Nitro alcohols, formation

In additionto the mononitro compounds, monohydric and dihydric dinitro alcohols have been prepared but are not available commercially. The formation, properties, and reactions of nitro alcohols have been reviewed (1,2). 

Nitro alcohols form salts upon mild treatment with alkahes. Acidification causes separation of the nitro group as N2O from the parent compound, and results in the formation of carbonyl alcohols, ie, hydroxy aldehydes, from primary nitro alcohols and ketols from secondary nitro alcohols. 

On dehydration, nitro alcohols yield nitro-olefins. The ester of the nitro alcohol is treated with caustic or is refluxed with a reagent, eg, phthaUc anhydride or phosphoms pentoxide. A mil der method involves the use of methane sulfonyl chloride to transform the hydroxyl into a better leaving group. Yields up to 80% after a reaction time of 15 min at 0°C have been reported (5). In aqueous solution, nitro alcohols decompose at pH 7.0 with the formation of formaldehyde. One mole of formaldehyde is released per mole of monohydric nitro alcohol, and two moles of formaldehyde are released by the nitrodiols. However, 2-hydroxymethyl-2-nitro-l,3-propanediol gives only two moles of formaldehyde instead of the expected three moles. The rate of release of formaldehyde increases with the pH or the temperature or both. 

The nitro alcohols available in commercial quantities are manufactured by the condensation of nitroparaffins with formaldehyde [50-00-0]. These condensations are equiUbrium reactions, and potential exists for the formation of polymeric materials. Therefore, reaction conditions, eg, reaction time, temperature, mole ratio of the reactants, catalyst level, and catalyst removal, must be carefully controlled in order to obtain the desired nitro alcohol in good yield (6). Paraformaldehyde can be used in place of aqueous formaldehyde. A wide variety of basic catalysts, including amines, quaternary ammonium hydroxides, and inorganic hydroxides and carbonates, can be used. After completion of the reaction, the reaction mixture must be made acidic, either by addition of mineral acid or by removal of base by an ion-exchange resin in order to prevent reversal of the reaction during the isolation of the nitro alcohol (see Ion exchange). 

The reduction of fi-nitro alcohols v/ith ammonium formate in the presence of Pd/C also proceeds v/ith retendon of their configuradons fEq. 6.53. ... 

Stereoselective preparation of ( )-allyl alcohols via radical elimination from anti-j-phenylthio-P-nitro alcohols has been reported.154 The requisite anti-P-nitro sulfides are prepared by protonation of nitronates at low temperature (see Chapter 4), and subsequent treatment with Bu3SnH induces anti elimination to give (E)-alkenes selectively (see Eq. 7.112). Unfortunately, it is difficult to get the pure yyw-P-nitro sulfides. Treatment of a mixture of syn- and anti-P-nitrosulfides with Bu3SnH results in formation of a mixture of (E)- and (Z)-alkenes. 

The Henry reaction of nitro sugars and sugar aldehydes is a powerful tool for the formation of C-glycosydic bonds. A recent example is the preparation of disaccharide precursor 60 stated in Scheme 21.45 It involves a Henry reaction of nitro sugar 58 and aldehyde 59 in acetonitrile in the presence of catalytic potassium fluoride, to give nitro alcohol 60, a precursor of the corresponding C-disaccharide. 

Scheme 118 shows enantioselective condensation of alkanals and ni-tromethane promoted by a binaphthol-modified rare earth alkoxide in wet THF. Reaction of the initially formed metal /3-nitro alkoxide and acidic nitromethane, leading to the j8-nitro alcohol product and chiral metal nitronate, makes the C—C bond formation catalytic (284). 

The alkaline solution must be added slowly to the acid, for the reverse procedure always forms an oil containing a saturated nitro alcohol. A large excess of acid at room temperature is used, conditions which facilitate the formation of the desired unsaturated nitro compound. 

Aliphatic nitro compounds are highly versatile building blocks in organic synthesis7 8 (see Scheme 1). For example, the nitroaldol addition (Henry reaction)9 leads to the formation of 1,2-nitro alcohols, 2, which are easily transformed into 1,2-amino alcohols, 3, by reduction, and into a-hydroxycarbonyl compounds, 4, by hydrolysis10 (Nef reaction). The former process, mostly using nitromethane, has been widely employed in carbohydrate chemistry.11... 

