Reverse electron demand Diels-Alder

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). 

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>. 

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... 

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... 

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... 

For a reverse electron-demand Diels-Alder with azadienes, Barluenga8 reacted stable silylated imines 65 of unenolisable aldehydes (R = Ar or cinnamyl) with acetylene dicarboxylic esters to give the 2-azadienes 67. 

Experimental protocol for Staudinger-Bertozzi, Cu(l)-catalyzed Huisgen alkyne-azide cycloaddition, and reverse-electron-demand Diels-Alder ligation to distinguish between pi, p2,and p5. 

A [4+2] benzannulation between acetylenic ketones 248 and a benzenediazo-nium 2-carboxylate proceeds effectively in the presence of a catalytic amount of AuCl, yielding functionalized anthracenes 250 in good yields (Scheme 12.67) [137]. It is suggested that the reaction involves a reverse electron demand Diels-Alder reaction between benzyne and the benzopyrylium aurate complex 249. 

The reactions described so far involve activation by means of decreasing the LUMO of the dienophile. Alternative approaches for catalytic activation in a Diels-Alder reaction is to increase the HOMO level of either the diene (normal electron demand) or the dienophile (reversed electron demand Diels-Alder reaction). Barbas and co-workers [25] disclosed asymmetric HOMO-racing based on catalytic formation of dieneamine 34 from proline-derivative 33 and a,p-unsaturated ketone 32. 

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). 

SCHEME 6.12. Secondary amine catalyzed reversed electron demand Diels-Alder reactions through in situ dienamine activation of 2-enals. 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

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. 

Concerted reactions are commonly used to join carbons. For example, the Diels-Alder reaction is the formation of a cyclohexene from a diene and an alkene. Usually the alkene is rendered electrophilic by conjugation with a carbonyl group, and the diene may be rendered nucleophilic by electron-donating substituents. In the case shown in Equation 7.38 the alkene is further electron depleted by association with a Lewis acid [64], a common technique for accelerating Diels-Alder reactions. In some cases, the alkene is nucleophilic and the diene is electrophilic as in Equation 7.39 [65]. Examples of this sort are called reverse-electron-demand Diels-Alder reactions. It is important to point out here that the concerted reactions differ from the foregoing in that no carbanion or cation intermediate is involved, and in many cases, electrophilic and nucleophilic factors are not present, as in the very favorable dimerization of cyclopentadiene. These reactions are covered in more detail in Chapter 5. 

In the reverse electron demand Diels-Alder reaction of sulfonyl pyrone with chiral vinyl ether, MAD acts as an effective Lewis acid to give the corresponding cycloadduct, which is synthetic intermediate of la,25-dihydroxyvitamin D3 in 93% yield as a 98 2 ratio of the endo-diastereomers (Scheme 6.125) [149]. 

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