Pyridazine substitution reactions

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... 

Only a few electrophilic substitution reactions have been reported. The nitration of both (110a) and (110b) occurs in position 2 (68MI31700, 72CPB936). The nitration of 4,7-dichlorofuro[2,3-mixed acid resulted in the recovery of starting material. However, when (112) was allowed to react with acetyl nitrate, (113) was formed (73CPB885). 

The most important experimental data about NMR, IR, and UV spectroscopy have been reported in CHEC-I. In addition, an AMI SCF-MO study has been published <88JOC3900>. The relaxed reaction profile for aromatic nucleophilic substitution of some chloropyrimido[4,5-J]pyridazine has been investigated using the MNDO procedure <90JST(63)45>. Kinetic measurements and MNDO calculations show that the C-8 position of the pyridazine ring is more reactive than C-5 in nucleophilic substitution reactions, and these follow a two-step SNAr mechanism <89T4485>. 

Spectroscopic and crystallographic techniques were used to good effect in the study of pyridazines. Spectrophotometry and H NMR spectroscopy were used to investigate the ligand substitution reactions of pyridazine in Pt(II) coordination complexes <07M1>. The electron densities and tautomeric equilibria of 6-(2-pyrrolyl)pyridazin-3-one 11 and 6-(2-pyrrolyl)pyridazin-3-thione 12 <07ARK114>. Optical, dielectric and x-ray diffraction studies of pyridazine perchlorate showed distinct structural differences between phases <07MI086219>. 

N-Methoxycarbonyl-A- -azetine reacted with a tetrazine at room temperature to give predominantly a substituted pyridazine. The reaction involves ring scission of the azetidine ring (77CC806). 

The pyridazine ring is electron deficient and needs electron-releasing groups to facilitate electrophilic substitution. Reactions include nitration, halogenation (86SC543), protonation, and the Mannich reaction (84MI2). 

T he exchange of the chloro substituents in the pyridazine part of substituted 1,4-dichloropyri-do[3,4-fi ]pyridazines by reaction with cyclic amines, such as morpholine, substituted morpholines, pyrrolidine, and piperidine at reflux temperature gives products 12.119,121,135,138 The crude dichloro compound may be used.119... 

The most common substitution reaction on hydroxy-substituted pyridazino[4.5-c/]pyridazines is the substitution by chlorine atoms. This is achieved by reaction of the hydroxy compound with phosphoryl chloride, a mixture of phosphoryl chloride and phosphorus pentachloride, or a mixture of phosphoryl chloride and pyridine at elevated temperatures. In most cases, yields are only moderate. 

A simple approach to pyridazine-substituted pyrimidine nucleosides (52) in the reaction of alkyne derivatives (51) with tetrazine diester (48) was reported by Maggiora and Mertes (Equation (2)) <86JOC950> use of the 1,2,4-triazine triester as diene yields the corresponding pyridine derivatives. A new route to the novel C-nucleosides (55) with substituted pyridazines as aglycones by the reaction of tetrazines (48) and (53) with the sugar alkyne (54) has been described (Equation (3)) <94AP(327)365>. 

Eq. (84)]. All electrophilic substitution reactions reported to date for the pyrrolol l,2-Z> pyridazine nucleus are in complete accord with the calculated charge densities which show the 7 and 5 positions to have the greatest electron densities of the seven carbon atoms comprising this bicyclic ring system.231... 

Beyond the few simple substitution reactions summarized below, the dominant chemistry reported for the fully-unsaturated diazocines (15) and (16) involves their thermal and photochemical ring contraction. Both the thermal and photochemical reactions appear to proceed via intermediate formation of bicyclo[4.2.0]octatriene valence tautomers. However, the product distribution differs considerably between the thermal and photochemical reactions. Thus, thermolysis of (15) in dode-cane solution at 140°C affords benzene (43.2%) and pyridine (56.8%) at 175°C, benzene becomes the major product (55.7% vs. 44.3% pyridine) (Scheme 3). Pyridazine, however, is not formed. In contrast, photolysis in tetrahydrofuran at >300 nm affords only benzene neither pyridine nor pyridazine are detected <79JOCl264>. 

Inverse electron demand cycloaddition of 1,2,4,5-tetrazine with alkenes and alkynes. Inverse electron demand Diels-Alder addition has also been employed for the synthesis of pyridazines and condensed pyridazines. The reaction of olefinic and acetylenic compounds with 3,6-disubstituted 1,2,4,5-tetrazines 142 to yield substituted pyridazines 144 by the intermediacy of 143 was first reported by Carboni and Lindsey (1959JA4342). Analogous reaction of 142 with a variety of aldehydes and ketones 145 in base at room temperature proceeded smoothly to yield the corresponding pyridazines 144. Compounds 146-148 are proposed nonisolable intermediates (1979JOC629 Scheme 26). 

Patents have been published which deal with nucleophilic substitution in tetrafluoro-4-nitropyridine (c/. ref. 264), the preparation and reactions of perfluoro-quinoline and -isoquinoline (cf. ref. 267), the preparation and nucleophilic substitution reactions of perfluoro-pyridazine (cf. ref. 269) and -pyrazine (cf. ref. 270), and the preparation of reactive dyestulfs containing fluoro-pyridazine or -pyrimidine residues via displacement of fluorine from polyfluoropyridazines or 5-chlorotrifluoropyrimidine, respectively, with amino- or phenoxy-compounds. The results of the work on perfluoropyrazine are summarized in Schemes 39 and 40. 

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