Reactive dienophiles

Benzoqumone is a very reactive dienophile It reacts with 2... 

Benzyne is a reactive dienophile and gives Diels-Alder products when generated m the presence of dienes In these cases it is convenient to form benzyne by dissociation of the Grignard reagent of o bromofluoro benzene... 

Like benzocyclobutadiene, benzazetes are reactive dienophiles, but fail to react as dienes except in the special case of dimerization. Thus 2-phenylbenzazete is inert to cyclopentene, but-2-yne, iV-phenylmaleimide and iV,iV-dimethylaminopropyne. 

The behavior of strained,/Zuorimiret/ methylenecyelopropanes depends upon the position and level of fluorination [34], l-(Difluoromethylene)cyclopropane is much like tetrafluoroethylene in its preference for [2+2] cycloaddition (equation 37), but Its 2,2-difluoro isomer favors [4+2] cycloadditions (equation 38). Perfluoromethylenecyclopropane is an exceptionally reactive dienophile but does not undergo [2+2] cycloadditions, possibly because of stenc reasons [34, 45] Cycloadditions involving most possible combinations of simple fluoroalkenes and alkenes or alkynes have been tried [85], but kinetic activation enthalpies (A/f j for only the dimerizations of tetrafluoroethylene (22 6-23 5 kcal/mol), chlorotri-fluoroethylene (23 6 kcal/mol), and perfluoropropene (31.6 kcal/mol) and the cycloaddition between chlorotnfluoroethylene and perfluoropropene (25.5 kcal/mol) have been determined accurately [97, 98] Some cycloadditions involving more functionalized alkenes are listed in Table 5 [99. 100, 101, 102, 103]... 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

Fluorinated cyclopropenes have long been known to be reactive dienophiles [9], and the past 20 years have provided us with a few more nonexceptional examples [S3, 84, S5]. 

Allene itself is not a good dienophile, its reaction with cyclopentadiene requires temperatures of >200 °C and gives a 49% yield [90] Fluoraallene and 1,1-difluoroaIIene are much more reactive dienophiles, the latter reacting instantly and quantitatively at -20 °C [91, 92], and the former taking 4 days to react quantitatively with cyclopentadiene at 0 °C [25, 27, 93] (equation 78)... 

Fluoroalkyl-suhstituted acetylenic acids are more reactive dienophiles than dimethyl acetylenedicarboxylate [100] (equation 85)... 

Bis(trifluoromethyl)-l,l-dicyanoethylene is a very reactive dienophile. It undergoes facile and high-yield [2+4] cycloadditions with 1,3-dienes, cyclopen-tadiene, and anthracene [707] (equation 86). It is reactive enough in a Diels-Alder reaction with styrene [702] (equation 86). 

The dienophilic character of imines parallels that of carbonyl compounds Consequently, electron deficient imtnes are the most reactive dienophiles of this class, particularly those having C perfluoroalkyl [5, 146, 150, 228], /V-acyl [/2i5 127], or A/-sulfonyl groups [148, 229 230]... 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

The reaction has wide scope in respect of the dienophUe / -substituent. The representative less reactive dienophiles, crotonoyl- and cinnamoyl-oxazolidinone, react with cyclopentadiene at -15 °C and 25 °C for 20 h and 24 h giving cycloadducts in 99% ee and 96% ee, respectively. The 3-chloropropenoyl derivative also affords the adduct in high optical purity (96% ee) this adduct is transformed to 2-(methoxycar-bonyl)norbornadiene, a useful chiral building block. Thus, the 3-chloropropenoyl derivative can be regarded as a synthetic equivalent of an acetylene dienophile. 

Because of their strong aromatic character, benzene and naphthalene are very unreactive as dienes however anthracene 19 reacts with highly reactive dienophiles, such as dehydrobenzene (benzyne) 20 ... 

Dienophile (Section 14.5) A compound containing a double bond that can take part in the Diels-Alder cycloaddition reaction. The most reactive dienophiles are those that have electron-withdrawing groups on the double bond. 

Even with the highly reactive dienophile cyclohepta-2,6-dien-4-ynone, generated from 1-aminocycloheptatriazol-6-(1 H)-one by lead(IV) acetate oxidation, only the adduct of benzene oxide 3 can be isolated.231... 

Extensive studies by Gorman and Gassman have shown that an allyl cation can be a 27r-electron component in a normal electron-demand cationic Diels-Alder reaction and, since a carbocation is a very strong electron-withdrawing group, the allyl cation is a highly reactive dienophile [19a, 21]. 

Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels-Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. 

Thiophenes are less reactive than furans and therefore react with very reactive dienophiles. They behave somewhat differently from furans and in many cases the intermediate addition products are unstable and undergo cheleotropic extrusion of sulfur [30]. Thiophenes 30 undergo cycloaddition reactions with DMAD (Equation 2.11) to afford bicyclic cycloadducts which lead to phthal-ates by sulfur extrusion, thus offering a one-pot synthesis of dimethylphthalates [31]. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

Silylthioaldehydes 103, reactive dienophiles formed in situ from acetals according to a general method, are directly trapped with dienes to afford sulfur-containing heterocyclic compounds in good yield (Equation 2.29). Silylthioaldehydes are quite reactive in comparison with the aliphatic ones [102] which are rather inert in the cycloaddition reactions. 

