Pyridazin-4 -ones, 2,3-dihydro

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). 

Pyridazin-3(2H)-one, 4-amino-5,6-diphenyl-methylation, 3, 16 Pyridazin-3(2f/)-one, 2-aryl-Mannich reaction, 3, 20 Pyridazin-3(2H)-one, 6-aryl-4,5-dihydro-reaction... 

A novel class of tricyclic lymphocyte specific kinase (Lck) inhibitors containing the 9,10-dihydro-8//-pyrazolo[l,2-tf]pyrimido[4,5-c]pyridazin-8-one moiety has been reported <2006BML4257, 2006H(68)2037>. The most promising compound, 708, advanced to pharmacokinetic evaluation <2006BML4257>. 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

Pyridazines continued to play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3//-pyridazino 5,4,3-17 acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2//-... 

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. 

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-... 

Substituted 3,5-dihydro-4//-pyridazino[4,5-, ]indol-4-ones 50 <2001H(55)1105, 2002T10137> and 2,5-dihydro-l/7-pyridazino[4,5-7]indol-l-ones 52 <2006T121> have been synthesized from 5-(2-aminophenyl)pyridazin-3(2/0-ones 49 and 4-(2-aminophenyl)pyridazin-3(27/)-ones 51, respectively. For this purpose diazotization of the amino groups was followed by a nucleophilic substitution with sodium azide affording aryl azides. Upon heating of these compounds, the ring-closed products were obtained most probably via the formation of an electrophilic nitrene (Scheme 10). 

The 1,3-dipolar cycloaddition of diarylnitrile imines 98, generated in situ from arylhydrazones with chloramine T or from a-chlorobenzylidenephenylhydrazine with triethylamine, to some 5-substituted 2-methylpyridazin-3(2//)-ones 88, 99-101 has been shown to afford l,3-diaryl-l,5-dihydro-4//-pyrazolo[3,4- ]pyridazin-4-ones 102 regioselectively (Scheme 21) <2000JMT(528)13>. 

Stanovnik and co-workers (100,101) systematically investigated the cycloaddition reactions of diazoalkanes with unsaturated nitrogen heterocycles, such as azolo-[l,5-fl]pyridines, pyridazin-3(2/7)-ones, and [fo]-fused azolo- and azinopyridazines. The Stanovnik group have studied the further transformations of the products and reviews of this chemistry are available. In a typical example, the reaction of 6-chlorotetrazolo[l,5-/7]pyridazine (37) with 2-diazopropane yields the NH,NH-dihy-dro-pyrazolo[4,3-(i]tetrazolo[l,5-/7]pyridazine 38 (102) (Scheme 8.11). The latter substrate reacts with acetone to produce an azomethine imine 39 that thermally rearranges to give the fused dihydro-1,2-diazepine 40. The azomethine imine obtained with glucose can be trapped with methyl acrylate to furnish the C-nucleoside 41 (103). 

Reaction of l-aryl-3-carbethoxy-6-phenyl-l,4,5,6-tetrahydropyridazin-4-ones 718 with activated olefins such as benzalacetophenone, benzalacetone, 3-benzylideneacetylacetone, diethyl 2-benzylidenemalonate, and a-cyano-/3-phenylacrylic acid in the presence of an organic base like pyrrolidine, morpholine, piperidine, or triethylamine gave the corresponding 2,8-dihydro-l//-pyrano[2,3-t7 pyridazines 719-723, respectively. The 1-oxo- and 1-imino derivatives of the pyrano[2,3-r/ pyridazine ring system were also prepared from the respective 6-oxo or 6-imino derivative of the starting pyridazine 718 under the same conditions (Equation 60) <1989IJB733>. 

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). 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

Cyclooctatetraene reacts as a dienophile with 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine to form, upon loss of N2, a cycloocta[4]pyridazine and a tetracyclic bis-Diels-Alder cycloadduct [95LA661]. In a nonpolar solvent, the former produced a dihydrobarrelenofrflpyridazine that could be oxidized (with 4-phenyltriazolinedione) to the barreleno[d]pyridazine, but in a polar solvent it gave a dihydrocycloocta[d]pyridazine in a multistep process. X-ray crystal structures of some of these compounds have been obtained. The attempted dehydrogenation of 4,4a-dihydro-5//[ 1 ]benzopyrano[4,3-c]pyridazin-3(2//)-ones with m-CgH NC SOjNa unexpectedly led to new 5-hydroxy[ 1 ]benzopyrano[4,3-c]pyridazin-3(2//)-ones [95JHC79]. 

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