Ethyl nitroacetate, acidity

Substitutedisoxazole-3,5-dicarboxylic acids have been prepared from ethyl nitroacetate and an aldehyde (63BCJii50). A related reaction leads to diethyl 4-hydroxyisoxazole-3,5-dicarboxylate (334) and involves the reaction of acetonedicarboxylic acid ester (333) with nitrosyl chloride (78JHC1519). 

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. 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

Primary nitro ketones, ethyl nitroacetate, and (phenylsulfony l)nitromethane react with alkenes in the presence of Lewis acids to give nitrile oxide cycloaddition.61a Similarly, the reaction of a-nitro ketones with TeCl4 generates the corresponding nitrile oxides, as shown in Eq. 6.36.61b... 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

The main starting compound is the labeled nitroguanidine 257 obtained from guanidine with isotope-labeled potassium nitrate. Reduction of 257 to hydrazine carboximidamide 258 was carried out with zinc and, then, ring closure to 3-amino[l,2,4]triazole 259 was carried out using formic acid. Finally, the ring closure to form the [l,2,4]triazine ring - similar to other procedures presented in Scheme 54 - was perfected by reaction with nitrous acid followed by treatment with ethyl nitroacetate to 260. 

However, this multistep procedure is experimentally complex. A simpler variation described in 199127 consists of the reaction of an aldehyde and a nitro compound in the presence of triethylamine, TBAF and tert-butyl-dimethylsilyl chloride. Under these conditions, nitro sugars are obtained in good yieds and higher diastereoselectivities than those afforded by the standard conditions. This procedure was used in several synthesis of 2-nitro-2-deoxyaldoses, as for the condensation of l,l-diethoxy-2-nitroethane and l,2 3,4-di-0-isopropylidene-a-D-galacto-hexodialdo-l,5-piranose.28 More recently, it was applied to the addition of ethyl nitroacetate to the D-glucose derived aldehyde 18, to give nitro sugar derivatives 26, key precursors of polysubstituted cyclohexane a-amino acids (Scheme 10).29... 

Commercially available ethyl nitroacetate is an interesting pronucleophile, because it can serve as the synthetic equivalent of either nitromethane or glycine. The ethoxycarbonyl group can also be considered as a protecting group against dialkylation. The allylic alkylation with ethyl nitroacetate did not require an additional base (salt-free conditions). As a consequence of the high acidity of the chirality center a to N, 1 1 mixtures of epimers were formed. 

Similarly, o-phthalaldehyde is cyclized by ethyl nitroacetate to give 2-nitro-2-ethoxycarbonyl-indane-l,3-diol (86) in 71% yield, which can be hydrogenated to the corresponding amino acid (87)... 

Nitroethanol,299 1-nitropropane,295 and ethyl nitroacetate cyclize normally with dialdehydes for example, 163b gives a mixture of 3-nitro-carboxylic acids, with 166c as one of the principal products.300-302 Surprisingly, when treated with ethyl nitroacetate under the same condi-... 

The -nitroketone 151, prepared by Michael addition of ethyl nitroacetate to the appropriate enone, reacts with formamidinesulfinic acid and triethylamine to afford pyrrole-2-carboxylate 153, presumably via the oxime or imine 152 (Scheme 80) <1995TL9469>. 

Although a nitro group has a large effect on thermodynamic acidity, rates of proton transfer are not increased by similar amounts. For nitroethane (pA- 8.60 [99]), water catalysed ionization occurs with a rate coefficient [37] of 3.7 x 10"8 sec-1 compared with the value of 1.32 x 10 2 sec-1 for acetylacetone [89] (pif 8.9 [17]) and the value (ca. 102 sec"1) which would be observed for a normal acid [59] with pK 8.5. Since nitroparaffins ionize slowly the reaction may be followed using classical methods and rates of proton transfer to a wide variety of bases have been measured nitroparaffins [100] and ketones were among the first carbon acids to be studied. Corrections may be required for the presence of the aci-isomer. Figure 4 shows results for the rates of base catalysed ionization of ethyl nitroacetate [101] obtained by spectro-photometric measurement of the increase in concentration of the anion (74) or by measuring the rate of bromination, (74) and (75), viz. 

Fig. 4. Bronsted plot of the dependence of the rate of proton transfer (log10 feg) from ethyl nitroacetate to bases (B) upon ApA, the difference in pA between the carbon acid and the base. Both feg and ApA are statistically corrected and negative ApA corresponds to thermodynamically favourable proton transfer from the carbon acid. The bases studied are water 1 carboxylate ions 2—7 pyridines 8—11 phenoxide ions 12, 13. Redrawn with permission from D. J. Barnes and R. P. Bell, Proc. R. Soc. A, 318 (1970) 421.

Ethyl nitroacetate is a relatively strong acid (pKa(H20) = 5.75, pK (DMSO) = 9.2) it may be deprotonated by 07 formed on reduction of dioxygen in air-saturated MeCN. The anion is useful in several kinds of synthesis. Direct reduction of ethyl nitroacetate produces some anion, but also some cleavage with formation of nitrile [19]. 

Reactions of carbonyl compounds with nitroalkanes like nitromethane (Henry reaction) are described in Volume 2, Chapter 1.10. The doubly activated ethyl nitroacetate readily reacts with aliphatic, aromatic and heteroaromatic aldehydes to give a,p-unsaturated-a-nitrocarboxylic acid esters in the presence of TiCU/V-methylmorpholine as mixtures of cis and trans isomers. ... 

Organic Syntheses contains detailed directions656 for preparation of ethyl 2-nitrobutyrate (75 % yield), which can be applied also to other haloalkanoic esters. Ethyl nitroacetate cannot be prepared in this way,657 but is obtained in 77 % yield by the action of silver nitrite on ethyl iodoacetate during several days at room temperature 658 oxidation of ethyl sulfuric acid can also be recommended.659... 

This approach has also been applied to the use of malonates as C-H acidic carbon pro-nucleophiles, observing that the reaction performed excellently with a wide range of different chalcones and (3-aryl substituted 2-butenones (Scheme 4.28). Moreover, other 1,3-dicarbonyl compounds and related derivatives such as malononitriles, (3-ketoesters, 2,4-pentanedione and ethyl nitroacetate have also been tested with success in the reaction using chalcone as Michael acceptor. In an independent work, the use of cyanoacetates was also surveyed with good results, although in this case mixtures of diastereoisomers were typically obtained. In all these cases, the stereochemical outcome of the reaction was consistent with the model proposed by Soos. 

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