Preparation of Benzofuroxans

Benzofuroxan may be obtained by oxidation of o-quinone dioxime. The first benzofuroxan derivative, 1,2-naphthofuroxan, was obtained by this method. Suitable oxidizing agents include alkaline ferri-cyanide, bromine water, chlorine, and nitric acid. The method is of practical value only when the o-quinone or its monooxime (o-nitrosophenol) is readily available, and since this is not generally the case, other routes, e.g., the oxidation of o-nitroanilines and the thermal decomposition of o-nitrophenyl azides/ are more commonly used. 

The oxidation of o-nitroanilines to benzofuroxans was discovered by Green and Rowe, who used alkaline hypochlorite. Although this method has been used extensively, it occasionally fails to 

Milonc and G. Tappi, Atti 10th Congr. Intern. Ghim., Rome, 2, 352 (1939)  

The most reliable method of preparing benzofuroxans is by decomposition of o-nitrophenyl azides. Decomposition can be achieved by irradiation, or more usually by pyrolysis temperatures between 100° and 1.50° are commonly used. Refluxing in glacial acetic acid is the recommended procedure for 4- or 5-sub-stituted 2-nitrophenyl azides, but with 3- or 6-substituted compounds higher boiling solvents are usually necessary. Quantitative studies on the reaction rate have been made, and a cyclic transition state invoked, an argument which has been used to account for the greater difficulty of decomposition of the 6-substituted 2-nitrophenyl azides. Substituent effects on the reaction rate have also been correlated with Hammett a constants,  

The action of hydroxylamine and sodium acetate in ethanol upon picryl chloride was stated to give 4,6-dinitrobenzofuroxan, and probably some of this compound was formed, although it was later shownthat much of the original work was faulty. A report that hydroxylamine and 2,4,5-trinitrotoluene give 5-methyl-6-nitro-benzofuroxan has been found to be incorrect. Benzofuroxan has not been prepared by V-oxidation of benzofurazan, and it seems unlikely that this could be achieved, since benzofuroxan itself is oxidizable by powerful reagents to o-dinitrobenzene (Section VI, B). A report of the oxidation by nitric acid of anthraceno[l,2-c]furazan to the furoxan is incorrectlv abstracted. 

5-chloro-4-methoxybenzofuroxan, rather than the 5-nitro compound (see Section VII, B). No benzofuroxan was obtained from 

2-nitro-p-phenylenediamine, 4-amino-3-nitroacetanilide, or 4-amino-3-nitrophenoP by this method. Naphtho[l,2-c]furoxan was prepared from both l-nitro-2-naphthylamine and 2-nitro-l-naphthyl-amine. Hofmann degradation followed by oxidation of the amide 

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The main modes of preparation of benzofuroxans have been previously reviewed <84CHEC-I(6)424>. Important aspects such as thermal and photochemical isomerization, ring cleavage, reactions with... 

The main modes of preparation of benzofuroxans have been previously reviewed in Volume 6 of CHEC-I <84CHEC-I(6)424>. The nitrobenzofuroxans (516) and (517) have been obtained via nucleophilic displacement of the dinitro derivatives (510) and (511) with azide ion followed by thermolysis in refluxing toluene and direct nitration of the unsubstituted furoxans (514) and (515) with 60% and 18% overall yields, respectively (Scheme 41) <91T7157>. 

The most common general procedure for preparation of benzofuroxans is based on thermolysis of the benzene compound containing adjacent nitro and azido groups in the ortho position [31, 32]. 

The amido-, thioamido-, sulfonamido-, and semicarbazido-benzofuroxans possessing different lateral chains (het-eroaliphatic, heterocyclic, and aromatic) were prepared by traditional methods by transformation of functional group of benzene fragment. The typical chemistry of benzofuroxanes did not take place in these cases <2002AP15>. 

Other methods can be used to prepare the furoxan system the most common are spontaneous decomposition of azidonitroolefms 26, dehydration of a-nitrooximes 25, thermolysis of o-nitro phenylazides 27 and oxidation of o-nitrosubstituted aromatic amines 28 (Scheme 6.7). All these procedures have been discussed in detail in Ref. [10]. The latter two methods are of paramount importance in the synthesis of benzofuroxan derivatives. 

Dinitrobenzofuroxan (DNBF) (68) has been prepared from the nitration of benzofuroxan (69) with mixed acid," and by treating picryl chloride (67) with sodium azide and heating the resulting picryl azide (70) in an inert solvent." " ... 

The reactions of the homocyclic ring of benzofuroxans, which are described in detail in Section 4.22.3.3, provide access to numerous derivatives. Nucleophilic displacement of halides is facile when activating nitro groups are present, allowing alkoxy, aryloxy, thio and amino groups to be introduced. Electrophilic substitutions, e.g. nitration, are also valuable. Further transformations may also be performed on benzo-ring substituents. Such modifications include acetoxy to hydroxy acetamido to amino and acyl halides to esters and amides. Some reactions of the substituents of monocyclic furoxans allow hetero-substituted analogues of benzofuroxans to be prepared. For example, pyridazinofuroxans are formed by condensation of diacylfuroxans with hydrazine. 

