3-Chloro-6-methoxypyridazine

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. 

Reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia exhibit characteristics consistent with a radical chain mechanism for substitution (8UOC294). 

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. ... 

Pyridazine and its derivatives were substituted with nucleophilic radicals. They react either with 1-formylpyrrolidine or with A/-acetylproline in the presence of radical generators to give 5-substituted pyridazines (78TL619 86MI6). Also, reactions of 3-chloro-6-methoxypyridazine with ketone enolates in liquid ammonia show typical characteristics of a radical chain (SrnI) mechanism, and ketones 105 are obtained (81JOC294). 

Methoxy-6-phenylpyridazine (74), prepared from 3-chloro-6-methoxypyridazine via Suzuki phenylation, has been utilized as a starting material in an alternative route for the synthesis of the antidepressant drug Minaprine [4-methyl-A-(2-morpholin-4-ylethyl)-6-phenylpyridazin-3-amine] (78) [47]. 

Transetherifications of alkoxy and aryloxy heterocycles with alkoxides have been observed (Sections III,B and IV, B). In 2,4-dialkoxyquinazoline, only the 4-alkoxy group exchanges. When 3-chloro-6-methoxypyridazine was treated with sodium alkoxides. 

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. 

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... 

The efficient At-nitration of secondary amines has been achieved by transfer nitration with 4-chloro-5-methoxy-2-nitropyridazin-3-one, a reagent prepared from the nitration of the parent 4-chloro-5-methoxypyridazin-3-one with copper nitrate trihydrate in acetic anhydride. Reactions have been conducted in methylene chloride, ethyl acetate, acetonitrile and diethyl ether where yields of secondary nitramine are generally high. Homopiperazine is selectively nitrated to At-nitrohomopiperazine or At, At -dinitrohomopiperazine depending on the reaction stoichiometry. At-Nitration of primary amines or aromatic secondary amines is not achievable with this reagent. 

Chloro derivatives of 4,5-dichloropyridazin-3(2//)-one and 4-chloro-5-methoxypyridazin-3(2//)-one have been synthesized by treating the pyridazinones with NaOCl in acetic acid <2005S1136>. These pyridazinones can be used as reagents for the chlorination of active methylene compounds (see Section 8.01.8.2). 

Inductive effects can sometimes influence product orientation. Whereas 3-methyl-6-methoxypyridazine methylates only at N-2, the 6-chloro- and 6-iodo analogues gave 21 and 22%, respectively, of the N-l product (67ACS1067). 

Groups in the 4-position influence the direction of N-oxidation largely through their inductive effects. 4-Chloro-3,6-dimethylpyridazine gave a 2 1 ratio of the isomeric 1- and 2-oxides (63CPB337), but the low yield (17%) of 1- and 2-oxides (2.5 1) isolated from 3,6-dichloro-4-methoxypyridazine (62CPB643) may imply some + M effect of methoxy. 

Although it is known that a chlorine atom at the 4-(or 5-)position is more reactive than at the 3- or 6-position for nucleophilic substitution, 3-acetamido-(or amino-)5-chloro-6-methoxypyridazine is resistant to hot aqueous sodium hydroxide and 30% sodium hydrogen sulfide solution, but susceptible to solvolysis in acetic acid containing anhydrous potassium acetate to yield the 5-hydroxy derivative. 

The introduction of a second amino group by halogen replacement requires more drastic conditions. 3-Amino-6-chloropyridazine is converted into 3,6-diaminopyridazine in poor yield the reaction between 3,6-dichloropyridazine and most aliphatic amines stops at monosubstitution, but with aromatic amines 3-mono- and 3,6-disubstituted aminopyridazines have been obtained. Similarly, 3-alkylamino-6-chloropyridazines failed to react with aniline and 3,5-diamino-6-methoxypyridazine could not be produced from 3-amino-5-chloro-6-methoxypyridazine even at elevated temperatures. 

Oxidation of 4-methoxypyridazine has been carried out with hydrogen peroxide in acetic acid and a mixture of 4-methoxypyridazine 1-oxide (11%), 2-oxide (8%), and 4(l T)-pyridazinone (2%) was isolated,the last compound resulting from hydrolysis. If the reaction temperature is raised to 100°, in addition to the foregoing three compounds l-methyl-4(l//)-p3Tidazinone is formed in very low yield. Of other alkoxypyridazines to be mentioned, 6-chloro-3,4-dimethoxypyridazine when oxidized with monoperphthalic acid yielded only the 1-oxide in 50% yield. 

Other, more complex halopyridazine A-oxides are known. 5-Amino-3,4- and 4-amino-3,5-dichloropyridazine form the corresponding 1-oxide, but 3,6-dichloro-4-methoxypyridazine is oxidized with monoperphthalic acid in ethereal solution to yield a mixture of the 1-oxide (12%), 2-oxide (5%), and 6-chloro-4-methoxy-3(2A)-pyrid-azinone and 6-chloro-4-methoxy-3(2A)-pyridazinone (up to 7%). Of aminopyridazines, the 3 isomer gives a resin with monoperphthalic acid, while the 2-oxide resulted from oxidation with... 

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. ... 

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. ... 

In 1995, Queguiner reported a new route to antihypertensive 5,6-diarylpyridazin-3(2//)-ones starting from 4-acetyl-6-chloro-5-iodo-3-methoxypyridazine (79) [34]. 79 was synthesized of 79 from 6-chloro-4-(l-hydroxyethyl)-5-iodo-3-methoxypyridazine (37) by oxidation with Mn02 or PCC. The new route involves a chemoselective Suzuki arylation of a C—I over a C—Cl bond on a pyridazine nucleus. In a first Suzuki reaction, C-5 selective arylation of 79 could be obtained using only a slight excess of arylboronic acid. Subsequently, the obtained 4-acetyl-5-aryl-6-chloro-3-methoxypyridazines (80) were transformed into unsymmetrically arylated 4-acetyl-5,6-diaryl-3-methoxypyridazines (81) via a second Suzuki reaction. For this second arylation, an excess of arylboronic acid (2 equivalents) was used. By using 4 equivalents of 4-chlorophenylboronic acid on 79 symmetrically arylated 4-acetyl-5,6-bis(4-chlorophenyl)-3-methoxypyridazine was obtained in 85% isolated yield. 

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