Pyridazine-l-oxide

Removal of alkoxy groups from 3-(4-, 5-, or 6-)alkoxypyridazine 1-oxides in alkaline medium produces the corresponding hydroxy-pyridazine l-oxides. - - On the basis of UV spectra and pK values for 3-hydroxypyridazine 1-oxides it is postulated that there is a larger contribution of the phenolic structure (128) than of the tautomeric pyridazinone N-oxide structure (129). ... 

Pyridazine-l-oxide (1). Mol. wt. 98.09, m.p. 38-40°, very hygroscopic. The oxide is obtained from pyridazine by reaction with 2 equiv. of H2O2 (30%) in HOAc (88.6% yield). ... 

Likewise, 3-substituted pyridazine-l-oxides react with R-COCl/cyanide or (CH30)2S02/cyanide in analogy to a Reissert reaction thus functionalizing the 6-position, for example ... 

When chloro compounds are treated with sodium azide in ethanol or aqueous acetone the corresponding azides or tetrazolo[l,5-6]pyridazines are obtained. For example, 3-azido-and 4-azido-pyridazine 1-oxides are obtained from the corresponding chloro compounds ... 

Reaction of pyridazine 1-oxide with phenylmagnesium bromide gives 1,4-diphenyl-butadiene as the main product and l-phenylbut-l-en-3-yne and 3,6-diphenylpyridazine as by-products, while alkyl Grignard reagents lead to the corresponding 1,3-dienes exclusively (79JCS(P1)2136>. 

Various pyridazine-A-oxides (including cinnoline A-oxides) have been prepared as potential antitumour agents in Japan [276-278]. Among several 4-nitro-pyridazine 1-oxides tested for activity against rat ascites hepatoma AH-13, 3,6-dimethoxy-4-nitropyridazine 1-oxide (74) has been found to be the most potent compound a minimal effective dose of 5 mg/kg has been estimated [276], Also pyridazine A-oxides of type (75) bearing a bis(2-chloroethyl)ami-nomethyl side-chain at C-6 have been reported to be effective (0.5-5 mg/kg, i.p.) against AH-13 in rats [278]. Both types of compound (74), (75, R = H, Br), however, have been shown to be inactive against mouse lymphoid leukaemia L-1210. 

In the reaction of pyridazine 26 with perfIuoro-(2-butyl-3-propyloxaziridine) 38 both pyridazin-1-oxide 39 and T-(perf1uorobutanoyl)pyridazinium-l-aminide 40 were formed (Equation 9) <1996J(P1)2517>. In CHEC(1984) <1984CHEC(2)1> and CHEC-II(1996) <1996CHEC-11(6)1>, the N-amination with hydroxylamine-O-sulfonic acid and derivatives was covered. 

A similar anodic cyclization167,168 is the oxidation of benzilmonoxime phenylhydrazone to 2,4,5-triphenyl-1,2,3-triazole 1-oxide (83% yield) and of 3-hydroxyiminomethylenamino-6-chloropyridazine to 6-chloro-s-triazole-[l,5-b]pyridazine 3-oxide (28% yield).167... 

Pyridazino[l,2-pyridazine derivatives are easily reduced with either hydrogen over a catalyst or with metal hydrides. Reaction of the pyridazino[l,2- ]pyridazine-l,4,6,9-tetrone (44) with hydrogen over platinum oxide gives the hydrogenated product (45) (66JOC1311). This product can be further reduced with lithium aluminum hydride to give the octahy-dropyridazino[l,2- ]pyridazine (24) (67JA4875). 

Aminopyridine A-oxides can be diazotized and the diazonium salts 757 undergo coupling. These diazonium salts are resonance stabilized. Amino groups in pyridazine A-oxides can also be diazotized and the diazonium group further replaced by other functionality. Nitrosation of 3-amino-l,2,4-triazine 2-oxides and subsequent thermolysis of the diazonium tetrafluoroborate salts affords 3-fluoro-l,2,4-triazine 2-oxides. 

Analogous reactions are known also with 4-(or 5-)methoxypyrid-azine 1 -oxides. Examples are the formation of l-methoxy-(or ethoxy-)-4(l//)-p50 idazinone (together with 4-hydroxypyridazine 1-oxide) from 4-methoxy(or ethoxy)pyridazine 1-oxide and 1,3,4-trimethoxy-6( 1 A)-pyridazinone from 3,4,6-trimethoxypyridazine 1-oxide, while 5-methoxypyridazine 1-oxide gave exclusively 2-methy l-3(2A)-pyrid-azinone 1-oxide. 

Methylation with methyl iodide proceeds normally with 3,6-dimethyl-5-hydroxypyridazine 1-oxide to give the corresponding 5-methoxy derivative, although in low yield, whereas from 4-hydroxy-pyridazine 1-oxide and its 3,6-dimethyl analog the corresponding l-methoxy-4(l/f)-pyridazinones were obtained. - ... 

Dihydropyridazines have not been prepared by direct cycliza-tions reductions of pyridazines and oxidations of reduced pyridazines are known. 3,6-Diphenylp3n idazine is reduced with sodium and ethanol to the 1,2-dihydro derivative and the 1,2-dicarbethoxy analog is formed in a selenium dioxide oxidation of the corresponding 1,2,3,6-tetrahydro compound. 1-Carbethoxy- or 1,2-dicarbethoxy-1,2-dihydropyridazine was obtained similarly from an alkali treatment of 1,2-dicarbethoxyhexahydropyridazine. l,2-Dihydro-3,6-diphenylpyridazine is unstable and oxidizes to the parent pyridazine in the presence of air or on attempted acetylation. ... 

Pyrido 2,3-c pyridazin 6-Ethoxycar-bonyl-5-hydroxy- -2-oxid E9c, 8 3 -[NH - CH=C(COOR)2] - py-ridazin-l-oxid/A ... 

Pyridazin 4-Ethoxy-6-oxo-l-phenyl- 1,6-dihydro- VII/4, 369 Pyrimidin-l-oxid 4,6-Dimethyl-5-hydroxy-2-phenyl- E9b/2, 193 (N-Oxidat.)... 

Oxidation of the [4,3-/ ]pyridazine ring system with potassium permanganate occurs by cleavage of the C(7)—C(8) bond. Thus, 3-phenyl-[l,2,4]triazoIo[4,3-f)]pyridazine was oxidized to 3-phenyl-l,2,4-triazole-5-carboxylic acid (74MI41501). 

Reaction of halopyridazines with hydroxylamine to give hydroxyla-minopyridazine has been achieved only with activated compounds [79H(12)1157, 79JHC861], This has been ascribed to the low nucleo-philicity of hydroxylamine when compared to that of amines or hydrazines. A 3-hydroxylamino group reacted with bromoacetaldehyde at room temperature to give the first example of an imidazo[l,2-ft]pyridazine 1-oxide (8IT1787). 

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