Furoxans isomerization

It is apparent that the equilibrium constants for the furoxan isomerizations are determined by a combination of factors, not all fully understood, and of varying importance, depending on the substituents and the way in which they are able to interact with the two positions of the heterocyclic ring. Equilibria are conveniently measured by H NMR, at low temperatures for the benzofuroxans and other rapidly exchanging systems, or at normal temperatures for the slowly equilibrating types. The assignments of the spectra are made using the criteria outlined in Section III,C. 

Extensive mass spectral and electron impact studies have been reported for 3-hydroxy-1,2-benzisoxazole and its ethers. Similar work was also carried out with the isomeric A-alkyl-l,2-benzisoxazol-3-one (71DIS(B)4483). 1,2-Benzisoxazole A-oxide showed a mass spectral pattern than more closely resembled furoxans. The loss of NO predominated over the loss of O (Aft intense, [M— weak, [Af-30]" strong). 

A modihed Hantzsch synthesis has been utilized for the preparation of 1,4-dihydropyridines (Scheme 66). Thus, condensation of formylfurazans 116 with an acetoacetic ester and aminocrotonic acid ester in isopropanol at reflux led to 1,4-dihydropyridine derivatives 117 in about 70% yield (92AE921). Both isomeric furoxan aldehydes reacted in a similar way. 

In contrast to alkoxides, thiolates react with 3,4-bis(arylsulfonyl)furoxans to give both isomeric products 283 and 284 (Scheme 185) (96JHC327, 97JMC463). 

The isomerization of series of furoxans 7-9 was observed through the corresponding NMR spectra (proton and carbon), which showed complex groups of signals in the aromatic zone (7.30-8.50 and 110-155 ppm, respectively) at room temperature. The spectra simplified at higher temperature, where one of these isomers predominates C1999JME1941, 2000JFA2995>. 

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

Some routes of chemical transformations of nitrile oxides connected with the problem of their stability were briefly discussed in Section 1.2. Here only two types of such reactions, proceeding in the absence of other reagents, viz., dimerization to furoxans and isomerization to isocyanates, will be considered. All other reactions of nitrile oxides demand a second reagent (in some cases the component is present in the same molecule, and the reaction takes place intramolecularly) namely, deoxygenation, addition of nucleophiles, and 1,3-dipolar cycloaddition reactions. Also, some other reactions are presented, which differ from those mentioned above. 

The stability of o-sulfonylbenzonitrile oxides and their thiophene analogs probably depends on electronic factors. The same factors do not prevent dimerization, as can be seen from data concerning several differently substituted nitrile oxides of the thiophene series (103). Sterically stabilized 3-thiophenecarbonitrile oxides 18 (R = R1 = R2 = Me R = R2 = Me, R1 = i -Pr), when boiled in benzene or toluene, isomerized to isocyanates (isolated as ureas on reaction with aniline) while nitrile oxides 18 with electron-withdrawing substituents (R1 and/or R2 = SOiMe, Br) dimerized to form furoxans 19. 

This stereospecific oxidation does not occur for all dioximes, probably due to isomerisation of the dioxime during the reaction or to different reaction mechanisms involved in the use of different oxidants. When the lipophilic-hydrophilic balance of the two furoxan isomers is appropriate, they are easily separated by chromatography or fractional crystallisation. For example, the synthesis of 4-hydroxymethyl-3-furoxancarboxamide (CAS 1609), one of the most promising furoxancarboxamide vasodilators (see later), passes through the intermediate formation of a mixture of the two isomeric methyl hydroxymethylfuroxancarboxylic esters, which can easily be separated by recrystallisation from isopropyl acetate [18]. 

Jugelt et al. [136] studied the regioselectivity of the anodic oxidation of anti-98 and amphi-99 vicinal dioximes on the structure of furoxanes obtained after anodic oxidation under constant current. The furoxanes (101,102) were obtained in 22-65% yield but the ratio of the isomeric furoxane was dependent on the structure of the substrate (Scheme 54). 

The tetraazapentalene ring system forms the core of the thermally insensitive explosive TACOT (Section 7.10) and so its fusion with the furoxan ring would be expected to enhance thermal stability and lead to energetic compounds with a high density, y-DBBD (95) is prepared from the nitration of tetraazapentalene (91), nucleophilic displacement of the o-nitro groups with azide anion, further nitration to (94), followed by furoxan formation on heating in o-dichlorobenzene at reflux. The isomeric explosive z-DBBD (96) has been prepared via a similar route. ... 

The 1,2,5-oxadiazole ring is a stable system and annular-group tautomerism is not favored. Although three tautomeric forms can be drawn for 3-hydroxyfurazans (Scheme 3) IR and NMR data for chloroform solutions show only the presence of the hydroxy compound. Ring-chain tautomerism is an important feature of furoxan chemistry and the equilibration between the isomeric furoxans is discussed in detail later in this chapter (Section 4.05.5.2.1). 

H NMR analysis was used to monitor the oxidation of dioxime 30 by manganese dioxide. Earlier work suggested that this reaction produced mainly isomer 31 <1990CHE1195>. More recent work, however, has shown that two isomeric furoxans 31 and 32 are produced in approximately equal amounts <2001RCB874>. 

