Diels-Alder reactions of heterodienes

Preliminary examples suggest that the techniques of hydrophobic acceleration and dry-state adsorption conditions recently applied to the acceleration of the all-carbon Diels-Alder reaction should prove equally useful in the Diels-Alder reactions of heterodienes. Hydrophobic acceleration T. A. Eggelte, H. De Koning and H. O. Huisman, Tetrahedron, 1973, 29, 2491 R. Breslow and D. C. Rideout, J. Am. Chem. Soc., 1980, 102, 7816 R. Breslow, U. Maitra and D. C. Rideout, Tetrahedron Lett., 1983, 24, 1901 dry-state adsorption conditions (Si02, florisil, alumina) V. V. Veselovsky, A. S. Gybin, A. V. Lozanova, A. M. Moiseenkov, W. A. Smit and R. Caple, Tetrahedron Lett., 1988, 29, 175 H. Parlar and R. Baumann, Angew. Chem., Int. Ed. Engl., 1981, 20, 1014 H. Parlar, R. Baumann and F. Korte, Z. Natursforsch., Teil B, 1981, 36, 898. 

A number of examples have been reported of the asymmetric hetero Diels-Alder reaction of heterodienes or heterodienophiles such as imines, nitroso or carbonyl compounds.The chiral auxiliary is commonly attached to the nitrogen atom of the imine or nitroso compound, or a chiral ester or amide substituent may provide the necessary asymmetric induction. As an example, the a-cWoronitroso dienophile 132, bearing a sugar-derived auxiliary, has been found to be effective for the formation of cyclic hydroxylamines with high optical purity (3.95). The initial cycloadduct breaks down readily (see Scheme 3.32), via an iminium ion with subsequent methanolysis to release the chiral auxiliary and the product 133. 

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. 

There are only few examples of asymmetric inverse hetero-Diels Alder reactions using a,P-unsaturated aldehydes. As a recent example, a cinchona alkaloid was successfully used to catalyse the oxa-Diels Alder reaction of heterodienes such as 3-formylchromones with acetylene dicarboxylates, providing the corresponding tricyclic benzopyrones in moderate to high yields (54-87%) and enantioselectivities (46-84% ee), as shown in Scheme 6.12. ... 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

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. 

Jimenez et al. studied the asymmetric Diels-Alder reactions of 1-aryl-1,2-diaza-l,3-butadienes 114, heterodienes derived from sugars, with diethyl azodicarboxylate (115), a heterodienophile [85]. The reactions were performed without solvent in a focused microwave reactor for periods of a few hours. The reaction is stereoselective... 

In the [4 + 2] cycloadditions discussed so far, the enol ether double bond of alkoxyallenes is exclusively attacked by the heterodienes, resulting in products bearing the alkoxy group at C-6of the heterocycles. This regioselective behavior is expected for [4+2] cycloadditions with inverse electron demand considering the HOMO coefficients of methoxyallene 145 [100]. In contrast, all known intramolecular Diels-Alder reactions of allenyl ether intermediates occur at the terminal C=C bond [101], most probably because of geometric restrictions. 

Novel 2-amino-substituted- 3-methylenedihydropyrans 2 have been obtained from inverse electron demand Diels-Alder reactions of allenamides with heterodienes <99TL6903> and the reaction of styrenes with a,p-unsaturated 2-oxonitriles yields predominantly the cis-2-aryldihydropyran-6-carbonitriles 3 <99HCA1122>. 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

The enantioselective hetero Diels-Alder reaction of 1-oxa-1,3-butadienes using chiral non-racemic Lewis acids is a widely unexplored field. The first successful example was the intramolecular cycloaddition of the heterodiene 2-194,... 

A recent study performed by Ghosez et al. deals with the use of unsaturated SAMP hydrazones as chiral 1-aza-1,3-butadienes for asymmetric cycloadditions [226]. In this investigation, the reaction of the chiral heterodiene 3-21 with N-methylmaleimide afforded the cycloadduct 3-22 in excellent induced diastereoselectivity (Fig. 3-7). Thus, the selectivities obtained are very promising, but the application of this method is restricted to highly reactive electron-deficient dienophiles. The complementary approach, an aza Diels-Alder reaction of an 1-aza-l,3-butadiene with a chiral dienophile.has been investigated by Waldner [227]. 

