Pyridazines 2- chloro

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... 

Pyrido[2,3-d]pyridazine, 1 -chloro-4-hydrazino-biological activity, 3, 261 Pyrido[2,3-(i]pyridazine, 4-chloro-l-hydrazino-biological activity, 3, 261 Pyrido[2,3-(i]pyridazine, 5,8-dichloro-nucleophilic substitution, 3, 242 Pyrido[2,3-(i]pyridazine, polyhalo- H NMR, 3, 234... 

H-Pyrimido[l, 2-6]pyridazin-2-one, chloro-nucleophilic displacement reactions, 3, 343 2H-Pyrimido[l,2-6]pyridazin-2-one, 7-chloro-synthesis, 3, 354... 

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