Diels-Alder reactions of nitroalkenes

Node and co-workers have found that the Diels-Alder reaction of nitroalkenes v/ith 1-methoxy-3-trimethylsilyloxy-l,3-butadiene (Danishefsky s dienesi exhibit abnormal exo-se-lecdvity Electrostadc repulsion between the nitro and the silyloxy group of the diene induces this abnormal exc-selecdvity (Tq 8 10 This selecdve reacdon has been used for the asymmetric synthesis of various naniral products as shovm in Scheme 8 6... 

The Diels-Alder reaction of nitroalkenes with Danishefsky s dienes is applied to synthesis of truncated carbocyclic analogues of a potent neuraminidase inhibitor 4-guanidino-NemAc en fsee Scheme 8.5. Carbocyclic analogs are found to retain interesting levels of antiviral activity comparable to those shovm by their oxygen-containing compounds in Scheme 8.5. 

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. 

The Diels-Alder reaction of nitroalkenes followed by the Nef reaction is frequently used in natural product synthesis.7 For example, Scheme 8.3 shows an elegant synthesis of rf/-mesem-brane starting from the Diels-Alder reaction of 1-arylnitroethene with l,3-butadiene.7a... 

Another example of the preparing of aromatic compounds via the Diels-Alder reaction of nitroalkenes is presented in Eq. 8.16.26 Cycloaddition of methyl propiolate affords a high yield of the isomeric product. 

Although Lewis acid-catalyzed-Diels-Alder reactions of enones are common, there are few reports on the catalysis of Diels-Alder reaction of nitroalkenes. The reaction of nitroalkenes with alkenes in the presence of Lewis acids undergoes a different course of reaction to give cyclic nitronates (see Section 8.3). Knochel reported an enhanced reactivity and selectivity of the intramolecular Diels-Alder reaction using silica gel as Lewis acid in hexane (Eq. 8.19).31... 

A typical regioselectivity and endo/exo selectivity has been reported in the Diels-Alder reaction of 2-(/V-acylamino)- 1,3-diene with nitroalkenes (Eq. 8.27).43 Thus, exo products are predominantly formed, which is general for the Diels-Alder reaction of nitroalkenes with sterically hindered dienes. 

Asymmetric Diels-Alder reactions have been performed by using either chiral dienophiles or chiral dienes in the presence or the absence of catalysts.47 The progress in this field is remarkable catalytic asymmetric Diels-Alder reactions are generally carried out either by the use of chiral dienophiles or by the use of chiral dienes. Here, the reactions of chiral nitroalkenes with dienes or the reactions of nitroalkenes with chiral dienes are discussed. Many different chiral auxiliaries are now available, and some of them have been used in asymmetric Diels-Alder reactions of nitroalkenes. 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

A novel synthetic approach toward the AB -ring system of 9-azasteroids using the Diels-Alder reaction of nitroalkene and subsequent reductive cyclization has been shown (Scheme 10.24).132... 

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 hitherto discussed transformations clearly demonstrate the great value of using chiral dienophiles for hetero Diels-Alder reactions of nitroalkenes. Recent studies deal with the application of various chiral alcohols in order to get... 

The described sequential transformations involving hetero Diels-Alder reactions of nitroalkenes represent a very mature synthetical tool. Its application to the total synthesis of several alkaloids will be briefly discussed in the Sect. 7 of this article. 

MAPh promoted hetero Diels-Alder reaction of nitroalkene with chiral vinyl ether having external alkene mainly gave nitronate (151b) with good stereoselectivity (Scheme 6.154). Resulting mixture of (151b) and (151a) in a ratio of 15 1 was converted to the tricyclic nitrosoacetal by thermal [3 + 2]cycloaddition under basic conditions [182]. 

Domingo, L. R., Asensio, A., Arroyo, R (2002a). Density functional theory study of the Lewis acid-catalyzed Diels-Alder reaction of nitroalkenes with vinyl ethers using aluminum derivatives. J. Phys. Org. Chem. 15,660-666. 

Functionalized nitroalkenes are important chenophiles in the Diels-Alder ri example, fE -methyl fi-nitroactylate is an impottant reagent in organic synthesis The nitre group can be readily eliminated the Diels-Alder reaction of fi-nitroactylate is equivalent to that of ethyl propiolate with an inverse regiochemistry fEq. 8.4. ... 

