Nitroalkenes Diels-Alder reactions

The final class of reactions to be considered will be the [4 + 2]-cycloaddition reaction of nitroalkenes with alkenes which in principle can be considered as an inverse electron-demand hetero-Diels-Alder reaction. Domingo et al. have studied the influence of reactant polarity on the reaction course of this type of reactions using DFT calculation in order to understand the regio- and stereoselectivity for the reaction, and the role of Lewis acid catalysis [29]. The reaction of e.g. ni-troethene 15 with an electron-rich alkene 16 can take place in four different ways and the four different transition-state structures are depicted in Fig. 8.16. 

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. 

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 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 in which nitroalkenes act as dienophiles are acceleratedin thepresence of 4 M l.iClOi) in nitromethane This acceleration is higher than that observed when l.iClO is used in diethyl ether The diastereoselecdve Diels-Aider reaction using homochiial nitroalkenes shown in Eq 8 31 has been demonstrated... 

Another combination of hetero-Diels-Alder reactions and a [3+2] cycloaddition of a nitroalkene was described by Avalos and coworkers [46]. Using the chiral substrate 4-134 derived from a sugar, the domino process can be performed as a three-component transformation using an electron-rich dienophile and an electron-poor... 

Dehydration of P-nitro alcohols provides an important method for the preparation of nitroalkenes. Because lower nitroalkenes such as nitroethylene, 1-nitro-1-propene, and 2-nitro-l-propene tend to polymerize, they must be prepared carefully and used immediately after preparation. Dehydration with phthalic anhydride is the most reliable method for such lower nitroalkenes.42,43 Such lower nitroalkenes have been used as important reagents for Michael acceptors or dienophiles in the Diels-Alder reaction, which will be... 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

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... 

Aromatization is often observed during the Diels-Alder reaction using nitroalkenes. Jung24 and Ono25 have reported that 2-phenylsulfinyl-l-nitroalkenes act as nitroacetylene equivalents in Diels-Alder reactions to give aromatic compounds, as shown in Eqs. 8.14 and 8.15, respectively. 

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. 

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. 

In intramolecular Diels-Alder reactions, two rings are formed in one step. The reaction has been used to synthesize a number of interesting ring systems.29 The intramolecular cyclization of ( )-l-nitrodeca-l,6,8-triene at 80 °C affords an endo cycloadduct with the tram ring fusion preferentially, as shown in Eq. 8.18. In contrast, (Z)-nitroalkenes produce a nearly 1 1 mixture of cis- and tra/w-fused cycloadducts.30... 

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... 

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... 

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. 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

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. 

Nitroalkenes with Chiral Auxiliaries The use of carbohydrates as chiral auxiliary in Diels-Alder reactions for the stereoselective preparation of carbocyclic and heterocyclic chiral rings is well documented.48 For example, D-manno-nitroalkene reacts with 2,3-dimethyl-1,3-butadiene to give a 65 35 mixture of adducts, as shown in Eq. 8.29. The configurations at C-4 and C-5 have been determined to be (4R,5R) and (45,55), respectively. Hydrolysis of the product followed by degradative oxidation of the sugar side chains leads to enantiomerically... 

Uncatalyzed Diels-Alder reactions between l-(trimethysiloxy)- or 1-acetoxy-l,3-butadiene and sugar-derived nitroalkenes having D-galacto or D-manno configurations proceed with complete regioselectivity. Diastereofacial selectivity is also complete with the D-galacto dieno-phile, whereas it is only moderate with the D-manno (Eq. 8.30).51... 

Asymmetric Diels-Alder reactions using chiral sulfinylalkenes have been extensively studied by Koizumi and coworkers.55 Fuji and coworkers have extended this strategy to chiral l-(alkyl-sulfinyl)-2-nitroalkenes. Such nitroalkenes react with reactive dienes such as Danishefsky s dienes to produce an adduct with a high enantiomeric excess (ee) (see Eqs. 8.34 and 8.35).57... 

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. 

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. 

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. 

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. 

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... 

The reactions of 4-nitrobenzodifuroxan 242 with a series of common dienes, such as cyclopentadiene, cyclohexa-diene, isoprene, 2,3-dimethylbutadiene, and 1-acetoxybutadiene, with ethoxymethyleneacetylacetone were found to proceed very readily to afford stable cycloadducts, which are the result of highly stereoselective normal electron-demand (NED) Diels-Alder reactions. Due to the additional activation provided by the two adjacent furoxan rings, the nitroalkene double bond of compound 242 is also prone to undergo NED reactions with less reactive dienic structures, such as the enol form of ethoxymethyleneacetylacetone and the in situ generated 2-ethoxy-4-(2-furfur-yl)buta-l,3-diene <2004TL1037, 2005T8167>. 

The behavior of complexes of nitroalkenes (42) with LA toward conjugated dienes is yet another factor underlying the role of these complexes. Conjugated nitroalkenes (42) are considered as active dienophiles in classical Diels-Alder reactions (104, 105). On the contrary, in the presence of SnCl4, nitroalkenes (42) react with cyclopentadiene and 1,3-cyclohexadiene exclusively at one double bond (103). Therefore, it is highly probable that the 42 + 43 cycloaddition proceeds by a nonconcerted mechanism in the presence of LA (see Scheme 3.40). 

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