The Nitro Group in Organic Synthesis

162 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS

A very mild oxidative transformation of nitro compounds into ketones using tetrapropylammonium perruthenate (TPAP) has been developed. A stoichiometric amount of TPAP in the presence of N-methylmorpholine N-oxide (NMO) and 4 A molecular sieves (MS).18a As the reaction conditions are neutral and mild, this method is compatible with the presence of other sensitive functionalities (Eq. 6.11). This transformation can be carried out with 10 mol% of TPAP and 1.5 equiv of NMO in the presence of potassium carbonate, 4 A MS, and silver acetate (Eq. 6.12).18b

Secondary nitro compounds are converted into ketones under very mild conditions using n-propyl nitrite and sodium nitrite in DMSO.21

The Nef reaction of primary nitro compounds gives aldehydes or carboxylic acids, depending on the reaction conditions. Each transformation provides an important tool in organic synthesis. Primary nitro compounds are converted into carboxylic acids with concentrated mineral acids.22 Because such harsh conditions also lead to side reactions, a milder method is required in organic synthesis. Basic phosphate-buffered KMnO4 rapidly converts primary nitroalkanes into carboxylic acids in 90–99% yield (Eq. 6.13).23

KMnO4, KOH

HO(CH2)11CH2NO2 HO(CH2)11CO2H (6.13)

K2HPO4, t-BuOH

Scheme 6.1 shows a simple preparation of (+)-isomintlactone, isolated from a sample of peppermint oil. The addition of pyrrolidino enamine of (R)-3-methylcyclohexanone to ni-

Scheme 6.1.

6.1 NEF REACTION (ALDEHYDES, KETONES, AND CARBOXYLIC ACIDS) 163

troethylene followed by reduction with baker’s yeast and the Nef reaction gives the condensed lactone. Methylation followed by olefination using α-phenylselenation and oxidation yields the desired lactone (Scheme 6.1).24

Strong oxidizing agents such as KMnO4 are not always useful for synthesis of highly sensitive compounds. In 1956, Kornblum found that a mixture of nitrite ester and sodium nitrite oxidizes primary nitro paraffins to the corresponding carboxylic acids.25 However, the reaction was prone to poor yields and long reaction time. Forty years later, a very efficient related reaction using a mixture of sodium nitrite and acetic acid in DMSO has been reported (Eqs. 6.14 and 6.15).26 Because carbon–carbon double and triple bonds and other various functional groups are compatible with this reaction condition, this method is useful for natural product synthesis. For example, one-synthesis of alkaloid, (–)-horsfiline is shown in Scheme 6.2, in which the creation of chiral quaternary carbon centers via an addition-elimination process is used as the key reactions.27 This strategy has been used very effectively for the synthesis of various natural products; this is discussed in Chapter 4 on the Michael addition to nitroalkenes.

Because primary alkyl bromides can be converted into the corresponding nitro compounds by the action of NaNO2 in DMSO, primary alkyl bromides are converted directly into the corresponding carboxylic acids by the reaction with an excess of sodium nitrite in acetic acid (Eq. 6.16).26

Me

N

MeO

N O R

(–) - horsfiline

Scheme 6.2.

164 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS

96% (6.16)

6.1.3 Reductive Method

The Nef reaction can also be carried out with reducing agents. Aqueous titanium chloride reduces nitro compounds to imines, which are readily hydrolyzed to carbonyl compounds (Eq. 6.17).28 The Michael addition of nitroalkanes to enones followed by reaction with TiCl3 provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cis-jasmone is readily obtained,28 as shown in Eq. 6.18.

(6.18) The TiCl3 solution is very acidic such that acid-sensitive compounds do not survive. In such cases, sodium acetate or ammonium acetate is added to the reaction mixture to control pH at 5–6.29 Highly functionalized substrates are synthesized by the Nef reaction using TiCl3 and

sodium acetate, as shown in Eq. 6.19,30 and Eq. 6.20.31

Vanadium chloride,32 chromium chloride,33 and the combined use of tributylphosphine and diphenyldisulfide34 are also effective in promoting the reductive Nef reaction.

6.1 NEF REACTION (ALDEHYDES, KETONES, AND CARBOXYLIC ACIDS) 165

6.1.4 Direct Conversion of Nitroalkenes to Carbonyl Compounds

Because nitroalkenes are directly prepared by the condensation of aldehydes with nitroalkanes, the conversion of nitroalkenes into carbonyl compounds provides a powerful tool in organic synthesis. In general, the reduction of nitroalkenes followed by the hydrolysis or oxidation gives carbonyl compounds. Old procedures for this transformation involve the reduction with FeHCl35 or Zn-AcOH.36 There are many modified procedures for the conversion of 1-phenyl-2- nitropropene into phenylacetone (Eq. 6.21); method A37: Raney Ni-NaH2PO2, method B38: Cr(2)Cl, method C39: LiBHR3/HCl, method D40: CdCl2-Mg-H2O, method E41: electrochemical reduction using Pb as an electrode.

(6.21)

The direct conversion of nitroalkenes into ketones is especially useful for the preparation of arylacetones. They are readily prepared by the condensation of aromatic aldehydes with nitroethane and by the subsequent Nef reaction.42 Typical examples are presented in Eq. 6.2237 and Eq. 6.23; the product of Eq. 6.23 is used for total synthesis of perylenequinone, calphostin D, which is a potent inhibitor of protein kinase C.42b

Iodotrimethylsilane generated in situ from chlorotrimetylsilane and sodium iodide effects the reduction of nitroalkenes into ketones at 0 °C. This method is useful for the conversion of nitro steroids or nitro terpenoids to the corresponding ketones (Eq. 6.24).43

166 CONVERSION OF NITRO COMPOUNDS INTO OTHER COMPOUNDS

Ballini and his coworkers have used the strategy based on the Nef reaction after the carbon–carbon bond formation for the synthesis of various natural products.44 The requisite nitroalkenes are simply prepared by the nitro-aldol condensation using Al2O3. When double bonds are present in nitroalkenes, the reductive Nef reaction gives saturated compounds, as shown in Eq. 6.25.45 A new simple, cheap, and practical procedure for the direct transformation of nitroalkenes into ketones has been obtained by the NaBH4/H2O2 system. By this method, other functional groups such as double bonds, acetals, or aromatic nitro groups are preserved. A convenient synthesis of dihydrojasmone and brevicomine using this transformation is presented in Eqs. 6.25 and 6.26, respectively.46 Other applications of the Nef reaction to the synthesis of natural products such as spiroketalic pheromones and lactonic pheromones are demonstrated in Eqs. 6.27 and 6.28.47