Of pyridazine N-oxides

Photolysis of pyridazine N-oxide and alkylated pyridazine iV-oxides results in deoxygenation. When this is carried out in the presence of aromatic or methylated aromatic solvents or cyclohexane, the corresponding phenols, hydroxymethyl derivatives or cyclohexanol are formed in addition to pyridazines. In the presence of cyclohexene, cyclohexene oxide and cyclohexanone are generated. 

When nitration of pyridazine N-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the N-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

When 3-cyclopropenyl ketones (230), formed by irradiation of pyridazine N-oxides (229), were heated with n-butylamine under reflux for 1 h or stirred at room temperature for 3-4 h a mixture of pyrroles was formed in 80% yield (equation 151). ... 

Nucleophilic substitution of pyridazines had been limited to reactions of pyridazine N-oxides or halogen-substituted pyridazines (84MI2). One report of substitution of hydrogen at the C-5 position of a pyridazine has appeared. Reaction of methoxide, morpholine, or N-methylpiperazine with 4-substituted pyridazine 201 gives mixtures of ring-substituted products 202 and 203, with minor amounts of the 4-(a-substituted benzyl)pyridazines 201 and 204 (84M1171) (Scheme 1). 

Many studies on electrophilic and nucleophilic reactions of pyridazines and pyridazine N-oxides show their marked similarity to those of pyridines and their N-oxides. There are, however, some differences in nucleophilic substitution of pyridazine N-oxides, position fi to the N-oxide group being more reactive than a- and y-positions. 

Photoreactions of pyridazine N-oxides have been misinterpreted in part. Thus, the reported hydroxymethylation of some pyridazine N-oxides ° with concomitant loss of oxygen is probably due to secondary reaction of the parent pyridazine. Igeta et al. reported on the photochemistry of several pyridazine N-oxides that resulted mainly in deoxygenation " in the presence of benzene, toluene, or cyclohexane, the hydrocarbons were oxygenated to give phenols or cyclohexanol in moderate yield. Cyclohexene gave cyclohexene oxide and cyclohexanone in a ratio of 5 1 and polymethylbenzenes, the corresponding phenols or hydroxymethyl derivatives. ... 

Treatment of pyridazine 1-oxides with phosphorus oxychloride results in a-chlorination with respect to the N-oxide group, with simultaneous deoxygenation. When the a-position is blocked, substitution occurs at the y-position. 3-Methoxypyridazine 1-oxide, for example, is converted into 6-chloro-3-methoxypyridazine and 3,6-dimethylpyridazine 1-oxide into 4-chloro-3,6-dimethylpyridazine. 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

There are several examples of replacement of methoxy and ethoxy groups in substituted pyridazine N- oxides, with ammonia or hydrazine producing the corresponding amino and hydrazino compounds. 

Methylpyridazine can be oxidized with selenium dioxide to give 3-formylpyridazine, and methyl groups attached to any position in pyridazine N-oxides are transformed with pentyl nitrite in the presence of sodium amide in liquid ammonia into the corresponding... 

Pyridazines form complexes with iodine, iodine monochloride, bromine, nickel(II) ethyl xanthate, iron carbonyls, iron carbonyl and triphenylphosphine, boron trihalides, silver salts, mercury(I) salts, iridium and ruthenium salts, chromium carbonyl and transition metals, and pentammine complexes of osmium(II) and osmium(III) (79ACS(A)125). Pyridazine N- oxide and its methyl and phenyl substituted derivatives form copper complexes (78TL1979). 

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the N-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the jV-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

Pyridazine N- oxides react with benzyne to give a mixture of 1-benzoxepin (129) and arylpyridazine (130), while N- acetylpyridaziniumimide forms a cycloadduct (131) which is further transformed into (132) and (133) (Scheme 44). 

Tsuchiya, T., Arai, H. and Igeta, H. (1973) Photochemistry - IX. Formation of cyclopropenyl ketones and furans from pyridazine N-oxides by irradiation. Tetrahedron, 29 (18), 2747-2751. 

A few examples of Mannich reactions exist in the series. Pyridazine N-oxides, substituted at the 3- or 5-position by hydroxy, are alkylated at either of the vacant ring positions, although activated methyl groups may react preferentially (68CPB939 73CPB1510 75CPB923). 

---