Cope rearrangement allylic systems

The dissociative mechanism of the Cope rearrangement casually mentioned above222 can be illustrated by two examples of Pd-catalyzed reactions. The migration of an allyl group from carbon to carbon in the pyridine system 466 occurs in the presence of a Pd° catalyst236. Refluxing dilute solutions of precursors 466 (R1, R2 = H, Me) in toluene for 7 h or in n -heptane for 24 h gave derivatives 468. The pyridine allyl ether 469 was also... 

There is no unity of opinion in the literature concerning a classification, i.e, whether to call these transformations aza-Claisen or aza-Cope rearrangements. It is accepted that the term aza-Claisen should be reserved only for those processes in which a carbon atom in the allyl vinyl ether system has been replaced by nitrogen357. Three different types of aliphatic 3-aza-Cope reactions which were studied theoretically are the rearrangements of 3-aza-l,5-hexadienes (610, equation 262), 3-azonia-l,5-hexadienes (611, equation 263) and 3-aza-l,2,5-hexatrienes (612, equation 264) (the latter is a ketenimine rearrangement )357. 

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. 

Allylation of the 2,3-Wittig products (167) leads to diallylic ethers (171) in which one of the allylic double bonds is part of a 1,5-diene system. These ethers undergo 3,3-oxy-Cope rearrangement to afford vinyl allyl ethers (170), which rearrange in situ by a 3,3-Claisen process to yield the ( )-dienals (169). Some typical results are summarized in Table 14. The cyclopentanols (175) were shown to arise from aldehydes (169) by an intramolecular thermal ene reaction. ... 

The scope of the Claisen-Cope rearrangement is very great but you have been given enough mechanistic and stereochemical detail to unravel all but the most difficult. The disconnection is always simple - the reaction corresponds to an allylation of an enolate and, providing you remember to turn the allylic system inside out, you will find the starting materials. All that remains is to identify which method to use and how to control the stereochemistry. Oh, and you also have to make the starting materials ... 

Addition of vinylmagnesium bromide to tricyclononenone 10, prepared in three steps from cycloheptatriene, results in the formation of a 4 1 epimeric mixture of allylic alcohol 11, which undergoes oxy-Cope rearrangement to give tricyclic enone 12, the ring system of the aristolane sesquiterpene10715. 

The absence of a substituent a to the carbonyl group in such systems does not necessarily preclude a successful Claisen-Cope reaction sequence. Thus, reaction of allylic alcohol 50 with acetal 51 produces the Claisen product 53. Double-bond isomerization of 53 to give a,/J-unsaturated aldehyde 54 is not observed. Instead, 53 is transformed to Cope product 57, probably via a conjugation-deconjugation-Cope rearrangement sequence1162. 

Substituent effects provide other insights into the nature of the TS for the Cope rearrangement. Conjugated substituents at C(2), C(3), C(4), or C(5) accelerate the reaction. Donor substituents at C(2) and C(3) have an accelerating effect. The net effect on the reaction rate of any substituent is determined by the relative stabilization of the TS and ground state. The effect of substituents on the stabilization of the TS can be analyzed by considering their effect on two interacting allyl systems. We consider the case of phenyl substituents in detail. 

The Diels-Alder reaction is a thermal cycloaddition involving 1,3-dienes and alkenes, and [3+21-cyclo-addition reactions involve a Ji bond and a 1,3-dipole. The Cope, oxy-Cope, and Claisen rearrangements are thermal, intramolecular reactions of 1,5-dienes. [2+2]-Cycloadditions usually involve reaction between two alkenes, or certainly two Ji bonds. A reaction that is different from any seen so far occurs with certain alkenes and allylic systems. In its fundamental form, it is "the indirect substituting of a compound with a double bond... 

Some perspective is necessary here. As indicated in Chapter 7, Section 4.1 on the Cope rearrangement, the free energy for formation of a cyclohexane-1,4-diyl is 50-53 kcal/mol and that for formation of two allyl radicals is roughly 57 kcal/mol. However, in the current system, the diyl is destabilized by roughly 20 kcal/mol due to the bicyclo[2.2.1]ring system that must be generated. Such a species is kinetically inaccessible due, in part, to a substantial negative entropy despite the fact that the activation enthalpy for its formation would appear to be 50-55 kcal/mol. 

Similar activation parameters have been observed for Cope rearrangements in diene systems that incorporate a heteroatom. For the rearrangement of allyl vinyl ether to 4-pentenal, the activation energy is 30.6 kcal/mol and the entropy of activation is -8 eu ... 

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