Nitroalkanes, Nef reaction

The Henry reaction of ketones with nitroalkanes in the presence of etbylenediamine gives allylic nitro compounds, which give a,fi-imsanirated carbonyl compounds via the Nef reaction fEq. 6.30. ... 

As previously described, in basic conditions the proUne-derived a-sulfonyl amide 141 generates the imine function, which afterwards undergoes addition by a nucleophile, e.g., a nitronate ion see the diastereoselective synthesis of the diamino nitroalkane derivative 172, which is the precursor of the piperazine-2-carboxyUc acid 173, through a Nef reaction [45]. Similarly, the addition of the Uthium enolate of ethyl acetateto the a-sulfonyl amide 174 gave the diamino ester derivative 175, wich was then converted to (-)-l-aminopyrrolizidine 176 (Scheme 27). 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

The Michael addition of nitro compounds is a useful method for the preparation of various natural products. The Michael addition of nitroalkanes to dehydroalanines gives y-nitro-a-amino acids, which provides a convenient synthesis of side-chain modified a-amino acids (Eq. 4.114).152 Transformations of y-nitro-a-amino acid derivatives into a-amino acids occur by reductive denitration (see Section 7.2) into y-oxygenated a-amino acids by the Nef reaction (Eq. 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

Conjugate addition of nitroalkanes to ailyl Baylis-Hillman acetates in the presence of NaOH (0.6 N) in THF gives 2-alkylidene-4-nitro ketones with high stereoselectivity these are converted via the Nef reaction into the corresponding 1,4-diketones (Eq. 4.119).164... 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

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 KMn04 rapidly converts primary nitroalkanes into carboxylic acids in 90-99% yield (Eq. 6.13).23... 

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, cw-jasmone is readily obtained,28 as shown in Eq. 6.18. 

The conversion of nitroalkanes to ketoximes can be achieved by the reduction with Zn in acetic acid,112 or Fe in acetic acid.113 Nitroalkenes are direcdy reduced into saturated ketoximes by these reagents, which are precursors for ketones (see Section 6.1.4 Nef reaction). Reduction of 3-O-ace-ty lated sugar 1 -nitro-1 -alkenes with Zn in acetic acid gives the corresponding 2,3-unsaturated sugar oximes in high yield, which is a versatile route to 2,3-unsaturated sugar derivatives (Eq. 6.58).114... 

Kaplan and Shechter found that certain oxidants react with the nitronate salts of secondary nitroalkanes to yield vic-dinitroalkanes (111) in a reaction referred to as oxidative dimerization. These reactions are believed to involve transfer of an electron from the secondary alkyl nitronate to the oxidant with the production of a nitroalkyl radical. The radical can then dimerize to the corresponding vtc-dinitroalkane (111) (Equation 1.2) or lose nitric oxide to form a ketone via the Nef reaction (Equation 1.3). Unfortunately, formation of the ketone is a major side-reaction during oxidative dimerization and is often the major product. 

Studies into oxidative dimerization have shown that only the persulfate anion is of synthetic value in these reactions. Reaction pH is also crucial with reactions proceeding fastest when a pH of 7.2-9.4 is maintained. " The reaction medium becomes more acidic as the oxidation progresses and needs either buffering or the slow addition of alkali throughout the reaction. If the reaction medium is allowed to become acidic then the starting nitroalkane is regenerated and the Nef reaction predominates. 

The chemistry of nitro compounds forms the basis of a number of well-known processes, such as the Henry or the Nef reactions . Transformations such as the latter permit the interconversion between nitro and other functional groups and are therefore of prime importance. The most commonly employed methods for the reduction of primary nitroalkanes to oximes involve the use of BusSnH, Se/NaBH4, CS2 or SnCla (often in combination with thiophenol) . 

Nitroolefins are excellent Michael acceptors which react with a broad range of nucleophiles in a Michael fashion. The resulting functionalized nitroalkanes can be readily converted into amines by reduction reactions or to carbonyl compounds by a Nef reaction . The addition of nucleophiles to nitroolefins is complicated by the subsequent addition of the resulting nitronate to remaining nitroolefin. Whereas such a side-reaction is quite fast for lithium and magnesium nitronates. it is slow for zinc... 

The hydrolysis of the conjugate base of a primary nitroalkane to an aldehyde under acidic conditions is known as the Nef reaction (cf. Section 5.8.7, p. 623). 

This method offers therefore a means of preparation of primary and secondary nitroalkanes which then provides a facile route to primary amines (by reduction, Section 5.16.2, p. 774), aldehydes and ketones (the Nef reaction, Sections 5.7.7, p. 599, and 5.8.7, p. 623), and to the rapidly developing strategy of carbon-carbon bond construction by way of the mesomerically stabilised anions (Section 5.15.3, p. 768). 

