and the isoelectronic Claisen rearrangement [19], in which one methylene group is replaced by an oxygen atom, reaction via the chair transition state is favored over that via the boat unless the former is prohibited by steric constraints [13]. Although the unconstrained hexadiene molecule can take up either a syn (C2t ) or an anti (C2/1) conformation, its preference for reaction via the chair TS has been repeatedly confirmed by a variety of computational methods [2, 20, 21, 22, 23, 24, 25]. 

5-Dienes under thermal conditions undergo [3, 3]-sigmatropic shift known as Cope-rearrangement. Stereochemical outcome of this reaction can be rationalized through chair-shaped transition state as given below  

Oxy-Cope rearrangement Cope-rearrangement reaction is reversible and gives equilibrium mixture of two 1, 5-dienes which are richer in thermodynamically more stable isomer. But, reaction of 3-hydroxy-l, 5-diene can not be reversed, because 3-hydroxy-l, 5-diene tautomerises to carbonyl compound as given below. This rearrangement is known as Oxy-cope rearrangement. 

This rearrangement provides a useful route for the synthesis of 5, e-unsaturated aldehydes and ketones with —OH substituent at C-3 and C-4 of the diene 1, 6-dicarbonyl compounds are produced. 

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Many rearrangements forming C—C bonds have been applied to the preparation of heterocyclics. The Cope rearrangement is prominent, and an example is shown in Scheme 8. The staring material usually most accessible is an alkene, which is converted to the required cyclopropane at some stage before the rearrangement step. 

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 ... 

The Cope rearrangement usually proceeds through a chairlike transition state. The stereochemical features of the reaction can usually be predicted and analyzed on the basis of a chair transition state that minimizes steric interactions between the substituents. Thus, compound 26 reacts primarily ttuough transition state 27a to give 28 as the major product. Minor product 29 is formed flirough the less sterically favorable transition state 27b. 

There is a second possible transition state for the Cope rearrangement in which the transition state adopts a boatlike geometry ... 

The stereochemical features of the Claisen rearrangement are very similar to those described for the Cope rearrangement, and reliable stereochemical predictions can be made on the basis of the preference for a chairlike transition state. The major product has the -configuration at the newly formed double bond because of the preference for placing the larger substituent in the pseudoequatorial position in the transition state. ... 

Like the Cope rearrangement, the Claisen rearrangement is sensitive to substituents on the reacting system. Cyano groups promote the rearrangement by a factor of 10 at positions 2 and 4 and have smaller effects at the other positions, as shown below. Data are also available for methoxy groups at positions 2, 4, 5, and 6. ... 

Figure 15.29 The Cope rearrangement and Dewar benzene ring-opening reaction...

The structures in the (1,0) and (0,1) comers are not necessarily stable species, they may correspond to hypothetical structures. In the Cope rearrangement it appears that the reaction only involves a single TS, independently of the number and nature of substituents. The reaction path may change from B A C depending on the system, but there are no intermediates along the reaction coordinate. 

The Cope rearrangement of hexa-l,5-diene does not allow for differentiation of starting material and product this is called a degenerate Cope rearrangement. Another example is the automerization of bicyclo[5,l,0]octa-2,5-diene 7 ... 

The required temperatures for the Cope rearrangement are generally lower, if the starting material contains a substituent at C-3 or C-4 which can form a conjugated system with one of the new double bonds. 

The Cope rearrangement is of great importance as a synthetic method e.g. for the construction of seven- and eight-membered carbocycles from 1,2-divinylcyclopropanes and 1,2-divinylcyclobutanes respectively (e.g. 11 12),... 

Two other important sigmatropic reactions are the Claisen rearrangement of an allyl aryl ether discussed in Section 18.4 and the Cope rearrangement of a 1,5-hexadiene. These two, along with the Diels-Alder reaction, are the most useful pericyclic reactions for organic synthesis many thousands of examples of all three are known. Note that the Claisen rearrangement occurs with both allylic aryl ethers and allylic vinylic ethers. 

When 1,5-dienes are heated, they isomerize, in a [3,3] sigmatropic rearrangement known as the Cope rearrangement (not to be confused with the Cope elimination reaction, 17-8)When the diene is symmetrical about the 3,4 bond, we have the unusual situation where a reaction gives a product identical with the starting material ... 

The predictions of the reactivities by the geminal bond participation have been confirmed by the bond model analysis [103-105] of the transition states and the calculations of the enthalpies of activation AH of the Diels-Alder reaction [94], the Cope rearrangement [95], the sigmatropic rearrangement [96], the Alder ene reaction [100], and the aldol reaction [101] as are illustrated by the reactions of the methyl silyl derivatives in Scheme 38 [102], The bond is more electron donating than the bond. A silyl group at the Z-position enhances the reactivity. 

In contrast to the synthesis of carbocyclic rings, the Cope rearrangement has been used sparsely for generating azepinones. Recently, the enantioselectivity of the conversion of 2-aza-divinylcyclopropane 286 has been investigated. The synthesis started from the optically active cyclopropanecarboxylic acid (90% ee), which had been converted into the isocyanate 286 by initial azidation to 285 and a consecutive Curtius rearrangement. Furthermore, the conditions of the iso-... 

When there is a hydroxy substituent at C(3) of the diene system, the Cope rearrangement product is an enol that is subsequently converted to the corresponding... 

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. 

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