Pyridazin-6-ones

In neutral and alkaline media, the rate of exchange at the 3 and 6 position of 4-aminopyridazine is independent of acidity but decreases markedly when the media become more acidic. This was interpreted in terms of a rate-determining removal of the 6-proton by deuteroxide ion to give the ylid (XXIV), which reacts with deuterium oxide in a fast step. A similar result for the 3 and 6 positions of py-ridazin-4-one suggests the same mechanism. For reaction at the 5 position, the rate-acidity profile indicated reaction on the free base as did that for the 5 position of pyridazin-3-one, though the appearance of a maximum in the rate at — HQ = 0.8 was anomalous and suggested incursion of a further mechanism. 

A special class of synthesis is the utilization of retro-Diels-Alder (RDA) reactions. A double RDA sequence was used to prepare the pyrimido[l,2-A]pyridazin-3-one 118. In this versatile method both reactants of the parent compound were constructed from cyclopentadiene. The parent compound 117 contains two norbornene units and decomposes on heating in toluene in a double RDA reaction leaving two double bonds in the target heterocycle. Similarily, the parent compound 119 decomposes in a single RDA reaction to yield the benzologue, pyridazino[6,l-3]-quinazolin-10-one 120 (Scheme 13) <2000SL67>. 

The copper-catalysed V-arylation of diazinones by aryl halides, but mainly using 2-fluoro-4-iodoaniline, was described as part of a paper devoted primarily to pyridones. Pyrazin-2-one, pyrimidin-4-one and pyridazin-3-one all reacted successfully but pyrimidin-2-one failed to give any product <06TL7677>. 

Cycloaddition reactions of nitrile oxides with 5-unsubstituted 1,4-dihydro-pyridine derivatives produced isoxazolo[5,4-Z>]pyridines in moderate to good yield. In each case examined, the reaction produced only a single isomer, the structure of which was assigned by NMR spectra and confirmed by X-ray diffraction analysis of 102 (270). A study of the cycloaddition behavior of substituted pyridazin-3-ones with aromatic nitrile oxides was carried out (271). Nitrile oxides undergo position and regioselective 1,3-dipolar cycloaddition to the 4,5-double bond of pyridazinone to afford 3a,7a-diliydroisoxazolo 4,5-<7]pyridazin-4-ones, for example, 103. 

The electroreductive hydrogenation of pyridazine-3-ones performed at the first wave, in acidic or basic medium, takes place at the 4,5-double bond. A further reduction of 4,5- dihydropyridazin-3-ones in basic media, affords the corresponding tetrahydro derivatives (Scheme 139) [252]. 

Over 50 different pyridazin-3-ones were evaluated for biological activity in a wheat (Triticum aestivum L.) test system described previously (1). Briefly, seeds were germinated in 9-cm petri dishes on three layers of filter paper. Pyridazinones were dissolved in acetone and the filter papers were impregnated with 1 ml of acetone solution. After the soluent evaporated, 10 ml of distilled water were added to form an inhibitor concentration of 100 yM. Seeds were planted directly on the moist papers and germinated for 4 days in a controlled environment chamber on a 16-hr photoperiod with 27+lC day temperature and 21+lC night temperature. Light intensity from both fluorescent and incandescent bulbs was 28 klux at dish level. Lipids were extracted and recovered from 1 g of lyophilized shoot tissue, separated into membrane and non-membrane lipids, and analyzed by gas chromatography as described (1). 

Table II. Experimentally Determined 18 2/18 3 Ratios of Differentially Substituted 4-chloro-5-dimethylamino-pyridazin-3-ones and the Corresponding and o Values.

Applying Equation 8, the calculated 18 2/18 3 ratio was very similar to the experimentally determined ratio for all compounds except 2-(4-hydroxyphenyl)-4-chloro-5-dimethylamino-pyridazin-3-one (4.18 calculated vs. 0.84 experimental. Table III). This large difference could be explained by the well known ability of chemicals with phenolic HO- groups to form conjugates which result in bound residues. Therefore, repeating the process of calculation as shown in Equation 8, excluding the 4-chloro-5-dimethylamino-pyridazin-3-one with the 4-hydroxyphenyl substituent in two-position of the heterocycle, results in Equation 9 ... 