Despite many attempts it has not been possible to oxidize 2-substituted 1,2,3-triazoles 382 to the corresponding 1-oxides 326. Peracetic acid, 3-chloroperbenzoic acid, dichloropermaleic acid, trifluoroperacetic acid, peroxydisulfuric acid, and f-pentyl hydrogen peroxide in the presence of molybdenum pentachloride all failed to oxidize 382 (1981JCS(P1)503). Alkylation of 1-hydroxytriazoles 443 invariantly produced the isomeric 3-substituted 1,2,3-triazole 1-oxides 448 (see Scheme 132). However, the 2-substituted 1,2,3-triazole 1-oxides 326 can be prepared by oxidative cyclization of 2-hydroxyiminohydrazones (1,2-hydrazonooximes, a-hydrazonooximes) 345 or by cyclization of azoxyoximes 169. Additional methods of more limited scope are reaction of nitroisoxazoles 353 with aryl-diazonium ion and base, and reaction of nitroimidazoles 355 with hydroxy-amine- or amine-induced rearrangement of nitro-substituted furoxanes 357. 

Auricchio et al. have proposed the formation of 1,2-diazetidine-l,2-dioxide as a possible intermediate in the thermal isomerization of furoxanes and benzofuranoxane derivatives (Scheme 34 and 35) <1997T17407>. 

For the isomerization of furoxan 326a and b, a lower limit of 24 kcal mol 1 was estimated for the free energy of activation for the rearrangement (74JOC2956). 

Phenylsulfonyl)furo[2,3- ]quinoline and its parent unsubstituted heterocycle were found to have very similar absorption maxima hence, the sulfone group does not provide an additional conjugative effect <83JOC774>. In addition, furo[2,3-/ quinoline and its isomeric furo[3,2-< ] counterpart were found to exhibit UV absorption maxima that are almost identical. An absorption maximum at 435 nm consistent with the presence of a 2H-1,4-benzothiazine chromophore was one of the key pieces of data that enabled the structure determination of compounds based upon the new 1,2-dihydro-3//,8//-pyrrolo[2,3-/z][l,4]benzothiazine skeleton <87T5357>. The UV spectrum of l,4-benzodioxano[6,7-c]furoxan was found to exhibit four characteristic band maxima in the 350-480 nm region <88JHC803>. 

In marked contrast the structure of furoxans was for many years a matter of some controversy. Among the formulations proposed, and thus frequently to be found in the early literature, were the dioxadiazine (or glyoxime peroxide) (7) and the bicyclic arrangements (8) and (9). It was not until the isomerism characteristic of asymmetrically substituted furoxans was fully appreciated (see Section 4.22.3.2.1) that the N-oxide structure (2), originally proposed by Wieland (03LA(329)225) and by Werner (B-04MI42200) some 60 years previously, finally became universally accepted. 

Reactions of the Heterocyclic Ring of Furoxans and Benzofuroxans 4.22.3.2.1 Thermal and photochemical isomerization... 

Photochemical isomerization of furoxans has also been reported. For example, irradiation of 7-chloro-4-nitrobenzofuroxan generates the thermally less favoured 4-chloro-7-nitro isomer. 

The ring closure can be achieved stereospecifically, thus allowing the individual isomers of asymmetrically substituted furoxans to be prepared. For example, the two amphi forms (100) and (101) of p-methoxybenzil dioxime are specifically oxidized by ferricyanide to (102) and (103), whereas the syn and anti isomers (104) and (105) give mixtures of the two furoxans. With some oxidants the process is non-stereospecific, either due to a change of mechanism, or as a result of isomerization of the dioxime prior to cyclization. 

Pseudonitrosites and a-nitro ketone oximes were identified as intermediates in this process. This route has since been developed to provide access to mono- and poly-cyclic furoxans from readily-available alkenes and cycloalkenes. Treatment of the alkene with dinitrogen trioxide affords the nitro-nitroso adduct, which is readily isolated as its nitroso dimer (pseudonitrosite) thermal isomerization to the a-nitro ketone oxime, followed by dehydration with cyclization leads to the furoxan (Scheme 19). 

Nitrotetrazolo compounds are an additional source pyrido[2,3-c]furoxan (42) is formed from the nitropyridotetrazole (114), presumably via the isomeric azidonitropyridine (Scheme 22). 

Bis(acetamido) derivative of furoxan undergoes the aforementioned rearrangement to form a mixture of two isomeric nitrotriazolylfuroxans in the 1 2 ratio [558] (Scheme 103). 

Nitrile oxides display three types of reactivity (apart from isomerization and deoxygenation) 1,3-cycloaddition, 1,3-addition, and dimerization to furoxans. The first can give isoxazolines and isoxazoles directly. The second can give isoxazolines and isoxazoles indirectly. The third (which may be regarded as a carbenoid reaction,62 but see also Lo Vecchio et al.63) is an undesirable side reaction as far as the synthesis of isoxazoles is concerned. Thus, although many methods for generating nitrile oxides are available, and in some cases they may be isolated and used, methods capable of generating them in the presence of the substrate are preferred. 

Early attempts to prepare /i-nitrovinyl azides led to the formation of furoxans.20 The -/i-nitrovinyl azide 54 has however been isolated.56 Its thermolysis in benzene afforded the azirine 57 in 60% yield the same compound was obtained on photolysis, together with a small amount of the furoxan 56, which is ascribed to photochemical -Z isomerism, leading initially to 55 (Eq. 16). In the aromatic series it is known that o-nitro-aryl azides undergo anchimerically assisted nitrogen elimination, giving benzofuroxans.57... 

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