Pyridazines reactions

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... 

Reaction with protonated form of pyridazine. ) Reaction with neutral form of quinoxaline. ... 

IV-Methylation of polysubstituted pyridazinones is frequently accompanied by some side reactions, mainly substitutions. For example, methylation of 4-nitro-5,6-diphenyl-pyridazin-3(2//)-one with methyl iodide in the presence of sodium methoxide affords... 

Table 10 Experimental and Calculated Ni/N Methylation Product Ratios for the Reaction of 3-X,6-Y-Pyridazines with Methyl Iodide in Acetonitrile...

AIkyI-substituted pyridazine-3(2//)-thiones undergo reaction with methyl iodide at the sulfur atom. Methylation of 4,5-diaminopyridazine-3(2ff)-thione with excess methyl iodide produces 4,5-diamino-l-methyIthiopyridazinium iodide (81JOC2467). 

Disubstituted pyridazine-3,6(l//,2//)-diones add halogens to the 4,5-double bond, followed by dehydrohalogenation to give 4-halo derivatives. 1,2-Disubstituted 5-bromopyridazine-3,6(l//,2F0 diones react with bromine to give the corresponding 4,5-dibromo derivative. The Mannich reaction with 2-arylpyridazin-3(2//)-one occurs at position 4. 

When nitration of pyridazine iV-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the iV-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

Mannich reaction with pyridazinone 1-oxides takes place at the a- or y-positions relative to the iV-oxide group, in contrast to the reaction in the pyridazinone series, where N-substituted products are formed. Pyridazin-3(2FT)-one 1-oxide gives first the corresponding 6-substituted derivative with excess of the reagents, 4,6-disubstituted products are obtained. When position 6 is blocked the corresponding 4-dialkylaminomethyl derivatives are obtained. 

Reaction of various pyridazine derivatives with nitromethane or nitroethane in DMSO affords the corresponding 5-methyl and 5-ethyl derivatives. The reaction proceeds as a nucleophilic attack of the nitroalkane at the position 5. In this way, 3,6-dichloro-4-cyano-pyridazine, 4-carboxy- and 4-ethoxycarbonyl-pyridazin-3(2//)-ones and 4-carboxy- and 4-ethoxycarbonyl-pyridazin-6(lH)-ones can be alkylated at position 5 (77CPB1856). 

A substituted acyl amino group can be introduced by reaction of pyridazine 1-oxide with A-phenylbenzonitrilium hexachloroantimonate 3-A-benzoylanilinopyridazine is formed (75JOC41). 

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the A/-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the A-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

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). 

Alkyl- and aryl-pyridazines can be prepared by cross-coupling reactions between chloropyridazines and Grignard reagents in the presence of nickel-phosphine complexes as catalysts. Dichloro[l,2-bis(diphenylphosphino)propane]nickel is used for alkylation and dichloro[l,2-bis(diphenylphosphino)ethane]nickel for arylation (78CPB2550). 3-Alkynyl-pyridazines and their A-oxides are prepared from 3-chloropyridazines and their A-oxides and alkynes using a Pd(PPh3)Cl2-Cu complex and triethylamine (78H(9)1397). 

Halogenated pyridazines are generally inert as arylating agents in Friedel-Crafts reactions. The only example is the reaction of 3,6-dichloropyridazine with resorcinol and hydroquinone to give 3-aryl-6-chloropyridazines. 

Reaction of pyridazine 1-oxide with phenylmagnesium bromide gives 1,4-diphenyl-butadiene as the main product and l-phenylbut-l-en-3-yne and 3,6-diphenylpyridazine as by-products, while alkyl Grignard reagents lead to the corresponding 1,3-dienes exclusively (79JCS(P1)2136>. 

It has already been mentioned that some radical reactions can occur as side reactions by irradiation of pyridazine derivatives, especially in hydroxylic solvents. 

Protonated pyridazine is attacked by nucleophilic acyl radicals at positions 4 and 5 to give 4,5-diacylpyridazines. When acyl radicals with a hydrogen atom at the a-position to the carbonyl group are used, the diacylpyridazines are mainly converted into cyclo-penta[ f]pyridazines by intramolecular aldol reactions (Scheme 43). 

Pyridazine and its 3-methyl and 4-methyl derivatives react with sym-trioxanyl radicals. The reaction takes place selectively at positions 4 and/or 5, and partially at the a-position to a ring nitrogen atom, leading thus to the formylmethylpyridazine derivatives (80JHC1501). 

Pyridazine carboxylates and dicarboxylates undergo cycloaddition reactions with unsaturated compounds with inverse electron demand to afford substituted pyridines and benzenes respectively (Scheme 45). 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

The most commonly used methods for the preparation of pyridazinesulfonamides are the condensation of aminopyridazines with p-acylaminobenzenesulfonyl chloride and the reaction of halosubstituted pyridazines with sulfanilamide by fusion or in an appropriate solvent. 

The aza-transfer reaction between 3-hydrazinopyridazines and aromatic diazonium salts or heterocyclic diazo compounds affords the corresponding tetrazolo[l,5-6]pyridazines, while 3-hydrazinopyridazine 1-oxide gives 3-azidopyridazine 1-oxide (76TL3193, 76X725). 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

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