5-Amino-4-nitropyridazine 1-oxides

The nitro group plays an important role in activation of diazine iV-oxides for the amination reaction, and indeed, treatment of 4-nitropyridazine 1-oxide or 3,6-dimethoxy-4-nitropyridazine 1-oxide with potassium permanganate in liquid ammonia affords the corresponding 5-amino-4-nitropyridazine 1-oxides in reasonable to good yields (Scheme 24) [50]. 

Nitropyridazines are reduced catalytically either over platinum, Raney nickel or palladium-charcoal catalyst. When an N-oxide function is present, palladium-charcoal in neutral solution is used in order to obtain the corresponding amino N-oxide. On the other hand, when hydrogenation is carried out in aqueous or alcoholic hydrochloric acid and palladium-charcoal or Raney nickel are used for the reduction of the nitro group, deoxygenation of the N- oxide takes place simultaneously. Halonitropyridazines and their N- oxides are reduced, dehalogenated and deoxygenated to aminopyridazines or to aminopyridazine N- oxides under analogous conditions. 

Oxidative amination of 4-nitropyridazine does not require the use of potassium amide. With liquid ammonia/potassium permanganate at —45 °C 5-amino-4-nitropyridazine is obtained, although, in a rather low yield (88JHC831). The 3-aryl- and 3,6-diaryl-4-nitropyridazines are however aminated in very high yield into the corresponding 5-amino compounds (Scheme 26). 

Oxidative amination of 4-nitropyridazine A-oxide and some methoxy- and chloro-derivatives using liquid ammonia and potassium permanganate exclusively gave the corresponding 5-aminopyridazine A-oxides in reasonable yields (86JHC621). No replacement of the methoxy group and/or chloro atom by the amino group was observed (Scheme 26). 

Study of the reaction between 6-chloro-3-methoxy-4-nitropyridazine 1-oxide or related compounds and methanolic ammonia or liquid ammonia to give the 3-amino compounds upon amino-demethoxylation, revealed the formation of an intermediate sigma-adduct. By H-NMR and C-NMR spectroscopy it could be established that the sigma-adduct involved addition at the 5-C-atom. ... 

This amination reaction has been applied to methoxypyridazines, and 3-methoxypyridazine gave the 4-isomer selectively, along with a bipyridazine byproduct. The more electron deficient nitropyridazines and pyridazine AT-oxides are sufficiently reactive to form the initial adducts in the absence of added amide ion and 5-nitropyridazine 1-oxides give 4-amino derivatives (Scheme 10). The formation of the intermediate u-adducts was demonstrated by H NMR <86JHC62l>. 

If pyridazine is substituted at the 4-position, amination occurs at C-5 for example, 30a gives 31a in a 38% yield (variant 1). In the presence of an oxidant, electron-withdrawing groups facilitate oxidative amination of pyridazines and thus push the reaction even in the absence of amide salt. In liquid NH3,4-nitropyridazine gives 5-amino-4-nitropyridazine in an excellent 98% yield, while the nitropyridazine 30b gives the amino adduct 31b in 93% yield (variant 2). 

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