Diels-Alder cycloadditions with heterodienes

Velerianine (546), a monoterpene alkaloid, was synthesized by using a Diels-Alder cycloaddition of heterodiene 542 with enol ether 543 (Scheme 69) (70AG(E)891). Heating cyclopentenecarbaldehyde 542 with the enol ether at 200-203°C afforded a 47% yield of the dihydropyranyl ether 544, which consisted of three diastereomers. Hydrolysis of the ether 544 with acid gave iridodial (545), which was condensed with a nitrogen source to afford racemic valerianine (546). 

Diaza-l, 3-butadienes undergo hetero-Diels-Alder cycloaddition with Cgo to afford fused tetrahydropyridazine derivatives 85. The heterodienes are produced in situ upon heating of 2,5-dihydro-l,3,3-thiadiazole-l,l-dioxide 84 (06TL4129). 

Warrener reported that when 3,6-disubstituted-s-tetrazine 147 was employed as a heterodiene in Diels-Alder cycloadditions with alkenes such as 146, tandem [4 + 2]/[4 + 2] reaction takes place under high pressure (8-14 kbar, 16h) (Scheme 36) [55]. Due to its high reactivity, initial [4 + 2] cycloaddition of tetrazine 147 and nor-bornene 146 is carried out at atmospheric pressure. Spontaneous elimination of nitrogen from primary formed Diels-Alder adduct liberates the second diene, 1,2-dihydropyridazine. By addition of another equivalent of alkene 148 and application of high pressure, the second [4 + 2] cycloaddition generates the central diazabicy-clo[2.2.2]octene skeleton in high yield. A number of functionalized polynorbornane systems were prepared by this synthetic protocol [56]. 

V-Acyliminium ions act as dienophiles in [4 + 2] cycloaddition reactions with conjugated dienes13, while A-acylimimum ions that (can) adopt an x-cis conformation are able to act as heterodienes in an inverse electron demand Diels-Alder process with alkenes or alkynes3 (see Section D. 1.6.1.1.). 

The reactivity of the prototype o-QM as heterodiene in Diels-Alder cycloaddition reactions with several substituted alkenes such as methyl vinyl ether (MVE), styrene,... 

While disilene 5 does not undergo Diels-Alder reactions with 1,3-dienes, the [4+2]-cycloaddition products are formed with heterodienes, e.g. 1,4-diazabutadienes [17] or a-ketoimines [19]. It can be deduced that the electron deficient properties of such dienes cause them to readily take part in hetero-Diels-Alder reactions, which have inverse electron demands. This is corroborated by theoretical calculations which predict an inverse electron demand of the Si-Si double bond it is strongly electron donating rather than electron accepting towards butadienes and other compounds [24,25]. 

Cycloadditions and cyclization reactions are among the most important synthetic applications of donor-substituted allenes, since they result in the formation of a variety of carbocyclic and heterocyclic compounds. Early investigations of Diels-Alder reactions with alkoxyallenes demonstrated that harsh reaction conditions, e.g. high pressure, high temperature or Lewis acid promotion, are often required to afford the corresponding heterocycles in only poor to moderate yield [12b, 92-94]. Although a,/3-unsaturated carbonyl compounds have not been used extensively as heterodienes, considerable success has been achieved with activated enone 146 (Eq. 8.27) or with the electron-deficient tosylimine 148 (Eq. 8.28). Both dienes reacted under... 

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. 

Due to their two electron-withdrawing groups, / ,/ -diketoenamines are reactive towards nucleophilic reagents. Attack usually occurs at the a-carbon. With dinucleophiles, the substitution of the amino group is followed by ring closure to 5- or 6-membered heterocycles. However, due to the enaminedione structure, few successful reactions with electrophiles are known. Only if an electrophilic group is incorporated into the enaminone molecule is such intramolecular reaction observed. Enaminediones are also suitable heterodienes in 4 + 2-cycloaddition. Their electron-deficient character as heterodienes requires the use of electron-rich dienophiles. The result is a Diels-Alder reaction with inverse electron demand. 

Besides Michael additions the mild reaction conditions of CIR are also compatible with cycloadditions. Since chalcones can also be considered as heterodienes, Diels-Alder reactions with inverse electron demand are suitable elementary steps that are applicable for heterocycle synthesis. Therefore, after CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, (hetero) cyclic and acyclic morpholino enamines 98 are added and, finally, after adding... 

Finally, Diels-Alder cycloaddition of a heterodiene containing a thiocarbonyl group and /Y-phenylmaleimide occurs with full stereoselectivity giving the c/.v-isomer of the cycloadduct 5 exclusively in the crude reaction product63. 

