Reverse-electron-demand Diels-Alder reaction

The Diels-Alder reaction, reverse electronic demand Diels-Alder reaction, as well as the hetero-Diels-Alder reaction, belong to the category of [4 2]-cycloaddition reactions, which are concerted processes. The arrow-pushing here is merely illustrative. 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

The potential of reversing the diene/dienophile polarity of the normal Diels-Alder reaction was first discussed in the course of the early work on the [4 + 2] cycloaddition reaction Bachmann, W. E., and Deno, N. C. (1949). J. Am. Chem. Soc. 71, 3062. The first experimental demonstration of the inverse electron demand Diels-Alder reaction employed electron-deficient perfluoroalkyl-l,2,4,5-tetrazines Carboni, R. A., and Lindsey, R. V., Jr. (1959). J. Am. Chem. Soc. 81,4342. A subsequent study confirmed the [4 + 2] cycloaddition rate acceleration accompanying the complementary inverse electron demand diene/dienophile substituent effects Sauer, J., and Wiest, H. (1962). Angew. Chem. Int. Ed. Engl. 1, 269. 

The HOMO activation of dienophiles (reversed electron demand DA) was reported by Chen and co-workers [32]. They found that the catalytic reaction of crotonaldehyde with prolinol ether 46 resulted in formation of a 1,3-dieneamine 49 that selectively reacted as a dienophile on the terminal double bond in a reversed electron demand Diels-Alder reaction with electron-deficient dienes 48 to give access to highly diastereo- and enantioenriched cyclohexen derivatives 50 (Scheme 6.12). 

There are Diels-Alder reactions known where the electronic conditions outlined above are just reversed. Such reactions are called Diels-Alder reactions with inverse electron demand For example the electron-poor diene hexachlorocy-clopentadiene 21 reacts with the electron-rich styrene 22 ... 

In another aspect of the mechanism, the effects of electron-donating and electron-withdrawing substituents (p. 1065) indicate that the diene is behaving as a nucleophile and the dienophile as an electrophile. However, this can be reversed. Perchlorocyclopentadiene reacts better with cyclopentene than with maleic anhydride and not at all with tetracyanoethylene, though the latter is normally the most reactive dienophile known. It is apparent, then, that this diene is the electrophile in its Diels-Alder reactions. Reactions of this type are said to proceed with inverse electron demand ... 

They reported that the DFT calculations of 114 at the B3LYP/6-31G level showed that the ji-HOMO lobes at the a-position are slightly greater for the syn-n-face than for the anti face. The deformation is well consistent with the prediction by the orbital mixing rule. However, the situation becomes the reverse for the Jt-LUMO lobes, which are slightly greater at the anti than the syn-n-face. They concluded that the iyn-Jt-facial selectivity of the normal-electron-demand Diels-Alder reactions... 

In the case of the reverse-electron-demand Diels-Alder reactions, the secondary orbital interaction between the Jt-HOMO of dienophile and the LUMO of 114 or the effect of the orbital phase enviromnents (Chapter Orbital Phase Enviromnents and Stereoselectivities by Ohwada in this volume) cannot be ruled out as the factor controlling the selectivity (Scheme 55). 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

The quinolizinium ring can behave as the diene component in reverse electron demand Diels-Alder reactions. For example (Equation 1), the reaction between a dienophile generated in situ by acid-catalyzed dehydration of precursor 72 and quinolizinium 73 gave the l,4-ethanobenzo[A]quinolizinium derivative 74 <2001BML519>. 

Although Diels-Alder reactions can occur in the unsubstituted case, the reaction is most successful when the diene and the dienophile contain substituents which exert a favorable electronic influence [19]. In the normal electron demand case, the most favorable interactions are between dienes with electron-donating groups and dienophiles with electron-withdrawing groups. Cases have been reported in which inverse electron demand occurs and the electronic nature of the diene and dienophile are reversed [20], [21], [22]. This case of inverse electron demand is accounted for in the system. 

An AMI semiempirical method was used to investigate the Diels-Alder cycloaddition reactions of vinyl sulfenes with buta-1,3-dienes.156 The reactivity and stereoselectivity of vinyl boranes have been reviewed.157 Aromatic methyleneamines undergo reverse-electron-demand Diels-Alder reactions with cyclopentadiene, norbom-ene, and vinyl sulfides.158... 

Thus the reaction of 3,4-bis(methoxycarbonyl)-l,2-dithiete 19f with alkenes and alkynes gave the corresponding dihydrodithiins or thiophenes 120-126, respectively (Scheme 14). This reaction was considered as a reverse electron-demand hetero-Diels-Alder process (see Section 2.18.2) <2000JOM(611)106, 1999JOC8489>. 

Diels-Alder reactions also may occur when the electronic situation of the substrates is completely reversed, that is, when electron-rich dienophiles react with electron-poor dienes. [4+2]-Cycloadditions of this type are called Diels-Alder reactions with inverse electron demand. 1,3-Dienes that contain heteroatoms such as O and N in the diene backbone are the... 

A rarer type is the reverse electron demand Diels-Alder reaction in which the dienophile has electron-donating groups and the diene has a conjugated electron-withdrawing group. 

The reaction is clearly a cycloaddition but at first sight the regioselectivity is all wrong. The answ comes from a realization that this is a reverse electron demand Diels-Alder reaction. The diene very electron-deficient with two conjugated carhonyl groups so the dienophile needs to be electro." rich. The enone is not electron-rich enough but its enol is. The enone could be prepared by Eire reduction... 

The double bond of unsubstituted benzvalene is considered to be an electron-rich system which reacts with electron-deficient 1,3-dienes namely the Diels-Alder reaction is reverse electron demanding. Two Diels-Alder reactions of benzvalene are described in the following. Benzvalene does not react with usual 1,3-diene but with electron-deficient 1,3-dienes like 1,2,4,5-tetrazine (80) or hexachlorocyclopentadiene (81)74). Dihalogenocarbene also adds to the double bond (82) 75). The obtained... 

Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile 38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition, the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct 40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield.3... 

Sulfonamides are the most widely used electrophilic 1-azadienes, e.g. 51, and they react with electron-rich dienophiles such as enol ethers in reverse electron demand Diels-Alder reactions.6... 

It is significant that if an electron-poor diene is utilized, the preference is reversed and electron-rich alkenes, such as vinyl ethers and enamines, are the best dienophiles. Such reactions are called inverse electron demand Diels-Alder reactions, and the reactivity relationships are readily understood in terms of frontier orbital theory. Electron-rich dienes have high-energy HOMOs that interact strongly with the LUMOs of electron-poor dienophiles. When the substituent pattern is reversed and the diene is electron poor, the strongest interaction is between the dienophile HOMO and the diene LUMO. The FMO approach correctly predicts both the relative reactivity and regioselectivity of the D-A reaction for a wide range of diene-dienophile combinations. 

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