Pyridazine reactivity

The reactivity of halogens in pyridazine N- oxides towards nucleophilic substitution is in the order 5 > 3 > 6 > 4. This is supported by kinetic studies of the reaction between the corresponding chloropyridazine 1-oxides and piperidine. In general, the chlorine atoms in pyridazine A-oxides undergo replacement with alkoxy, aryloxy, piperidino, hydrazino, azido, hydroxylamino, mercapto, alkylmercapto, methylsulfonyl and other groups. 

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Selective substitutions have been most studied in the pyrido[3,4-tf]pyridazine field. The 1,4-dichloro derivative (334) was more reactive than 1,4-dichlorophthalazine, and was expected from MO calculations to show a more reactive 4-chlorine group. In practice, however, almost equal amounts of monosubstitution products were observed on hydrolysis, although slight differences in the use of alkaline and acid conditions, or on hydrazination, have been reported (69CPB2266). Reaction of this 1,4-dichloro compound, or substituted... 

Pyrazino[2,3-d]pyridazine-5,8-dione chlorination, 3, 347 lithiation, 3, 347 synthesis, 3, 359 Pyrazino[2,3- d]pyridazin-5-one reactivity, 3, 347 synthesis, 3, 360... 

Pyrimido[5,4-c]pyridazine-6,8-diones synthesis, 3, 357 Pyrimidopyridazines rearrangement, 5, 342 Pyrimido[ 1,2- 6]py ridazines HNMR, 3, 334 reactivity, 3, 343... 

A variety of 3,6-disubstituted pyridazines have been quatemized and the structures of the salts determined by unambiguous synthesis, degradation, or reactivity, On the basis of these data the following... 

Some substituents such as the acylamino group are readily decomposed by many nucleophiles to give a poorer leaving group (e.g., amino). Others, such as nitroamino and sulfonylamino, are less reactive when they are anionized by the nucleophile. 3-Nitroamino-pyridazine (117) and its 6-methyl derivative are readily aminated with benzylamine (130°, short time ). 4,6-Dimethyl- and 6-methyl-2-nitroaminopyrimidine undergo 2-substitution on warming a few minutes with hydroxylamine, hydrazine, primary or secondary alkylamines, or anilines. 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

Direct deactivation by a methoxy group makes 3-chloro-6-methoxy-pyridazine unreactive toward sulfanilamide anion in contrast to its 6-chloro, 6-methyl, and 6-hydrogen analogs. Both direct and indirect deactivation of the two chlorines in 3,6-dichloro-4-methoxy-pyridazine (160) are possible the greater reactivity at the... 

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