The Nitro Group in Organic Synthesis

The Nitro Group in Organic Synthesis. Noboru Ono

Copyright © 2001 Wiley-VCH

ISBNs: 0-471-31611-3 (Hardback); 0-471-22448-0 (Electronic)

7

SUBSTITUTION AND ELIMINATION OF NO2 IN R–NO2

The aliphatic nitro groups can be displaced by various nucleophiles via one electron transfer reactions (SRN1)1 or ionic reactions2 using palladium-catalyzed reactions of allylic nitro compounds, Lewis acid-catalyzed reactions, or intramolecular nucleophilic substitution reactions. These reactions have been well summarized by Kornblum1 and Ono;2 therefore, duplication of these is minimized here. The SRN1 reaction has also been applied to the direct replacement of the nitro group by hydrogen. This transformation is relatively new compared with the Nef reaction of nitro compounds or the reduction of the nitro group to the amino group, but it has already been widely accepted as a useful transformation in organic synthesis (Section 7.2). Elimination of the nitro group to afford alkenes proceeds either via radical or ionic processes, which provides a useful strategy for olefin synthesis (Section 7.3).

7.1 R–Nu FROM R–NO2

7.1.1 Radical Reactions (SRN1)

In 1970, a new reaction, the displacement of a nitro group from α-nitro esters, α-nitro nitriles, α-nitro ketones, and α,α-dinitro compounds by nitroalkane salts, was described.3 These displacements, which are exemplified by the reaction presented in Eq. 7.1, take place at room temperature and give excellent yields of pure products. The reaction proceeds via a radical chain mechanism involving one electron-transfer processes as shown in Scheme 7.1; the details of the mechanism are described in a review.1

When α,α-dinitro compounds are employed, the nitro group is displaced by various stabilized carbanions as shown in Eqs. 7.2–7.5.4

182

Scheme 7.1. SRN1 mechanism

α,α-Dinitro compounds are very reactive substrates for SRN1 reactions. They are readily prepared by oxidation of nitroalkane salts in the presence of nitrite ion with potassium ferricyanide.5 In a similar way, α-nitrosulfones and α-nitronitriles are prepared in excellent yields (see Eqs. 7.6–7.8).5 The modified procedure using persulfate and a catalytic amount of ferricyanide is very effective for the preparation of these compounds.6

71%

Various α-nitronitriles are readily prepared by the reaction of Eq. 7.7; the reaction of α-nitronitriles with nitroalkane salts provides an excellent method for the preparation of β-nitronitriles (Eq. 7.9).7

The reaction of tertiary nitro compounds with the sodium salt of nitromethane followed by the Nef reaction provides a good method for the preparation of quaternary aldehydes (Eq. 7.10).8 Because the nitromethyl group can be transformed into other groups such as CN, CO2H, or CH2NH2, the SRN1 reaction of tertiary nitro compounds with the anion of nitromethane is a synthetically useful method (Kornblum reaction).10 For example, the nitromethylation of tertiary nitro compounds has been applied for preparing starting materials for cascade polymers (Eq. 7.11).9

Vasella has used deoxy-nitro sugars for the synthesis of various biologically important carbohydrates,10 and the radical nitromethylation of deoxy-nitro sugars has been used for synthesis of fructose 6-phosphate11 and 6-C-methyl and 6-C-(hydroxymethyl)analogues of N-acetylneuraminic acid (see Scheme 7.2).12

The key step in the synthesis of the branched sugars presented in Scheme 7.2 is a Kornblum reaction of the nitropyranose. A mixture of anomers is obtained in the reaction of nitrofuranose, but the reaction with nitropyranose proceeds diastereoselectively to give a single product with an equatorially oriented side chain.

