Dioximes, oxidative cyclization

Syntheses of this type have been reported only recently (78H(9)1367, 79JOC3524). Unsaturated 1,4-dioximes are transformed by oxidative cyclization into pyridazine 1,2-dioxides... 

The other common synthetic procedure for Bfx and Fx preparation is the oxidative cyclization of 1,2-dioximes. 1,2-Dioximes are excellent starting materials for the syntheses of the 1,2,5-oxadiazole N-oxide system in presence of oxidizing conditions to promote the cyclization. Its utiUty is restricted for Bfxs syntheses because the restriction of o-quinone dioximes availability, contrarily a-glyoximes, which are useful to prepare Fx, are more easily to prepare. In Table 1, products, conditions, and comments for the most recent Fx synthesis using 1,2-dioximes are shown. 

Furoxans are not formed by direct oxidation of furazans, but they can readily be prepared by ring closure or cycloaddition pathways. The most synthetically useful routes are the oxidative cyclization of 1,2-dioximes, the dehydration of a-nitroketoximes and, for symmetrically substituted furoxans, dimerization of nitrile oxides. For asymmetrically substituted analogues care must be taken in selecting the route in order to avoid formation of mixtures of 2- and 5-oxide isomers. 

Pyridazines were also formed from dioximes by oxidative cyclization [78H(9)1367 79JOC3524 82M118]. As oxidants, lead tetraacetate or phe-nyliodoso bis(trifluoroacetate) were used, and substituted pyridazine 1,2-dioxides 55 are obtained accompanied by isoxazoles, isoxazoloisoxazoles, and open chain compounds. It was also established that a compound to which the structure of 3,6-diphenylpyridazine 1,2-dioxide was previously assigned is, in fact, a dihydroisoxazoloisoxazole derivative (79JOC3524). 

Cyclization of unsaturated iminoxyl radicals has been proposed to rationalize the products resulting from the reaction of 2-butene-1,4-dione dioximes (BDD) with oxidizing agents such as lead tetraacetate (Scheme 48A). As yields of dihydroisoxazoloisoxazoles (CyS) of up to 60% may be obtained (R = Ph), this would be a remarkable reaction since it would involve the generally much disfavored Cy5/Cy4 cyclization. But it must be noted that the (Cy 5) radical is stabilized, particularly when R = Ph. Examples of oxidative cyclization of oximes of a -ethylenic ketones to dihydroisoxazoles have been reported in the steroid series and could involve an analogous mechanism. ... 

Oxidative cyclization of 1,4-diketone dioximes was cited in last year s Report as an improved route to 3,6-diaryl-p5fridazine 1,2-dioxides. Related is the oxidative cyclization of 1,3,4,6-tetraketones (195) to the explosive 3,6-diacyl-4,5-dioxo-4,5-dihydropyridazine 1,2-dioxides (196), using dinitrogen tetroxide (N2O4). A full report on the unexpected nuclear alkylation of... 

Disubstituted 2-phenyl-277-1,2,3-triazole-1-oxides (150) can be easily obtained from the corresponding bis(hydroxyimino)butanes 148 in three steps. Thus, treatment of dioximes 148 with diluted HCl in dioxane with subsequent interaction with PhNHNH2/EtOH/AcOH afforded a-hydrazinooximes 149 in excellent yields. Reaction of 149 with A-iodosuccinimide (NIS) in CCI4 or with CUSO4 in aqueous pyridine afforded triazoles 150 (equation 65) . Similar cyclization in the presence of SOCI2 also leads to... 

The synthesis of 1,2,5-oxadiazoles is based on cyclization of l,2-dioximes or a-nitrooxime derivatives. The chemistry of dioximes is reviewed by Kotali and Papageorgiou. Thus, reaction of dioximes 270 with 5% aqueous NaOCl in the presence of NaOH in EtOH afforded l,2,5-oxadiazole-2-oxides 271 in good yields (equation 116) . Bromocyan , N2O4/CH2CI2 , bis(trifluoroacetoxy)iodobenzene and Si02 at 150 were also used as reactants in the cyclization of 1,2-dioximes to 1,2,5-oxadiazoles. 

Bicyclic derivatives of furazan A-oxide are prepared by nitrile oxide dimerization reaction. Dioxime 272 (R, R = Me) undergoes cyclization to the corresponding 4,4-tetramethylperhydrocycloocta[c]furazan A-oxide 273 (84% yield) by treatment with NaOCl/HaO/CHaCla at 0°C and then refuxing in toluene (equation 117). However, in the cases of sterically less hindered oximes 272 (R = H, Me R = H) only complex mixtures of oligomerization and cyclization products could be obtained ". Interestingly, the reaction of pyridyl oxime -274 with TsCl afforded 1,2,5-oxadiazole 275 as single product (equation 118). On the other hand, the reaction of Z-isomer of oxime 274 leads only to 0-tosylated oxime. ... 

There are few examples of the preparations of heterocyclic compounds containing two or more heteroatoms which involve cyclization with formation of a bond between two heteroatoms. The best known instances of this type of reaction, all of which are [6 + 0] reactions, are the preparations of benzocinnolines as outlined in equations (l)-(4). A similar type of approach to that outlined in equation (4) has been used for the direct preparation of the di-N-oxide (2) from the dioxime (1 equation 5). The naphthotriazine betaine (4) is obtained as one of the products of the thermal decomposition of the azidoazo compound (3 equation 6). 1,2-Dithiins and their dibenzo derivatives have been prepared by oxidation of appropriate dithiols and related starting materials as outlined in equation (7). All of these reactions are, however, somewhat specialized and there has been essentially no systematic study of the preparation of six-membered heterocycles via formation of a bond between two heteroatoms. 

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. 

A crystalline dioxime of (14) was prepared and the structure was verified by oxidation (CrOa/acetic acid) to the crystalline tetra-O-acetylgalactaric acid. Compound (14) was strongly reducing. Wolfrom and Usdin prepared a crystalline hexa-O-acetyl-1,6-dibromo derivative (15), by treating (14) with acetyl bromide. Only one compound was obtained (in high yield), although both the meso and the dl isomers are stereochemically possible. All attempts to cyclize (14) or (15) to an inositol have failed. 

Oxadiazoles and 1,2,4-oxadiazoles are heterocyclic aromatic compounds that appear in many bioactive molecules. Previous methods for the synthesis of 1,2,4-oxadiazoles include the coupling of amidoximes with carboxylic acid derivatives, aerobic C—H oxygenation of amidoximes, or a cyclization of nitrile oxides to nitriles. Telvekar and Takale developed the preparation of 1,2,4-oxadiazoles from substituted diketone derivatives through a Beckmann rearrangement process tScheme S.3S1. When treated with diphosphorus tetraiodide in dichloromethane at room temperature, dioximes 150 formed the Beckmann products, 1,2,4-oxadiazoles 151, in excellent yields. 

---