The Nitro Group in Organic Synthesis

Scheme 4.5.

Diastereoselective conjugate addition of oxygen and nitrogencentered nucleophiles to nitroalkenes derived from (+)-camphorsulfonic acid and ozonolysis give α-hydroxy and α-amino thiol acid derivatives (Eq. 4.39). In all cases, the (R)-diasteromer is formed as the major component.49

1-(Phenylthio)nitroalkenes are also excellent intermediates for the synthesis of other heterocyclic ring systems. For example, tetrahydropyran carboxylic acid derivatives are formed by the intramolecular addition of oxygen nucleophile to 1-(phenylthio)nitroalkene predominantly as the cis-isomer (9.1:1) (see Eq. 4.40). The reaction may proceed via the chair-like transition state with two pseudo-equatorial substituents.50

HF, pyridine

SPh

SiO Ph

NO2

4.1.3 Conjugate Addition of Carbon-Centered Nucleophiles

4.1.3a Active Methylene Compounds Nitroalkenes are powerful Michael acceptors that can serve as synthons of the type +C-C-NH2 and +C-(C=O)R. Classically, the reactions of nitroalkenes with carbon-centered nucleophiles have been limited to reactions carried out under mildly basic conditions using relatively acidic reaction partners such as malonate derivatives and 1,3-diketones.56 The Michael addition of such active methylene compounds to nitroalkenes is catalyzed by various bases, including ROM (M = metal), triton B, and triethylamine. For example, the reaction of acetyl acetone or ethyl acetate with nitrostyrene proceeds in the presence of catalytic amounts of triethylamine at room temperature to give the adduct in 98% or 78% yield, respectively. The addition products are useful intermediates for the preparation of furans or pyrroles.57 Metal complex catalysts such as Ni(acac)2 are also effective to induce the Michael addition of acetyl acetone to nitrostyrene.58 Yoshikoshi and coworkers have found that the potassium fluoride-catalyzed addition of 1,3-dicarbonyl compounds to nitroalkenes leads to the formation of furans (Eq. 4.42) or Michael adducts and their Nef products (Eqs. 4.43 and 4.44), depending on substrates and conditions.59

The Michael addition of nitroalkanes to nitroalkenes is catalyzed by triethylamine to give 1,3-dinitro compounds (Eq. 4.45).60 In some cases, the intramolecular displacement of the nitro group takes place to give cyclic nitronates (Eq. 4.46).61

the Michael-type addition of lithium enolates, sulfur-substituted organolithium reagents, and

other reactive carbanions to nitroalkenes. Some typical examples are presented in Eqs. 4.48 and 4.49.64a

Dianions or trianions derived from 1,3-dicarbonyl compounds react with nitroalkenes at low temperature to give the adduct, which undergoes a nitro-aldol type cyclization (Eq. 4.50).64c

Nitroethylene is extremely reactive and sensitive to strong basic conditions, but various ketone and ester enolates undergo alkylation with nitroethylene at low temperature (Eq. 4.5165 and Table 4.1).

2)NO2

74%

Nitroalkenes react with lithium dianions of carboxylic acids or with lithium enolates at –100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives γ-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives α,β-unsaturated ketones (Eq. 4.53).67

1)LDA

2)Et

82% (E/Z = 2/1)

4) DBU

90 MICHAEL ADDITION

radical denitration (Section 7.2) or is transformed into the carbonyl group by the Nef reaction (Section 6.1) (Eq. 4.56).70

A variety of carbanions have been employed for the conjugate addition to nitroalkenes; recent results are shown in Table 4.1.

Seebach and coworkers have developed a useful multiple coupling reaction using nitropropenyl pivalate. This opens a possibility of successive introduction of two different nucleophiles, as exemplified in Eq. 4.57 (see also Section 3.2).75

1)S Ph

Asymmetric Michael addition of chiral enolates to nitroalkenes provides a useful method for the preparation of biologically important compounds. The Michael addition of doubly deprotonated, optically active β-hydroxycarboxylates to nitroalkenes proceeds with high diastereoselectivity to give erythro-hydroxynitroesters (Eq. 4.58).76

Chiral enolates of 1,3-dioxalan-4-ones, methyl 1,3-oxazolidine-4-carboxylates, and 1,3-imi- dazolidine-4-ones derived from chiral natural sources such as (S)-proline, (S)-serine, and (S)-threonine are added to nitroalkenes in high diastereoselectivity (Scheme 4.12).77

Enantioselective synthesis of the antidepressant rolipram can be done by the asymmetric Michael addition of the enolate of N-acetyloxazolidone to nitrostyrene. Chirally branched pyrrolidones like rolipram are highly active antidepressants with novel postsynaptic modes of action. The synthesis is shown in Scheme 4.13.78

Seebach and Brenner have found that titanium enolates of acyl-oxazolidinones are added to aliphatic and aromatic nitroalkenes in high diastereoselectivity and in good yield. The effect of bases on diastereoselectivity is shown in Eq. 4.59. Hydrogenation of the nitro products yields γ-lactams, which can be transformed into γ-amino acids. The configuration of the products is assigned by comparison with literature data or X-ray crystal-structure analysis.