Nitroalkenes Using Dienophiles

Nitroethene undergoes rapid cycloaddition to 1,3-dienes the subsequent Nef reaction gives cyclohexenones, which are formally produced by the Diels-Alder reaction of ketene with 

The Diels-Alder reaction of morphinan-6,8-dienes with nitroethene affords a novel type of opium alkaloids (Eq. 8.3).10a High reactivity of nitroethylene is demonstrated for the Diels-Alder reaction with thermally unstable dienes, and this is used for synthesis of polycyclic kopsane-like alkaloids.1013 

Functionalized nitroalkenes are important dienophiles in the Diels-Alder reaction. For example, ( )-methyl P-nitroacrylate is an important reagent in organic synthesis. The nitro group can be readily eliminated the Diels-Alder reaction of P-nitroacrylate is equivalent to that of ethyl propiolate with an inverse regiochemistry (Eq. 8.4).11 

Another example is presented in Eq. 8.5, in which the nitro group is more effective in controlling the direction of addition than the carbonyl group.12 

Various dienes substituted with heteroatoms such as 1-oxabuta-l,3-dienes have been used in organic synthesis, as shown in Eq. 8.613 and Eq. 8.7.14 

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Dienophiles substituted with appropriate heteroatoms may offer a number of advantages such as (1) provide dienophilic equivalents of C-—C and moieties which do not undergo [4 + 2] cycloadditions to 1,3-dienes because of low (e.g. isolated alkenes, alkynes, allenes) or different reactivities (e.g. ketenes) (2) enhance or invert the regiochemistry of the Diels-Alder process (3) permit facile removal of the activating and/or regiocontrolling group after cycloaddition with or without introduction of further functionalities. The use of nitroalkenes as dienophiles demonstrates these issues most strikingly. 

The Influence of Dienophile Structure on Reactivity and Stereoselectivity in [4+2] Cycloadditions of Nitroalkenes Various dienophiles have been used successfully in nitroalkene [4 + 2] cycloadditions, such as vinyl ethers [77], enamines [78], ketene acetals [79], unactivated alkenes [58, 80, 81], 1,3-dienes [47, 82], allylic silanes [83], and allenes [84] (Scheme 16.10). Because of their high... 

Dehydration of fi-nitro iilcohols provides an important method for the preparation of nitroalkenes. Because lower nitroalkenes such as nitroethylene, Tnitro-Tpropene, and 3-nitro- Tpropene tend to polymerize, they must be prepared careftdly and used immediately after preparation. Dehydration v/ith phthalic anhydride is the most reliable method for such lower nitroiilkenes. Such lower nitroalkenes have been used as important reagents for Michael acceptors or dienophiles in the Diels-Alder reacdon, which v/ill be... 

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... 

Nitroalkenes are good dienophiles and the variety of transformations available for nitro groups makes them versatile intermediates.65 Nitro groups can be converted to carbonyl groups by reductive hydrolysis, so nitroethylene can be used as a ketene equivalent.66... 

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... 

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. 

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. 

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-... 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

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. 

The reaction of vinyl ethers and enamines with nitroalkenes is highly regiose-lective, with only the head-to-head adduct observed. The endo approach of the dienophile is preferred in the thermal cycloaddition, however, the mode of approach can be controlled by the choice of the Lewis acid promoter (214). Facial discrimination has been obtained by the use of chiral groups on the both the nitroalkene (215,216) and the enamine (217) or vinyl ether (218), as well as with chiral Lewis acids (46,66,94,219,220). 

Bicyclic nitroso acetals were able to be synthesised by employing ethyl vinyl ether (dienophile), styrene (dipolarophile) and the previously discussed resin-bound ni-troalkenes in a one-pot tandem [4+2]/[3+2]. As illustrated in Scheme 7.30, several aromatic and aliphatic substituents could be introduced to the bicyclic scaffold. Reductive cleavage of the cycloadducts with lithium aluminium hydride (LLAIH4) gave rise to the 3a-methyl alcohol substituted nitroso acetals in moderate overall yields. All these examples demonstrate that resin-bound nitroalkenes can be readily synthesised by microwave synthesis and thereafter can be used as starting materials, in a variety of high pressure-promoted cycloadditions. 

