4.5- Dichloro-6 -pyridazinones

Phosphorus pentasulfide in pyridine can be used also for simultaneous substitution of oxygen and chlorine in polysubstituted pyridazinones. For example, 4,5-dichloro- and... 

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

Factor b above is discussed in Sections II, B, 1 II, B, 4 and II, C. A hydrogen-bonded structure such as 221 can account for the facile reaction of 5-bromouracil or for the unique, so-called hydrolyzability of carboxymethylthio-azines (237). The latter may also react via the intramolecular mechanism indicated in 136. The hydrogen-bonded transition state 238 seems a reasonable explanation of the fact that 3,4,6- and 3,4,5-trichloropyridazines react with glacial acetic acid selectively to give 3-pyridazinones while other nucleophiles (alkoxides, hydrazine, ammonia, or sulfanilamide anion) react at the 4- and 5-positions. In this connection, 4-amino-3,5-dichloro-pyridazine in liquid hydrazine gives (95°, 3hr, 60%yield)the isomer-... 

This procedure is similar to the previous one, except that the cyclization happens on the carbon at the /3-position of the nitrogen atom. The synthesis of oxazepine 145 started with the reaction of 4,4 -dichloro-2-methyl-3-(2//)-pyridazinone 142 with 3-benzylamino-l-phenylpropen-l-ol 143. The obtained product 144 was cyclized in basic conditions to the desired 1,4-oxazepine 145 (Scheme 20) <1996JHC583>. 

Several compounds have been synthesized starting from 2-benzyloxymethyl-4,5-dichloro-3(2//)-pyridazinone (133) (Scheme 24) <93H(36)519>. First, it was allowed to react with A-benzylamino-ethanol in water or toluene. The ring closure of the precursors (134) and (136) to oxazinones (135) and (137) was achieved with sodium ethoxide in ethanol. The protection groups could be selectively removed as described in Section 7.19.3.1.2 <8iMl 7i9-oi>. 

Several compounds have been synthesized starting from 2-benzyloxymethyl-4,5-dichloro-3(2//)-pyridazinone (213) (Scheme 36) <93H(36)519>. First, reaction with iV-benzylaminoethanol in water... 

Similar products (220) and (221) were obtained by the intramolecular cyclization of 4-chloro-5-(2-chloroethylamino)-2-methyl-3(2//)-pyridazinone with sodium sulfide. The isomeric pyridazino[4,5- ][l,4]thiazinone has been prepared by cyclocondensation of 4,5-dichloro-2-methyl-3(2//)-pyr-idazinone with sodium 2-aminothioethylate <82CPB1030>. Although the reaction is similar to the one mentioned above, in this case the protecting groups could not be cleaved in the way reported by Zara-Kaczian and Matyus <93H(36)519>. 

Nevertheless, direct chlorinations are also known. 3,6-Dichloro-pyridazine can be converted by means of PCI 5 into 3,4,5,6-tetra-chloropyridazine. In 5,6-(or 4,6-)dichloro-2-phenyl-3(2. I)-pyTid-azinone chlorine enters position 4 or 5, and chlorination of molten 2,6-dimethyl-3(2 I)-pyridazinone gives four substances, two of which were identified as its 5-chloro- and 4,5-dichloro derivatives. l-Methyl-2-phenyl-3,6-pyridazinedione (68) adds bromine or chlorine... 

Reactive chlorine atoms at the 4-position may also be replaced by nitro groups using sodium nitrite in dimethylformamide. Thus, 4,5-dichloro-3(2H)-pyridazinones have been converted into 4-hydroxy-5-nitro-3(2H)-pyridazinones, the replacement of the second chlorine by a hydroxyl taking place simultaneously. ... 

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... 

Rearrangement of 2-phenyl-4,6-dichloro-3(2. f)-pyridazinone into l-phenyl-3-pyrazolone-5-carboxylic acid, described previously, is recorded in connection with the synthesis of some pyrazolone derivatives. ... 

Dichloropyridazine was transformed with sodium 2,2,2-trifluoroethoxide into mono- or di-alkoxy derivatives, but with other sodium fluoroalkoxides, polysubstitution occurred (85CJC3037). 4,5-Dichloro-2-methyl-3(2// )-pyridazinone was used to prepare herbicidal py-ridazino-l,2,4-triazines (87MI16). 

An orientation of leaving group to azinone moiety suitable for activation or, at least, appreciable reactivity exists in various 3-pyridazinones. 6-Bromo- and 6-chloro-2-phenyl-3-pyridazinones react at 20° with methylamine. In 4,6,-dichloro-2-phenyl-3-pyridazin-one, ° inductive meta activation by the partly cationic ring-nitrogen... 

Density functional calculations were used to determine protonation enthalpies, geometric parameters, and dipole moments of pyridazine (94T2405) as well as the total energy values for 4,5-dichloro-2-methyl-3(2//)-pyridazinone [94H(38)1957].The same physical properties were calculated also by MM3 force-field methods (93JA11906) and by statistical methods based on spectroscopic data (94JIC195). 

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