Pyridazine 1-oxides nitration

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... 

Oxidative ring cleavage of pyrido[2,3-t/]pyridazine is effected by passing chlorine through a 1 % aqueous solution of the compound. The products are pyridine-2,3-dicarbaldehyde (4) in 71 % yield, nitrogen and hydrogen chloride.83 Nitric acid oxidation of pyrido[2,3-<7]pyridazine (potassium nitrate/sulfuric acid, 180-200 °C, 6 h) gives pyridine-2,3-dicarboxylic acid (5) in... 

When nitration of pyridazine iV-oxides is carried out with acyl nitrates (prepared in situ from acyl chlorides and silver nitrate) the reaction takes place at the /3-position relative to the iV-oxide group. Under these circumstances only mononitro derivatives are formed. For example, nitration of pyridazine 1-oxide with acetyl nitrate yields 3-nitropyridazine 1-oxide (17%) and 5-nitropyridazine 1-oxide (0.8%), whereas with benzoyl nitrate a better yield of 5-nitropyridazine 1-oxide is obtained. 

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... 

Pyridazine aldehydes and ketones with the carbonyl group at the ring or in a side chain react in the usual manner. They form hydrazones, semicarbazides, oximes, etc. Side-chain aldehydes can be easily oxidized to pyridazinecarboxylic acids with silver nitrate and side-chain ketones are oxidized to carboxylic acids by treatment with potassium permanganate or hydrogen peroxide. 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Pyridazine 1-oxide and many of its substituted derivatives undergo nitration with nitric and sulfuric acids to form the corresponding 4-nitropyridazine 1-oxides. If the 4-position is occupied nitration can occur at the 6-position. 

Nitration of pyridazine A-oxides with acyl nitrates prepared from acyl chlorides and silver nitrate also occurs at the (3-position relative to the /V-oxide group. Thus, pyridazine 1-oxide yields 3-nitropyridazine 1-oxide. 

The major reaction described for furopyridazines is ring opening. The furo[2,3-c]pyridazine (35) is converted, in 50% yield, to the chloropyridazine (36) on treatment with phosphoryl chloride in chlorobenzene with DMF as catalyst <88JOC5704>. The symmetric furo[3,4-d]pyridazine (37 R = H, Ph) is oxidatively cleaved with ceric ammonium nitrate to give the pyridazine (38) (Equations (7) and (8)) <83Sioi8>. 

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. ... 

However, if nitration of pyridazine A-oxides is carried out with silver nitrate in the presence of an acid chloride the reaction takes... 

Hydroxypyridazine 1-oxide is readily brominated to give the 4,6-dibromo derivative.301 This is another example of a- and y-activation for electrophilic substitution by an N-oxide group since the des-N-oxide does not react. Chlorination proceeds similarly, but upon nitration only the 4-nitro derivative is formed.302 5-Hydroxypyridazine 1-oxide is also brominated to give the 4,6-dibromo derivative if position 6 is blocked, the corresponding 4-bromo derivative is formed.303 1,2-Disubstituted 5-bromo-pyridazine-3,6-diones are brominated to 4,5-dibromo compounds.304... 

Oxidative cleavage of 7-oxo-6,7-dihydroisoxazolo[3,4-i/]- and diphenylfuro[3,4-with ceric ammonium nitrate gives 5-acyl-4-nitro-3(2//)-pyridazinones and 4,5-dibenzoylpyridazines (Scheme 117), some of which can be difficult to synthesize in other ways <8381018,89S213). 

A-Oxides, just as in the pyridine series, show a remarkable duality of effect - they encourage both electrophilic substitutions and nucleophilic displacements. The sequence below shows pyridazine A-oxide undergoing first, electrophilic nitration, then, the product, nucleophilic displacement, with nitrite as leaving group. 

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