C-Nitroalcohols

The above method of producing a carbohydrate C-nitroalcohol is now of only minor interest since subsequent experiments have shown that substituted aldoses with a free reducing group as well as the unsubsti-tuted aldose sugars will undergo the aldehyde-nitroparaffin condensation reaction.29 

4-Bemylidene-D-Erythrose.—The condensation of this benzylidene sugar with nitromethane80 constitutes the most satisfactory example of the reaction to date both with regard to yield of products and to the absence of marked epimeric preference in the formation of the two 

Hydrolysis of the benzylidene acetals with dilute sulfuric acid produced the unsubstituted sugar nitroalcohols. The configurations of the latter were proved by converting them via the Nef reaction (see page 307) to the corresponding known aldose sugars. 

The following experimental details, and those appearing subsequently, are included to describe typical examples of the preparation and reactions of the carbohydrate C-nitroalcohols. 

Experimental Details—A solution of 12.8 g. of 4,6-benzylidene-D-gIucose, m. p. 185-186°, in 150 cc. of 95% ethanol was shaken with hydrogen in the presence of 1.5 g. of platinum oxide (Adams catalyst) at room temperature and an initial pressure of 50 pounds per square inch. The reduction was complete in eighteen hours with the absorption of approximately one mole-equivalent of hydrogen. Concentration of the filtered solution yielded 10.5 g. (82%) of 4,6-benzylidenesorbitol, m. p. 131-134°. Recrystallization from ethanol by the addition of ether yielded the pure compound, m. p. 132-133°. 

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A relatively large excess of nitromethane normally is employed in order to favor the formation of the carbohydrate C-nitroalcohols in the equilibrium and to allow for some destruction of nitromethane by the alkali. 

The conversion of a carbohydrate C-nitroalcohol to the corresponding sugar is achieved simply by adding an aqueous solution of the sodium oci-nitroalcohol to a moderately concentrated aqueous sulfuric acid solution at room temperature. A copious evolution of nitrous oxide occurs during the addition and the resulting sugar then can be obtained from the reaction solution in yields of from 60 to 80 percent, depending upon the ease of isolation of the particular aldose produced. 

The decomposition of the sodium C-nitroalcohols with aqueous sulfuric acid to give the corresponding higher-carbon aldose sugars proceeds smoothly, and the resulting sugars are either crystallized directly or isolated as a convenient derivative. 

The mixed, epimeric C-nitroalcohols, obtained in nearly equal amounts in a combined yield of approximately 60%, are readily separated by fractional crystallization. Decomposition of the individual sodium C-nitroalcohols with aqueous sulfuric acid then affords the hexoses in good yield. The L-glucose may be crystallized directly, and the L-mannose is isolated conveniently via the phenylhydra-zone. 

A double condensation of nitromethane with a pentose dialdehyde has been applied to effect ring closure, yielding a mixture of C-nitrodeoxyinosi-tols. The sodium salts of these cyclic C-nitroalcohols, in contrast to the straight-chain analogs, were found to be stable to aqueous sulfuric acid when attempts were made to convert them to the corresponding ketoses (inososes) (153),... 

Another general method for the 2-deoxyaldoses utilizes the C-nitroalco-hols (p. 109). When the acetylated C-nitroalcohols are refluxed in benzene or ether solution with sodium bicarbonate, the a-acetoxy group is eliminated (234) to produce an acetylated C-nitroolefin. Selective reduction of the double bond, deacetylation, and decomposition of the oci-nitro salt with aqueous sulfuric acid then gives the 2-deoxysugar 148y 235). 

Method A ct,ct-Donbly deprotonated nitroalkanes react with aldehydes to give intermediate nitronate alkoxides, which afford iyti-nitroalcohols as major products d8 7-47 3 by kmedc protonadon at -100 C in THF-HMPA. The carcinogenic hexamethylphosphorons triamide fHMPAi can be replaced by the ntea derivadve (T)MPU. ... 

Figure 6.13 displays H-NMR analysis of the resulting (3-nitroalcohol DCL. Aher mixing benzaldehydes (24, 26, 27, 36, and 37) with 2-nitropropane (38), equilibration was initiated by the addition of triethyl-amine. To allow faster equilibration, the exchange took place at 40°C, and all adducts were clearly present at equilibrium that was established afier 18 hours. Equilibration also worked well at ambient temperature, albeit showing slower rates. Temperatures above 40°C, however, had a negative influence on the enantioselectivity of the subsequent enzymatic reaction and also caused slow decomposition of the (3-nitroalcohol substrates. 

Lipase-catalyzed transesterification of (3-nitroalcohol substrates had not previously been reported and required careful optimization of the reaction conditions. A series of enzymes were screened, followed by acyl donors. From these results, the lipase Pseudomonas cepacia (PS-C I) (for more... 

