Hydrazines 3 -pyridazinones

One of the most common and versatile methods for the S3mthesis of polyfunctional pyridazines consists in the formation of the diazine ring from maleic anhydride or its mono- and disubstituted analogs and an unsubstituted, mono-, or disubstituted hydrazine. Pyridazinones of the types 21 and 22 are obtained in good yields. 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

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-... 

It was found that the reaction of the lactone glycosides (5/ )- and (5S)-5-methoxy-5-(2,3,5-tris-(9-benzoyl-/3-D-ribofuranosyl)-2(5//)-furanone270and271 with hydrazine hydrate in methanol gave two products the pyridazinone 272 and a mixture of diastereomeric A -aminopyrrolinones 273, which could not be separated, in yields of 26 and 71%, respectively (Scheme 70) (87JOC4521). 

Pyridazinone (39), prepared via reacting 37 with A/, A -dimethylace-tamide dimethyl acetal, afforded pyrazolo[4,3-c]pyridazine (38) upon treatment with hydrazine (Scheme 6) (81JHC333). 

The structure of the pyridazine-based antidepressant agent minaprine (34-6) departs markedly from both the older tricyclic drugs and the more recent selective serotonin re-uptake inhibitors. There is evidence that the compound acts via a dopa-mimetic route. Friedel-Crafts acylation of benzene with itaconic anhydride (34-1) leads to the keto-acid (34-2). Condensation with hydrazine leads to the formation of the hydrazine and hydrazide bonds the double bond shifts into the ring to give the fully unsaturated pyridazinone (34-3) this is then converted to the chloride (34-4) in the usual way. The displacement of halogen by the amine on 3-(A -morpho-lino)propylamine (34-5) affords (34-6) [36]. 

The keto-acid function is then converted to a pyridazinone by treatment with hydrazine (35-4). Catalytic hydrogenation then converts the nitro group to an amine (35-5) cyclization of the resulting ortho amino amide by means of a strong acid leads to the formation of the corresponding benzimidazole. There is thus obtained pimobendan (35-6) [37]. 

The quinazolinone moiety (36-3) for the cardiotonic agent prindoxan (36-5) is formed by reaction of diamine (36-1) with carbonyl diimidazole (36-2). Friedel-Crafts acylation of the product with the half-acid chloride from methyl succinate gives the corresponding keto-ester (36-4). The pyridazinone (36-5) is then obtained by condensation of that product with hydrazine [38]. 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

Dicarbonyl compounds with a double bond in the 2,3-position condense with hydrazine to give pyridazines (e.g. 91 — 92). If one of the carbonyl groups in the starting material is part of a carboxyl group or a potential carboxyl group, then reactions with hydrazines or hydroxylamine lead to pyridazinones or 1,2-oxazinones (e.g. 93 — 94 Z = NH, NPh, O). Similarly a cyano group leads to an amino or imino product. 

Only one unrefuted synthesis of this ring system has been reported in the literature (76MIP21700). A mixture of (142) and the desired ring system (143) are reported as the products from the reaction of the anhydride (141) with an excess of hydrazine hydrate in water at reflux temperature for 3.5 hours. If the reaction is carried out using equimolar amounts of the starting anhydride and hydrazine hydrate in aqueous ethanol for 5 days, the formation of the pyridazinone (144) is reported. 

Xanthone is unreactive towards hydrazine and phenylhydrazine. The oxime is obtained by reaction of xanthione (xanthene-9-thione) with hydroxylamine, or from xanthone and hydroxylamine in pyridine. When the oxime is heated in water with phenylhydrazine, the phenylhydrazone is formed. In acid solution, xanthone reacts normally with 2,4-dinitro-phenylhydrazine but xanthone-1 -carboxylic acid (435) gives the pyridazinone (436), possibly via the hydrazone (57JCS1922). When the oxime is heated with phosphorus pentachloride it undergoes a Beckmann rearrangement to give the amide (437) (70MI22300). 

Dihydro-2H-3-pyridazinones 113 are obtained in excellent yields from several methyl 2-siloxycyclopropanecarboxylates with hydrazine hydrate as a reagent75). 

A synthetic approach designed to produce pyridazino[4,5-c]pyridazinones unexpectedly yields pyrrolopyridazines, although in poor yields. The acid-catalyzed reaction between the hydrazine (101) and ketodiesters (102) results in formation of the pyrrolo[2,3-d]pyridazine (103) (Equation (31)) <92JHC1313>. 

Heating of 1-methyl-l-(3-pyridazinyl)hydrazines (15) or their hydrazones at 240-250°C gives exclusively a pyridazino[3,4-t]pyridazine derivative (16). This reaction probably proceeds via a pyridazinone intermediate (17) which undergoes an intramolecular Michael addition leading to the pyridazino[3,4-c]pyridazine (16) (Scheme 3) <89T1793>. 

The synthesis of pyridazinone is by reaction between a hydrazine and a carbonyl carboxylic acid... 

The action of hydrazine or hydroxylamine on certain other nitropyrimidine systems leads to 4-nitropyrazoles and 4-nitrooxazoles [549], When 1,5-disubstituted 4-nitro-6-pyridazinone derivatives are heated in an alkaline medium the derivatives of 4-nitropyrazole are formed with high yields. 1-Substituted 4-nitropyrazole-5-carboxyiic acids [550, 551] or 1-substituted 4-nitropyrazoles [552-554] can be obtained, depending on the conditions. Another promising method of synthesis has been opened up for the production of 4-nitropyrazole derivatives. 4-Nitropyrazole is obtained with a high yield in the reaction of 3,5-dinitro-2-pyridone with hydrazine [555] (Scheme 99). 

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