Although the early examples of the 4ir participation of heterodienes in [4 + 2] cycloaddition reactions describe their reactions widi electron-deficient aJkenes, e.g. the thermal dimerization of a,3 unsaturated carbonyl compounds, the introduction of one or more heteroatoms into the 1,3-butadiene framewoiic does convey electrophilic character to the heterodiene. Consequently, such systems may be expected to participate preferentially in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, or simple alkene and alkyne dienophiles. The complementary substitution of the heterodiene with one or more electron-withdrawing substituents further lowers the heterodiene Elumo, accelerates the rate of heterodiene participation in the LUMOdioie-conn-olled Diels-Alder reaction, and enhances the observed regioselectivity of the [4 + 2] cycloaddition reaction. ... 

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. 

The thermal and photochemical [4 + 2] cycloadditions of o-quinones with olefinic and acetylenic dienophiles have been extensively reviewed4,5,200 and include their 4tt heterodiene Diels-Alder reactions with olefins,201-204 vinyl ethers,205 enamines,206 selected dienes,207-209 dipheny-lketenimines,210 ketenes,209,210 fulvenes,211 and selected heterocycles including furan,207-209,212 benzofuran,209,212,215 indoles,213 azepines,214 and 1,2-diazepines.214 The tetrahalo-substituted o-quinones, tetrachloro- and tetrabromo-o-quinone, generally participate in heterodiene [4 + 2] cycloadditions at an increased rate over the unsubstituted systems and generally provide higher overall yields of the Diels-Alder products.4,5 With simple olefins, the dienophile geometry is maintained in the course of the thermal [4 4- 2] cycloadditions [Eq. (52)],203,204... 

In a study described by Kappe et al. (Section 11.4.1) [58], the intermolecular Diels-Alder cycloaddition reaction of the pyrazinone heterodiene 52 with ethylene led to the bicyclic cycloadduct S3 (Scheme 11.15). Under conventional conditions these cycloaddition reactions must be conducted in an autoclave at an ethylene pressure of 25 bar at 110 °C for 12 h. In contrast, under the action of microwaves, he Diels-Alder addition of pyrazinone precursor 52 to ethylene in a sealed vessel flushed with ethylene before sealing was complete after 140 min at 190 °C. It was not, however, possible to further increase the reaction rate by increasing the temperature. At temperatures above 200 °C an equilibrium between the cycloaddition 52 S3 and the competing retro Diels-Alder fragmentation process was observed (Scheme 11.15) [58]. By use of a microwave reactor enabling pre-pressurization of the reaction vessel with 10 bar ethylene, however, the Diels-Alder addition 52 S3 was definitely more efficient at 190 °C 85% yield of adduct 53 was obtained within 20 min [65b]. 

Synthesis of Pyridine Derivatives. Tetrahydropyridine derivatives are readily formed by Diels-Alder cycloadditions of a 1-azadiene with activated alkenes. A review makes clear the many uses of this type of heterodiene in Diels-Alder and other heterocycle-forming processes. An example of tetrahydropyridine synthesis is shown in Scheme 5.4. 

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. 

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). 

Nitro compounds have been converted into various cyclic compounds via cycloaddition reactions. In particular, nitroalkenes have proved to be useful in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes and react with dienes to yield 3-nitrocy-clohexenes. Nitroalkenes can also act as heterodienes and react with olefins in the presence of Lewis acids to yield cyclic alkyl nitronates, which undergo [3+2] cycloaddition. Nitro compounds are precursors for nitrile oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3+2]cycloaddition reactions. Thus, nitro compounds play important roles in the chemistry of cycloaddition reactions. In this chapter, recent developments of cycloaddition chemistry of nitro compounds and their derivatives are summarized. 

On the basis of available experimental data, it is impossible to choose a definite pathway of elimination of silanol. However, study of silylation of methyl P -nitropropionate (411) with BSA in the presence of trapping agents rigorously proved that silyl nitronate D is initially formed. This compound can be detected in the [3 + 2]-cycloaddition reaction with methyl acrylate product (413). If silylation of AN (411) is performed in the presence of ethyl vinyl ether, a-nitrosoalkene E can be successfully trapped in as heterodiene a Diels-Alder reaction. Dihydroox-azine (414) is formed, and its silylation affords isolable product (415). 

Evans et al. (219, 220) examined the use of electron-poor heterodienes as partners in cycloadditions with electron-rich alkenes under copper catalysis. In particular, a,p-unsaturated acylphosphonates and keto-esters afford hetero-Diels-Alder adducts in high selectivities when treated with enol ethers in the presence of catalysts 269c and 269d. 

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