The Nitro group in organic sysnthesis - Feuer

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.

Scheme 4.12.

Thus, (S)-chiral auxiliary gives rise to combination of the trigonal centers of enolate and nitroalkene with Si/Si topicity.79

The titanated bislactim ethers of cyclo(L-Val-Gly-) are added to nitroalkenes with high diastereo-selectivity (Eq. 4.60).80a Michael addition of lactam bearing (S)-2-(1-ethyl-1- methoxypropyl) pyrrolidine as auxiliary on the lactam nitrogen to nitroalkenes proceeds with high selectivity (de >96%, ee >96%).80b

Scheme 4.13.

Nitroalkens are effective Michael acceptor B units for sequential, convenient A + B + C coupling reactions, as shown in Eq. 4.61.81 This process is very simple and convenient to synthesize nitrogen heterocycles. Reductive cleavage of the PhS group and reduction of the nitro group to amino group can be accomplished with NiCl2/NaBH4 to give pyrrolizidinones (see Chapter 10).

O

2. ∆

O ~100%

The Michael addition of enamines to nitroalkenes proceeds with high syn selectivity. The syn selectivity is explained by an acyclic synclinal model, in which there is some

favorable interaction between the nitro group and the nitrogen lone pair of the enamine group (Eq. 4.67). 86a–b Both Z- and E-nitrostyrenes afford the same product in over 90%

diastereoselectivity.

(4.67) The chiral enamines provide the opportunity for the enantioselective Michael addition to

nitroalkenes, as shown in Eq. 4.68, where the ketone is obtained as a single diastereomer with an ee >90%.87

70% (de > 90%)

The reaction of enamines with 2-nitro-2-propen-1-yl pivalate gives 4-nitrocyclohexanones, which is regarded as formal [3 + 3] carbocyclization. The reaction proceeds in high diastereoselectivity (60% to >95% selectivity), see Eq. 4.69.88 If chiral enamines such as that in Eq. 4.68 are employed, the products are obtained with high ee.

The Michael addition of formaldehyde hydrazone of (S)-1-amino-2-(methoxymethyl)pyr- rolidine to nitroalkenes gives β-nitrohydrazones in good chemical yield and stereoselectivity (Eq. 4.70).89

O2N

(4.70)

MeO N N

88% (80% de)

The addition of 2-nitropropene to the chiral imine derived from 2-methylcyclopentanone and (S)-1-phenylethylamine gives the adduct in high regioand stereoselectivity (Eq. 4.71).90 The product is converted to a chiral 1,4-diketone via the Nef reaction.

The Michael type reaction of (3R)-5-t-butyldimethysiloxy-3-phenyl-1H-pyrrolo[1,2- c]oxazole with nitroethylene proceeds in the presence of Lewis acid to give the alkylated product in good chemical yield and diastereoselectivity. In the case of nitroethylene, the Diels-Alder type transition state is favored to give the syn-adduct selectively (Eq. 4.72).91

4.1.3d Organometallic Reagents The conjugate addition of various organometallic reagents such as RLi, RMgX, R2Zn, R2CuLi, and R3Al to nitroalkenes provides a useful method for nitro-alkylation. As the nitro group is transformed into various functional groups, this type of addition has been extensively used in organic synthesis. The 1,4-addition of Grignard reagents to β-nitrostyrene gives 1,1-diarylnitroethanes (Eq. 4.73).92 Addition of cerium chloride improves the yield of addition of RMgX to nitroalkenes (Eq. 4.74).93

Michael acceptors and 1,4-addition of alkyl group is a normal process. The reaction mechanism is not clear, but the process via addition of alkyl radicals and subsequent elimination of NO2 radical is one of the possible routes. Recently, several related reactions have been reported, as shown in Eq. 4.7698, Eq. 4.77,99 and Eq. 4.78,100 in which alkyl radicals are involved. The reaction of trialkylgallium compounds with nitrostyrene gives also a similar substitution product (Eq. 4.79).101

β-Nitrostyrene reacts with allylzinc reagents in dry DMF at room temperature to give the addition products in excellent yield (Eq. 4.80).102 The reaction of allyl tin compounds or allyl silanes with nitroalkenes requires the assistance of Lewis acids to give the addition products in good yield (Eq. 4.81).103

53% (anti/syn = 7/3)

Stannylallenes react with nitroalkenes in the presence of TiCl4 to give the propargylation products (Eq. 4.82).104

Knochel and coworkers have developed the addition of highly functionalized zinc-copper reagents RCu(CN)ZnI to nitroalkenes. The polyfunctionalized zinc organometallics are readily transmetalated to the copper derivatives by the addition of the THF-soluble copper salt CuCN 2LiCl. These copper reagents add to nitroalkenes in good yields, leading to highly functionalized nitroalkanes (Eq. 4.83).105

This procedure is applied to synthesis of 1,3-diamines by the addition of metallated tert-butyl N,N-dimethylcarbamate to nitroalkenes and subsequent reduction (Eq. 4.84).106

The Michael addition of the copper-zinc reagent derived from ethyl 4-bromobutyrate to the piperonal-derived nitroalkene proceeds cleanly to give the nitro ester, which is an intermediate for the synthesis of lycoricidine alkaloids (Eq. 4.85).107

Reactions of zinc-copper reagents bearing acidic hydrogen and sulfur functionalities with various electrophiles, including nitroalkenes, have been reported, as shown in Eq. 4.86108 and Eq. 4.87,109 respectively.