The Diels-Alder reaction: an update

Journal of the Brazilian Chemical Society

Brocksom, Ursula¹  Universidade Federal de São Carlos, São Carlos, Brazil¹  Nakamura, Joanita¹  Ferreira, Maria Lúcia¹  Brocksom, Timothy John¹ 

关键词: Diels-Alder reaction;    intramolecular;    transannular;   

DOI  :  10.1590/S0103-50532001000500004

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

In this update on the Diels-Alder reaction we would like to present an overview on how this very important reaction has progressed in the last decade, since the last spate of monographs and reviews appeared in the literature1-3, and which deal with the reaction in the overall sense.Initially we present the Diels-Alder reaction in a generalised form, much as discovered over seventy years ago1-3, so that its present relevance as probably the single most important reaction in the synthetic organic chemist's tool-box is clear.Thus, the original version of the Diels-Alder reaction (Scheme 1) joins together a wide variety of conjugated dienes and alkenes with electron withdrawing groups (the dienophiles), to produce a cyclohexene ring in which practically all six carbon atoms can be substituted as desired. The reaction may be executed under relatively simple reaction conditions by heating together the two components, diene and dienophile, in non-polar solvents, followed by evaporation which leads usually to high yields of the product(s). The reaction is disciplined by the Woodward-Hoffmann rules 4-6 as a [p4s+p2s ] cycloaddition occurring in a concerted but probably not symmetrically synchronous fashion, thus leading to highly predictable product structures in which two new carbon-carbon sigma bonds are formed in a stereospecific manner with the creation of up to four new stereogenic centres. The classical empirical rules have now found strong theoretical basis in the Woodward-Hoffmann rules, with regards to regiochemistry ("ortho" and "para" orientations) and stereochemistry (endo transition state kinetically favoured over the exo transition state in most of the reactions)1-6. The practising synthetic organic chemist will certainly be well aware of the kinds of dienes and dienophiles that may be combined successfully, and by way of simple frontier orbital theory4,5 be perfectly capable of predicting the major (or unique) product to be expected from the reaction. The reverse process of retrosynthetic analysis7 is also well established for transforming cyclohexene/cyclohexane containing structures into appropriate diene-dienophile combinations.   Having thus established a background point, this update plans to take the reader into the newer possibilities that have become fact in the last decade. It is not our intention to review earlier developments involving Lewis acid catalysis, very high pressures or other special techniques1-3, 8, or the inverse electron demand version1-4. Newer aspects of cycloadditions9 and carbocycle constructions10,11 have been reviewed, including developments in Diels-Alder chemistry, as well as the related [4+3] IMDA reaction of dienes with allylic carbocations12. The use of sequential Diels-Alder reactions has also been highlighted recently13. The Diels-Alder reaction has now become an important research area for theoretical chemists, with regard to the finer details of the transition state and the energetics of the process, and with special concern for entropy and activation energies14-16.On a completely different front it is now well accepted that the Diels-Alder reaction can be an important biosynthetic process15, 17-23, and several publications include discussions on the existence of the enzyme Diels-Alderase15, 19-23. The presentation which follows shows that the correct combination of diene and dienophile, using some kind of chemical linkage to hold the partners in the correct orientation and at the correct distance, can lead to very low activation energies and therefore to situations in nature in which a true enzyme may be superfluous24.A final introductory point illustrates a powerful synthetic strategy of Diels-Alder chemistry as a protecting group and temporary scaffold (or template), for the manipulation of the sensitive multiple functionalities of diene or dienophile types. In this approach the sensitive diene or dienophile portions of the molecules are tied up with a convenient partner in a Diels-Alder reaction, the cycloadduct is then chemically modified in accordance with the synthetic plan and finally undergoes a retro Diels-Alder reaction to liberate the desired product25. For example, the cycloaddition product of a reactive a,b-enone function with cyclopentadiene, can be submitted to the required chemo-, regio- and stereoselective reactions, dominated in part by the expected endo-cycloadduct structure, before retro Diels-Alder reaction unravels a much more complex product. Clearly the same synthetic sequence could not have been executed on the enone itself, with the desired efficiency and selectivity, as demonstrated for the transformation of para-benzoquinone into the monoterpene (-)-iridolactone (Scheme 2; equation 1)26. In a similar vein the cyclopentadiene dimer itself (Scheme 2; equation 2) can be suitably modified and then a retro Diels-Alder reaction furnishes a useful chiral cyclopentenone derivative, as a diene precursor for a further Diels-Alder cycloaddition27. In both of these examples intermediates undergo kinetic enzymatic resolutions with lipases, thus producing enantiopure cyclopentene derivatives.    The IMDA Variation With the basic and relevant empirical facts well established, and the Woodward-Hoffmann rules allowing predictability of the expected structures to be produced in the classical intermolecular reaction, it became of interest to study ways to alter or circumvent the observed chemo-, regio- and stereoselectivities, and induce enantioselectivity28. These aspects will be considered within the discussion of the intramolecular Diels-Alder (IMDA) reaction29-36. In the period under review (1990 to the present) over 650 publications have appeared which deal directly with the IMDA reaction in synthesis, and this has determined a very selective presentation.The first reports on the IMDA reaction appeared in the fifties and sixties and were based upon the desire to produce polycyclic structures incorporating this cycloaddition as the key step (Scheme 3). The triene precursor strongly suggests a carbonyl group conjugated to the alkene dienophile partner. As the initial and principal objective was the synthesis of bicyclic products containing the expected cyclohexene ring fused to a five, six, or seven membered ring, the accumulated knowledge of the IMDA reaction provided detailed information about the diene portion, the dienophile portion and the kind of carbon chain (with or without heteroatoms) necessary for a successful reaction29-33.   It had also been established that IMDA reactions should be conducted under thermolytic conditions, as very high pressures were prematurely considered irrelevant, and Lewis acid catalysis seemed to have little effect as far as selectivity was concerned. These aspects have been very well detailed in several excellent reviews29-33. Competing ReactionsThe question of the IMDA reaction acting in competition with the bimolecular intermolecular reaction does not seem to have been specifically investigated, which suggests that the IMDA is kinetically much more favoured and therefore the intermolecular reaction products are not observed in significant amounts (Scheme 3). We have however noted that many IMDA reactions are run at relatively low concentrations (generally around 10-3 mol.L-1) perhaps with an intuitive respect for the possibility of competing intermolecular reactions. Also, [4+2] cycloadditions can co-exist with [1,5] sigmatropic hydrogen shifts and Alder-ene rearrangements (Scheme 3; see below for further discussion), under normal thermolytic conditions, and these other two pericyclic reactions are quite relevant in the intramolecular situation, and specially so in the TADA variation.Electronic EffectsThe Diels-Alder reaction is a pericyclic reaction under complete stereoelectronic control, but is strongly influenced by electronic and steric effects in both diene and dienophile. However, the importance of these two effects is quite different in the intermolecular version and in the IMDA and TADA reactions.As to the basic electronic loading on the dienophile partner, which requires conjugated electron withdrawing groups for activation, this is not necessarily the

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