Pyridazines nucleophilic aromatic

Nucleophilic aromatic substitution of activated substrates (pentafluoropyridine, octafluorotoluene, hexafluorobenzene, metal arene jc-complexes) by anions of diethyl cyanomethylphosphonate has been achieved. The reaction is carried out with satisfactory yields in DMF, MeCN, or THF at room temperature in the presence of NaH, CsF, KjtX), or CS2CO3." In a similar manner, 3,6-dihalopyridazines react with sodium diethyl cyanomethylphosphonate in refluxing THF to give phosphonosubstituted pyridazines in 22-68% yields. ... 

Using electrophilic and nucleophilic aromatic substitution in five- and six-membered heterocycles. Chemo- and regioselectivity The synthesis of pyridazines... 

The synthetic strategy is simple by way of a nucleophilic aromatic substitution—normally using C-, 0-, S-, or A-nucleophiles (303)—a chain with the 27c-unit is anchored to the tetrazine ring (302). The subsequent intramolecular (4 -F 2) cycloaddition (304) (305) follows the normal course of Scheme 53. In most cases alkyne units have been used as the 27i-component, forming bicyclic pyridazines (305) directly. 

The reactivity of pyridazines, cinnolines, and phthalazines toward substitution and coupling reactions was investigated in 2013. The Giomi group examined nucleophilic aromatic substitutions on 4,5-dicyanopyridazine... 

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. 

Molecular modeling of the reaction predicts attack of the CN" ion on the re face of the iV-allyl benzaldimine carbon to provide an (5)-adduct. The aromatic ring of the imine and the quinuclidine hydrogen bond stabilizes the iminium above the pyridazine, blocking the rear face of the imine bond. Nucleophilic attack by CN is... 

Formal replacement of a CH unit in pyridine 5.1 by a nitrogen atom leads to the series of three possible diazines, pyridazine 10.1, pyrimidine 10.2, and pyrazine 10.3. Like pyridine they are fully aromatic heterocycles. The effect of an additional nitrogen atom as compared to pyridine accentuates the essential features of pyridine chemistry. Electrophilic substitution is difficult in simple unactivated diazines because of both extensive protonation under strongly acidic conditions and the inherent lack of reactivity of the free base. Nucleophilic displacements are comparatively easier. 

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>. 

The heterocyclic rings of (benzo)pyridazine systems are electron deficient and thus susceptible to attack by nucleophiles. However, in the absence of a suitable leaving group this is usually unfavoured due to loss of aromaticity. For example, covalent hydration is not observed, though pseudobase formation can occur with subsequent disproportionation to give, for example, phthalazinones and dihy drophthalazines. 

As seen with pyridazines, palladium catalyzed coupling reactions were also frequently applied in the phthalazine field. For example, commercially available 1,4-dichlorophthalazine 185 was aminated to give 186 in good yield by aromatic nucleophilic substitution with A -methylpiperazine <01S699>. Then, 186 was coupled with various substituted arylboronic acids to obtain 187 by Suzuki-type cross-coupling reactions. Best results were obtained with electron-donating substituents on the arylboronic acid. 

The compound actually prefers to exist as the second tautomer (in the green frame). Reaction with POCI3 in the way we have seen for pyridine gives the undoubtedly aromatic pyridazine dichloride. Now we come to the point. Each of these chlorides can be displaced in turn with an oxygen or nitrogen nucleophile. Only one chloride is displaced in the first reaction, if that is required, and then the second can be displaced with a different nucleophile. 

Another combination of reagents, in which 3-cyclohexylaminopyrimido-pyridazine 47g is used as substrate and propylamine or butylamine as nucleophile, affords imidazolines 56a,b, isomeric to compounds 49c,d. Apparently, the process starts with oxidation of 3-alkylamino group of the starting aromatic substrate and proceeds as shown in Scheme 33. 

Several methods for the preparation of ehain-fluorinated pyridazines relied on the so-called anionic Friedel - Crafts reactions (i.e. aromatic nucleophilic substitution with perfluoroalkyl anions or their synthetic equivalents) with tetra-fluoropyridazine, which was discussed in the corresponding section on chemistry of ring-fluorinated diazines. 

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