Nitroalkenes as Heterodienes

The introduction of heterodienes has extended the synthetic versatility of cycloaddition reactions in organic synthesis.150 Denmark and coworkers have developed the use of nitroalkenes as dienes in [4+2] cycloaddition. Nitroalkenes react with simple alkenes in the presence of SnCl4 as a promoter. For example, the reaction of nitrocyclohexene with cyclopentene gives three products. The major product is awh-isomer, which arises from an exo approach of cyclopentene toward nitrocyclohexene (see Eq. 8.94).151 

The reaction of nitrostyrene with cyclopentadiene gives the normal Diels-Alder adduct. However, the Lewis acid-catalyzed cycloaddition affords two isomeric nitronates, syn and anti in an 80-to-20 ratio. The major isomer is derived from an endo transition state. The preference of yy/i-fused cycloadducts can be understood by considering secondary orbital interactions (Eq. 8.95).152 

Intramolecular [4+2] cycloaddition of E,E- or L.Z-nitrodienes gives tranr-nitronates or ci.v-nitronates, respectively, with high stereoselectivity (Eq. 8.96).153 These products have been converted into y-lactones by the Nef reaction. 

The powerful nucleophilicity of enamines allows the addition of nitroalkenes to take place without the presence of Lewis acids. The isolation of secondary products, which can be explained by an initial Michael addition, suggests the participation of zwitterionic intermediates in the mechanism of the reaction (Eq. 8.97).154 

An interesting Diels-Alder reaction using chiral enamines is reported by Backvall, in which a cyclic nitronate is formed in good yield and excellent diastereoselectivity (Eq. 8.98).155 

An interestmg Diels-Alder reaction using chiral enammes is reported by Backvall, m which a cychc nitronate is formed m good yield and excellent diastereoselecnvity fEq 8 98  

A few examples of cycloaddidons between nitroalkenes and vinyl ethers without the nse of Lewis acids have been reported fEq 8 105, in whichadchtionalactivating electron-withdrawing groups are generally required 

High-pressnre promoted cycloadditions of nitroalkenes and enol ethers eliminate the nse of Lewis acids fEq 8 106 Thus, even sterically hmdered nitroalkenes react with 2,3-thhydro-furan to give the exo cyclic nitronates stereoselecdvely without using Lewis acids 

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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. 

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. 

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Cycloadditions involving nitroalkenes as heterodiene have been employed as part of Denmark s domino [4 + 2] / [3 + 2] cycloaddition protocol for the synthesis of natural products. Since also this methodology has just been exhaustively reviewed [5], its value for alkaloid synthesis might be exemplarily demonstrated... 

Several triflates and metal salt hydrates were tested as Lewis acid catalysts (each 10 mol%) and the best results were obtained using Yb(OTf or Ni(C104)2-6H20. The stereoselective formation of bicyclic y-lactones (7) could be obtained from bicyclic nitronate (9) via the hydrolytic process by the action of a strong acid generated from Lewis acid with a small amount of water in both nitroalkene (5) and the Lewis acid. This new methodology of one-pot reaction also involves a new type of intramolecular HAD reaction of nitroalkenes as heterodienes, which provides stereochemically defined bicyclic nitronates. 

Wada, E. and Yoshinaga, M. 2003. A new methodology of intramolecular hetero-Diels-Alder reaction with (3-alkoxy-snbstituted conjugated nitroalkenes as heterodienes Stereoselective one-pot synthesis of tra -fused bicyclic y-lactones. Tetrahedron letters, 44(43) 7953-6. 

Highly stereoselective inter [4+2]/intra [3+2] cycloadditions of nitroalkenes as heterodienes have been developed by Denmark et al. ° Applications in the synthesis of alkaloids have been reviewed/ ... 

The most well-documented tandem [4 + 2]/[3 + 2] cycloadditions involve nitroalkenes as heterodienes as developed in the Denmark and Scheeren laboratories (Schemes 16.2 and Figure 16.3). In this process, a nitroalkene (47t-component) acts as an electron-poor heterodiene and engages in an inverse-electron-demand [4 + 2] cycloaddition with an... 

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