Reactions of the Homocyclic Ring

Nitration proceeds readily in benzofuroxan, giving first the 4-nitro, then the 4,6-dinitro compound. 5-Nitrobenzofuroxan, according to Drost, is nitrated further in the adjacent 6-position. Bailey and Case reported that the major product is the 4,6-dinitro compound, but they did succeed in isolating a small amount of the 5,6-dinitro derivative from the reaction. 

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 6,6-dinitro derivative (47). However, sulfona- 

181 Netherlands Patent Appl. No. 6,510,031 (1965) (to Shell Internationale Research, Maatschappij, N.V.) Chem. Ahatr. 64, 11216 (1966). 

Ponzio, Oazz. Chim. Ital. 36 II, 316 (1906). The authors of Ref. 58 were responsible for the assignment of structure 47 to the product, on very slender evidence. 

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The reactions of the homocyclic ring are considered in three parts attack by electrophiles attack by nucleophiles and transformations involving substituent groups, together with miscellaneous reactions. Unless otherwise stated common behaviour is assumed for benzofurazans and benzofuroxans. 

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. 

One of the nitro groups in furazan (78) can be substituted by chloride and azide, and displacement of sulfonyl groups has also been reported. Nucleophilic reactions in the homocyclic ring of benzofuroxans may be accompanied by deoxygenation of the A-oxide 4-nitrobenzofuroxan with dialkyl-amines affords 4-dialkylamino-7-nitrobenzofurazans as the major product. Substitution reactions... 

It would be anticipated that 1,2-benzisoxazoles undergo electrophilic substitution in the homocyclic ring, and this has been borne out by experiment. The absence or presence of substituents in the 3-position has no influence on the course of the reaction. In qualitative terms it would also be expected that substitution would occur in the 5- or 7-position (see Section 4.16.2.1.1) but most electrophilic substitutions take place at the 5-position. 

Nucleophilic reactions take place in the homocyclic ring, SwAr or AEc when it is activated by electron-withdrawing substituents. It has been described that halides can be displaced by a great number of nucleophiles via a normal and cine substitution [54,55]. Nitro containing Bfx has represented a class of neutral lO-TT-electron-defident system which exhibit an extremely high electrophilic character in many covalent nucleophihc addition and substitution processes. 4,6-Dinitrobenzofuroxan and others 4-nitro-6-substitutedbenzofuroxans (Scheme 2) have been defined as superelectrophiles and used as convenient probes to assess to the C-basicity of... 

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... 

In the benzofuroxan series nucleophilic attack occurs preferentially at the homocyclic ring if activating nitro groups are present, halides being readily displaced (see Section 4.22.3.3.2). Otherwise reaction generally takes place at N(5) of the oxadiazole thus... 

A unique method of anthranil (119) formation, making bonds 5—6 and 7—7a and building up the homocyclic ring, occurs in polyphos-phoric acid as the result of a series of reactions starting from the oxime... 

Relatively little is known of the chemistry of antimony rings compared to arsenic rings. The reactions of arsenic homocycles have been reviewed several times " . They include cleavage of the As—As bonds with halogens and insertion of chalcogens or unsaturated hydrocarbons and reductive cleavage with potassium metal. Representative examples are given in equations 15-18. 

Almost all the known reactions of the pyrylium nucleus involve addition of a nucleophile, usually at an a-position, occasionally at C-4, as the first step. A feature of pyrylium chemistry is the ring opeinng of adducts produced by such additions, followed by cyclisation in a different manner, to give a new heterocyclic or homocyclic product (ANRORC processes). 

Indoles are usually prepared from non-heterocyclic precursors by cyclisation reactions on suitably substituted benzenes they can also be prepared from pyrroles by construction of the homocyclic aromatic ring, and from indolines by dehydrogenation. 

The intermediate (45a) previously employed1" in a synthesis of aspidospermine has been neatly prepared52 by a potentially general method which has already been applied to the syntheses of several other alkaloid systems. The key step is the reaction of a cyclic enamine, in this case (46a), with methyl vinyl ketone and the formation of a homocyclic ring and the required carbonyl function. Scheme 16... 

The reactions of furoxans and benzofuroxans have recently been comprehensively surveyed (81 AHC(29)25l) earlier reviews are available for furazans and benzofurazans (b-61MI42200, 62HC(17)283, 75H(3)651). Unless otherwise stated the material contained in this section is cited therein. Seperate sections are dtevoted to the reactions at the heterocyclic rings of furazans (including benzofurazans) and of their furoxan counterparts in view of their distinctive chemistries. Transformations involving the homocyclic rings of benzofurazans and benzofuroxans, and of the substituents at the 3- and 4-positions of monocyclic furazans and furoxans are treated in a unified manner. 

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