Nef-reaction

The mechanism of the Nef reaction has been extensively studied. Under the original reaction conditions, the nitronate salt is first protonated to give the nitronic acid, which after further protonation is attacked by a molecule of water. The process is strongly dependent on the pH of the reaction medium. Weakly acidic conditions favor the regeneration of the nitro compound and by-product formation (oximes and hydroxynitroso compounds), whereas strongly acidic medium (pH 1) promotes the formation of the carbonyl compound. The most popular reductive method (TiCb) proceeds via a nitroso compound that tautomerizes to form an oxime and finally upon work-up the desired product is obtained. 

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. 

The total synthesis of spirotryprostatin B was accomplished by K. Fuji et al using an asymmetric nitroolefination to establish the quaternary stereocenter. The conversion of the nitroolefin to the corresponding aldehyde was carried out under reductive conditions using excess titanium(lll) chloride in aqueous solution. The initially formed aldehyde oxime was hydrolyzed in situ by the excess ammonium acetate. 

In the laboratory of B.M. Trost, the second generation asymmetric synthesis of the potent glycosidase inhibitor (-)-cyclophellitol was completed using a Tsuji-Trost allylation as the key step. The synthetic plan called for the conversion of the a-nitrosulfone allylation product to the corresponding carboxylic acid or ester. Numerous oxidative Nef reaction conditions were tested, but most of them caused extensive decomposition of the starting material or no reaction at all. Luckily, the nitrosulfone could be efficiently oxidized with dimethyidioxirane under basic conditions (TMG) to afford the desired carboxylic acid in high yield. 

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. 

The conversion of a primary or secondary nitro alkane 1 to a carbonyl compound 3 via an intermediate nitronate 2 is called the Nef reaction. Since carbonyl compounds are of great importance in organic synthesis, and nitro alkanes can on the other hand be easily prepared, the Nef reaction is an important tool in organic chemistry. 

Various side-reactions may complicate the course of the Nef reaction. Because of the delocalized negative charge, the nitronate anion 2 can react at various positions with an electrophile addition of a proton at the a-carbon reconstitutes the starting nitro alkane. 1. The nitrite anion can act as leaving group, thus leading to elimination products. 

The required nitro compounds are easy to prepare, and are useful building blocks for synthesis. Treatment with an appropriate base—e.g. aqueous alkali—leads to formation of nitronates 2. Various substituted nitro compounds, such as nitro-ketones, -alcohols, -esters and -nitriles are suitable starting materials. 

The Nef reaction has for example been applied for the 1,2-transposition of carbonyl groups  

Another important feature of the Nef reaction is the possible use of a CH-NO2 function as an umpoled carbonyl function. A proton at a carbon a to a nitro group is acidic, and can be abstracted by base. The resulting anionic species has a nucleophilic carbon, and can react at that position with electrophiles. In contrast the carbon center of a carbonyl group is electrophilic, and thus reactive towards nucleophiles. 1,4-Diketones 4 can for example be prepared from a-acidic nitro compounds by a Michael additionfNef reaction sequence  

Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 176, Springer-Verlag Berlin Heidelberg 2009 

263-342. John Ulrich Nef (1862—1915) was bom in Switzerland and emigrated to the US at the age of four with his parents. He went to Munich, Germany to study with Adolf von Baeyer, earning a Ph.D. In 1886. Back to the States, he served as a professor at Purdue University, Clark University, and the University of Chicago. The Nef reaction was discovered at Clark University in Worcester, Massachusetts. Nef was temperamental and impulsive, suffering from a couple of mental breakdowns. He was also highly individualistic, and had never published with a coworker save for three early articles. 

Makosza, M. Saha-Moeller, C. R. Zhao, C.-G. Synlett 1998, 1335-1336. Thominiaux, C. Rousse, S. Desmaele, D. d Angelo, J. Riche, C. Tetrahedron  

Nef reaction. In Name Reactions for Functional Group Transformations, Li, J. J., Corey, E. J., Eds John Wiley Sons Hoboken, NJ, 2007, pp 645-652. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 189, Springer International Publishing Switzerland 2014 

Makosza, M. Saha-Moeller, C. R. Zhao, C.-G. Syniettl99H, 1335. 

