Pyridazine 1-oxides halogenation

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. 

Amino groups in pyridazine A-oxides can be diazotized and the diazonium group further replaced by halogens, hydroxy group or hydrogen. So, 3-, 4-, 5- and 6-bromopyridazine 1-oxides can be prepared from the corresponding amino A-oxides. 

Reactivity increases in the diazines as compared with pyridines. 3-Chloropyridazine (910) and 2-chloropyrazine, for example, undergo the usual nucleophilic replacements (cf. Section 3.2.3.10.6.ii) rather more readily than does 2-chloropyridine. 2-, 4- and 6-Halogen atoms in pyrimidines are easily displaced. The reactivity of halogens in pyridazine 1-oxides toward nucleophilic substitution is in the sequence 5 > 3 > 6 > 4. 

As an alternative for the PMF strategy, Stevenson reported the synthesis and use of a pyridazin-3(2FZ)-one with two different halogen atoms namely, 5-chloro-4-iodo-2-methylpyridazin-3(2FZ)-one (4) [15]. While disubstitution could not be completely suppressed, in all cases tested using this substrate only one monoarylated product (129) is obtained. This illustrates the greater reactivity of the C—I bond in the oxidative addition reaction of the catalytic cycle. 

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). 

There are numerous investigations of the reactivity of di- and polyhalo-pyridazines, particularly polyfluoropyridazines. Aminolysis of l-phenyl-4,5-dichloropyridazin-6-one has been studied in detail. In this and other reactions with nucleophiles, the halogen atom at position 4 is substituted preferentially, although a mixture of 4-amino and 5-amino derivatives is formed in the reaction between 4,5-dihalopyridazin-6-ones and ammonia or amines. It has been now firmly established that displacement reactions on 3,6-dichloropyridazine 1-oxide with sulfur nucleophiles take place at position 6 in contrast to nitrogen or oxygen nucleophiles, where the 3-chlorine atom is replaced preferentially. In connection with the previously observed self-condensation of 3-chloro-6-methylpyridazine to a tricyclic product, the reaction between 3,6-dichloropyridazine and pyridine N-oxides was investigated. 3,6-Dichloropyridazine with 2-methylpyridine N-oxide at 100°-110°C affords three compounds (171, 172, and 173). With 2,6-dimethylpyridine N-oxide, an ether (174) is also formed. The isolation of... 

Biomimetic Cu(II) and Fe(II) complexes with bis- and tris-pyridyl amino and imino thioether ligands and vacant (or potentially so) coordination positions (Fig. y are active as catalyst precursors for the solvent- and halogen-free MW-assisted oxidation of 1-phenylethanol by TBHP, in the presence of pyridazine or other N-based additives. Maximum TOF of 5220 h (corresponding to 87% yield) was achieved just after 5 min of reaction time under the low power MW irradiation. The same authors reported" the catalytic activity of related copper, iron, and vanadium systems with mixed-N,S pyridine thioether hgands. The Cu and Fe complexes proved to be useful catalysts in various MW-assisted alcohol oxidations with TBHP, at 80 °C. Thus, 5-containing ligands can also be used to create effective catalyst precursors. 

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