Diels-Alder reactions of conjugated cycloalkenones provide a very important method for rapidly constructing complex polycyclic molecules. Since cycloalkenones are very poorly reactive dienophiles, acceleration by special physical and catalytic methods is required in order to avoid high reaction temperatures and long reaction times which often lead to low product yields [8],... 

By using unactivated K-10 montmorillonite in the absence of solvent, the endo-exo selectivity of the cycloadditions of acrolein and methyl vinyl ketone with cyclopentadiene and cyclohexadiene is low [8] (Table 4.2, entry 3), while highly reactive dienophiles such as 1,4-benzoquinone and N-phenyl... 

Diels-Alder reactions of vinylpyrazoles 45 and 46 only occur with highly reactive dienophiles under severe conditions (8-10 atm, 120-140 °C, several days). MW irradiation in solvent-free conditions also has a beneficial effect [40b] on the reaction time (Scheme 4.11). The indazole 48, present in large amounts in the cycloaddition of 45 with dimethylacetylenedicarboxylate, is the result of an ene reaction of primary Diels-Alder adduct with a second molecule of dienophile followed by two [l,3]-sigmatropic hydrogen shifts [42]. The MW-assisted cycloaddition of 46 with the poorly reactive dienophile ethylphenyl-propiolate (Scheme 4.11) is significant under the classical thermal reaction conditions (140 °C, 6d) only polymerization or decomposition products were detected. 

The photo-induced exo selectivity was observed in other classic Diels-Alder reactions. Data relating to some exo adducts obtained by reacting cyclopentadiene or cyclohexadiene with 2-methyl-1,4-benzoquinone, 5-hydroxynaphtho-quinone, 4-cyclopentene-l,3-dione and maleic anhydride are given in Scheme 4.13. The presence and amount of EtsN plays a decisive role in reversing the endo selectivity. The possibility that the prevalence of exo adduct is due to isomerization of endo adduct under photolytic conditions was rejected by control experiments, at least for less reactive dienophiles. 

Base-catalyzed Diels-Alder reactions are rare (Section 1.4). A recent example is the reaction of 3-hydroxy-2-pyrone (145) with chiral N-acryloyl oxazolidones 146 that uses cinchona alkaloid as an optically active base catalyst [97] (Table 4.25). Only endo adducts were obtained with the more reactive dienophile 146 (R = H), the best diastereoselectivity and yields being obtained with an i-Pr0H/H20 ratio of 95 5. The reaction of 146 (R = Me) is very slow, and a good adduct yield was only obtained when the reaction was carried out in bulky alcohols such as t-amyl alcohol and t-butanol. 

Quinone-mono-ketals 46 and 47 are also low reactive dienophiles and are sensitive to Lewis-acid catalysts. The use of high pressure overcomes this limitation [17]. As shown in Equation 5.7, cycloadditions with a variety of substituted 1,3-butadienes 48 occur regioselectively and c This approach provides access to a variety of annulated benzenes and naphthalenes after aromatization of adducts 49. 

The more reactive furan (139a) undergoes thermal Diels-Alder reaction [52] with reactive dienophiles such as maleic anhydride and maleimide (Scheme 5.21). Whereas the cycloaddition with the maleic anhydride afforded the exoadduct at room temperature, the stereochemistry of the reaction of maleimide depends on the reaction temperature. 

Iminium ions bearing an electron-withdrawing group bonded to the sp carbon of the iminium function are very reactive dienophiles. Thus, iminium ions 26 generated from phenylglyoxal (Scheme 6.15, R = Ph) or pyruvic aldehyde (R = Me) with methylamine hydrochloride, react with cyclopenta-diene in water at room temperature with good diastereoselectivity [25] (Scheme 6.15). If glyoxylic acid is used, the formation of iminium salt requires the free amine rather than the amine hydrochloride. 

Alkenes can add to double bonds in a reaction different from those discussed in 15-19, which, however, is still formally the addition of RH to a double bond. This is called the ene reaction or the ene synthesis For the reaction to proceed without a catalyst, one of the components must be a reactive dienophile (see 15-58 for a definition of this word) such as maleic anhydride, but the other (which supplies the hydrogen) may be a simple alkene such as propene. Cyclopropene has also been used. ° The reaction is compatible with a variety of functional groups that can be appended to the ene and dienophile. N,N-Diallyl amides give an ene cyclization. 

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 ... 

Another type of steric effect results from interactions between diene substituents. Adoption of the s-cis conformation of the diene in the TS brings the d.v-oricnlcd 1- and 4-substituents on a diene close together. /(-1,3-Pcnladicnc is 103 times more reactive than 4-methyl-l,3-pentadiene toward the very reactive dienophile tetracyanoethylene. This is because the unfavorable interaction between the additional methyl substituent and the C(l) hydrogen in the s-cis conformation raises the energy of the TS.20... 

The use of 2-vinyldioxolane, the ethylene glycol acetal of acrolein, as a dienophile illustrates application of the masked functionality concept in a different way. The acetal itself would not be expected to be a reactive dienophile, but in the presence of a catalytic amount of acid the acetal is in equilibrium with the electrophilic oxonium ion. 

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