The freshly prepared dienamine (0.01 mol) was added to an ethereal solution of benzofuroxan (or Cl/Me-substituted benzofuroxan) (0.01 mol) at rt. The color of solution slowly turned to red and, after some time, a red crystalline solid began to separate. The reaction was followed by TLC and worked up after all the benzofuroxan had been consumed. The solvent was removed under reduced pressure and the residue crystallized from an appropriate solvent, giving a red crystalline solid. 

Anhydrous potassium phenoxide was prepared by the method of Komblum and Lurie (47). Picryl chloride was prepared from picric acid by published procedures (48). DNBF (16) was prepared by nitration of benzofuroxan (49) and recrystallized from glacial acetic acid. The potassium salt of the methoxy adduct 17 was obtained from the reaction of methanolic DNBF with potassium hydroxide (50). PiDNBT (30) was prepared by cyclization of 2,2, 4,4, 6,6 -hexanitrohydrazobenzene (51) with concentrated sulfuric acid and recrystallized from glacial acetic acid yellow plates mp 291-294 °C (decomposition) NMR [100 MHz, (CH3)2SO-d6] 9.09 (d, 1 HJ = 1.9 Hz), 9.48 (s, 2 H), 9.45 (d, lH,/= 1.9 Hz). 

The previous review in this series6 summarized the synthetic routes to fused furoxans up to 1968, and, despite the very considerable development in the applications of benzofuroxans since that time, the standard methods for their preparation are still applied, and no original synthesis has been developed. 

When phenolate anions are used as substrates, phenazine dioxides are produced. The same product—2-hydroxyphenazine dioxide (173 R1 = H, R2 = OH)—is formed, whether phenol, resorcinol, hydroquinone, or benzoquinone is used,9,390,392 illustrating the variability of the relationship between the oxidation levels of the substrates and products. Benzofuroxan, a trialkylphosphine, and a quinone produce blue-violet phos-phonium betaine derivatives (e.g., 173 R1 = PR3+, R2 = 0-).393 The ether 173 (R1 = H, R2 = O-alkyl) is produced from a hydroquinone monoether.390 1-Hydroxyphenazine dioxide (173 R1 = OH, R2 = H) can be prepared from benzofuroxan, cyclohexane- 1,2-dione, and a base, followed by oxidation of the mixture of mono- and di-iV-oxide formed.394 /J-Naphthol provides benzo[a] phenazine dioxide (174).9,390... 

Tervalent phosphorus compounds (phosphorous derivatives) are weil-established reagents for the deoxygenation of amine oxides and nitrones, and they provide a clean and convenient method for the preparation of furazans from furoxans. Mukaiyama et al.425 and Grundmann426 used trialkylphosphites, and they have been widely employed since that time, both with and without solvents.80,85,93,95,97,352 The simple dialkyl- and diarylfuroxans usually require more vigorous conditions (e.g., refluxing triethyl phosphite) than do strained derivatives or the benzofuroxans.85,97... 

The reduction of furoxans by lithium aluminum hydride to give amines,182,283,423,424 and of fused furoxans to diamines283,423 (Section V,D), has potential utility ring cleavages brought about by this reaction show a number of synthetic possibilities. The catalytic hydrogenation of tetrahydrobenzofuroxan to hexamethylenediamine is also potentially useful.279,420 o-Benzoquinone dioxime may be prepared very easily by reduction of benzofuroxan (Section V,D,5). 

This method of quinoxaline di-JV-oxide formation is known as the Beirut reaction and is extremely useful, particularly in view of the limitations of direct oxidative procedures for preparing di-N-oxides. Probably several hundred quinoxaline di-iV-oxides have been prepared in this way. Only a selection of those exemplified in the patent literature are included in the table at the end of this chapter. Valuable reviews on the conversion of benzofuroxans into quinoxaline di-JV-oxides have been written by Haddadin and Issidorides and by Ley and Seng. ... 

The first report of the preparation of quinoxaline di-N-oxides from benzofuroxans was by reaction with enamines. Benzofuroxans are themselves conveniently prepared by oxidation of the appropriate o-nitroanilines with hypochlorite or by pyrolysis of the corresponding nitrophenyl azides. A variety of enamines react satisfactorily, but the less reactive morpholine enamines give higher yields and more easily isolata-ble products (Scheme 5). " ... 

Quinoxaline di-iV-oxides without substituents in the pyrazine ring have been prepared by reaction of benzofuroxans with synthons of the type RCH==CHX, where R = COMe or 4-substituted benzoyl and X = ONa, or where R = H and X = NR2 or OAc. - Two cases are known of mono-N-oxide rather than di-N-oxide formation using benzofuroxan. Thus reaction with benzofuran-3(2H)ones gives 3-(o-hydroxyaryl)quinoxaline... 

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