Dienophiles electron-rich, reactive

Contrary to the normal Diels-Alder processes, the FMO (Frontier Molecular Orbitals) involved in inverse electron demand Diels-Alder reactions are the LUMO of the diene (1,2,4,5-tetrazine) and the HOMO of the dienophile (electron-rich al-kene). The reactivity of tetrazines 1 toward ethyl vinyl ether would depend on the LUMO diene-HOMO dienophile gap. Thus, the combination LUMO-HOMO having a smaller energy gap will lead to the faster reaction. In this case the LUMO for la has a lower energy than that of lb and this will be reflected in their relative reactivities. Energy gaps between tetrazines 1 and ethyl vinyl ether are 6.61 eV for la and 6.64 eV for lb. In consequence, tetrazine la will be more reactive toward ethyl vinyl ether than lb. 

FMO theory requires that a HOMO of one reactant has to be correlated with the LUMO of the other reactant. The decision between the two alternatives - i.e., from which reactant the HOMO should be taken - is made on the basis of which is the smaller energy difference in our case the HOMO of the electron rich diene, 3.1, has to be correlated with the LUMO of the electron-poor dienophile, 3.2. The smaller this HOMO-LUMO gap, the higher the reactivity will be. With the HOMO and LUMO fixed, the orbital coefficients of these two orbitals can explain the regios-electivity of the reaction, which strongly favors the formation of 3.3 over 3.4. 

For the ordinary Diels-Alder reaction the dienophile preferentially is of the electron-poor type electron-withdrawing substituents have a rate enhancing effect. Ethylene and simple alkenes are less reactive. Substituent Z in 2 can be e.g. CHO, COR, COOH, COOR, CN, Ar, NO2, halogen, C=C. Good dienophiles are for example maleic anhydride, acrolein, acrylonitrile, dehydrobenzene, tetracya-noethylene (TCNE), acetylene dicarboxylic esters. The diene preferentially is of the electron-rich type thus it should not bear an electron-withdrawing substituent. 

Ethylene disulfonyl-1,3-butadiene (43) is an example of an outer-ring diene with a non-aromatic six-membered heterocyclic ring containing sulfur. It is prepared by thermolysis of sulfolenes in the presence of a basic catalyst. It is very reactive [43] and even though it is electron-deficient, it readily reacted with both electron-rich and electron-poor dienophiles (Equation 2.15). 

Nakayama and coworkers reported that 3,4-di-tert-butylthiophene 1-oxide 114 is thermally stable but still an extremely reactive substrate. They reported that the Diels-Alder reactions of 114 with varieties of electron-deficient and electron-rich dienophiles took place exclusively at the syn-n-face of the diene with respect to the S=0 bond (Scheme 53) [62, 63]. 

Lewis acids such as zinc chloride, boron trifluoride, tin tetrachloride, aluminum chloride, methylaluminum dichloride, and diethylaluminum chloride catalyze Diels-Alder reactions.22 The catalytic effect is the result of coordination of the Lewis acid with the dienophile. The complexed dienophile is more electrophilic and more reactive toward electron-rich dienes. The mechanism of the addition is believed to be concerted and enhanced regio- and stereoselectivity is often observed.23... 

Pyrones are useful dienes, although they are not particularly reactive. The adducts have the potential for elimination of carbon dioxide, resulting in the formation of an aromatic ring. Pyrones react best with electron-rich dienophiles. Vinyl ethers are frequently used as dienophiles with pyrones. The regiochemical preference places the dienophile donor ortho to the pyrone carbonyl. 

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with A-elecIron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of l-(phenylsulfonyl)-3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a A-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with... 

In the course of investigation of reactivity of the mesoionic compound 44 (Scheme 2) the question arose if this bicyclic system participates in Diels-Alder reactions as an electron-rich or an electron-poor component <1999T13703>. The energy level of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals were calculated by PM3 method. Comparison of these values with those of two different dienophiles (dimethyl acetylenedicarboxylate (DMAD) and 1,1-diethylamino-l-propyne) suggested that a faster cycloaddition can be expected with the electron-rich ynamine, that is, the Diels-Alder reaction of inverse electron demand is preferred. The experimental results seemed to support this assumption. 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

The number and position of electron-withdrawing substituents on the 1,2,4-triazine nucleus and the reactivity of the electron-rich dienophile determine the mode of cycloaddition (additions across C-5/N-2 as well as C-3/C-6 of the 1,2,4-triazine nucleus have been observed) as well as the... 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

