Pyridazine 1,2-dioxides reactions

Dioximes are known to generate isoxazoles and related compounds when oxidized with IBTA. However, these reactions are of limited use because of formation of side products. For example, oxidation of dioximes of /B-diketones 159 gives rise to a mixture of 3,5-disubstituted oxazoles 160 and pyrazole-di-N-oxides 161 (82MI1). In another case, oxidation of dioximes 162 affords a mixture of the isomeric dihydroisoxazolo-isoxazoles 163 and pyridazine dioxides 164 (76S837 79JOC3524 82MI1). 

Pyrido[2,3-, pyridazine derivatives 48 have been synthesized by refluxing equimolar amounts of an appropriate 5-benzylidene-2,2-dimethyl-l,3-dioxane-4,6-dione 47 with 5-amino-6-phenylpyridazin-3(2/7)-one 46 in methanol or a methanol acetic acid mixture. The electron-poor carbon atom of the polarized carbon-carbon double bond of 47 is the electrophile attacking C-4 of the 5-aminopyridazinone 46. Imino-enamine tautomerization of the intermediate is followed by ring closure and subsequent loss of acetone and carbon dioxide affording the reaction products 48 as stable crystalline solids in 70-90% yield (Scheme 9) <2000T2473>. 

Only two examples of the synthesis of pyrrolo[3,4-r-]pyridazines that begin with a pyridazine have been reported. The first involves a Diels-Alder reaction. Thus pyridazine 88 under thermal conditions provides the heterodiene 89 intermediate with loss of CO2, which is trapped / situ with A -phenyldiazamaleimide to form 90 in the yields shown (Scheme 8) <20010L3647>. Alternatively, the thiadiazole 1,1-dioxide 91 can produce 89 by loss of SO2. 

Makhluf J. Haddadin was born in Main, Jordan. He holds B.S. and M.S. degrees (Professor C. H. Issidorides) from the American University of Beirut and a Ph.D. degree from the University of Colorado, USA (Professor A. Hassner). He was a research fellow at Harvard University (Professor L. F. Fieser). The art of heterocyclic chemistry has been his main hobby as he worked on heterocyclic steroids, isobenzofurans, isoindoles, quinoxaline 1,4-dioxides (the Beirut reaction), pyridazines, tetrazines, 277-indazoles, and other heterocycles. He rejoined his alma mater in 1964 and currently serves as professor of chemistry. He was vice-president for academic affairs (1987-99). 

Pyridazine 3-carbaldehyde can be prepared from 3-hydroxymethylpy-ridazine by oxidation with selenium dioxide (82BSB153). Its 2-oxide was obtained similarly (78JMC1333). Contrary to aromatic aldehydes, py-ridazine-4-carbaldehydes behave differently under the reaction conditions typical for benzoin condensation or cyanhydrin formation. In the first case, a crossed Cannizzaro reaction takes place and, with an equivalent amount of hydrocyanic acid, compound 80 is obtained. This is transformed with acetic anhydride into a mixture of E- and Z-isomers of 81. On attempted chromatographic separation, the mixture is converted into methyl 4-pyridazinecarboxylate (78JHC637). 

Few reports on the light-induced reactions of pyridazine 1,2-dioxides have been published. Irradiation of pyridazine 1,2-dioxides, first thought to give... 

The primary adducts, cyclohexadiene derivatives, formed by [4+2] cycloaddition of thiophene dioxides with dienophiles, may further undergo [4+2] cycloaddition with the dienophiles. Thus, the adducts 84 of 3,4-di-ferf-butylthiophene dioxide 83 with maleic anhydride and AT-phenylmaleimide further react with these dienophiles to give excellent yields of bis-adducts, which are composed of the endo-endo and endo-exo isomers, 85a and 85b (Scheme 49) [160]. A similar reaction was also observed with 3,4-dichlorothiophene 1,1-dioxide with N-butyl- and A-p-nitrophenylmaleimides (Scheme 50) [133]. The reaction of highly congested thiophene dioxides 87 with 4-phenyl-1,2,4-triazoline-3,5-dione provides a unique pyridazine synthesis since the bis-adducts 88 are converted into the corresponding pyridazines 89 in one pot and in good yields by treatment with KOH in methanol (Scheme 51) [174]. 

The reaction of ethyl 3-formylquinoxaline-2-carboxylate Af/V -dioxide (9) with hydrazine results in the formation ofpyridazino[4,5-h]quinoxalin-l-ol 5,10-dioxide (10) (2,3-benzo-annulat-ed pyrazino[2,3-<7]pyridazin-5-ol).92... 

An unexpected example of the less common N—N bond formation in the preparation of pyridazines is provided by the reaction of 3-methyl-1,2-benzisoxazoles with strong base in the absence of an electrophile (Scheme 122). The reaction, which is postulated to proceed via an o-hydroxyphenyl-azirine, gives about 40% yields of the dihydropyridazines (159) which are very labile with respect to oxidation and tautomerization, but manganese dioxide oxidation without purification of the crude intermediate (159, R = OH) gives a 61 % yield of 3,5-bis(2,6-dihydroxyphenyl)pyridazine (160, R = OH) <89JOC4970>. 

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