3-Chloro-6- pyridazine

Alkoxy- or aryloxypyridazines and the corresponding diethers are usually made from a halo- or dihalopyridazine and an equivalent amount of sodium alkoxide or phenoxide. As by-products 6-alkoxy-3(2 )-pyridazinones may be formed (particularly if aqueous bases are used) or other products may result from alkoxide exchange. A detailed examination of the reaction between 3,6-dichloropyridazine and various alkoxides revealed that the crude products, i.e., 3-alkoxy-6-chloropyridazines, are always contaminated with the starting material and the 3,6-bisalkoxy derivative. Lower temperatures and prolonged heating favor the preparation of 3-alkoxy-6-chloro-pyridazines and similar optimum reaction conditions for the synthesis of 3,6-dialkoxy- and phenoxypyridazines are reported. 

Occasionally, this method is superior to the formation of amino-pyridazines from monohalopyridazines, since aminolysis of polyhalo-pyridazines to aminohalopyridazines is easier to perform. Chloro-pyridazines with attached dimethylamino or methoxy groups are more easily dehalogenated compared with chloropyridazinones. ... 

Halopyridazines were likewise successfully iV -oxidized. 3-Chloro-pyridazine gives the corresponding 1-oxide with perbenzoic acid, whereas the isomeric 2-oxide is prepared indirectly by adding powdered copper to a diazotized solution of 3-aminopyridazine 2-oxide in hydrochloric acid-. " After earlier reported - failures to prepare 3,6-dichloropyridazine A-oxide from 3,6-dichloropyrid-azine and hydrogen peroxide in acetic acid [6-chloro-3(2/ )-p3nrid-azinone was isolated due to hydrolysis], the desired A-oxide was later obtained in low yield. " The yield of 3,6-dichloropyridazine A-oxide can be improved when using monoperphthalic acid in ethereal solution or perbenzoic acid in chloroform. ... 

Various perhalo aromatic compounds as well as a series of heterocyclic precursors, such as, for instance, chloro-pyridazine or -triazine derivatives, gave rise to the corresponding azides, too." -" -" ... 

Greenhouse evaluation in a random herbicide screen showed that 3-chloro-4-methyl-6-[m-(trifluoro-methyl)phenyl)pyridazine was sufficiently active to serve as a lead for a synthesis project. Related 3-chloropyridazines were prepared by a sequence based on the addition of acyl anion equivalents of substituted benzaldehydes to the appropriately substituted acrylate esters. Using 3-chloro-pyridazines as key intermediates, a variety of other 3-substituted-pyridazines were prepared. The effect of altering substitution at each position of the pyridazine and phenyl rings on herbicidal activity was examined. 

The ring contraction of pyridazinones to pyrazoles has been further in-vestigated. l-Phenyl-4,5-disubstituted pyridazin-6-ones are transformed with hot alkali into pyrazoles (264), accompanied sometimes by other substituted pyridazines. Unexpectedly, l-phenyl-4-methylthio-5-chloro-pyridazin-6-one gave in addition to 264 also another pyridazine [Eq. (31)], which originates by the attack of the liberated methylthio anion on the starting compound. 

Oxidative decyanation of phenyl-3-pyridazinylacetonitriles, by passing a brisk stream of oxygen into an aqueous sodium hydroxide/DMSO solution of the substrate containing tri-ethylbenzylammonium chloride, is a convenient method for the synthesis of phenyl 3-pyridazinyl ketones (Scheme 55). Modified reaction conditions allow the one pot conversion of a-(6-chloro-pyridazin-3-yl)phenylacetonitrile into ketones with concomitant hydrolysis or methoxylation of the chloro substituent the direct one pot preparation of 3,6-dibenzoylpyridazine from 3,6-dichloro-pyridazine is achieved in 48% yield <93JHC1685>. 

Diazotisation was reviewed in CHEC-I <84CHEC-l(3B)l>. In general the reaction has limited use because the diazonium salts are very susceptible to hydrolysis to give pyridazinones, with the exception of amino derivatives of 7V-oxides which may react normally to give, for example, chloro-pyridazine 7V-oxides. 

In the reactions described the tert-butyl group survives comparatively drastic conditions although as might be expected the use of aluminium chloride sometimes causes de-tert-butylation.Thecompound2,4-di-tert-butyl-6-(5-chloro-pyridazin-2-yl)methylphenol in dichloromethane with aluminium chloride (3 equivs.), upon stirring at ambient temperature for 15 mins, followed by careful work-up of the mixture by quenching with water over 30 mins, gave the 4-mono tert-butyl product in 73% yield (ref.98). 

A simple fragmentation pattern is also characteristic for chloro-, methyl- and amino-pyridazines. Pyridazinone fragments by loss of carbon monoxide followed by loss of N2 (Scheme 2). 

Pyridazin-3(2H)-ones rearrange to l-amino-3-pyrrolin-2-ones (29) and (30) upon irradiation in neutral methanol (Scheme 10), while photolysis of 5-amino-4-chloro-2-phenylpyridazin-3(2H)-one gives the intermediate (31) which cyclizes readily to the bis-pyridazinopyrazine derivative (32 Scheme 11). 