The nitro group is converted to versatile functionalities. A carbon-carbon double bond can be produced from nitroalkane by elimination of a nitro group with vicinal hydrogen as nitrous acid. The Nef reaction is also often used for transformation from nitroalkanes to ketones. The most useful chemical modification of a nitro group is the reduction furnishing oximes and amines, and further chemical conversion to various functionalities can be performed via diazonium salts. 

Addition reaction of zinc-copper reagents to nitro olefins is a versatile method for preparing polyfunctional nitroalkanes.20 A direct ozonolysis of the intermediate zinc nitronate furnishes the corresponding ketone (Nef-reaction).20... 

Transformations of the nitro function in 142 to a carbonyl group employing variants of the Nef reaction or its reduction to a cyclic nitrone 143, which is capable to undergo 1,3-dipolar cycloadditions, underscore the high synthetic potential of these nitroalkane adducts (Eq. 62)84). 

Self-catalysed Michael Addition reactions of selected nitroalkanes (427) with dicyclohexylammonium 2-(diethoxyphosphoryl)acrylate (428) afforded 4-nit-roalkanoates (429) (Scheme 101). It was also demonstrated that the Nef reaction on the resulting primary and secondary 4-nitroalkanoates involved intramolecular catalysis by the carboxylic acid group. ... 

The a-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3NO2, 10.2 CH3CH2NO2, 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (the Henry-Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine-HMPA complex of molybdenum (VI) peroxide. Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. 

In this chapter the Nef reaction refers to the reaction of nitroalkanes. As nitro compounds are readily available and can be involved in a variety of reactions, the Nef reaction often represents the key transformation in a reaction sequence. A review of this topic appeared in 1990 and an article has been published on the chemistry of nitroaliphatic compounds, including the Nef reaction. ... 

The original procedure for the Nef reaction involved the aqueous sulfuric acid hydrolysis of the salts (170) obtained by the treatment of primary and secondary nitroalkanes with sodium hydroxide (equation 30). In contrast, if a neutral primary nitro derivative is treated in hot concentrated mineral acid, the corresponding carboxylic acid (172) is formed via the hydroxamic acid (171 equation 31). This reaction is known as the Meyer reaction and was first described in 1873. Protonation of salts of nitroalkanes occurs preferentially at the oxygen atom to give the aci form (173 equation 32). 

A kinetic study of the effect of water on the hydrolysis of (173) established the existence of two reaction pathways leading to the carbonyl derivatives, depending on water concentration. The unsatisfactory results observed in many instances led to modifications of the hydrolysis conditions. The supposed limitation of the Nef reaction due to steric hindrance is probably a result of the low solubility of nitroalkanes in aqueous alkali, as demonstrated by the success of the reaction if THF-H20," alcoholic sodium hydroxide" or alkoxide" is used. Silica gel" ° as a reaction medium is of great advantage when the use of organic solvents is undesirable. A two-layer method represents an improvement for the conversion of aromatic nitroalkanes. ... 

Reaction of nitroalkanes with Michael acceptors, followed by the Nef reaction, represents a versatile synthetic route for the preparation of 4-oxoalkanals, 1,4-diketonesand 4-oxo esters. 

The synthesis of the bisbenzannelated spiroketal core of the y-rubromycins was achieved by the research team of C.B. de Koning." The key step was the Nef reaction of a nitroolefin, which was prepared by the Henry reaction between an aromatic aldehyde and a nitroalkane. The nitroolefin was a mixture of two stereoisomers, and it was subjected to catalytic hydrogenation in the presence of hydrochloric acid. The hydrogenation accomplished two different tasks it first converted the nitroalkene to the corresponding oxime and removed the benzyl protecting groups. The oxime intermediate was hydrolyzed to a ketone that underwent spontaneous spirocyclization to afford the desired spiroketal product. 

In order to treat influenza infections, the development of neuraminidase inhibitors is required. The currently available compounds are not potent enough, and they have a number of side effects. The stereoselective total synthesis of one potent inhibitor, BXC-1812 (RWJ-270201), was achieved by M.J. Muller and co-workers. The key intermediate substituted nitromethane was prepared via a Pd-catalyzed allylation of nitromethane under basic conditions. The transformation of this nitroalkane to the corresponding carboxylic acid methyl ester was carried out in two steps. The Nef reaction was conducted in DMF instead of the usual DMSO because DMSO as the solvent caused extensive epimerization of the product. The initially formed carboxylic acid was then esterified. 

Ballini, R., Bosica, G., Fiorini, D., Petrini, M. Unprecedented, selective Nef reaction of secondary nitroalkanes promoted by DBU under basic homogeneous conditions. Tetrahedron Lett. 2002,43, 5233-5235. 

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