Nitroacetic reaction with

Dicarbonylimidazole reacted with the anthranilic acid derivative (498) to produce the fused isoxazolone IV-oxide (499) (77ZOR462). Methyl nitroacetate reacted with indole-3-carbaldehyde to produce (500) (70KGS1505). Treatment of (501) with base gave 3,4,5-triphenyl-2-isoxazoline IV-oxide (Scheme 142) (69JOC984). The reaction was reported to be a direct displacement as (502) did not give a product and no incorporation of deuterium was found using DOMe. 

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... 

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 nitroaldol reaction of methyl nitroacetate (199, Scheme 38) with 1,2 3,4-di-0-isopropylidene-a-D-ga/acfo-hexodialdo-l,5-pyranose (200) and 2,3-O-isopropyli-dene-D-glyceraldehyde (202) catalyzed by silica gel proceeded in almost quantitative yield, with high selectivity for attack on the aldehyde carbonyl group, giving derivatives 201 and 203, respectively. Two of the four possible diastereomers were detected as main products, and were obtained as a mixture. For the nitroaldol reaction with 200 gave similar results in either the presence or absence of silica gel, whereas the reaction with 202 did not proceed in its absence, showing that catalytic action of silica is mandatory in this case.176... 

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. 

Support-bound indoles can be modified in several ways. N-Alkylation of polystyrene-bound indoles has been achieved by treatment with reactive alkylating agents (Mel, BnBr, BrCH2C02R) in conjunction with NaH or KOrBu as a base in DMF at room temperature (Entries 1 and 2, Table 15.7). The aminomethylation of indole at C-3 proceeds smoothly on cross-linked polystyrene. The resulting (aminomethyl)in-doles are thermally unstable and undergo substitution reactions with various carbon nucleophiles (e.g. cyanide or nitroacetates) at higher temperatures (Entry 4, Table... 

Microwave-assisted Knoevenagel reactions have also been used for preparation of resin-bound nitroalkenes [56]. A variety of resin-bound nitroalkenes has been generated by use of resin-bound nitroacetic acid, which was condensed with a variety of aldehydes under microwave conditions. To demonstrate the potential of these resin-bound products in combinatorial applications, the readily prepared nitroalkenes were subsequently employed in Diels-Alder reactions with 2,3-dimethylbutadiene [56]. 

Introduction of a C-glycyl [—CH(NH2)C02H] side-chain has been accomplished in the case of the 3-ulose in Scheme 2, by either reaction with methyl 2-nitroacetate, followed by reduction and hydrolysis, or by reaction of the corresponding C-formyl derivative with sodium cyanide, ammonium carbonate, and carbon dioxide, followed by hydrolysis (Bucherer hydantoin procedure) (Scheme 4). A C-formyl side-chain can be established from a nitromethyl side-chain by oxidation of the sodium acinitronate salt by Ti chloride at pH 1. Several C-formyl branched-chain sugars have been synthesized in this way. ... 

Reaction of nitroacetic ester with Mannich bases... 

Primary nitro compounds, on base addition, can undergo reactions with dipolarophiles to isoxazole derivatives with loss of water (henceforth called condensations ) only if their acid strength is high enough a screening of many primary nitro compounds indicates that condensation occurs when pATa is lower than 7 (see Table 3 in Ref. [63] and Table 2 in Ref [64]), whereas nitroalkanes carmotbe condensed in these conditions. Those compounds will be indicated hereinafter as active nitro compounds, which include compounds of the type X-CH2-NO2, where X is an EWG as in nitroacetic esters or amides, or in a-nitroketones, or nitroacetonitrile, etc. even phenylnitromethane (pXa 6.8) undergoes condensation with dipolarophiles. However, without addition of a base, condensations in most cases are not observed. 

Similarly, ethyl nitroacetate afforded, with 1,4-naphto-quinones, fair yields of condensed isoxazoline derivatives as a result of dehydration followed by elimination or dehydrogenation [80]. Later, more examples of condensations of ethyl nitroacetate and alkenes in the same reaction conditions have been reported to compete with oxidation [81]. The intramolecular version, using allyl nitroacetate 16 in the presence of Cu(II) and Mn(III), gives mainly the bicyclic isoxazoline 17 as the condensation product, predominant over monoelectronic oxidation 18 (Scheme 8.6). Noticeably, the intramolecular cyclization occurs with Cu (II) or Co(II) instead of Mn(III) acetate. As expected, secondary nitro compounds undergo only radical reactions. Condensations are reported to occur via intermediate nitrile... 

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). 

It was reported that the Niemeiitowski synthesis of 4-hydroxy-3-iiitro-7-pheiiyl-l,8-iiaphthyridiii-2(lH)-oiie (25) from ethyl 2-amiiio-6-pheiiyhii-cotiiiate (23) and ethyl nitroacetate (24) in the presence of sodium was unsuccessful, producing only traces of (25), while condensation of ethyl 2-amino-6-phenylnicotinate (23) with the less reactive ethyl acetate resulted in the formation of 4-hydroxy-7-phenyl-l,8-naphthyridin-2(lH)-one in good yield [66JCS(C)315]. It seems that the more reactive nitroacetate tends to precipitate rapidly from the reaction mixture as its sodio derivative, which explains the low yield of (25). 

A great number of N-substituted 4-hydroxy-3-nitro-l,8-naphthyridin-2 (IH)-ones are obtained by reaction of N-substituted azaisatoic anhydrides with ethyl nitroacetate carbanion (Section II,A,4,a). A very specific method, more recently developed, is that of the inverse Diels-Alder method, involving the reactions of enamines with 5-nitropyrimidine (Section II,A,4,b). 

C-Alkyldtkin takes place in the reaction of methyl nitroacetate with ilkyl h ilicles the products are useful intermediates for preparing amino acids fEq. 5.1 /The requisite nitro acetate is prepared by seif condensadon of nitromethane. ... 

Aluminum oxide catalyzed addition of ethyl nitroacetate to racemic 2,3-cpoxy aldehydes 7 affords substituted 4,5-dihydroisoxazole 2-oxides through a regio- and stereospecific tandem nitroaldol cyclization process. High diastereoselectivities are observed in the reaction of cis-epoxyaldehydes to yield the ethyl, vi7 -4.5-dihydro-4-hydroxy-5-( I -hydroxyalkyl)-3-isoxazole-carboxylate 2-oxides, with tram configuration at the ring positions, whereas reactions of trans-and 3,3-disubstituted 2,3-epoxyaldehydes proceed with lower selectivities28. 

The reaction mixture is cooled to —15° 3° and 116 g. (1.16 moles) of concentrated sulfuric acid is added with vigorous stirring over approximately 1 hour at such a rate that the reaction temperature is maintained at —15°. The reaction mixture is allowed to warm to room temperature over a 4-hour period and to stir for another 4 hours at room temperature. The precipitate is removed by suction filtration and the filtrate is concentrated on a rotary evaporator under reduced pressure at 30-40°. The residual oil is dissolved in benzene and washed with water, The benzene layer is dried over anhydrous sodium sulfate and the benzene is removed by distillation. Further distillation under reduced pressure yields 30-32 g. (66-70%) of methyl nitroacetate, b.p. 80-82° (8 mm.). 111-113° (25 mm.) (Note 5). 

Application of sulfuric acid as the catalyst is considered more practical for esterification because of its higher boiling point, its incompatibility with benzene, and the stability of nitroacetic acid in the reaction mixture that allows the omission of the final neutralization step. 

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. 

---