The Nitro Group in Organic Synthesis

3.2 DERIVATIVES FROM β-NITRO ALCOHOLS 41

filtered from the reaction mixture and may be reused.61 With the use of this new heterogeneous catalyst, nitroolefins are prepared directly by heating a mixture of aldehyde and nitroalkane at 100 °C in the absence of solvents (Eq. 3.36).

Application of ultrasound62 or microwave irradiation63 greatly assists these condensation reactions as shown in Eqs. 3.37 and 3.38, respectively, rendering the use of a Dean-Stark apparatus unnecessary.

Reactions of methyl nitroacetate with aldehydes are induced by TiCl4 in pyridine. They afford

nitroalkenyl-esters,64 which are used in the preparation of various nonnatural amino acids (Eq. 3.39).65

Nitroalkenes prepared from aromatic aldehydes are especially useful for natural product synthesis. For example, the products are directly converted into ketones via the Nef reaction (Section 6.1) or indoles (Section 10.2) via the reduction to phenylethylamines (Section 6.3.2). The application of these transformations are discussed later; here, some examples are presented to emphasize their utility. Schemes 3.3 and 3.4 present a synthesis of 5,6-dihydroxyindole66 and asperidophytine indole alkaloid,67 respectively.

Seebach and coworkers have developed the multiple coupling reagent, 2-nitro-2-propenyl 2,2-dimethylpropanoate (NPP). The reaction of nitromethane with formaldehyde gives 1,3- dihydroxy-2-nitropropane in 95% yield. Subsequent acylation with two equivalents of pivaloyl chloride and elimination of pivalic acid affords NPP. The reaction may be run on a 40to 200-g

Chiral multiple-coupling reagents have been prepared in enantiomerically pure form by enantio-selective saponification of diesters of meso-2-nitrocyclohexane-1,3-diols (Eq. 3.44) with pig liver esterase (PLE).69

The nitro-aldol reaction followed by dehydration gives 2-nitro-1,3-dienes, which are useful reagents for cycloaddition (Eq. 3.45).70

44 THE NITRO-ALDOL (HENRY) REACTION

The nitro-aldol approach is impractical for the synthesis of 2,2-disubstituted 1-nitroalkenes due to the reversibility of the reaction when ketones are employed as substrates. Addition-elimination reactions are used for the preparation of such nitroalkenes (see Chapter 4).

3.2.2 Nitroalkanes

Reduction of nitroalkenes with NaBH4 has been widely used for the synthesis of nitroalkanes.71 In some cases, however, small amounts of dimeric products are also formed, although their formation can be completely suppressed using acidic conditions.72 Silica gel is also effective in preventing the dimerization of nitrostyrenes. 2-Aryl-1-nitroethanes are obtained in near quantitative yields by the reduction with NaBH4.73 This route provides a simple route to phenylethylamines of biochemical and pharmacological interest.74 A simple and efficient method for the large-scale preparation of phenylnitroethanes has been reported, in which solutions of nitrostyrenes in 1,4-dioxane are added to an efficiently stirred suspension of NaBH4 in a mixture of 1,4-dioxane and ethanol (Eq. 3.46).75 Hydrogenation of nitrostyrene derivatives with bis(triphenylphosphine)rhodium chloride (Wilkinson catalyst) gives also good yields of products.76

The reduction of nitroalkenes with ZnBH4 in 1,2-dimethoxyethane (DME) gives the corresponding oximes or nitroalkanes depending on the structure of nitroalkenes. α-Substituted nitroalkenes are reduced to the oximes, whereas those having no α-substituents afford the nitroalkanes (Eq. 3.47).77

MeO

86%

Very selective reduction of nitroalkenes into the corresponding nitroalkanes is achieved using NaCNBH3 in the presence of the zeolite H-ZSM 5 in methanol (Eq. 3.48).78