Pyridazine 2- -, cyclization

Pyridazin-3(2H)-ones rearrange to l-amino-3-pyrrolin-2-ones (29) and (30) upon irradiation in neutral methanol (Scheme 10), while photolysis of 5-amino-4-chloro-2-phenylpyridazin-3(2H)-one gives the intermediate (31) which cyclizes readily to the bis-pyridazinopyrazine derivative (32 Scheme 11). 

When an acetylamino group is attached at an ortho position the replacement of chlorine is followed by cyclization. For example, 4-acetylamino-5-chloro-l-phenylpyridazin-6(lH)-one is converted with hydrogen sulfide in DMF to 2-methyl-6-phenylthiazolo[4,5- f]pyridazin-7(6//)-one (116). 

Syntheses of this type have been reported only recently (78H(9)1367, 79JOC3524). Unsaturated 1,4-dioximes are transformed by oxidative cyclization into pyridazine 1,2-dioxides... 

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

Early experiments with pyridine-2,3-dicarboxylic mono- and bis-phenylhydrazides were unsuccessful (32JIC145), but later these were cyclized in acetic acid (66CPBIOIO) to give only the 7-phenylpyrido[2,3-[Pg.242]

An important early method simulated the well-known Widman-Stoermer cinnoline synthesis. 3-Aminopyridine-2- or -4-alkenes such as (348) gave pyrido-[3,2-c]- or -[3,4-c]-pyridazines on diazotization and alkaline cyclization (66JCS(C)2053>. 

The only example from a pyridazine intermediate is of the Dieckmann-type used so widely in the pyridopyrimidine field (Section 2.15.5.4.2). The 3-carboxyalkylamino-4-ester (365) is cyclized by strong base to give the pyrido[2,3-c]pyridazine-6-carboxylate (366) (77JAP(K)7733695). 

The vast majority of syntheses of pyrido[2,3-t/]- and pyrido[3,4-t/]-pyridazines fall into this category, resulting from the cyclization of various o-substituted pyridine derivatives (2,3- or 3,4-, respectively) with hydrazine or its congeners. 

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... 

Synthesis of substituted pyridazines using novel cyclization reactions of mono-and dichloroazodienes 99JHC301. 

The intramolecular cyclization of 2-alkynylaryldiazonium salts (Richter reaction) leads not only to 4-hydroxy- but also to 4-bromo- and 4-chlorocinnolines. The behavior of alkynylpyrazolediazonium chlorides differs from that of their benzene analogs. The Richter reaction of the series of alkynylaminopyrazoles gives only 4-halo derivatives of l//-pyrazolo[3,4-c]pyridazines and l//-pyrazolo[4,3-c] pyridazines, and mainly hydroxy derivatives of 2//-pyrazolo[3,4-c]pyridazines. 

A derivative of an isomeric azapurine ring system interestingly exhibits bronchodilator activity, possibly indicating interaction with a target for theophylline. The starting pyridazine 97 is available from dichloro compound 96 by sequential replacement of the halogens. Treatment of 97 with formic acid supplies the missing carbon and cyclizes the intermediate formamide with consequent formation of zindotrine (98) [16]. 

Diazotization of 4,5-diphenyl-3-amino-l//-pyrazolo[4,3-c]pyridazine gave diazonium salt 290, whose condensation with 2-naphthol gave 291, which cyclized to 292 (91H901) (Scheme 62). 

The l,4-dihydropyrimido[l,2- ]pyridazine 101 was obtained by tandem cyclization from [4+2, 6+0] atom fragments by reacting [3-keto nitriles and the 2-cyanopropylhydrazine 100 (Equation 10) <2000MI639>. 

The linearly condensed pyridazino[6,l-A]quinazolines can be synthesized by tandem [6+0 (a)] cyclizations, forming the pyrimidine and the pyridazine rings in the same step. Thus, 1,2,3,4-tetrahydro-10//-pyridazino[6, l+]quinazolin-2,10-dione 108 was prepared by thermal cyclization of 106 or 107 (Scheme 12) <1999RJ0286, 1998RJ0534>. Heating/ra r-2-amino-l-cyclohexanecarbohydrazide with 3-(/>-chlorobenzoyl) propionic acid in toluene, the appropriate 2-(/<-chlorophenyl)-3,4,5 ,6,7,8,9,9 -octahydro-10//-pyridazino[6,l- ]quinazolin-10-one was prepared in 35% yield <1998JHC201>. 

The quinazoline and the pyridazine rings of 110 are formed by tandem cyclizations from [5+1, 6+0] fragments when heating the benzoxazinones 109 with hydrazine or phenylhydrazine (Equation 11) <1996CHJ437, 1996CHJ532>. 

