Furoxans rearrangements

Extensive nuclear magnetic resonance and ultraviolet spectroscopy methods were reviewed in <1996CHEC-II(7)363>, as well as mass spectral fragmentation patterns of [l,2,3]triazolo[4,5-/ ]pyridines (Section 7.10.8.1). More recently, furoxan rearrangement of some pyridofuroxan derivatives has been studied by H, and... 

Chloro- and 5-methylbenzofuroxans are readily nitrated in the 4-position the product rearranges easily to form 7-substituted 4-nitro compounds (see Section VIII), also obtained by nitration of the corresponding 4-substituted benzofuroxans. Dinitration of 5-methylbenzofuroxan is said to give a product of m.p. 133°, while the 4-methyl gives a dinitro compound m.p. 122°-123°. For other benzofuroxans to have been nitrated see refs. 19, 36, 81, 97,121. There appears to be some confusion over the site of electrophilic substitution of naphtho[l,2-c]furoxan. Early reports in the literature state that nitration gives the 5,6-dinitro derivative (47). However, sulfona-... 

The 1-oxide 3-oxide tautomerism [Eq. (3), p. 4] has been discussed earlier (Sections II and III,C) in connection with the problem of the structure of benzofuroxan. A second type of rearrangement involves the furoxan ring and an adjacent substituent group, and arose out of a suggestion of Bailey and Case that 4-nitro-benzofuroxan might be a resonance hybrid of type (57)-(-> (58), rather than 57. NMR ruled out this possibility the three protons present in... 

The rearrangement has been extended to other 4-substituted benzofuroxans of type 61, giving 62 i30-i32. although in no ease to date has the benzofuroxan been isolated, they are presumed intermediates in the formation of 63 and 64 from 5-dimethylaminobenzo-furoxan with 2,4-dinitrobenzenediazonium chloride and nitrous acid, respectively, and of 66 from 6, 68 from 67,and 70 from 69.132... 

Another example of this rearrangement has been used to prepare 1,2,3-triazole 146 from furazanic phenylhydrazone 147 (Scheme 84) [93JCS(P1)2491]. Interestingly, furoxanic Z-phenylhydrazones 150 underwent thermal recyclization to 1,2,3-triazole A-oxides 152, evidently through intermediate 151. Treatment of the hydrazone 150 with rerr-BuOK leads to the nitromethyl derivative 149 [OOOMIl] (Scheme 84). Lead tetraacetate oxidation of 147 with subsequent Lewis acid treatment of the initially formed intermediate afforded indazole 148 (Scheme 84) (85JHC29). 

Nitrile oxides are very reactive dipoles which, apart a few members, need to be prepared in situ for their tendency to dimerize to furoxans [86], This behaviour represents a limit to their use with alkylidenecyelopropanes that is only in part compensated by their reactivity. The cycloadditions of several nitrile oxides with alkylidenecyelopropanes were extensively studied in connection with the rearrangement process leading to dihydropyrid-4-ones 336 [64, 87],... 

Furoxans and benzofuroxans undergo thermal and photochemical ring cleavage, reactions with nucleophiles, Boulton-Katritzky rearrangement, reduction and deoxygenation, ring transformation, etc. (see also Section 5.05.6.2). 

The thermally induced rearrangements in the furoxan series have also been found. In particular, the transformation of 3-R-substituted 4-(3-ethoxycarbonylthioureido)-l,2,5-oxadiazole 2-oxides into derivatives of 5-amino-3-(a-nitroalkyl)-l,2,4-thiadiazole and into (5-amino-l,2,4-thiadiazol-3-yl)nitroformaldehyde arylhydrazones has been reported (Equation 8) <2003MC188>. 

It was shown that furoxans can be transformed to 1,2,3-triazoles. Thus, 4-acetylamino-3-arylazo-l,2,5-oxadiazole 2-oxides undergo two successive (cascade) mononuclear heterocyclic rearrangements in an aqueous basic medium with the formation of 4-acetylamino-2-aryl-5-nitro-2/7-l,2,3-triazoles (Equation 12) <2001MC230>, or 3,3 -disubsti-tuted 4,4 -azo-l,2,5-oxadiazole 2-oxides were found to undergo a rearrangement into 2-(furoxan-4-yl)-4-nitro-2//-1,2,3-triazole 1-oxides on heating in pertrifluoroacetic or peracetic acids (Equation 13) <2003MC272>. 