Node and coworkers have used this aromatization strategy for the synthesis of (-) aphanor-phine.27 The Diels-Alder reaction of chiral nitroalkene, prepared by the asymmetric nitroolefi-nation reaction of a-methyl-8-valerolactone, with the Danishefsky s diene followed by aromatization is used as a key step for this total synthesis, as shown in Scheme 8.6. 

Microwave irradiation at solvent-free conditions induces pyrazoyl 2-azadienes to undergo Diels-Alder reactions with nitroalkenes, within 5-10 min good yields of pyrazolo[ 3,4-b pyridine s are obtained (see Eq. 8.25).39 Without irradiation the reaction produces only traces of products on classical heating. 

Dinitro-ll-oxatricyclo[6.2.1.01,6]undec-9-ene has been prepared by an intramolecular Diels-Alder reaction of the furan with a nitroalkene group as shown in Eq. 8.26. This tricyclic compound is a versatile synthetic tool for the preparation of ergot alkaloids.41... 

Dienes with Chiral Auxiliaries The use of dienes with the chiral auxiliary attached to the C-l position of the dienes is the most popular in asymmetric Diels-Alder reactions.59 In 1980, Trost reported high asymmetric induction in the Diels-Alder reaction using l-(S)-0-methylmandeloxy-l,4-butadiene59a However, the result obtained by Trost et al. has remained unique for more than a decade, at least in terms of enantioselectivity. The asymmetric Diels-Alder reaction of chiral diene-amines with nitroalkenes gives aminocyclohexenes with good diastereoselectivity (Eq. 8.37).60 The development in the area of chiral dienes is slow it may be due to the difficulty of preparing these compounds. 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

J. A. Serrano, L. E. Cdceres, and E. Romdn, Asymmetric Diels-Alder reactions of a chiral sugar nitroalkene, J. Chem. Soc. Perkin Trans. 1 941 (1992). 

A DFT study of the polar Diels-Alder reaction of 4-aza-6-nitrobenzofuroxan with cyclopentadiene found only one highly asynchronous transition state structure associated with the formation of the 4 + 2-adduct.178 4-Nitrobenzodifuroxan has been shown to be a highly reactive nitroalkene in Diels-Alder reactions with common dienes (cyclopentadiene) to produce stable NED adducts and with ethyl vinyl ether to produce IED adducts.179 Unlike a-acylfuran, 2-nitrofurans have been shown to be active dienophiles in thermal NED Diels-Alder reactions with a variety of buta-1,3-dienes, including Danishefsky s diene.180... 

Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphon-ates (281), a new class of chiral iminodienophiles, and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts (282). Hydrogenation of (282) results in a ring opening that affords the first examples of optically pure quaternary piperidine phosphonates. Two step synthesis of an enantiomeric pure cyclic phosphite (283) and its application as a chiral phosphorus nucleophile in the asymmetric Michael addition to nitroalkenes (284) provides an efficient... 

Serrano, J A, Caceres, L E, Roman, E, Asymmetric Diels - Alder reactions of chiral sugar nitroalkene diastereofacial selectivity and regioselectivity, J. Chem. Soc. Perkin. Trans, 1, 941-942, 1992. 

Scheme 8.32. Diastereoselective Diels-Alder reaction of chiral l-(alkylsulfinyl)-2-nitroalkenes.

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. 

Nitroalkenes have found some use as dienes in the Diels-Alder reaction. The nitroalkene is electron-dehcient and therefore reacts best with electron-rich dienophiles such as enol ethers. Good yields of the cycloadduct can be obtained by using a Lewis acid catalyst such as SnCU or TiCl2(0 Pr)2 at low temperature. For example, cycloaddition with cyclopentene gave the nitronate 69 in high yield (3.56). ° The nitronate cycloadducts can undergo a variety of different transformations, such as a subsequent 1,3-dipolar cycloaddition with an alkene (see Section 3.4). 

The use of the same substrates (2,4-dienals and nitroalkenes) in the Diels-Alder reaction were investigated by Chen. Unsubstituted 2,4-hexadienals and 2,4-heptadienals were inactive under the same conditions. Jorgensen reported trienamine Diels-Alder reactions of 2,4-dienals with olefins. ... 

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