3-methoxypyridazines

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. 

Methoxypyridazine 1-oxide reacts with methyl /3-aminocrotonate in the presence of benzoyl chloride to give a-(6-methoxy-3-pyridazinyl) /3-aminocrotonate (112) which can be converted by mild hydrolysis into the corresponding acetate (113 Scheme 34) <78JHC1425). 

Dichloropyridazine 1-Oxide produces both isomers with alkoxides. However, the ratio is dependent on the size of the alkoxy group. In the reaction with sodium methoxide 80% of 6-chloro-3-methoxypyridazine 1-oxide and 7.5% of 3-chloro-6-methoxypyridazine 1-oxide are formed. Similar results are also obtained with sodium ethoxide, while sodium propoxide affords only 6-chloro-3-propoxypyridazine 1-oxide. Amines react similarly, while only chlorine at the 3-position can be substituted with an azido group to give 3-azido-6-chloropyridazine 1-oxide. 

Hydroxyaminopyridazine 1-oxides are usually formed by catalytic hydrogenation of the corresponding nitro derivatives over palladium-charcoal in methanol, provided that the reaction is stopped after absorption of two moles of hydrogen. 3-Hydroxyaminopyridazine 1-oxide and 6-amino-4-hydroxyamino-3-methoxypyridazine 1-oxide are prepared in this way, while 5-hydroxyamino-3-methylpyridazine 2-oxide and 5-hydroxyamino-6-methoxy-3-methylpyridazine 2-oxide are obtained by chemical reduction of the corresponding nitro compounds with phenylhydrazine. 

An interesting example of the result of conjugation of substituents is the behavior of 3-methoxy-6-methylsulfonylpyridazine studied in our Laboratories. In 6-chloro-3-methoxypyridazine and in 3,6-dimethoxypyridazine, the methoxy groups are unreactive toward sulfanilamide anion, and the chloro group is deactivated relative to... 

Azido-3-methoxypyridazines 1 are transformed into 6,7-dimethoxy-477-1,2.5-triazepines 3 by irradiation in the presence of sodium methoxide. The reaction proceeds via the unstable 277-tautomers 2, which were detected by NMR spectroscopy and can be trapped as the 2-acetyl derivatives 4 by adding acetyl chloride to the crude photolysate.371 The synthesis fails for azidopyridazines lacking the 3-methoxy substituent. 

The irradiation of 4-azido-3-methoxypyridazine (I, R = H 0.5 g, 6.6 mmol) was carried out as described above, except that only 1 cquiv of NaOMe was used. After the mixture had been evaporated the residue was dissolved in ice-cold pyridine (3 4 mL), AcCl (0.4 g, 5.1 mmol) was added, the solution was stirred at 20 C for 5-6 h then poured into ice-water (20 mL). The mixture was extracted with CH2C12 and the extract was washed successively with sat. aq NaHCOj and H20 and dried. Evaporation, followed by chromatography of the residue (alumina, 9% Et20,/CH2CI2) gave the product yield 0.34 g (26%) pale-yellow plates (hexane) mp 112-113LC. 

The N-amination of 3-aminopyridazines occurs next to the amino function (75JHC107 81T1787), while 3-methylpyridazine and its 6-methoxy derivative followed the trend of N-alkylation being aminated at N-2 (72CPB1814). 3-Methoxypyridazine gave the 1-amino salt as expected (71CPB2106). 

Methoxypyridazine when treated with hydrogen peroxide in acetic acid yielded 3-methoxypyridazine 1-oxide, obtainable also by catalytic dehalogenation of 3-methoxy-6-chloropyridazine... 

Chloro or nitro groups at position 4 possess a greater reactivity than chlorine at position 6. Thus, the reaction of 6-chloro-3-methoxy-4-nitropyridazine 1-oxide with acetyl chloride yields 4,6-dichloro-3-methoxypyridazine 1-oxide, which when heated with sodium meth-oxide produces 6-chloro-3,4-dimethoxypyridazine 1-oxide. ... 

With pyridazine iV-oxides with an unsubstituted ortho position, the reaction with phosphorus oxychloride seems to give primarily the ortho chloro-substituted pyridazine. 3-Methoxypyridazine 1-oxide thus gives 3-chloro-6-methoxypyridazine. ... 

There are only two examples of attempted side chain bromination of pyridazine iV-oxides. 3-Methoxy-5-methylpyridazine 1-oxide did not react with iV-bromosuccinimide, but 3-methoxy-6-methyl-pyridazine 1-oxide yielded 6-bromomethyl-3-methoxypyridazine 1-oxide. 

Hydrolysis of 3-chloropyridazine 1-oxide with dilute sodium hydroxide solution gives 3-hydroxypyridazine 1-oxide (identical with that synthesized by another method ) and likewise 6-chloro-3-methoxypyridazine 1-oxide (126) with acetic acid and sodium acetate yields 3-methoxy-6-hydroxypyridazine 1-oxide or its tautomeric form, i.e., l-hydroxy-3-methoxy-6(ljH )-pyridazinone (127). ... 

Compound 127 exists in the l-hydroxy-3-methoxy-6(lH)-pyrid-azinone form, on the basis of UV and IR data. By contrast, 6-chloro-3-methoxypyridazine 1-oxide when heated with 5% sodium hydroxide afforded 6-ehloro-3(2H)-pyridazinone 1-oxide. ... 

Methoxypyridazine 1-oxide (138) when treated with dimethyl sulfate gives the methosulfate (139) this is transformed by potassium cyanide into 3-methoxy-6-cyanopyridazine (140), which can in turn be obtained directly from 138 by the Reissert reaction. ... 

The effect of monosuhstitution in the phenyl ring of selected 3-methoxypyridazines is shown in Figure 4. In general substituents in the 6-phenyl ring decreased the level of activity across a spectrum of weeds in the order meta ortho > para. 

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