Pyridazine ring

Quatemization of various pyridazinethiones and pyridazinyl sulfides is dependent on the substituents attached to the pyridazine ring. For example, 3-methylthiopyridazine and 6-methyl-3-methylthiopyridazine react with methyl iodide to form the corresponding 1-methyl-3-methylthio and l,6-dimethyl-3-methylthio derivatives (85). On the other hand, if a larger group, such as methoxy or phenyl, is attached at the 6-position, quaterniza-tion takes place at position 2 to give 6-substituted 2-methyl-3-methylthiopyridazines (86 Scheme 24). 

Addition of Grignard reagents and organolithium compounds to the pyridazine ring proceeds as a nucleophilic attack at one of the electron-deficient positions to give initially... 

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the A/-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the A-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

Pyridazinecarboxylic acids are more acidic than benzoic acids, due to the electronegativity of the pyridazine ring, but oxopyridazinecarboxylic acids are weaker than the corresponding pyridazinecarboxylic acids (Table 11). 

Some 4,5-disubstituted pyridazines exhibit ring-chain isomerism involving heterospiro compounds. For example, 5-(o-aminophenylcarbamoyl)pyridazine-4-carboxylic acid exists in a zwitterionic form in the solid state, but in a solution of DMSO it is almost exclusively 3, 4 -dihydro-3 -oxospiro[pyridazine-5(2//),2 (l //)-quinoxaline]-4-carboxylic acid (134). The equilibrium is strongly influenced by the nature of the solvent, the substituents on the pyridazine ring and the nucleophilicity of the group attached to the phenyl ring (Scheme 48) <80JCS(P2)1339). 

Ring-opening reactions are best known in the pyridazine ring. For example, the N-aryl cyclic hydrazides (321) undergo ring opening with alkali to give the N-aminoimides (322),... 

A derivative of 5-(indol-2 -yl)dihydropyridazine 44 (R = H) exists in DMSO-iig solution exclusively as tautomer 44a (within the limits of 400-MHz H NMR detection). However, the introduction of methyl groups both into the indole ring and into the pyridazine ring favors a shift of the tautomeric equilibrium... 

The reaction of several substituted imidazo[4,5-c/]-, pyrazolo[3,4-r/]- and triazolo[4,5-zf]pyrid-azines 3 with ynamines, in competition with [4 + 2] cycloaddition, leads to [2 + 2] derivatives 4, which rearrange to l,2-diazocines5.7 8 The reaction seems to be sensitive to the substituents, as replacement of the electron-withdrawing group R on the pyridazine ring of the pyrazolo compound (A = N, B = CH) by chlorine completely inhibits both the [4 + 2] and [2 + 2] cycloaddition reactions. The X-ray structure of the imidazo derivative 5 (R = Ms, A = CH, B = N) reveals a tub conformation of the eight-membered ring. 

Die Reduzierbarkeit cyclischer Hydrazone mit Hydriden ist stark strukturabhangig. 7,8-Dihydro-( 1,3,4-triazolo-[4,3-b]-pyridazin) (I) und auch l,3,4-Triazolo-[4,3-b ]-pyridazin (II) werden durch 10 Mol-Aquiva-lente Natriumboranat in siedendem Athanol mit guten Ausbeuten unter Sattigung des Pyridazin-Rings zu 5,6,7,8-Tetrahydro- (1,3,4-triazolo-[4,3-b]-pyridazin) reduziert2 ... 

Halo-substituted phthalazines react with two equivalents of ynamines to give penta-substituted pyridines 17 through N-N bond cleavage of the pyridazine ring <96H(43)199>. 

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>. 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Ejection of dinitrogen from the triazoline adducts to form the related aziridines was promoted by ultraviolet irradiation (300 nm, benzene) and usually proceeded in excellent yield. An exception was found in the irradiation of the triazoline substrate 59, where cleavage of the cyclobutane ring occurred as the dominant reaction pathway to form the pyridazino norbomadiene 61 (and secondary photoproducts derived therefrom), together with the triazole-4,5-diester 62. A role for the pyridazine ring and the 2-pyridyl substituents in stabilising the diradical intermediate 60 has been proposed for this abnormal outcome (Scheme 8). 

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>. 

Morozov and co-workers electrochemically demonstrated the pyridazine ring fragmentation induced by electron transfer agents. This reaction proceeded by elimination of chloride ions, cleavage of the pyridazine ring, and the formation of phthalonitrile 202 from 201 <00MC34>. 

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

Some derivatives of the [l,2,4]triazolo[4,3-3]pyridazine ring system 33 were subjected to a special type of nucleophilic substitution called vicarious nucleophilic substitution (VSN) <2006TL4259>. In the course of this transformation a formal substitution of az aromatic hydrogen atom - occurring via an addition-elimination mechanism - takes place. 

The pyridazine ring has also been introduced as a substituent into antibacterial carbapenems (131) [364, 365],... 

Therefore, the N(9) radical should be more stable than the N(6) one. That is why both radicals coexist in the system and both N(9) and N(6) deprotonations take place. In the case of the guanine cation-radical, the presence of the carbonyl group in the pyridazine ring brings about two additional effects Deprotonation infringes on this ring exclusively, and double deprotonation leads to the formation of a distonic anion-radical. Scheme 1.25 depicts the differences mentioned. Adhikary et al. (2006) substantiated it experimentally (ESR and UV) and theoretically (B3LYP). 

The usually very powerfully ortto-directing groups such as secondary carboxamide surprisingly do not always lead to ortholithiation on pyrazine and pyridazine rings lithi-ation of 253 and 254, for example, takes place principally (at least kinetically) at the meta and para positions (Scheme 125) . ... 

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