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In this preparation, phenyi-2-nitropropene is reduced to phenyl-2-nitropropane with sodium borohydride in methanol, followed by hydrolysis of the nitro group with hydrogen peroxide and potassium carbonate, a variety of the Nef reaction. The preparation is a one-pot synthesis, without isolation of the intermediate. 

Alkaline solutions of mononitroparaffins undergo many different reactions when stored for long periods, acidified, or heated. Acidification of solutions of mononitro salts is best effected slowly at 0°C or lower with weak acids or buffered acidic mixtures, such as acetic acid—urea, carbon dioxide, or hydroxyl ammonium chloride. If mineral acids are used under mild conditions, eg, dilute HCl at 0°C, decomposition yields a carbonyl compound and nitrous oxide (Nef reaction). 

The sequence (81 84) has been proposed - to account for this process which involves decomposition of the aci-nitro anion by strong acid. The a-carbonyl group presumably stabilizes the aci-salt and thus could be responsible for inhibiting the normal Nef reaction. A similar transformation has been observed in the case of a 16-nitro-17-0X0 steroid. 

Breslow and co-workers discovered the thermal ring expansion of the nitrobutenone (86) to the fV-hydroxymaleimide (88) which may be mechanistically similar to the abnormal Nef reaction of a-nitro-camphor. Breslow postulated the fV-hydroxyoxaziran intermediate Ph... 

This reaction is of wide scope it is limited only by the availability of the appropriate 1,4-diketone. 1,4-Diketones are easily accessible, e.g. by the Nef reaction. 

Conjugate Addition of Heteroatom Nucleophiles and Subsequent Nef Reaction... 

Valendn and coworkers have studied extensively the reaction of enamines v/ith nltroalkenes. The reaction proceeds under rruld conditions to give y-nitroketones, which are converted into 1,4-diketones by the Nef reaction CEq. 4.65. ... 

The addition of 2-nitropropene to the chiral imlne derived from 2-methylcyclopentanone and fS -Tphenylethylamine gives the adduct in high regio- and stereoselectivity fEq 471 The product is converted to a chiral 1,4-diketone via the Nef reaction... 

Ballini and coworkers have used the Michael ddition of tutro compounds followed by the Nef reaction for the synthesis of vanons spiroketahc pheromones fScheme 4 21 ... 

Sodium chlorite under phase-transfer catalysis conditions ( CH,Cl,-Na0H-BmNHS04i is also a good choice for the Nef reaction of primary and secondary nitro compounds fEq. 6.10. ... 

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. "Typical examples are presented in Eq. 6.22 and Eq. 6.23 the product of Eq. 6.23 is used for total synthesis of perylenequinone, calphosdn D, which is a potent inhibitor of protein kmase C. "... 

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. ... 

The ethyl ester can also be prepared from ethyl acetoacetate (ethyl 3-oxobutanoate) by the method of Rodionov8 as well as via Steinkopf s method.3 Ethyl nitroacetate can be prepared in >70% yields from the dipotassium salt, ethanol, and sulfuric acid, with the addition of anhydrous magnesium sulfate in order to avoid the Nef reaction.9 The propyl and 2-propyl esters can also be obtained by this method. 

Primary or secondary aliphatic nitro compounds can be hydrolyzed, respectively, to aldehydes or ketones, by treatment of their conjugate bases with sulfuric acid. This is called the Nef reaction Tertiary aliphatic nitro compounds do not give the reaction because they cannot be converted to their conjugate bases. Like 16-2, this reaction involves hydrolysis of a C=N double bond. A possible mechanism is" ... 

When primary nitro compounds are treated with sulfuric acid without previous conversion to the conjugate bases, they give carboxylic acids. Hydroxamic acids are intermediates and can be isolated, so that this is also a method for preparing them. Both the Nef reaction and the hydroxamic acid process involve the aci form the difference in products arises from higher acidity, for example, a difference in sulfuric acid concentration from 2 to 15.5 M changes the product from the aldehyde to the hydroxamic acid. The mechanism of the hydroxamic acid reaction is not known with certainty, but if higher acidity is required, it may be that the protonated aci form of the nitro compound is further protonated. 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

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