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

Figure 4-7 shows a typical hetero Diels-Alder reaction of a nitrosoalkene. Upon in situ generation of the heterodiene 4-34 from the oxime 4-33, cycloaddition occurred in the presence of the silyl enol ether 4-35 to give the 5,6-dihydro-4H- 1,2-oxazine 4-36 in excellent yield [366]. Such conversions are very suitable for achieving kinetic resolutions of -/Z-isomeric silyl enol ethers since the Z-isomers are distinctly less reactive towards 4-34 [367]. 

If nitroalkenes are employed as heterodienes in hetero Diels-Alder reactions instead of nitrosoalkenes, cyclic nitrones are formed. These cycloadducts undergo numerous subsequent reactions, and especially the combination of this hetero Diels-Alder reaction with a 1,3-dipolar cycloaddition is an extremely powerful tool for the synthesis of polycyclic alkaloids. This domino [4+ 2]/[3+ 2] cycloaddition chemistry has been comprehensively reviewed by Denmark and Thorarensen very recently, and this review also covers many hetero Diels-Alder reactions of nitroalkenes being not part of this sequential transformation [5]. Therefore the present article will focus on some selected examples which might highlight the advanced state of the art concerning stereocontrol of these reactions. On the other hand, an insight shall be given into the multitude of polycyclic structures accessible by means of nitroalkene cycloaddition chemistry. 

The advanced state of the art in carbohydrate synthesis basing on hetero Diels-Alder reactions of 1-oxa-l,3-butadienes has opened an access to enan-tiopure sugar derivatives. Thus, our group found the cycloaddition of the chiral heterodiene 7-1 and the electron-rich alkene 7-2 under the influence of Me2AlCl to give the dihydropyran 7-3 in excellent endo selectivity (endo/exo >50 1) and as well excellent induced diastereoselectivity (54 1) [478]. A short sequence involving one simple recrystallisation then led to the ethyl-/)-D-mannopyrano-side 7-4 in enantiomerically pure form (Fig. 7-1). 

Although Diels-Alder reactions of disilenes to 1,3-dienes rather represent an exception, [2+4]-cycloaddition is the preferred reaction route for the photolysis of 1 in the presence of 1,4-heterodienes. Thus, for example, 1,4-diaza-1,3-butadienes react smoothly to yield the six-membered ring products 15 when the spatial demands of the substituents at nitrogen are not too great. 

Inverse electron demand hetero-Diels-Alder reactions of acyl phosphonates or a-keto ester heterodienes and enol ethers are also catalyzed by (5, iS )-t-Bu-box complexes. High levels of enantioselectivity are obtained with y-alkyl-, -aryl-, -alkoxy-... 

Knoevenagel products are highly reactive compounds because of their low energy LUMO. They can act as dienophiles in the normal Diels-Alder reaction, as heterodienes in the hetero Diels-Alder reaction with inverse electron demand,- as dipolarophiles in 1,3-dipolar cycloadditions, as enophiles in the ene reaction and as acceptors for the addition of allylsilanes. Sigmatropic rearrangements and photochemical reactions have been described. 

Nitrostyrene (15a) can react as a dienophile in the Diels-Alder reaction with 2-alkoxy butadienes producing cyclic enol ethers (Scheme 9.23). By using an excess of nitrostyrene a domino reaction should take place with the in situ-generated enol ether. j -Nitrostyrene (15a) may react subsequently as a dienophile in the Diels-Alder reaction with a 2-alkoxy butadiene, as a heterodiene in the inverse Diels-Alder reaction of alkoxy cyclohexene which is formed primarily, and as a di-substituted dipolarophile in the 1,3-dipolar cycioaddition of the nitronate formed in the inverse Diels-Alder reaction. 2-Methoxy-l,3-butadiene (61) was selected for the Diels-Alder reaction, since it reacted in a completely regioselective manner with nitroalkenes. 