Reduction of 2-methyl-4-phenyl-3//-pyrido[l,2-Z)]pyridazin-3-one (44) with NaBH4 in ethanol afforded the 5,6,7,8-tetrahydro derivative [76JCS(CC)275 78JOC2892],... 

When pyridinium A -imine salts 157 were reacted with methylphenyl-cyclopropenone (158, R = Ph, R = Me) in the presence of a base, dihydro-pyrido[l,2-h]pyridazin-3-ones (159) were formed, which subsequently underwent oxidation to produce 3//-pyrido[l,2-h]pyridazin-3-ones (160) under the reaction conditions [76JCS(CC)275 78JOC2892], In some cases the dihydro intermediates (159) could be isolated. 3-Substituted derivatives (157, R = 3-Me, 3-CN R = H) gave mixtures of isomers of 160 (R = 5-... 

Methylation (Me2SO4 or MeOTs) of pyridazin-3-ones (138) followed by deprotonation of the salts (139) gives good yields of the crystalline pyridaziniuni-3-olates(137 R = Me)(vc=o 1550cin ). These betaines (137 R = Me) appear to be unreactive toward dipolarophiles. ... 

The pyridazin-3-ones are interesting because they include herbicides having two different modes of action, distinguished only by small changes in substitution pattern. Thus pyrazon (8) (61GEP1105232) is a photosynthesis inhibitor, while other discussed later are carotenoid biosynthesis inhibitors. The pyridazin-3-one ring is constructed by condensation of phenyl-hydrazine with 3,4-dichloro-2,5-dihydro-5-hydroxyfuran-2-one (9), in turn produced by chlorination of furan-2-carbaldehyde. Amination of (10) then occurs exclusively at the 5-position to give pyrazon (Scheme 4). 

Substitution of a trifluoromethyl group in the 3-position of the benzene ring and alkylation of the 4-amino group, as in norflurazon (16) (69FRP1575643), turns the pyridazin-3-ones into inhibitors of carotenoid biosynthesis. A similar substitution pattern occurs in fluridone (17) (74GEP2537753). The long-established l,2,4-triazol-3-ylamine, known as amitrole, and... 

A rather similar method was reported by Matsuo et al. <78JAP(K)53002497, 87JA2717). 4-Chloro-5-(2-hydroxyethylamino)-3(2//)-pyridazin-3-ones (138) were converted upon treatment with base to the corresponding pyridazino[4,5-6][l,4]oxazinones (139). The ring closure fails for compound (138 R = H) (Equation (17)). 

Another way of obtaining similar compounds is by reaction of 4,5-dichloro-2-methyl-6-nitro-3(2//)-pyridazin-3-one (145) with aminoethanols <78JAP(K)53002499>. The 4-chloro substituent can be converted into pharmaceutically interesting groups. 

A Suzuki coupling of 5-chloro-2-methyl-6-phenyl-2H-pyridazin-3-one (10) ultimately led to diazino-fused indole 11 and cinnoline 12 and allowed access to a novel pyrimidoisoquinoline ring system in a one-pot fashion <02T10137>. Mn(II)-azido networks of the type [Mn(N3)2(L)] like 13 with new 3-D topologies were obtained using both pyridazine and pyrimidine ligands <02CC64>. 

Spectroscopic and crystallographic techniques were used to good effect in the study of pyridazines. Spectrophotometry and H NMR spectroscopy were used to investigate the ligand substitution reactions of pyridazine in Pt(II) coordination complexes <07M1>. The electron densities and tautomeric equilibria of 6-(2-pyrrolyl)pyridazin-3-one 11 and 6-(2-pyrrolyl)pyridazin-3-thione 12 <07ARK114>. Optical, dielectric and x-ray diffraction studies of pyridazine perchlorate showed distinct structural differences between phases <07MI086219>. 

Of comparable origin is the reactivity of 5-chloro-2,6-dimethyl- and 5-chloro-l,6-dialkyl-pyridazin-3-ones with ammonia, amines, aJkoxides, and cyanide ion. The exact relation of the reactivity of these azinones to the corresponding parent compound is not clear without a direct qualitative comparison or kinetic data. 

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