The pyridazine ring of 111 is formed from [4+2] atom fragments in the cyclization of 3-amino-2-chloromethyl-quinazolin-4-one with activated acrylthioamides. The saturated pyridazine ring of 111 aromatized spontaneously to give 112 (Equation 12). Reaction with io-nitrostyrene yielded the 3-nitro analogue of 112 <2003MOL401>. 

Compound 248 treated with (EtOhP in refluxing xylene provides an 89% yield of 19 (Equation 37) <2005AGE7089>. Similarly, [l,2,3]triazolo[4,5- /]pyridazine 249 provided a 68% yield of the corresponding mesomeric betaine 250 (Equation 38). However, reductive cyclizations of the analogous 3-(2-nitrophenyl)-377-[l,2,3]triazolo[4,5-//Jpyrimidine, 3-(3-nitropyridin-2-yl)-3//-[l,2,3]triazolo[4,5-. 

Corsaro and co-workers studied the reaction of pyridazine, pyrimidine, and pyrazine with benzonitrile oxide and utilized H NMR spectral analysis to determine the exact structure of all the cyclized products obtained from these reactions <1996T6421>, the results of which are outlined in Table 1. The structure of the bis-adduct product 21 of reaction of pyridazine with benzonitrile oxide was determined from the chemical shifts of the 4- and 5-isoxazolinic protons at 3.76 and 4.78 ppm and coupled with the azomethine H at 6.85 ppm and with the 5-oxadiazolinic H at 5.07 ppm, respectively. They determined that the bis-adduct possessed /(-stereochemistry as a result of the large vicinal coupling constant (9.1 Hz). Similarly, the relative stereochemistry of the bis-adducts of the pyrimidine products 22-25 and pyrazine products 26, 27 was determined from the vicinal coupling constants. 

Amino-substituted thiazol-4-ylthiazole 317 undergoes diazotization and cyclization to the dithiazolo[4,5-f 4, 5 -tf]pyridazine 318 upon treatment with nitrous acid (Equation 85) <1997JHC1291>. 

Analogously, l,2-diphenyl-4,4-diacetyl- and -4,4-dibenzoyl triafiilvene are reported292 to be transformed by hydrazine to pyridazine derivatives 494, involving attack of the nucleophile at C1 2 and cyclization of intermediate 493 ... 

Pyrimido[4,5-d]pyridazine-2,5-diones were synthesized in a similar manner, employing several hydrazines (R3 = H, Me, Ph) for the nucleophilic substitution prior to cyclative cleavage. Due to the high nucleophilicity of the hydrazines, reaction times for the substitution step could be reduced to 30 min. In the case of phe-nylhydrazine, concomitant cyclization could not be avoided, which led to very low overall yields of the isolated products. 

Condensations with hydrazine also yield pyridazines. For example, Shvartsberg and coworkers treated pen -acetylenic naphthoquinones 156 with hydrazine to give the six-membered pyridazine ring 158 after cyclization <00TL771>. 

New tri- and tetracyclic compounds containing the pyridazine moiety were synthesized in a multistep reaction sequence from commercially available pyridazine 173 <00AP231>. Acid chloride 173 reacted- readily with 174 to yield 175. Cyclized product 176 was then produced by treatment of tethered pyridazine 175 with sodium hydride in an intramolecular SNAr displacement. 

Some special ring closures utilizing cyclization of the pyridazine ring should also be discussed in more detail these are shown in Scheme 48. 

Oxidative cyclization of hydrazones to fused [l,2,4]triazoles by means of cupric chloride was already discussed above for a related pyridazine derivative. The same method was also applied successfully for ring closure of 428 to 429 in good to excellent yields (Scheme 53) <2005T5942>. 

The thermal cyclization of 3-pyridazinylaminomethylenemalonate N-oxide (1052) by heating in diphenyl ether at 250°C for 15 min gave pyrido[2,3-c]pyridazine-6-carboxylate jV-oxide (1053) in 70% yield (72JHC351). 

Triazolo[4,3-6]pyridazine (1404) was prepared in 75% yield, in the cyclocondensation of 3-chloro-6-hydrazinopyridazine and EMME in boiling acetonitrile for 3 hr, or in 94% yield in the cyclization of hydrazinomethy-lenemalonate (195) in boiling acetonitrile for 4 hr (80JHC1527). 

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). 

Substitution of the halogen in 387 and 388 by nucleophiles has also been reported (81M245 83AP697), as has the cyclization of 389 into 390 (83G219). Ethyl l,5-diaryl-3-trifluoromethyl-4-oxopyrazolo[3,4-c/] pyridazin-7-ylacetate afforded bicyclic 5(5-oxopyrazol-3-yl)pyrazolines upon treatment with ethanolic sodium ethoxide (88JHC134). 

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