Direct chlorination of 3,6-dichloropyridazine with phosphorus pentachloride affords 3,4,5,6-tetrachloropyridazine. The halogen is usually introduced next to the activating oxo group. Thus, 1,3-disubstituted pyridazin-6(l//)-ones give the corresponding 5-chloro derivatives, frequently accompanied by 4,5-dichloro compounds as by-products on treatment with chlorine, phosphorus pentachloride or phosphoryl chloride-phosphorus pentachloride. 

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. 

Chloro-4-methyl- and 6-methoxy-4-methyl-pyridazine 1-oxides give the corresponding 4-acetoxymethyl derivatives, while the corresponding 6-substituted 5-methylpyridazine 1-oxides do not react at the methyl group. 

When an acetylamino group is attached at an ortho position the replacement of chlorine is followed by cyclization. For example, 4-acetylamino-5-chloro-l-phenylpyridazin-6(lH)-one is converted with hydrogen sulfide in DMF to 2-methyl-6-phenylthiazolo[4,5- f]pyridazin-7(6//)-one (116). 

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 ... 

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

Amino-6-chloro-4-methyl- and 3-amino-6-chloro-5-methyl-pyridazine and 3-amino-6-methylpyridazin-4(l//)-one are transformed with sodium nitrite in the presence of acid into the corresponding oxo compounds. If concentrated hydrochloric acid is used, in some instances the corresponding chloro derivatives are obtained as side products. On the other hand, 3-, 4-, 5- and 6-aminopyridazine 1-oxides and derivatives are transformed into stable diazonium salts, which can easily be converted into the corresponding halo derivatives. In this way 3-, 4-, 5- and 6-bromopyridazine 1-oxides, 5-chloropyridazine 1-oxide, 3,4,5-trichloropyridazine 1-oxide and 6-chloropyridazine 1-oxide can be obtained. 

Pyridazine itself is best prepared (in about 60-67% yield) from 2,5-diacetoxy- or 2,5-dimethoxy-2,5-dihydrofuran (50ACS1233, 56JOC764) or by hydrodehalogenation of 3-chloro-... 

Hydroxyphthalazin-l(2//)-one is obtained in a smooth reaction between phthalic anhydride and hydrazine hydrate and this is again the starting compound for many 1-substituted and/or 1,4-disubstituted phthalazines. The transformations of 1,4-dichloro-phthalazine, which is prepared in the usual manner, follow a similar pattern as shown for pyridazines in Scheme 110. On the other hand, phthalonitrile is the preferential starting compound for amino- and hydrazino-phthalazines. The most satisfactory synthesis of phthalazine is the reaction between a,a,a, a -tetrachloro-o-xylene and hydrazine sulfate in sulfuric acid (67FRP1438827), alt iough catalytic dehalogenation of 1-chloro- or 1,4-dichloro-phthalazine or oxidation of 1-hydrazinophthalazine also provides the parent compound in moderate yield. 

No natural products or their analogues are included among the pyridopyridazines, but several interesting biologically active compounds have emerged. Some l-chloro-4-hydrazino- and 4-chloro-l-hydrazino-pyrido[2,3-d]pyridazines (460) are very active hypotensives, whilst related dialkoxy compounds have anticonvulsant activity (65CPB586). 

Pyrimidin-4-one, 2,5,6-triamino- N NMR, 3, 64 (78HCA2108) Pyrimido[4,5-d]pyridazin-5-amine, JV-benzyl-8-chloro-2-phenyl-pXa, UV, 3, 337 <76BSF(2)1549) Pyrimido[4,5-d]pyridazin-5-amine, JV-butyl-8-chloro-2-phenyl-... 

Imtdazo[4,5-d]pyridaztne, l-benzyl-4,7-dtchloro-nucleophtlic displacement reactions, 5, 629 Imidazo[l,5-6]pyridazine-5,7(3H,6H)-dione, 4-acetyl-2-phenyl-synthesis, 5, 651 Imidazo[l, 2-6]pyridazines reactions, 5, 628 synthesis, 5, 650 Imidazo[ 1,5-6]pyridazines synthesis, 5, 651 Imidazo[4,5-c]pyridazines reactions, 5, 628-629 synthesis, 5, 651 Imidazo[4,5-d]pyridazines reactions, 5, 629 synthesis, 5, 436, 468, 651-652 3H-Imidazo[l,2-6]pyridazin-2-one, 6-chloro-3-dichloromethylene-synthesis, 3, 355... 

Pyrazino[2,3-d]pyridazin-8-one, 5-chloro-synthesis, 3, 347 Pyrazino[l, 2-a]pyrimidine reactions, 3, 350 structure, 3, 339-340 synthesis, 3, 256, 365 Pyrazino[ 1,2-a]pyrimidine, 2-hydroxy-alkylation, 3, 351... 

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