Nitro alcohols, synthesis

The nitro alcohols are useful as intermediates for chemical synthesis. In particular, they are used to introduce a nitro functionaHty and, by reduction of the resultant intermediate, an amino functionaHty. 

Nitromethane. The nitroparaffins are used widely as raw materials for synthesis. Nitromethane is used to produce the nitro alcohol (qv) 2-(hydroxymethyl)-2-nitro-l,3-propanediol, which is a registered biocide useful for control of bacteria in a number of industrial processes. This nitro alcohol also serves as the raw material for the production of the alkanolamine (qv) 2-amino-2-(hydroxymethyl)-l,3-propanediol, which is an important buffering agent useful in a number of pharmaceutical appHcations. 

The nitro-dldolredcdon between nitrodlkdnes and carbonyl compounds to yieldfi-nitro alcohols was discovered in 1895 by Henry. Since dien, diis reaction has been used extensively in many important syndieses. In view of its significance, diere are several reviews on die Henry reaction." These reviews cover syndiesis of fi-nitro alcohols and dieir applications in organic synthesis. The most comprehensive review is Ref 3, which summarizes the literature before 1970. More recent reviews are Refs. 4 and 5, which summarize literatures on the Henry reaction published until 1990. 

Regioselecdve reducdon of 2-nitrocycloalkanones withsndiiun borohydnde affords Oj-nitro alcohols. This reacdon is applied to the synthesis of spiroketals as shovm in Eq. 5.17, in which spiro[4,5 - and spiro[4,6 ketal systems are obtained in good yields. "... 

Baker s yeast reducdon of y-nitroketones offers the corresponding chiral nitro alcohols, which areusefid bndding blocks for the synthesis of chiral naniral compounds. For example, opdcally acdve 2-subsdnited pyrrolidine can be prepared using the chiral nitro alcohol fEq. 10.751. ... 

Because the a-nitroketones are prepared by the acylation of nitroalkanes (see Section 5.2), by the oxidation of (3-nitro alcohols (Section 3.2.3), or by the nitration of enol acetates (Section 2.2.5), denitration of a-nitro ketones provides a useful method for the preparation of ketones (Scheme 7.10). A simple synthesis of cyclopentenone derivatives is shown in Eq. 7.66.76... 

The reduction of nitro ketones with baker s yeast is a good method for the preparation of chiral nitro alcohols.89 The reduction of 5-nitro-2-pentanone with baker s yeast gives the corresponding (5)-alcohol, which is an important chiral building block. Various chiral natural products are prepared from it. In Scheme 7.16, the synthesis of the pheromone of Andrena haemorrhoa is described, where the acylation of the chiral nitro alcohol followed by radical denitration is involved as key steps.89a... 

When discussing the specific features of various leaving groups in the synthesis of nitronates presented in Scheme 3.12, the possibility of the use of the OH group as the leaving group should be separately discussed. As in the synthesis of acyclic nitronates, the Mitsunobu procedure (10) is apparently suitable for intramolecular cyclization of acyclic y-nitro alcohols (Scheme 3.17). 

Unfortunately, only two attempts were made to use this approach in the synthesis of five-membered cyclic nitronates (5), and only one of them could be considered as successful. In the latter case, isomeric nitrocyclopropane was obtained as the major product. Only a-functionalized nitro alcohols are readily involved in the Mitsunobu cyclization. However, the possibility of isomerization of by-products, nitrocyclopropanes, which was mentioned in the discussion of Scheme 3.16, caused the revision of this process as a procedure for the synthesis of five-membered cyclic nitronates. (A new approach to the synthesis of initial y-nitro alcohols from readily available AN was documented in Reference 64)... 

Primary nitro compounds RNO were oxidised to RCOOH (the Nef reaction e.g. nitroethane to acetic acid) [RuO ] from RuCl3/(Br03)7aq. M Na2(C03) activated primary aUcyl halides RCl to RCOOH and secondary alkyl halides were similarly oxidised to ketones [213]. Secondary nitro compounds were converted to ketones by TPAP/NM0/PMS/K3(C03)/CH3CN (c/ 5.6.4, Fig. 5.19) [514]. As part of the total synthesis of the natural product ( )-erythrodiene a nitro-alcohol intermediate was converted to the diketone by TPAP/NMO/PMS/CH Clj [127]. 

