The Nitro Group in Organic Synthesis

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.

100 MICHAEL ADDITION

A radical approach to asymmetric aldol synthesis, which is based on the radical addition of a chiral hydroxyalkyl radical equivalent to a nitroalkene, has been reported, as shown in Eq. 4.93.113 The radical precursor is prepared from the corresponding carboxylic acid by the Barton reaction,114 which has been used for synthesis of new β-lactams.115

4.2 ADDITION AND ELIMINATION REACTION OF >-HETEROSUBSTITUTED

NITROALKENES

Nitroalkenes with potential leaving groups in β-position such as a dialkylamino, an alkylthio, or a phenylsulfonyl group undergo addition-elimination reactions with nucleophiles. The

chemistry of nitroenamines has been extensively investigated, and their potential utility in organic synthesis has been well established.26b,116 Severin and coworkers have developed the

addition of elimination reactions of nitroenamines with carbon nucleophiles in 1960–1970, as exemplified in Eq. 4.94.117

Node and Fuji have developed stereoselective nitroolefination of various carbonyl compounds using β-nitroenamines (Eq. 4.95).118

They have developed direct asymmetric synthesis of quaternary carbon centers via additionelimination process. The reactions of chiral nitroenamines with zinc enolates of α-substituted- δ-lactones afford α,α-disubstituted-δ-lactones with a high ee through addition-elimination process, in which (S)-(+)-2-(methoxymethyl)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as α-substituted ketones, esters, and amides has failed to yield high ee.