Pyridazine A-Oxide

PAH in 59% yield (eq 17). These diazadi-boraphenyl analogs have potential applications in optical and electronic devices. 

Alternate Names pyridazine Al-oxide, pyridazine oxide. 

Solubility soluble in most polar common organic solvents. Mild solubility in water. 

Form Supplied in available as beige powder from many chemical providers. 

Handling, Storage, and Precautions extensive toxicity data are not known. Reagent should be handled in a laboratory fume-hood with appropriate personal protection equipment (laboratory coat, gloves, and glasses). In case of contact with eyes, rinse with copious amounts of water. Must be disposed of as hazardous waste. 

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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. 

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... 

Amino groups in pyridazine A-oxides can be diazotized and the diazonium group further replaced by halogens, hydroxy group or hydrogen. So, 3-, 4-, 5- and 6-bromopyridazine 1-oxides can be prepared from the corresponding amino A-oxides. 

When 6-amino-3-chloropyridazine 1-oxide is diazotized in 50% sulfuric acid, 6-hydroxy-3-pyridazinediazonium anhydro salt is formed. An azido group at either position in pyridazine A-oxides can readily be replaced with sodium alkoxides. 

Pyridazine A-oxides undergo 1,3-dipolar addition with benzyne and a number of its analogues to form adducts which, with loss of nitrogen, form 1-benzoxepines and this work has now been extended to 1,2,4-triazine 1-oxides. In this case the product is 1,3-benzoxazepine <96H(43)2091>. 

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 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. 

Certain pyridazine A-oxides are isomerized to the corresponding diazoketones, e.g., 1033 1034 conversion to the furan 1035 can then occur. 

Other physicochemical methods, especially ultraviolet and infrared spectroscopy, have been useful in combination with chemical transformations for structure determination. Pyridazine A-oxides which... 

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

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%... 

If the ortho position in pyridazine A-oxides is substituted by other than a methyl group, and if the para position relative to the A-oxide is substituted by methyl, then rearrangement may proceed to the 4-methyl group, but usually by-products are formed. An example of such a rearrangement is 3,6-dimethoxy-4-methylpyridazine 1-oxide which forms the expected 4-acetoxymethyl-3,6-dimethoxypyridazine... 

To ascertain the structure of the above aldoximes, various substituted pyridazine A-oxides have been treated with amyl nitrite and sodium amide in liquid ammonia. The products were the unstable a- or syn-aldoximes, which are readily isomerized to the stable /3 or anti isomers under the influence of heat or hydrochloric acid. ... 

Amino-substituted pyridazine A-oxides react normally to give with acetic anhydride the acetamido derivatives. ... 

With molybdenum(III) species, pyridazine A(-oxides are deoxygenated... 

Complexes of pyridazine A(-oxides with cupric chloride were prepared, and depending on the particular N-oxide 2 1 or 1 1 complexes were formed (78TL1979). 

An entirely different method for effecting, overall, an jp - p -coupling of aryl Grignard reagents is by reaction of the latter with pyridazine A-oxide (Scheme 20). In the simple cases studied, yields of enynes were 52-77%. The possibility of applying this approach to more highly substituted substrates does not appear to have been examined. 

The reaction of pyridazine A oxides with POCI3 allows the direct introduction of a chlorine atom in the oc-position with simultaneous elimination of the A-oxide function [21]. If the oc-position is blocked, substitution y to the A -oxide occurs [22]. 

The only reaction of this type mentioned in CHEC-I is the formation of 3-AT-benzoyl-anilinopyridazine from pyridazine A-oxide and A-phenylbenzonitrilium ion <84CHEC-l(3B)l>. 

Cycloaddition reactions were illustrated in CHEC-I by, for example, reactions of benzyne with pyridazine A -oxides and A -acetylimides (to give 2-hydroxy- and 2-acetylaminophenylpyridazines), inverse electron demand cycloaddition reactions of pyridazinecarboxylates with electron rich acetylenes (to give pyridines and benzenes) and dipolar cycloaddition reactions of a pyridazinone with... 

Further examples of inter- and intramolecular cycloaddition reactions of pyridazine A(-oxides have been reported. Flash vacuum pyrolysis of 6-benzylpyridazine 1-iV-oxide gave a low yield (14%)... 

Finally, an example of a 1,3-dipolar cycloaddition has appeared. Reaction of pyridynes and quinolynes with pyridazine-A-oxides 747 gave pyrido-oxepins 750 in 20-30% yields. The reaction is thought to involve cycloaddition to give 748 which, after a 1,3-shift of the oxygen from N to C and nitrogen loss, gives the product. The pyridynes were produced by lead tetraacetate oxidation of 1-aminotriazolopyridines. 

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. 

This methodology has also been applied to the Ar-H arylation of diazine IV-oxides such as pyrazine IV-oxides (eq 20) and pyridazine A -oxides (eq 21). ... 

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