Compared to the hetero-Diels-Alder reaction of carbonyl compounds and derivatives with dienes, where only a limited number of catalytic and enan-tioselective reactions have been reported, the number of asymmetric hetero-Diels-Alder reactions in which the ketone or imine functionality is part of a heterodiene is much higher. In contrast, there are only a few examples of using a,p-unsaturated aldehydes in inverse hetero-Diels-Alder reactions. In the case of the inverse electron demand hetero-Diels-Alder reaction, the ketone or imine functionality is part of an a,(I-unsaturated system, which reacts in a cycloaddition reaction with an electron-rich alkene. The inverse electron demand hetero-Diels-Alder reaction is primarily controlled by a LUMOdiene-HOMOdienophiie interaction, which can be found, for example, in the reactions... 

A review of the cycloaddition reactions of o-benzoquinones as carbodiene, heterodiene, dienophile, or heterodienophile has been published. In the Diels-Alder reaction of furans with masked o-benzoquinones (145), the furans unexpectedly behaved as dienophiles to yield cycloadducts (146) (Scheme 56). Masked benzoquinones behave as dienes which undergo Diels-Alder reactions with electron-rich dienophiles such as enol ethers and thienol ethers.The asymmetric Diels-Alder reactions of 5-substituted and 5,6-disubstituted (S)-2-(p-tolylsulflnyl)-l,4-benzoquinones with cyclopentadiene and fran -piperylene show complete regio- and jr-facial selectivities. The hetero-Diels-Alder reactions of o-benzoquinones with tetracyclone produce cyclopenta[I ][l,4]benzodioxinone derivatives in high yield. 

Nair and coworkers [19] reported a hetero-Diels-Alder reaction of pentafulvene 36 (acting as a 2% component) with tetracyclic enone 70 (the 4jt-heterodiene), to give the polycyclic cage compound 71 containing a pyran moiety (Scheme 7.18). 

Pyrazolin-5-ones with an exocyclic double bond at the 4-position (369 X = CMe2> react as heterodienes towards alkyl vinyl ethers (77G91). The kinetics of this Diels-Alder reaction giving pyrazolopyrans (370) have been studied. 

Fluorinated heterodienophiles and heterodienes Diels-Alder reactions in which the dienophiles have perfluoroalkyl-substituted multiple bonds between carbon and a heteroatom are quite common Reported earlier were reactions of perfluoroketones, thiones, ketimines, thioesters, nitroso compounds, and nitriles [9] Examples of a-fluoroimines [107], co-hydroperfluorothioaldehydes [108], perfluorosulfines [109, IIO], and selenocarbonyidifluoride [III] (equations 89-92) have been reported recently... 

Nitro compounds have been converted into various cyclic compounds via cycloaddidon reactions. In particular, nitroalkenes have proved to be nsefid in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes ind react v/ith dienes to yield 3-nitrocy-clohexenes. Nitroalkenes c in also act as heterodienes ind react v/ith olefins in the presence of Lewis acids to yield cyclic alkyl nkronates, which undergo [3- 2 cycloaddidon. Nitro compounds are precursors for nitnie oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3- 2 cycloaddldon reacdons. Thus, nitro compounds play important roles in the chemistry of cycloaddidon reacdons. In this chapter, recent developments of cycloaddinon chemistry of nitro compotmds and their derivadves are summarized. 

The /zetero-Diels-Alder reaction permits heterocyclic-six- membered rings to be constructed by the interaction of heterodienes and/or heterodienophiles. Both the intermolecular and intramolecular versions of the /zctcro-Diels Alder reaction are, therefore, very important methods for synthesizing heterocyclic compounds. 

Denmark and coworkers have developed an elegant method for generating cyclic nitronates using nitroalkenes as heterodienes in the Diels-Alder reaction (Eq. 8.78). The synthetic utility of this reaction is discussed in Section 8.3. 

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