Tertiary nitro compounds are converted into the corresponding thiols by the reaction with sodium sulfide and sulfur (S8) in DMSO followed by the reduction with Al-Hg. (Eq. 7.12). Secondary and primary nitro compounds do not give thiols in these reactions; instead, a complex set of product is formed.13

85%

186 SUBSTITUTION AND ELIMINATION OF NO2 IN R–NO2

In 1982, a new reaction was reported by Tamura and Ono; namely, allylic nitro compounds

undergo replacement of the nitro group by various nucleophiles in the presence of a palladium

(0) catalyst.17a–b, 18a–b The details of these reactions are discussed in Ref. 2b; here, only some typical examples are presented. Carbon, sulfur, nitrogen, and phosphorous centered nucleophiles replace the nitro groups at the allylic positions. The reaction of allylic nitro compounds with triphenylphosphine is applied to the highly stereoselective olefination of aldehydes (Eqs. 7.15–7.18).19

Allyl acetates are more commonly used as electrophiles for the palladium-catalyzed allylic alkylation than allylic nitro compounds.20 However, the reaction of allylic nitro compounds has found wider applications. Allylic nitro compounds are readily available by nitration of alkenes. The regioand stereoselective introduction of electrophiles and nucleophiles into alkenes is possible as outlined in Eq. 7.19. In fact, this strategy is applied to the synthesis of terpenoids.21

75%

The starting allylic nitro compound is obtained by nitration of 2-methylpropene with NO2. Subsequent Michael addition to methyl vinyl ketone followed by Pd-catalyzed allylic alkylation affords terpenoids.

Recently, elegant synthesis of anti-MRS carbapenum has been reported. Sequential reaction of nitromethane via conjugate addition-elimination to α,β-unsaturated esters followed by Pd-catalyzed substitution of the resulting allyl nitro compound with the naphthosultam affords the allylation product which is an anti (Eq. 7.20).22

O

CO2PNB

34% (7.20)

Allylic nitro derivatives undergo the SN1 reaction in aqueous acetic acid. Allylic sulfones in the presence of a sulfinate salt (Eq. 7.21) or allylic lactones if the substrate contains a suitably located ester group are formed in these reactions (Eq. 7.22).22

Tamura and coworkers have reported a related substitution reaction; cyclic α-(nitroalkyl) enones undergo regioselective substitution of the nitro group by sulfinate ion, amino, and carbon nucleophiles (Eq. 7.23).24 Several reaction pathways are envisioned for this useful

188 SUBSTITUTION AND ELIMINATION OF NO2 IN R–NO2

transformation involving electron-transfer mechanisms, such as SRN1,25 or a simple additionelimination process.24

This reaction is nicely applied to total synthesis of Clavularin A26b as shown in Scheme 7.3. The key reactions involve a high enantioselective addition-elimination process26a and stereoselective synthesis of cis-2,3-disubstituted cycloheptanones.27

Me

Me

41% (cis/trans = 94/6)

Clavularin A

Scheme 7.3.

Lewis acids are also effective to induce the nucleophilic substitution of allylic nitro compounds. These compounds react with allyltrimethylsilane,28 silyl enolates,28 or cyanotrimethylsilane29 in the presence of SnCl4 to give substitution products, respectively (see Eqs. 7.24–7.26).

75%

Thus, the nitro group at the allylic position is replaced by nucleophiles in the following three ways: (1) assistance by transition metal, (2) assistance by Lewis acids, and (3) assistance by proton. Zard and coworkers have reported a short total synthesis of estrone derivatives, where acid catalyzed allylic 1,3-shift of nitro group is used as a key step as shown in Scheme 7.4.30 The Knoevnagel reaction of 6-methoxytetralone with nitromethane in the presence of ethylenediamine followed by the nitro-aldol reaction and the Michael addition gives the required allylic nitro compounds. Subsequent treatment with acetic acid induces 1,3-shift of the nitro group. Base catalyzed cyclization gives the estrone derivative. Finally the nitro group is removed by radical denitration (see Section 7.2).

Allylic nitro groups are readily displaced by nucleophiles via an SN1-type mechanism. Thus, nitro groups with heteroatoms at the α- or β-positions (for example, α- or β-nitrosulfides) are expected to be cleaved in a similar way. In fact, the nitro group in α-nitrosulfides is replaced by nucleophiles in the presence of a Lewis acid31 or acetic acid.32 The nitro groups in the reaction of Eqs. 7.27 and 7.28 are cleanly replaced by CN, allyl, or PhS group on treatment with Me3SiY (Y = CN, allyl) in the presence of SnCl4 or simple treatment with PhSH in AcOH.

Scheme 7.4.