The Nitro Group in Organic Synthesis

272 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

Scheme 8.27.

β-Nitrosulfides, formed by Michael addition of allyl mercaptan to β-nitroenones, undergo either INOC or ISOC to give tetrahydrothiopheno[3,4-c] isoxazolines. In this case, stereoselectivity of ISOC is also better than that of INOC (Eq. 8.88).140

Asymmetric 1,3-dipolar cycloaddition of nitronates using chiral alkenes has been reported, as shown in Eq. 8.89141,142 and Eq. 8.90.143

274 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145

Nitronates show a similar reactivity to that of nitrones, and nitrones are one of 1,3-dipoles that have been successfully developed to catalyzed asymmetric versions, as discussed in the section on nitrones (Section 8.2.1). However, asymmetric nitronate cycloadditions catalyzed chiral metal catalysts have not been reported. Kanemasa and coworkers have demonstrated that nitronate cycloaddition is catalyzed by Lewis acids (Eq. 8.93).146 This may open a new way to asymmetric nitronate cycloaddition catalyzed by chiral catalysts.

1,3-Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between N-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148

8.3 NITROALKENES AS HETERODIENES IN TANDEM [4+2]/[3+2] CYCLOADDITION

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 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

Me

85%

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

(8.98)

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.

(total yield 96%)

Denmark and coworkers have found that methylaluminum bis (2,6-di-tert-butyl-4-methyl- phenoxide) (MAD) or methylaluminum bis(2,6-diphenylphenoxide) (MAPh) is effective as the Lewis acid promoter for cycloaddition of 2,2-disubstituted 1-nitroalkenes (Eq. 8.100).158 Other Lewis acids such as SnCl4, TiCl4, and TiCl2(Oi-Pr)2 fail to promote the cycloaddition of 2,2-disubstituted 1-nitroalkenes. The products are converted into 3,3-disubstituted pyrrolidines via hydrogenolysis.158 Reductive cleavage of N–O bonds produces oxime hemiacetals, which are further reduced to amido aldehydes and finally to pyrrolidines. This reaction provides a useful synthetic method for pyrrolidines, which is discussed later.

The mode of cycloaddition of (E)- and (Z)-1-propenyl ether with (E)-nitrostyrene (exo versus endo) and attendant stereostructure of the final product is dependent on the configuration of the vinyl ether and the Lewis acids employed (Scheme 8.30). Reactions conducted with TiCl2(O-i-Pr)2 produce nitronates that are enriched in isomers derived from an endo (EtO) approach of the dienophiles. It is believed that the transition structure of the titanium-promoted nitroalkene [4+2] cycloaddition is highly polarized, placing a partially positive charge on the nitrogen atom of the alkene. Therefore, the participating vinyl ether assumes an endo orientation of the electron-rich alkoxy group due to stabilizing interactions. In contrast, reactions performed using MAPh produce nitronates that are enriched in isomers derived from an exo approach. A preference for the exo orientation of a vinyl alkoxy group in nitroalkene [4+2] cycloaddition promoted by MAPh is the general trend. It is believed that the bulk of the aluminum-based Lewis acid forces the alkoxy group to take up an exo orientation to minimize nonbonded interactions.

Hydrogenolysis of the individual nitronate diastereomers presented in Scheme 8.30 provides the corresponding transand cis-3,4-disubstituted pyrrolidines in good yields (Eq. 8.101).158

278 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

Scheme 8.30.

2-Substituted 1-nitroalkenes undergo highly diastereoselective Lewis-acid-promoted [4+2] cycloadditions with chiral vinyl ethers derived from (R)-2,2-diphenylcyclopentanol and (1R, 2S)-2-phenylcyclohexanol to afford cyclic nitronates in high yields. The resulting nitroates are reduced with hydrogen at 160 psi in the presence of platinum oxide to afford enantiomerically enriched pyrrolidines in good yields, as shown in Eqs. 8.102 and 8.103.159 The chiral auxiliaries are recovered in nearly quantitative yields after hydrogenation.

2-(Acyloxy)vinyl ethers undergo regioselective [4+2] cycloadditions with nitroalkenes to produce substituted 5-acetoxy nitronates in good yields. The resulting nitronates can be converted into 3-hydroxy-4-substituted-pyrrolidines by hydrogenolysis. A chiral 2-acetoxy- vinyl ether derived from (R)-2,2-diphenylcyclopentanol is employed in the cycloaddition-hy-

drogenation sequence to prepare optical active N-tosyl-3-hydroxypyrrolidines in 96% ee (Eq. 8.104).160

A few examples of cycloadditions between nitroalkenes and vinyl ethers without the use of Lewis acids have been reported (Eq. 8.105), in which additional activating electron-withdrawing groups are generally required.161

High-pressure promoted cycloadditions of nitroalkenes and enol ethers eliminate the use of Lewis acids (Eq. 8.106).162 Thus, even sterically hindered nitroalkenes react with 2,3-dihydro- furan to give the exo cyclic nitronates stereoselectively without using Lewis acids.

8.3.2 Tandem [4+2]/[3+2] Cycloaddition of Nitroalkenes

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.

8.3.2.1 Inter [4+2]/inter [3+2] The tandem intermolecular [4+2]/intermolecular [3+2] cycloadditions create bicyclic nitroso acetals with up to six stereogenic centers, which can be controlled by the choice of the stereochemistry of each component and the Lewis acids. The nitronate derived from 2-nitrostyrene and 1-trimethylsilyloxycyclohexene reacts with methyl acrylate to give the nitroso acetal in good yield and high diastereoselectivity (Eq. 8.107).154