Arylazo-4-(3-ethoxycarbonylureido)furoxans 62, which were synthesized by the reactions of 4-amino-3-arylazo-furoxans with ethoxycarbonyl isocyanate, were subjected to cascade rearrangements under the action of potassium r/-butoxidc in dimethylformamide or by heating in dimethyl sulfoxide to form 4-amino-2-aryl-5-nitro-2//-l,2,3-triazoles 63 (Scheme 13) <2001MC230, 2003RCB1829>. 

Although the Capdevielle reaction for one-pot conversion of aldehydes to nitriles is a very convenient and widely applicable synthetic procedure, 3-substituted furoxans appear to be susceptible to rearrangement when substitutions with amine nucleophiles are attempted, even under relatively mild conditions (Scheme 29) <1999JOC8748>. The formation of the final product 107 in this reaction was explained via phenyl abstraction by carbamoyl radical cation from the second molecule of intermediate product 106 < 1999JOC8748>. 

As mentioned in CHEC-II(1996), three main routes have been reported for the formation of furazan rings (1) the dehydrative cyclisation of 1,2-dioxims (2) the deoxygenation of furoxans and (3) the Boulton-Katritzky rearrangement of other five-membered heterocyclic systems <1996CHEC-II(4)229>. In this section the recent publications on the synthesis of furazans published after 1996 are discussed. 

The side products of the reaction between benzoylnitromethane 279 and dipolarophiles (norbornene, styrene, and phenylacetylene) in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) were identified as furazan derivatives (Scheme 72). The evidence reported indicates that benzoylnitromethane gives the dibenzoylfuroxan as a key intermediate, which is the dimerization product of the nitrile oxide. The furoxan then undergoes addition to the dipolarophile, hydrolysis, and ring rearrangement to the final products (furazans and benzoic acid) <2006EJ03016>. 

In general, furoxans are fairly stable compounds in acid solution but are sensitive to bases [6, 9]. This is true in particular for the parent ring and for the 4- and 3-monosubstituted compounds. The former undergoes extensive decomposition, while the latter two produce a-hydroxyimino substituted nitrile oxides 5 and a-nitro substituted nitriles 6, respectively. 4-Aryl-3-methylfuroxans 7, unlike their 4-methyl isomers, give Angeli s rearrangement, namely they are converted to the corresponding 3-arylisoxazolin-4-one oximes 8, by the action of concentrated alkali hydroxides or alkoxides (Scheme 6.1). 

A third example to illustrate the construction of G graphs is the furoxan-furazan rearrangement (see Scheme L8), Based on the principles outlined previously it is evident that this rearrangement can be pictured by the Go, Gi, G2, and G3, graphs as presented in Scheme 1.12. They also show the mirror plane symmetry. 

A similar base-induced rearrangement has been reported to occur at room temperature with the Z-isomer of 3-methyl-4-benzoylfuroxan oxime (143), yielding the 3-(a-nitroethyl)-4-phenylfurazan (144) (82G181), and with 3,4-diformaldoxime furoxan (145), which gives 3-(a-nitroacetal-doxime)furazan (146) (Scheme IV.57) (81AHC(2G)251). 

Dipolar cycloadditions of nitrile oxides 216 onto 1 gave much poorer yields of cycloadducts 217 than those of nitrones 205. The cycloadditions of 216 to 1 require higher temperatures and unfavorably compete with their dimerization to furoxanes. However, stable nitrile oxides 216 with bulky substituents R that hamper dimerization, can be used. The thermal rearrangements of 5-spirocyclopropane-annelated isoxazolines 217 always required higher temperatures than the isoxazolidine counterparts. Under these conditions the second cyclopropane ring was also cleaved to give furopyridines 218 (Scheme 48) [136, 137]. 

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... 

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