Pyridazine, 4-nitro-, 1-oxide oxidation

Pyridazine 1-oxides substituted at position 3 or positions 3 and 6 afford the corresponding 5-nitro derivatives. A methyl group at position 6 (a with respect to the iV-oxide group) is frequently converted into the cyano group, and a methoxy group at position 6 is demethy-lated by benzoyl chloride/silver nitrate. For example, 3-substituted 6-methylpyridazine 1-oxides give the 5-nitro derivatives (96) and the 6-cyano-5-nitro derivatives (97), whereas... 

The second most important nucleophilic substitution in pyridazine A-oxides is the replacement of a nitro group. Nitro groups at the 3-, 4-, 5- and 6-position are easily substituted thermally with a chlorine or bromine atom, using acetyl chloride or hydrobromic acid respectively. Phosphorus oxychloride and benzoyl chloride are used less frequently for this purpose. Nitro groups in nitropyridazine A-oxides are easily replaced by alkoxide. The... 

Various pyridazine-A-oxides (including cinnoline A-oxides) have been prepared as potential antitumour agents in Japan [276-278]. Among several 4-nitro-pyridazine 1-oxides tested for activity against rat ascites hepatoma AH-13, 3,6-dimethoxy-4-nitropyridazine 1-oxide (74) has been found to be the most potent compound a minimal effective dose of 5 mg/kg has been estimated [276], Also pyridazine A-oxides of type (75) bearing a bis(2-chloroethyl)ami-nomethyl side-chain at C-6 have been reported to be effective (0.5-5 mg/kg, i.p.) against AH-13 in rats [278]. Both types of compound (74), (75, R = H, Br), however, have been shown to be inactive against mouse lymphoid leukaemia L-1210. 

Nitration of pyridazine 1-oxide (113, R = Rx = H) - and many of its 3- or 6-substituted and 3,6-disubstituted analogs (113, R and/or Rj= alkyl, alkoxy, or chloro) with a mixture of fuming nitric and concentrated sulfuric acid afforded the corresponding 4-nitro-pyridazine 1-oxide derivatives (114). Under similar reaction conditions nitration of 3-methylpyridazine 1-oxide could not be accomplished and even after 6 hours at 100° starting material was recovered, whereas 3-methylpyridazine 2-oxide is nitrated to give 3-methyl-5-nitropyridazine 2-oxide in excellent yield. ... 

Another large group of nucleophilic replacements involves the nitro group in pyridazine A-oxides. One or two nitro groups at positions 3, 4, 5, or 6 in the pyridazine A-oxide ring are easily substituted with chlorine when nitropyridazine A-oxides are heated with acetyl chloride in chloroform solution ose-eso, 664 15-20%... 

Several 4-amino-3,6-disubstituted pyridazines were nitrated with fumic nitric add to give the 5-nitro derivatives in good yield. Pyridazine N-oxides are relatively easily nitrated with mixed add to give the 4-nitro derivatives. If this position is blocked, as with 3,6-dimethyl-4-hydroxy-pyridazine 1-oxide, the 5-nitro derivative is formed. Nitration of... 

Triaminopyridazine and 4,5-diamino-3-methoxy-6-methyl-pyridazine have been prepared by reducing the 4-nitro group, but more common is the simultaneous catalytic reduction of the nitro and A-oxide groups of nitropyridazine-A-oxides (see Section IV, G). 

Pyridazine 5-Amino-6-chloro-6-methoxy-4-nitro- -1-oxid E9a, 618 (H -> NH2)... 

---