The Nitro Group in Organic Synthesis

Scheme 4.16.

Nitroalkenes are generally prepared by the substitution reaction of β-nitro sulfides and sulfoxides with a variety of carbon nucleophiles via an addition-elimination sequence. This method is particularly useful for the preparation of cyclic nitroalkenes (Eq. 4.100).126

A chiral sulfoxide can be used as a leaving group for the asymmetric induction via addition-elimination process. δ-Lactam enolates are converted into the corresponding nitroalkenes substituted with lactams (Eq. 4.101).127

91% (84% ee)

A total synthesis of (–)-physostigmine is accomplished from a chiral nitroolefin of Eq. 4.101 (Scheme 4.17).128

The addition-elimination reaction of copper-zinc organometallics RCu(CN)ZnX with (E)- 1-nitro-2-phenylsulfonylethylene gives highly functionalized (E)-nitroalkenes in excellent yields.129

Organometallics bearing esters (Eq. 4.102),13015 dienes (Eq. 4.103),131 or oxygen functions (Eq. 4.104)132 give nitroalkenes functionalized by these groups.

104 MICHAEL ADDITION

When electron-deficient alkenes are very reactive, weak bases such as triethylamine or triphenylphosphine (Eq. 4.105)134 are reactive enough as base. On the other hand, stronger bases

such as DBU or tetramethylguanidine (TMG) are necessary when less reactive alkenes such as vinyl sulfoxides (Eq. 4.106)135 or α-substituted α,β-unsaturated carbonyl compounds are used

(Eq. 4.107).136 TMG has been widely used for the Michael addition of nitroalkanes to various electron-deficient alkenes since the first report in 1972.137–140 High-pressure accelerates the

reaction to induce the Michael addition with less reactive alkenes.141

The reaction of conjugated nitroalkenes with α,β-unsaturated esters, ketones, nitriles, and

sulfones is catalyzed by TMG to give the Michael adduct of allylic nitro compounds (Eq. 4.108).142

Tetraalkylammonium fluorides or metal fluorides are also effective as catalysts for the Michael addition of nitroalkanes (see, Table 4.2).143–145

In recent years, there has been increased recognition that water is an attractive medium for organic reactions from the environmental point of view. The Michael addition of various nitroalkanes to conjugated enones can be performed in NaOH (0.025 M) and in the presence of cetyltrimethylammonium chloride (CTACl) as cationic surfactant in the absence of organic solvents (Eq. 4.109).146 The Michael addition of nitromethane to methyl acrylate is carried out in water using NaOH as a base to give the mono adduct (Table 4.2).147

Table 4.2. Michael Addition to nitro compounds

106 MICHAEL ADDITION

Ytterbium triflate is an extremely effective catalyst for the Michael addition of α-nitro esters to enones in water (Eq. 4.110).149

The heterogeneous catalytic systems have some advantages over homogeneous reactions. Chemical transformations under heterogeneous conditions can occur with better efficiencies, higher purity of products, and easier work-up. Ballini and coworkers have found that commercial amberlyst A-27 is the best choice for the Michael addition of nitroalkanes with β-substituted alkene acceptors (Eq. 4.111).150 The reaction is also carried out by potassium carbonate in the presence of Aliquat 336 under ultrasonic irradiation (Eq. 4.112).151

Recently very reactive solid bases have been devised, which are prepared by derivatization

of amorphous silica and hexagonal mesoporous silica (HMS) with the dimethylaminopropyl group (Eq. 4.113).151b

In Table 4.1, the Michael addition of nitro compounds to various electron deficient alkenes is shown.

The Michael addition of nitro compounds is a useful method for the preparation of various natural products. The Michael addition of nitroalkanes to dehydroalanines gives γ-nitro-α- amino acids, which provides a convenient synthesis of side-chain modified α-amino acids (Eq. 4.114).152 Transformations of γ-nitro-α-amino acid derivatives into α-amino acids occur by reductive denitration (see Section 7.2) into γ-oxygenated α-amino acids by the Nef reaction (Eq.

4.115).153 Condensation of glyoxalic acid, nitroalkanes, and amines provides a simple method for β-nitro-α-amino acids (Eq. 4.116).154

The base-catalyzed reaction of nitromethane with α-amidoalkyl sulfones gives the nitro compounds as in Eq. 4.117; the nitromethyl group is converted into a carboxylic group to give α-amino acids by the Nef reaction using KMnO4.155

The Michael addition of nitroalkanes to α,β-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see

Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a–h Various natural products have been prepared via this route.157 For

example, cis-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f

Scheme 4.20.

108 MICHAEL ADDITION

The Michael addition of nitromethane to cyclopentenone derivatives is used for synthesis of prostaglandins (Scheme 4.20).158 Here, the anion of nitromethane is used as a formyl anion synthon.

Ballini and coworkers have used the Michael addition of nitro compounds followed by the Nef reaction for the synthesis of various spiroketalic pheromones (Scheme 4.21).159

Asymmetric synthesis of spiroketalic pheromones is also reported, in which the asymmetric reduction of carbonyl group is carried out with baker’s yeast (Scheme 4.22).160

Scheme 4.22.

The Michael addition of nitro compounds to electron-deficient alkynes affords allylic nitro

compounds in good yields, in which KF-n-Bu4NCl in DMSO is used as a base and solvent (Eq. 4.118).161

2) CO2Me

3) H2C=CHC(O)Me

53%

A short enantioselective synthesis of (–)-(R,R)-pyrenophorin, a naturally occurring anti-fun- gal 16-membered macrolide dilactone, is prepared from (S)-5-nitropentan-2-ol via the Michael addition and Nef reaction (Scheme 4.23).162 The choice of base is important to get the E-alkene in the Michael addition, for other bases give a mixture of E and Z-alkenes. The requisite chiral (S)-5-nitropentan-2-ol is prepared by enantioselective reduction of 5-nitropentan-2-one with baker’s yeast.163