The first papers dealing with the use of optically active sulfinyl nitroalkenes were published by Fuji et al. in 1991 [71,72]. These papers describe the reaction of Danishefsky s diene with compound 70 (the dienophile containing a six-membered ring does not react) to afford a 1 1 mixture of two compounds (endo-71 and exo-71) resulting from desulfinylation of the endo t) and exo(t) adducts. The optical purity of these compounds ee > 95 %) indicates a complete 7r-facial selectivity in the cycloaddition. X-ray diffraction studies of dienophile 70 showed the s-trans conformation of the sulfinyl oxygen (like that depicted in Scheme 38) in the solid state. By assuming steric approach control for the Diels-Alder reaction, the stereochemistry of endo-71 and exo-71 suggests that such a con-... 

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 classical version of the Diels-Alder reaction uses a 1,3-diene as the 4it component and an alkene or alkyne containing electron-withdrawing groups (conjugated aldehydes, ketones, acids and their derivatives, nitroalkenes, etc.) as the 2n reactant. With appropriately chosen dienes and/or dienophiles, a wide array of purely carbocyclic or heterocyclic compounds can be easily synthesized. A representative set of simple examples is given in Scheme 2.118. 

Carbamoyl nitroso dienophiles, derived from chiral pyrrolidines, have been generated and their reactivity with cyclohexa-diene investigated. Using (—)-fra/w-2,5-dimethylpyirolidine as the auxiliary, the [4 + 2] cycloadduct is isolated in 82% yield and with 98% diastereomeric excess (eq 10). Similarly, chiral ynamine dienophiles have been utilized in asymmetric [4 + 2] cycloadditions with a,p-unsaturated nitroalkenes to afford cyclic nitronic esters. The resulting esters subsequently undergo a rapid [1,31-rearrangement to afford chiral cyclic nitrones in moderate yield and high diastereoselectivity (eq 11)-... 

Tandem double intramolecular [4- -2]/[3- -2] cycloadditions were performed using nitroalkenes tethered to both the dienophile and the dipolarophile. For example, the [4-1-2] cycloaddition of the linear triene 544 was promoted by SnCU to afford a 3 2 mixture of545 and 546 rapidly. The intramolecular [34-2] cycloaddition was taken to completion by stirring the mixture in toluene at room temperature, and the polycyclic nitroso acetal 546 was then isolated as a single diastereoisomer in 87% overall yield (Scheme 128) <2003JOC8015>. 

The in situ generation of TV-vinyl-AT-cyclohexylnitrosonium cations from the corresponding a-chloro nitrone, e.g., AT-(2-chloroethylidene)cy-clohexylamine N-oxide (25), and their subsequent [4+ + 2] cycloaddition with electron-rich, neutral, or selected electron-deficient dienophiles have been extensively investigated (Scheme 9-1X).173-175 The intermediate im-inium salts which are derived from the regio- and stereoselective [4+ + 2] cycloadditions are not generally isolated but are subjected to the useful transformations illustrated in Scheme 9-IX. The intramolecular [4+ + 2] cycloadditions of vinylnitrosonium cations and nitroalkenes have been detailed.176... 

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). 

In the inverse electron-demand (lED) HDA reaction systems, a,p-unsaturated ketones, thiones, nitroalkenes, and related compounds often serve as heterodiene units and the electron-rich olefins are usually used as dienophiles for the reaction [158]. A concerted mechanism has been suggested for the HDA reaction between an a,p-unsaturated ketone with a vinyl ether mediated by a titanium complex (Scheme 14.66), although the possibility of a stepwise, cationic pathway, particularly in the presence of a Lewis acid, cannot be completely excluded [160]. 

The use of oxygen-containing dienophiles in the form of silyl enol ethers, or ketene acetals has attracted considerable attention [66]. However, alkyl enol ethers are the most extensively employed dienophiles. The regioselectivity in the [4 + 2] cycloaddition step can be predicted in a straightforward way by FMO analysis. The larger coefficient in the LUMO of the nitroalkene (at the 3-carbon) will align with the... 

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