It was shown <1998CCC681> that [l]benzothieno[3,2-3]furan 60, due to its low furan aromaticity, possesses dienophilic behavior and reacts with electron-rich dienes with the formation of a new heterocyclic system [l]ben-zothieno[3,2-3][l]benzofuran 93. Furthermore, it was reported <1999CCC389> that introduction of a vinyl moiety at C-2 of 57 created a reactive diene 94, which reacted with various dienophiles. Thus, both cycloaddition reactions led to new derivatives of heterocycle 93 substituted in the benzofuran part of the heterocyclic system (Scheme 10). 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

Diets-Alder catalysis.2 This cation radical enhances the reactivity of a neutral or electron-rich eis-1,3-diene in Diels-Alder reactions. Thus 1,3-cyclohexadiene undergoes Diels-Alder dimerization only at temperatures around 200°. The presence of 5-10 mole % of this salt effects dimerization even at —78°, with the usual endo/ exo selectivity (5 1). It also permits facile condensation of 1,3-cyclohexadiene with a hindered dienophile such as 2,5-dimethyl-2,4-hexadiene (equation 1) the dimer of the former diene is a minor product (20% yield). 

Triazines are reactive electron-deficient dienes in Diels-Alder reactions with inverse electron demand. They react with alkenes, strained double bonds, electron-rich and electron-deficient alkynes and C=N double bonds. In most cases it is found that the dienophile addition occurs across the 3- and 6-positions of the triazine ring, but ynamines can also add across the 2- and 5-positions. The reactions are still under active theoretical and practical investigation. 

Neunhoeffer and Lehmann have shown that it is possible to reverse the diene character of the 1,2,4-triazine ring by introducing alkoxy or dialkylamino groups into the ring. Alkoxy-, dialkoxy- and dialkylamino-1,2,4-triazines are therefore less reactive toward ynamines but they still react with these dienophiles. Bis(dialkylamino)-, trialkoxy- and tris(dialkylamino)-l,2,4-triazines (425) behave as electron-rich dienes and give cycloaddition reactions with acetylenedicarboxylate (426) but not with ynamines. Compounds (425) and (426) afford the 2,4-bis(dialkylamino)pyrimidine-5,6-dicarboxylates (427) (77LA1413). 

Vinyl sulfides are not good dienophiles towards electron-rich dienes. Their reactivity is much enhanced by the presence of a geminal electron-withdrawing group. The corresponding capto-dative olefins have been widely used, such as the following ... 

Alder s rule suggests that the Boger and Fowler dienes should react more readily with electron-rich than electron-poor dienophiles. However, the global conclusion of rule 2 is that the reaction rate will increase as the frontier orbital gap between the reaction partners decreases. The most reactive dienes have very small HOMO-LUMO... 

Electron-rich 2//-thiopyrans react readily with reactive dienophiles such as maleic anhydride, generally giving the endo adduct in good yield. However, less reactive dienophiles such as acrylates requires catalysis to prevent the need for elevated temperatures which may cause decomposition of the thiopyran. Lewis acids facilitate such reactions which can exhibit high stereoselectivity. Thus 4-tri- z>propylsilyloxy-2//-thiopyran shows a preference for the exo... 

An increase in reactivity also can be observed in Diels-Alder reactions with normal electron demand if a given dienophile is reacted with a series of more and more electron-rich dienes. The reaction rates of the Diels-Alder reactions of Figure 15.22 show that the substituents MeO > Ph > alkyl are such reactivity-enhancing donors. The tabulated rate constants also show that a given donor substituent accelerates the Diels-Alder reaction more if located in position 1 of the diene than if located in position 2. 

Few reactions of the parent oxazole with the usual alkenic and alkynic dienophiles have been reported. Most oxazoles which yield Diels-Alder adducts contain electron-releasing substituents, the order of reactivity being alkoxy> alkyl 4-phenyl > acetyl > ethoxycarbonyl. This sequence suggests that the oxazole functions as the electron-rich component and that the reaction is governed by interaction of the highest occupied molecular orbital of the oxazole and the lowest unoccupied orbital of the dienophile. Cycloadditions with inverse electron demand of electron-deficient oxazoles with electron-rich dienophiles can be envisaged. 

Similarly to the homologous 1-oxa-1,3-butadienes, 1-thia-1,3-butadienes are known to be very suitable and reactive substrates for hetero Diels-Alder reactions. However, in contrast to the oxa-1,3-butadienes which in general act as electron-deficient component in such cycloadditions, thia-1,3-butadienes predominantly undergo normal electron demand Diels-Alder reactions with electron-deficient dienophiles. Nevertheless, also some reactions of thia-1,3-butadienes involving electron-rich dienophiles have been described [412,413], Thia-1,3-butadienes considerably tend to dimerize due to their high reactivity in hetero Diels-Alder reactions [414]. 

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