Pyridazine ring closure

Without additional reagents N-Condensed pyridazine ring closure 1,2,4-T riazolo[4,3- ]pyridazines... 

Pyridazine ring closure. 2,2 -Azonaphthalene in methylene chloride added to AIGI3 in the same medium, and refluxed 1 hr. -> benzo[f]naphtho[2,l-c]cinno-line. Y 90%. F. e. with lower yields, and limitations, s. P. F. Holt and C. W. Went, Soc. 1963, 4099. 

Diazocines are isolated, as byproducts, in another photochemical reaction which starts from fluorinated pyridazines. On irradiation of 6 a Dewar diazabenzene derivative is formed, via an electrocyclic ring closure, which looses a fluorinated nitrile to give the azacyclobutadiene system 7. This reactive intermediate then leads vide supra) to the 1,5-diazocine 8.50... 

A further example of an azo coupling reaction with an activated methylene compound (12.91), followed by ring closure to give a pyridazine derivative (12.92) in good yield (66%) was decribed by Gewald and Hain (1984). The reductive treatments of 12.92 give the pyrrole compounds 12.93 and 12.94 in 70% yield (Scheme 12-45). 

The azodiamidine (109) also gives Diels-Alder adducts with simple dienes. The initial adducts readily undergo ring closure to give 1,2,4-triazolo-pyridazines.170... 

Scheme 47 contains syntheses of [l,2,4]triazolo[4,3- ]pyridazine derivatives by ring closure of the triazole moiety. Kozhevnikov et al. reported <2005MC31> an interesting ring transformation treatment of the... 

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>. 

A variety of tricylic compounds [indenopyridazinones (19)] have been prepared as rigid structural modifications of compounds like CI-930 (16) [28,29]. Most of them have been found to retain the positive inotropic and direct vasodilator activity of the freely rotating pyridazinones [28]. Also, hydrazinopyridazines of type (20) have been investigated as structural analogues of CI-914 and Cl-930, respectively. Whereas considerable inotropic activity has been observed in this series as well, ring closure to triazolo[4,3-h]pyridazines resulted in significantly less potent compounds [30]. 

Both isomers of 5-benzoylpyridazine-4-carboxamide were isolated in the solid state (85LA167). The open-chain isomer obtained in the homolytic benzoylation of pyridazine-4-carboxamide is unstable and readily undergoes ring closure during recrystallization or chromatographic purification. 

In 2006 Maes and co-workers described the intramolecular Pd-catalyzed amination of A-(2-chloropyridin-3-yl)pyr-idazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine which involves intramolecular coordination of Pd(ll) to the N-2 nitrogen of the A-arylpyridazin-3-amine entity (Equation 8). A-(2-Chloropyridin-3-yl)pyridazin-3-amine and A-(3-bromopyridin-2-yl)pyridazin-3-amine are intermediates in the auto tandem amination of 2-chloro-3-iodo-pyridine and 2,3-dibromopyridine with pyridazin-3-amine, respectively <2004CC2466, 2006JOC260>. In the former case the ring closure proceeds partly via an SNAr process. 

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>. 

Imino-substituted pyridazine 68 reacted in the 5-position with the lithium enolate of ethyl 2-methylpropanoate 69 via an interesting cascade of nucleophilic addition, ring closure via addition-elimination and tautomerization (Scheme 13) <1996JHC1731>. 

Polyphosphoric acid (PPA) has recently been used for the intramolecular reaction of a properly positioned amino group with the carbonyl group of the lactam function of a pyridazin-3(2//)-one unit as exemplified by the ring closure of 2-(2-aminophenyl)phthalazin-l(2//)-one <2006T10018>. 

A novel ring-closure starting from 2-aryl-l-(12/-l,2,4-triazol-l-yl)alk-3-yn-2-ols has been reported <2006T8966>. Treatment of these alkynols with Bt2 at room temperature yielded 5-alkyl-7-aryl-6-bromo-7-hydroxy-7,8-dihydro-[l,2,4]triazolo[l,2- ]pyridazin-4-ium bromides which upon hydrolysis give 3-alkyl-5-arylpyridazines. 

Ring closure of 1,6-dioximes by treatment with dinitrogen tetroxide in dry ether has been previously used to give the fused pyridazine ring in this heterocyclic system <1996CHEC-II(7)489>, and was used more recently to give the A, A -dioxides 74 (Scheme 53) <2000CHE1091>. 

The central pyridazine ring of the condensed indole derivative in 4.31. was built up by the electrophilic attack of the pyridylpalladium intermediate on the indole ring.38 By blocking the 2-position of indole through substitution the ring closure was directed into the peri-position forming a diazepine ring.39... 

Pyridazine-3,4-dicarboxamide (187) undergoes the Hofmann reaction followed by ring closure to give pyrimido[4,5-c]pyridazine-5,7-dione (188) as the major product. In an analogous type of ring closure, 3-amino-6-methylpyridazine-4-carboxamide reacts with ethyl orthoformate to give 3-methylpyrimido[4,5-c]pyridazin-5-one (68JHC523). 

Cyclocondensation of 3-diethylamino-5-phenylethynyl-l,4-naphthoquinone with hydrazine resulting in the closure of a pyridazine ring is reported. This hydrazine condensation was unknown for peri-acetylenic derivatives of polycyclic quinones <2000TL771>. 

Starting from pyridazine 144, n-phenyl thiazepine 211 can be synthesized. The conversion of the hydroxy group of 144 to chloride 210 with thionyl chloride, followed by ring closure with sodium sulfide monohydrate in dimethyl sulfoxide (DMSO), yielded the desired thiazepine 95 (Scheme 37) <1996JHC583>. 

Another strategy is the conversion of isoxazolo[3,4-d]pyridazin-7(6//)-ones (63) via pyrazole derivatives (64) into the new pyrazolo[l, 5 l,6]pyrimido[4,5-c/]pyridazin-7(8//)-ones (65) by final ring closure with acetic anhydride (Scheme 12) <86H(24)3143>. 

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)). 

---