Reverse-demand Diels-Alder

Diels-Alder reactions of olefins, acetylenes, allenes with tetrazines or triazines to provide pyridazines or pyridines reverse demand Diels-Alder reactions (see 1st edition). 

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). 

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. 

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. 

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. 

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 reversibility of the DA reaction, known as the retro Diels-Alder reaction, can hamper the utilization of this chemistry for bioconjugation when the formation of thermally stable products is absolutely necessary. This limitation can be conveniently overcome by the use of dienes that form stable cycloadducts during the reaction. One such example is the inverse electron-demand Diels-Alder reaction of heterodienes with strained alkenes and alkynes. 

The reaction of an electron poor diene with an electron rich dienophile is referred to as an inverse electron demand Diels-Alder (iEDDA) reaction. The first experimental evidence that the normal electron polarity of the diene/dienophile pair can be reversed dates back to 1959 [79]. Although a number of azadienes can participate in iEDDA reaction [80], the highly electron deficient nature of 1,2,4,5-tetrazines made these dienes versatile building blocks in bioconjugation applications. 

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. 

---