This same reducing agent has been successfully employed in the synthesis of 2-amino-l-phenyl-l-propanol (70%). The formation of amino alcohols by catalytic hydrogenation over Raney nickel catalyst has been accomplished. However, because of the instability of the nitro alcohols in basic media, lower amines are also formed. 

The value of the catalytic transfer hydrogenation route is demonstrated by the selective, high yield and rapid reduction of nitro aliphatic compounds to their corresponding amine derivatives using anhydrous ammonium formate (equation 26). A wide variety of nitro compounds are reduced in the presence of other functional groups including acids, esters and nitriles. Furthermore, the method is stereospecific and proceeds with retention of configuration pure racemic syn-nitro alcohols (39a) and (39b) were converted to the 5yn-amino alcohols (40a) and (40b) and the axial nitrosteroid (41a) afforded the 63-amine (41b). 

The utilization of carbanions stabilized by various electron-withdrawing groups to effect carbon-carbon bond formation occupies a central position in organic synthesis. This chapter focuses on the reactions of nitro-stabilized carbanions (nitronate anions or their equivalents) with aldehydes and ketones. This route for the coupling of a carbonyl and a nitroalkane component, leading to vicinal nitro alcohols, was discovered in 1895 by Henry and is currently known as the Henry or nitroaldol reaction. 

Sulfur tetrafluoride was among the first reagents to be used for the direct substitution of hydroxy groups by fluorine. Good yields are only achieved with relatively acidic alcohols, such as nitro alcohols, polyhalo alcohols and hydroxy carbonyl compounds. The fluorination of simple aliphatic alcohols with sulfur tetrafluoride results in side reactions, such as formation of ethers, hence fluorination using other methods (vide infra) is preferred. Moreover, sulfur tetrafluoride cannot be handled without special pressure apparatus and requires precautions to be taken due to its physical and toxicological properties, hence it is, nowadays, frequently replaced by other reagents, but it is still in use for relatively inert substrates (see Vol.ElOa, p 321 ff, also Houben-Weyl. Vol. 5/3. pp 84-86). 

Dinitrogen tetroxide adds to olefinic double bonds with formation of dinitro compounds and nitro nitrites the latter are unstable and are readily oxidized to nitro nitrates or hydrolysed to nitro alcohols in the presence... 

A fascinating variant of the enzymatic cyanohydrin formation consists in the use of nitroalkanes (as nonnatural nucleophiles) instead of cyanide (Scheme 2.209) [1568,1569]. Overall, this constitutes a biocatalytic equivalent to the Henry-reaction producing vicinal nitro-alcohols, which are valuable precursors for amino alcohols. Using (5)-HNL, the asymmetric addition of nitromethane to benzaldehyde gave the nitroalcohol in 92% e.e., while for p-nitrobenzaldehyde the stereoselectivity dropped sharply. With nitroethane, two stereocenters are created Whereas the stereoselectivity for the alcoholic center was high (e.e. 95%), the recognition for the adjacent center bearing the nitro moiety was modest and other (dia)stereomers were formed in up to 8%. 

Carbon-carbon bond formation can also be used to assemble enantiomeiically-pure secondary alcohols. Herfried Griengl of Graz University of Technology has foimd (Adv. Synth. Cat. 2007, 349,1445) that a commercial nitrile lyase effects addition of nitromethane to an aldehyde such as 24 to give the nitro alcohol 25 in high ee. Markus Kalesse of Leibniz Universitat Hannover has constructed a catalyst (Organic Lett. 2007, 9, 5637) for the enantioselective addition of the ketene silyl acetal 27 to aldehydes. Hajime Ito and Masaya Sawamura of Hokkaido University (J. Am. Chem. Soc. 2007,129, 14856) (depicted), and Dennis G. Hall of the University of Alberta (Angew. Chem. Int. Ed. 2007, 46, 5913) have reported complementary enantioselective preparations of allyl boronates such as 31. 

In the mid-2000s, Griengl and coworkers reasoned that a small molecule with a similar pK as HCN, for example, nitromethane, could act as nucleophile for addition to carbonyl compounds (nitroaldol or Henry reaction Scheme 25.3) [111]. The Henry reaction is a classical name reaction in organic chemistry for the formation of C—C bonds. The resulting p-nitro alcohols can be transformed to nitroalkenes, 2-nitroketones, a-hydroxycarboxylic acids, and 1,2-amino alcohols. Although several other enzymes and proteins such as hydrolases and lipases [112], transglutaminase... 

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