Refro-Diels-Alder reaction

Most of the synthetic reactions leading to substituted carbon compounds can be reversed. Retro-aldol or refro-Diels-Alder reactions, for example, are frequently used in the de-gradative fragmentation of complex molecules to give simpler fragments. In synthesis, such... 

Pericyclic disconnections and sigmatropic and other rearrangements give rise to synthons which are themselves reagents. Such disconnections greatly simplify the target molecule (e.g. the refro-Diels-Alder reaction). These disconnections are most commonly applied in alicyclic and heterocyclic systems. 

In order to form the activated complex required for the formation of product D, rotational changes of the less dipolar anti-form A to the more dipolar s jn-conformer B are necessary, to give an activated complex C with more parallel bond dipoles, which is thus more dipolar and better solvated than the reactant molecule. In agreement with this explanation is the observation that the reverse refro-Diels-Alder reaction exhibits no large solvent effect, since the activated complex C is quite similar to the reactant D [807], A very subtle solvent effect has been observed in the Diels-Alder addition of methyl acrylate to cyclopentadiene [124], The polarity of the solvent determines the ratio of endo to exo product in this kinetically controlled cycloaddition reaction, as shown in Eq. (5-43). The more polar solvents favour endo addition. 

All Diels-Alder reactions of tropones 51 as dienes with different types of dienophiles shown in Scheme ll are accelerated by pressure, so that in some cases the desired cycloadducts are only formed at high pressure. An interesting synthetic equivalent of the unreactive acetylene in Diels-Alder syntheses is the oxanorbomadiene derivative 52 (Scheme 11 entry 2). 52 reacts with tropones forming the adducts 53, 54 and 55, which undergo a refro-Diels-Alder reaction leading to 56 and 57, the formal [4+2] cycloadducts of tropones to acetylene. 

The Diels-Alder reaction is reversible, and many adducts, particularly those formed from cyclic dienes, dissociate into their components at higher temperatures. Indeed, a refro-Diels-Alder reaction is the principal method for preparing cyclopenta-diene prior to its use in cycloaddition reactions. 

Dicyclopentadiene is a feedstock for both the fragrance and polymer industries. It forms spontaneously from cyclopentadiene by a Diels-Alder reaction and a refro-Diels-Alder reaction can be used to regenerate cyclopentadiene from it. A number of minor fragrance ingredients are produced by Diels -Alder reaction of the monomer with a variety of activated olefins in which the activating group, X, is usually an aldehyde, ketone, ester or nitrile. However, the main fragrance uses stem from the dimer. 

In the preceding example we did not consider cycloaddition reactions since these would not offer any suitable alternative synthetic pathway. The bicyclic isoquinuclidine derivative given below (G. Biichi, 1963, 1966A) contains only unstrained six-membered rings, and the refro-Diels-Alder transform is obviously the furthest-reaching simplification and the fastest antithetical route to commercial starting materials. Both bridgehead atoms can be introduced in one step. 

To enter the retrosynthesis of TM 2.2a, we need the retrosynthetic tool presented in the following chapters. This is functional group addition (Sect. 1.1.2, Table 1.1). Addition of the C=C bond at the proper position in the cyclohexane ring in TM 2.2a offers an unexpected opportunity. This FGA leads to a cyclohexene derivative amenable to refro-Diels-Alder (refro-D.-A.) disconnection to diene and dienophile. The retrosynthetic step and mechanism of the Diels-Alder reaction are discussed in Example 2.4. 

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