Nitroalkanes synthesis, nitromethane

Until recently there were few cases in which an alkali nitrite could replace silver nitrite in the synthesis of nitro compounds. Such a case was Kolbe s nitroalkane synthesis, in which an alkali salt of a 2-haloalkanoic acid was treated with a boiling aqueous solution of an alkali nitrite the 2-nitroalkanoic acid formed lost carbon dioxide under the reaction conditions and the nitroalkane distilled over in the steam. The Kolbe synthesis is, however, of practical use only for the preparation of nitromethane (38% yield from chloro-acetic acid648) and nitroethane (about 50% yield from 2-bromopropionic acid649) it is substantially valueless for higher fatty acids.649,650... 

The nitriles can also be directly reduced to di-astereomeric aldoses with PdO/BaSOa, by passing the lactone intermediate stage. Another reaction for the formation of monosaccharides is the nitroalkane synthesis. The epimeric nitro compounds, obtained by the reaction of an aldose with nitromethane as anions, are separated and converted to the corresponding aldoses by an acini-troalkane cleavage (A /-reaction) ... 

There exist a number of d -synthons, which are stabilized by the delocalization of the electron pair into orbitals of hetero atoms, although the nucleophilic centre remains at the carbon atom. From nitroalkanes anions may be formed in aqueous solutions (e.g. CHjNOj pK, = 10.2). Nitromethane and -ethane anions are particularly useful in synthesis. The cyanide anion is also a classical d -synthon (HCN pK = 9.1). 

Although the base-catalyzed addition of nitroalkanes to electron-deficient olefins has been extensively used in organic synthesis fsee Michael addition Chapter 4, it is only recently that the reaction has been extended to the cyclopropanadon reaction. In 1978, it was reported that the anion of nitromethane reacts with certain highly electron-deficient olefins to produce cycloptopanesingoodyieldrEq. 7.36. More recently, this reaction has been extended to more general cyclopropanadons, as shown in Eqs. 7.37 and 7.38, in which potassittm salts of nitroalkanes are employed in DMSO as alkylidene transfer reagents." ... 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Henry reactions have been extensively exploited for the synthesis of nitrate ester explosives. The condensation of nitroalkanes with aldehydes, followed by esterification of the hydroxy groups with nitric acid, leads to a number of nitrate ester explosives (see Chapter 3). The two examples given above (166 and 167) are synthesized from the C-nitration of the polyols obtained from the condensation of formaldehyde with nitromethane and nitroethane respectively. 

The asymmetric catalytic nitroaldol reaction, also known as the asymmetric Henry reaction, is another example of an aldol-related synthesis of high general interest. In this reaction nitromethane (or a related nitroalkane) reacts in the presence of a chiral catalyst with an aldehyde, forming optically active / -nitro alcohols [122], The / -nitro alcohols are valuable intermediates in the synthesis of a broad variety of chiral building blocks, e.g. / -amino alcohols. A highly efficient asymmetric catalytic nitroaldol reaction has been developed by the Shibasaki group, who used multifunctional lanthanoid-based complexes as chiral catalysts [122-125],... 

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. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

The course of the reaction between acylphosphonates and 1-nitroalkane carbanions depends on the nature of the acyl group. Thus, nucleophilic addition of nitromethane to acetylphosphonates in the presence of di- or triethylamine results in the formation of dialkyl 1-hydroxy-l-methyl-2-nitro-ethylphosphonates (R = Me, = H, Scheme 7.75)." " However, the procedure is not applicable to the synthesis of dialkyl 1 -hydroxy-l-pheny 1-2-nitrocthyIphosphonate because the electron-with-drawing ability of the benzene ring destabilizes the molecule toward alkali and results in C-P or C-C bond cleavage. The fact that diisopropyl 1-hydroxy-l-phenyl-2-nitroethylphosphonate was... 

The addition of a nitroalkane to an alkenylphosphonic diester is exemplified by the interaction of nitromethane with diethyl ethenylphosphonate in the presence of NaOEt, when the product is diethyl (3-nitropropyl)phosphonate and by a similar addition to 1,1-bis(diethoxyphosphinoyl)ethane . In the initial stages of a synthesis of (4,5,6-trihydroxy-3-oxohexyl)phosphonic acid, the nitro sugar 76 was made to add to dibenzyl ethenylphosphonate, but the resultant (3-nitropropyl)phosphonic dibenzyl ester 77 was then used without isolation. ... 

Phenylsulphonyl)nitromethane is C-alkylated preferentially by benzyl halides, primary alkyl iodides, and allylic acetates, the latter in the presence of catalytic tetrakis(triphenylphosphine)palladium, providing secondary a-nitrosul-phones (cf. Vol. 5, p. 197). The synthetic utility of this process, other than for the preparation of a-nitrosulphones themselves, has been enhanced by the development of efficient desulphonation processes, " thus providing an overall synthesis of nitroalkanes. Nitroalkanes are also the products of the replacement of tertiary nitro groups by nitromethyl via sodio nitromethane. ... 

Another key reaction for the addition of carbon nucleophiles to enals was reported by Wei Wang [34] and Hayashi in 2007 [35]. Hayashi developed the addition of nitromethane to enals catalyzed by 27. The reaction renders the final y-nitro-aldehydes in excellent yields and enantioselectivities with aromatic and aliphatic enals. At almost the same time Ye and coworkers reported the same reaction with slightly different reaction conditions (Scheme 33.11) [36]. The only limitation of the cited methodologies was the poor diastereoselectivities obtained when nitroalkanes other than nitromethane were reacted. Remarkably, these methodologies allow the synthesis of baclofen (a potent GABAP receptor agonist) or pregabalin in enantiopure form in a few chemical steps. 

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