Alkenes can react with nitric acid, either neat or in a chlorinated solvent, to give a mixture of compounds, including v/c-dinitroalkane, jS-nitro-nitrate ester, v/c-dinitrate ester, /3-nitroalcohol, and nitroalkeneproducts. Cyclohexene reacts with 70 % nitric acid to yield a mixture of 1,2-dinitrocyclohexane and 2-nitrocyclohexanol nitrate. Frankel and Klager investigated the reactions of several alkenes with 70 % nitric acid, but only in the case of 2-nitro-2-butene (1) was a product identified, namely, 2,2,3-trinitrobutane (2). 

Interestingly, two of the other species in Table 3 are nitrolates, i.e. ethers of a-nitrooximes, an otherwise thermochemically unprecedented class of compounds. We already have briefly discussed one, 3-nitroisoxazoline, and the second is 1-nitroacetaldehyde 0-(l,l-dinitroethyl)oxime (ONo-ld-dinitroethyl acetonitronate), MeC (NOala—O—N=C(N02)Me. The latter acyclic species is a derivative of 1,1-dinitroethanol—we know of the enthalpy of formation of no other a-nitroalcohol or derivative. Nonetheless, we may ask if the two calorimetric data are internally consistent. Consider the condensed phase reaction 47, which involves formal cleavage of the O — bond in the nitroisoxazoline by the C—H bond of the dinitromethane. It is assumed that the isoxazoline has the same strain energy as the archetypal 5-atom ring species cyclopentane and cyclopentene, ca 30 kJ mol . ... 

C), various (hetero)aromatic aldehydes were transformed into nitroalcohols 1-6 in consistently high yields (90-99%) and ee values (86-92%) as shown in Scheme 6.146. The protocol failed for aliphatic aldehydes such as cyclohexanecar-boxaldehyde and isobutyraldehyde that displayed incomplete conversion to the respective nitroalcohols even after 1 week reaction time and gave low ee values (<20%) of the adducts. Catalyst 132, the pseudoenantiomer of 131, gave access to nitroalcohols with the opposite configuration and comparable enantiomeric excess, as exemplified for three aldehydes (e.g., (R)-adduct 3 87% yield 93% ee). 

In order to increase the exchange rate, ten equivalents of triethylamine were added, and the dynamic system was generated at 40 °C. Figure 5 shows 1H-NMR spectra of the dynamic nitroaldol system at different reaction times. In the absence of any catalyst, none of the nitroalcohol adducts was observed, but addition of triethylamine resulted in efficient equilibrium formation (Fig. 5a). The aldehyde protons of compounds 18A-E were easily followed (10.0-10.5 ppm), as well as the a-protons of 2-nitropropane 19 and adducts 20A-E (4.5-6.5 ppm). The selected dynamic nitroaldol reaction proved to be stable without producing any side reactions within several days. 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

The nitroalcohol (5 g, 14.9 mmol) is dissolved in methanol (50 mL). The reaction mixture is cooled to -10 °C, and palladium on carbon (10%, purissimum, Fluka, 2.5 g) and dry ammonium formate (9.43 g, 150 mmol) are added while maintaining the reaction temperature at -10 °C. After stirring the reaction for 2 h, the catalyst is filtered off. The solvent is removed and EtOAc and saturated aqueous NaHCOs solution are added (pH a 7). The phases are separated and after two additional washings with EtOAc, the combined organic phases are washed with brine, dried over magnesium sulfate, and the solvent is removed in vacuo. The amino alcohol is obtained as a colorless yellow oil in a crude yield of 4.55 g (100%). 

The Henry reaction or the nitroaldol is a classical reaction where the a-anion of an alkyinitro compound reacts with an aldehyde or ketone to form a p-nitroalcohol adduct. Over the decades, the Henry reaction has been used to synthesize natural products and pharmaceutical intermediates. In addition, asyimnetric catalysis has allowed this venerable reaction to contribute to a plethora of stereoselective aldol condensations. Reviews (a) Ballini, R. Bosica, G. Fiorini, D. Palmieri, A. Front. Nat. Prod. Chem. 2005, 1, 37-41. (b) Ono, N. In The Nitro Group in Organic Synthesis Wiley-VCH Weinheim, 2001 Chapter 3 The Nitro-Aldol (Henry) Reaction, pp. 30-69. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. 

In 1992, Shibasaki et al. reported for the time an application of chiral heterobimetallic lanthanoid complexes (LnLB) as chiral catalysts in asymmetric catalysis, namely the catalytic asymmetric nitroaldol reaction (Henry reaction), which is one of the most classical C-C bond forming processes [11]. Additionally, this work represents the first enantioselective synthesis of (3-nitroalcohol compounds by the way of enantioselective addition of nitroalkanes to aldehydes in the presence of a chiral catalyst. The chiral BINOL based catalyst was prepared starting from anhydrous LaCl3 and an equimolar amount of the dialkali metal salt of BINOL in the presence of a small amount of water [9]. 

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