Furoxan-4-carboxylic acid

Treatment of nitrolic acid 34, which is in turn available from hydroximino malonaldehyde dioxime (N2O4 in CH2CI2, 20 min, 10-15°C), with TFA gives furoxan-4-carboxylic acid in 35% yield (93CHE952, 93KGS1117) (Scheme 39). 

Another mode of cleavage [type (c)] was found when unsymmetrical 3,4-disubstituted furoxans were subjected to thermolysis. Thus, 3-methyl-furoxan-4-carboxylic acid was found to afford the a-oximinonitrile oxide with concurrent... 

Furazan- and furoxan-carboxylic acids and their derivatives 341... 

Furazan- and furoxan-carboxylic acids are unstable compounds (see CHEC-II(1996) Section 4.05.7.1.3), but their ester and nitrogen derivatives are readily accessible and can be used for subsequent transformations. Thus,... 

Furazan- and furoxan-carboxylic acids are thermally and hydrolytically unstable decomposing to a-(hydroxyimino)nitriles, but their amide, ester, halide, and nitrile derivatives are readily accessible and all undergo the expected functional group interconversions. Dicyanofuroxan reacts with hydroxylamine to give the fused oxazino compound (63) and the pyridazino analogue (64) is similarly formed with hydrazine <82H(19)1063>. 

Furoxans are very feeble bases, even when an amino group is attached to the ring. 4-Amino-3-methylfuroxan behaves as a Hammett base [15], as does benzofuroxan (2, R=H) [7]. By contrast, the two methylfuroxan carboxylic acid isomers show equal high dissociation constants [9]. 

The furoxan ring is notably resistant to electrophilic attack and reaction normally takes place at the substituents. Thus aryl groups attached to monocyclic furoxans and the homocyclic ring of benzofuroxans are nitrated and halogenated without disruption of the heterocycle. Reaction with acid is also slow protonation is predicted to occur at N-5 <89KGS1261> and benzofuroxans have pKj, values of ca. 8, similar to those of benzofurazans. Monosubstituted furoxans are, as expected, less stable and can be hydrolyzed to the corresponding carboxylic acid. Treatment of the parent furoxan (3) with concentrated sulfuric acid results in rearrangement to (hydroxyimino)acetonitrile oxide (HON=CHC=N —O ) and subsequent dimerization to bis(hydroxyiminomethyl)furoxan... 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

In contrast to halogenation, nitration of indoxazene-3-acetic acid with fuming nitric acid at 0°C furnishes a mixture of nuclear (31 R1 = C02H, R2 = N02) (24%) and side-chain (32 R1 = H) nitration products together with a small amount (9%) of the furoxan 33.47 At room temperature a more complex mixture is obtained, consisting of the 5-nitroindoxazene-3-carboxylic acid (24%), the dinitro- and trinitromethyl derivatives (32 R1 = H and N02, respectively), and 6-nitroindoxazene-3-aldehyde (4%). As with bromination, the ester 30 (R1 = H, R2 = Me) and the corresponding 3-acetonitrile behave differently from the parent acid in that nitration yields only the 5-nitro derivatives (31 R2 = N02, R1 = C02Me and CN, respectively). 

Other reactions which form nitrile oxides or their cycloadducts from furoxans are known, but in the majority of these cases their course is not clear. 4-Phenylfuroxan with mild base rearranges to the isomeric a-oximino-phenylacetonitrile oxide (see Section VI). The distillation of 3-ethoxy-carbonylfuroxan-4-carboxylic acid (70) appears to generate the nitrile oxide 72, since one of the products isolated is diethyl furoxandicarboxylate (71).335,336 The diester (71) with anethole is reported to form ethyl 4-anisyI-5-methylisoxazole-3-carboxylate (73),337 but it is not established that the reaction involves the generation of 72 by dissociation of 71, as the authors suggested (see Section V,C,1). See also Section X. 

Decarboxylation and ring cleavage, followed by cycloaddition of the nitrile oxide 118, probably account for the formation of adducts (119) from 4-methylfuroxan-3-carboxylic acid (117).361 Analogously, 4-phenylfuroxan forms an adduct (or adducts) with mesityl oxide, apparently derived via the nitrile oxide 120, which is produced from the furoxan under a variety of extremely mildly basic conditions.362... 

Some further monosubstituted furoxans which have been reported are either of very doubtful authenticity or have been discredited. The phenacyl derivatives of Harries and Tietz,462 formed by the nitrosation of /J-aryl-oc,/ -unsaturated oximes, have been shown to be pyrazolone di-JV-oxides 463 The degradation of Holleman s peroxide (29) by hydroxylamine and alkali was reported to form structure 218, or its 3-substituted isomer, by Boyer and Chang.29 It does, however, seem unlikely that a monosubstituted furoxan could withstand such reaction conditions. Decarboxylation of furoxandi-carboxylic acid has been suggested to provide the 4-monocarboxylic acid,464 but Ponzio and De Paolini465 have assigned a nitrile oxide structure to the product. 

Furan-2-carboxaldehyde see furfural Furan-2-carboxylic acid 78 Furan-2-methanthiol 78 Furazan see 1,2,5-oxadiazole Furazan oxide see furoxane Furfural 77 Furocumarin 325 Furoxan 253... 

The structures of 5-nitro- [741] and 6-nitro-l,2-benzisoxazole-3-acetic acid, 6-nitro-l,2-benzisoxazole-3-yl acetonitrile [742], 6-nitro-l,2-benzisoxazole-3-carboxylates [742, 743] and 6-nitro-4-(R-sulfonyl)benzisoxazoles [744], 3-dini-tromethyl-5-nitro-l,2-benzisoxazoleandbis(5-nitro-l,2-benzisoxazol-3-yl)furoxan [741] were established with the use of proton spectra. 

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