A very short and elegant synthesis of the 16-rtiembered dilactone ( )-pyrenophorin (515) has been accomplished by the dipolar cycloaddition reaction of a trialkylsilyl nitronate (81TL735). Nitromethane was added to 3-buten-2-one and the carbonyl group of the product reduced with sodium borohydride. The nitro alcohol (511) was converted to the acrylate (512) which was then subjected to a dimerization-cyclization reaction by treatment with chlorotrimethylsilane and triethylamine in dry benzene. Hydrogenation of the mixture of isoxazoline products (513) over palladium on charcoal followed by double dehydration of the intermediate bis-/3-hydroxyketone (514) led to ( )- and meso-pyrenophorin (Scheme... 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

In this section the synthesis of fluoroalkyl (Section 15.1.4.1.3), a,a-difluoroalkyl (Section 15.1.4.2.3), and trifluoromethyl- and perfluoroalkyl ketones are discussed collectively. The second most widely used method for synthesizing peptide fluoromethyl ketones is the Henry nitro-aldol condensation reaction, which involves the use of (3-nitro alcohols to build the fluoromethyl ketones. As with the modified Dakin-West procedure, the Henry reaction has also been used to synthesize mono-, di-, tri-, and extended fluoromethyl ketones, making it another extremely versatile synthetic method.19 12 19 27 29 33 341 However, similar to the Dakin-West procedure, the products of the Henry reaction are not chiral, since an achiral carbanion is involved in the crucial carbon bond forming step. 

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],... 

Nitro alcohols are nonaromatic compounds containing both -OH and -N02 groups. A typical example of such a compound is 2-nitro-l-butanol, shown below. These compounds are used in chemical synthesis to introduce nitro functional groups or (after reduction) amino groups onto molecules. They tend to have low volatilities and moderate toxicities. The aromatic nitrophenol, / -nitrophenol, is an industrially important compound with toxicological properties resembling those of phenol and nitrobenzene. 

The initially isolated P-nitro alcohol can be catalyticaliy reduced to yield a P-amino alcohol. Thus this synthesis. is an excellent path for preparing the aforementioned compounds. 

A new synthetic approach to D-ribose has recently been made by Sowden.43 In this procedure 4,6-benzylidene-D-glucose (X) was reduced catalytically to 4,6-benzylidene-D-glucitol (XI) which was then oxidized with sodium metaperiodate to 2,4-benzylidene-D-erythrose (XII). Condensation of this latter compound with nitromethane gave a mixture of epimeric, crystalline, substituted C-nitro alcohols, 3,5-benzylidene-1-desoxy-l-nitro-D-arabitol and 3,5-benzylidene-l-desoxy-l-nitro-D-ribitol (XIII). After separation, the appropriate isomer was hydrolyzed to 1-nitro-l-desoxy-D-ribitol (XIV) which, in the form of its sodium salt was decomposed directly to D-ribose (XV), isolated as its benzylphenyl-hydrazone. This synthesis is of interest in that it may be used to obtain D-ribose labeled at carbon 1 with C.14... 

The synthesis of ephedrine shown in Method H is of commercial interest (316). Condensation of benzaldehyde with nitroethane gives a diastereomeric mixture of nitro alcohols. Reduction yields a separable mixture of ( )-norephedrine and ( )-norpseudoephedrine. Methylation of ( )-norephedrine yields ( )-ephe-drine, which can be resolved into optical antipodes by chemical methods. 

The catalytic hydrogenation of nitro alcohol to amino alcohol has been applied to the synthesis of an intermediate leading to sugar alcohols. The condensation of ni-tromethane with pentoses in the presence of sodium methoxide, followed by hydrogenation over platinum oxide and deamination with nitric acid, gave the alditols with one more carbon atom.22 The reaction sequence is as follows pentose — 2-epimeric sodio aci-nitro alcohols —> 2-epimeric hexitylamines —> 2-epimeric hexitols + 2-epi-meric 1,4-anhydrohexitols. The 2-epimeric sodio a -nitro alcohols were hydrogenated to 2-epimeric hexitylamines over platinum oxide in acetic acid. An example is shown in eq. 9.8 with D-ribose. 

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