3//-Pyrido pyridazin-3-ones

The final chapter by Istvan Hermecz (Chinoin, Ltd., Budapest, Hungary) deals with bicyclic systems containing one ring junction nitrogen and one heteroatom and their benzologs, i.e. pyrido-oxazines, pyrido-thiazines, pyrido-pyridazines, pyrido-pyrazines, pyrido-pyrimidines and their analogs. Much of this material has not been reviewed for forty years, during which time immense advances have occurred. 

The NMR spectra of pyrido[2,3-d]pyridazine Af-oxides reduced derivatives and quaternary salts have also been studied and alkaline deuterium exchange reactions investigated <77BSF919). 

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... 

Finally, the activated 3-aminopyridazine AT-oxide (381), mimicking 6-aminouracil, cyclizes with /3-ketoesters to give the pyrido[2,3-c]pyridazin-7-one AC-oxide (382). A reduced fused... 

The nucleophilic substitution reactions in pyrido-[2,3-f>]- and -[3,4-f ]-pyridazines in general follow the usual pattern of polyaza heterocycles. Oxo groups in the 2-, 3- and 6-positions of [2,3-f ]-ones, and in the 2- and 3-positions of [3,4-f ]-ones have been... 

Ab initio Hartree-Fock and density functional theory calculations were performed to study the transition state geometry in intramolecular Diels-Alder cycloaddition of azoalkenes 55 to give 2-substituted 3,4,4u,5,6,7-hexahydro-8//-pyrido[l,2-ft]pyridazin-8-ones 56 (01MI7). 

The chemistry of the pyrido[l,2-6][l,2] oxazines (1), pyrido[l,2-6][l,2]thi-azines (2), pyrido[l,2-fo]pyridazines (3) (Scheme 1) and their benzologs (5-13) (Schemes 2 and 3) has not previously been reviewed. Only one publication on pyrido[l,2-b][l,2]oxazines is mentioned in the early review of Mosby in 1961 [61HC(15)1211], and pyrido[l,2-6]pyridazinium (4) is discussed in Comprehensive Heterocyclic Chemistry [84CHEC(2)572]. 

Hexahydro-8//-pyrido[l,2-6]pyridazin-8-ones (23) are rrans-fused bicycles. The H NMR signal for the bridgehead hydrogen appears as triplet in the range of 3.3-3.5 ppm (7 11-12 Hz) and display further splitting [87JCS(P1)2511]. 

Perhydropyrido[l,2-6]pyridazine was prepared from perhydropyrido [l,2-fc]pyridazin-2-one by reduction with LAH (65MI1, 65URP170506 66KGS91 78JA4012), and from 4,4a,5,6,7,8-hexahydro-3//-pyrido[l,2-b] pyridazine by catalytic reduction over Pt02 in acetic acid (68YZ216). Re-... 

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],... 

Photolysis of the zwitterionic pyrido[l,2-h]pyridazines (89) and their 5,6-benzo and 2,3-tetramethylene derivatives afforded 6,7,8,9-tetrahydro-4//-pyrido[l,2-fl]pyrimidin-4-ones (90) and their 8,9-benzo [77H(8)377] and 2,3-tetramethylene derivatives (75JOC2201). Photoinduced ring transformation of 2-phenylpyrido[l,2-fe]pyridazinium-4-olate (73) was investigated in methanol (94T4699). 

Photolysis of A -ylide 132 gave a complex reaction mixture, from which pyrido[l,2-b]pyridazin-4-one 133 could be isolated in 15% yield (76JOC1570). 

Bischler-Napieralski cyclization of pyridazin-6-one 134 with POCI3, and subsequent hydrogenation of the cyclized product 135 over Pt02, gave rise to 2,3,4,6,7,llZ -hexahydro-l//-pyridazino[6,l-fl]isoquinoline (51) (75CPB3056). Treatment of Reissert compound 136 with NaH gave 116-cyano-l, 2,3,116-tetrahydro-4//-pyrido[2,l-fl]phthalazin-4-one (137) (80JHC433). 

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>. 

Alkylation of pyrido[2,3-with alkyl halides in the presence of KOH in MeOH gave the A-alkyl derivatives 102 (Equation 5) <1996X3261 >. 

Similarly, alkylation of the potassium salt of pyrido[3,4- pyridazin-l(277)-one 103 with methyl iodide or allyl bromide gave the N-alkylated derivatives 104 and 105, respectively. On the other hand, benzylation of 103 with benzyl bromide afforded a mixture of A-benzyl 106 and 0-benzyl derivatives 107 (Equation 6) <1996T3261>. 

The 3,4-pyridinedicarboxylic phenylhydrazide (337), however, did cyclize in one of the earliest pyrido[3,4-d ]pyridazine syntheses (1890M(11)133), as did the corresponding iV-unsub-stituted analogue at a higher temperature (12M(33)393,66CPB1010). 

---