Pyrido pyridazines, reaction with

The slightly lower lowest unoccupied molecular orbital (LUMO) energy of pyrido[3,4-r71pyridazine 5 compared to its isomer [2,3-r7] 6, calculated by the AMI method <1985JA3902>, explained the shorter time required for the pyrido[3,4-r7j-pyridazine to complete the [4+2] cycloaddition reaction with cyclic enamines of different ring sizes <1995M211, 2001ARK21>. 

The 4-aminopyridine derivative 92, prepared from the reaction of ethyl benzoylacetate and malononitrile dimer 91, undergoes the coupling reaction with aromatic diazonium salts to afford azo derivatives such as 93. Under refluxing conditions in ethanolic sodium hydroxide, these azo compounds cyclize to pyrido[3,2-f]pyridazines and pyrido[3,2-r]-pyridazino[2, 3 - ]quinazolines (Scheme 15) <2005AP329>. 

Employment of pyrido[3,4-d]pyridazine derivatives (18) as azadienes in inverse electron-demand Diels-Alder reactions with 1-pyrrolidino-l-cyclopentene, or its six-membered homologue, provides a good route to the isoquinolines (19) after aromatization of the dihydroisoquinoline intermediates (Equation (2)) <92TL7173>. 

In the displacement reaction with sodium ethoxide, the 4-chloro group in ethyl 4-chloro-6-flu-oro-7-(4-tolylsulfanyl)pyrido[2,3-r]pyridazine-3-carboxylatc (2) shows the higher reactivity compared to the fluorine in the 6-position (compare also the reaction with amines below), although the 4-ethoxy compound 5 is obtained in only 30% yield.9... 

An early synthesis of the pyrido[2,3-J]pyridazine system starts from 2-acetyl nicotinic acid 52 a hot aqueous solution of this acid reacts with phenylhydrazine to give 8-methyl-6-phenylpyri-do[2,3-cf]pyridazin-5(67/)-one. Reaction with 4-nitrophenylhydrazine occurred similarly.53 Reactions of hydrazines with other 2-acyl-,54 2-aroylnicotinic acids,48,5S-15I-152 Gr 2-acetylnico-tinic acid A-oxide, e.g. to give 13,56 are known. 

Position 6 of pyrido[2,3-r7]pyridazine-5,8(677,7i/)-dione can be alkylated by a Mannich reaction with formaldehyde/morpholine to give 13.91... 

The parent pyrido[2,3-d]pyridazine has been used as an azadiene in inverse-electron-demand Diels-Alder reactions with pyrrolidin-l-ylalkenes. After the aromatization of the intermediate dihydroquinolines by elimination of pyrrolidine this represents a route to 6,7-disubstituted quinolines.155... 

Methylmagnesium iodide undergoes addition to pyrido[2.3-c/]pyridazine to give a mixture of the 5,6-adduct 9 (20 %) and the 7,8-adduct 10 (80 %). The corresponding reaction with methyl-lithium also gives a mixture of 9/10 in a 40 60 ratio.3... 

Pyrido[3,2-c]pyridazine affords 4-(indol-3-yl)pyrido[3,2-c]pyridazines 2 in 28-65% yield by reaction with indoles in isobutyl alcohol at 100 °C for 30 hours.110... 

When the reaction with hydrazine is performed at room temperature, as with diethyl 2-methyl-6-(4-tolyl)pyridine-3,4-dicarboxylate in chloroform, the pyridine-3,4-dicarbohydrazide results. This may be converted into the corresponding pyrido[3,4-cf]pyridazine-1,4(2fl, 3//)-dione by refluxing with hydrazine in ethanol (vide supra). 

Pyrido[3,4-rf]pyridazines 6 bearing one, two, or three aryl substituents in the pyridine moiety are accessible from 4,5-diaroylpyridazines by condensation reactions with ethyl aminoacetate or benzylamine and l,8-diazabicyclo[5.4.0]undec-7-ene as base.131... 

In forcing conditions with excess of reagents the 5,8-bis derivative was obtained in the above cases, with hydrazine and with sulfur nucleophiles. Other authors have also observed selective reactions in the pyrido[2,3-[Pg.242]

Few reactions of this type are recorded. The azidopyridazinone ester (349) on reduction with triethyl phosphite, hydrazine or borohydride furnished the pyrido[2,3-c]pyridazin-7-one (350) (79JHC1559), whilst an A-aminopyrido[2,3-c]pyridazine (352) resulted from the... 

In the following sections, physicochemical properties, syntheses, reactions, and the utilization of the most important compounds are discussed. Within the individual sections, the pyrido[l,2-h][l,2]oxazines and their ben-zologs, followed by pyrido[l,2-ft][l,2]thiazines, pyrido[l,2-h]pyridazines, and their benzologs, are dealt with. 

The reaction of 2-phenyl-5(4//)-oxazolone (150) and 3-[( )-2-N,N-dimethylaminoethenyljpyridazine (149) in boiling acetic acid afforded 7-benzamido-8//-pyrido[l,2-b]pyridazin-8-one (151) (91BSB533). Treatment of dianion 152 with 1,4-dichlorobutane at -78°C gave 7,llh-diphenyl-2,3,4,llh-tetrahydro-l//-pyrido[2,l-fl]phthalazine (153) (86JHC13). 

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-... 

Pyrido[2,3-, pyridazine derivatives 48 have been synthesized by refluxing equimolar amounts of an appropriate 5-benzylidene-2,2-dimethyl-l,3-dioxane-4,6-dione 47 with 5-amino-6-phenylpyridazin-3(2/7)-one 46 in methanol or a methanol acetic acid mixture. The electron-poor carbon atom of the polarized carbon-carbon double bond of 47 is the electrophile attacking C-4 of the 5-aminopyridazinone 46. Imino-enamine tautomerization of the intermediate is followed by ring closure and subsequent loss of acetone and carbon dioxide affording the reaction products 48 as stable crystalline solids in 70-90% yield (Scheme 9) <2000T2473>. 

An aza analog of phthalazine 240 (pyrido[3,4-r/]pyridazine skeleton) was obtained via intramolecular addition-elimination reaction in azaphthalohydrazide 239 with the loss of hydrazine (Equation 56) <1997T8225>. In a similar approach also the 5,6-dihydro[l,2,3]triazolo[4,5-r/]pyridazin-4,7-dione skeleton was constructed <2002JHC889>. 

Similarly, reaction of hydrazine hydrate with pyridinedicarboxylates 281 in boiling alcohol, followed by cyclization of the resulting dihydrazides 282, gave the pyrido[3,4-r/ pyridazine-l,4-diones 283, where deacetylation has occurred during the formation of 282 (Equation 21) <1997T8225>. 

Ring transformation of ethyl 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- pyrimidine-5-carboxylates 317 with 80% hydrazine hydrate in boiling ethanol gave a mixture of 5-methyl/allyl/benzylamino-l,2,3,4-tetrahydro-l,4-dioxopyr-ido[3,4-i/ pyridazines 318, pyrido[2,3,4-< <7]pyridazino[3,4-/ [l,2,4]triazepines 319, and a low yield of 2,3,4,6,7-penta-azaphenalene 320. The reaction of 317 with hydrazine hydrate was also performed without a solvent in an oil bath at 125 °C for 1 h to give the same products, but higher yields of 318 and lower yield of 319 as well as traces of 320 were obtained (Equation 25) <1997FA657>. 

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