3 -Pyridazinone formation

The Michael-type addition of maleic hydrazide and other pyridazinones to activated alkenes, such as methyl acrylate, acrylonitrile, methyl vinyl ketone and other a,/3-unsatu-rated carbonyl compounds, results in the formation of mono-lV-substituted products. 

Scheldt and Chan have shown that NHC promoted homoenolate formation and addition to azomethine imines 37 generates pyridazinones 41 with high diastereoselectivity, via a proposed highly organised transition state 40 due to a key hydrogen bonding interaction (Scheme 12.6) [12]. 

The reaction of the 5-substituted-2-methyl-3(2-77)pyridazinone 383 with nitrile imine 384 generated in situ from the corresponding hydrazonoyl halide has been shown to afford 387 rather than 388. The formation of 387 is believed to proceed via the intermediacy of 385 (Scheme 33) <2000JST13>. 

Tetrahydropyrano[3,2-r ]pyridazinone derivatives 741 were prepared from the reaction of atylhydrazonoacetyl-acetone 739 and PhCHO in glacial AcOH in the presence of NaOAc, in a single synthetic step, via the formation of diphenylheptadienearylhydrazone intermediate 740 (Equation 63) <1989IJB167>. 

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]. 

Reaction of hydrazides 62 with acid chlorides in benzene leads to the formation of the diaroylhydrazines 67 from which, on cyclization with phosphorus oxychloride and an HCl/AcOH mixture, the corresponding 1,3,4-oxadiazoles 68 and pyridazinones 69 are formed, respectively (Scheme 20) (93CCC1925). 

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. 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

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>. 

The formation of pyridazines from 1,4-ketoacids (10) or their esters and unsubstituted or substituted hydrazines is one of the most widely used methods of synthesis. It is possible to conduct the reaction in a single step or via the intermediate hydrazones or semicarbazones. The resulting 4,5-dihydro-3(2.fif)-pyridazinones (11) are then converted into the corresponding 3(2fl )-pyridazinones (12) upon dehydrogenation. Bromine in glacial acetic acid is the commonest and most useful... 

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. 

The steric effect has an important influence on pyridazine formation. This is particularly the case when the double bond of the anhydride is incorporated in a cyclic system, or with cyclic 1,2 diesters. At least four types of products can be produced and they were identified as a monohydrazide as 24, a dihydrazide as 27, an iV-aminomaleimide derivative as 25, or a pyridazinone as 21. The dihydrazides are relatively easily converted into pyridazinones when heated with excess hydrazine or in dilute hydrochloric acid, and treatment with nitrous acid has the same effect. - ... 

A detailed investigation of the preparation of 3,6-dichloropyridazine from maleic hydrazide and POCI3 showed that the product can be contaminated by two other components, 6-chIoro-3(2 I)-pyridazinone and 66.311,428,429 ipj g former, as the attacking nucleophile, is responsible for the formation of 66. Likewise, reaction conditions have been found of importance when preparing 3-chloro-4-methyl-pyridazine and here structure 67 has been proposed for the by-product. ... 

During aminolysis side reactions may occur, the most common being the solvolytic displacement of the halogen or methoxy group with the formation of pyridazinones or methoxypyridazines. ... 

Analogous reactions are known also with 4-(or 5-)methoxypyrid-azine 1 -oxides. Examples are the formation of l-methoxy-(or ethoxy-)-4(l//)-p50 idazinone (together with 4-hydroxypyridazine 1-oxide) from 4-methoxy(or ethoxy)pyridazine 1-oxide and 1,3,4-trimethoxy-6( 1 A)-pyridazinone from 3,4,6-trimethoxypyridazine 1-oxide, while 5-methoxypyridazine 1-oxide gave exclusively 2-methy l-3(2A)-pyrid-azinone 1-oxide. 

Derivatives of 3(2if)-pyridazinone are stable to acids, but those of 4,5-dihydro-3(2.ff)-pyridazinones, readily accessible from 1,4-keto-acids and hydrazines, are labile to acids, alkalis, and chlorine. Decomposition results in the formation of substituted butyric acids 123,129,136,146,146,162 lability of 5-substitutcd 3-methyl... 

Frolov et al. [19] reported the formation of oxazole ring (vi) by the reaction of 5-amino-4-hydroxy-3(2H)-pyridazinone with various carboxylic derivatives using a microwave assisted procedure. 

An interesting example of carbon-carbon bond formation represents the reaction between 3(2//)-pyridazinone and pyridine A -oxide in the presence of platinized palladium-carbon catalyst at 150°C to give, in 2% yield, 6-(pyridyl-2 )-3(2//)-pyridazinone. Pyridazine itself did not react (78YZ67). 4,5-Diacylpyridazines were prepared from pyridazine and the corresponding aldehydes according to the Minisci reaction (78M63). 

Protected /3-D-ribofuranose and 3(2//)-pyridazinones gave the N-glucosides, whereas 4-amino-3-chloro-6(l//)-pyridazinone afforded the O-glycoside (87MI27). In the formation of pyridazine cyclonucleosides, either the 2 - (75) or 5 -hydroxy group (76) was involved in ring formation (83JOC3765). 

---