Pyridazine /V-oxide

Aminopyridine /V-oxides can be diazotized, and the diazonium salts undergo coupling, etc. These diazonium salts are stabilized by mesomerism (728), cf (726). Amino groups in pyridazine /V-oxides can also be diazotized and the diazonium group further replaced by other functionality. Nitrosation of 3-amino-1,2,4-triazine 2-oxides and subsequent thermolysis of the diazonium tetrafluoroborate salts afforded 3-fluoro-1,2,4-triazine 2-oxides (85H(23)1969). 

This section covers the deoxygenation of compounds containing the structural units (24) and (25). Compounds of the first type include not only aliphatic and aromatic azoxy compounds, but also heterocyclic compounds, such as pyridazine /V-oxides those of the second type include dimers of nitroso compounds and heterocycles, such as pyridazine 1,2-dioxides. 

With molybdenum(IIl) species, pyridazine /V-oxides are deoxygenated... 

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. 

Pyridine and quinoline /V-oxides react with phosphorus oxychloride or sulfuryl chloride to form mixtures of the corresponding a- and y-chloropyridines. The reaction sequence involves first formation of a nucleophilic complex (e.g. 270), then attack of chloride ions on this, followed by rearomatization (see also Section 3.2.3.12.5) involving the loss of the /V-oxide oxygen. Treatment of pyridazine 1-oxides with phosphorus oxychloride also results in an a-chlorination with respect to the /V-oxide groups with simultaneous deoxygenation. If the a-position is blocked substitution occurs at the y-position. Thionyl chloride chlorinates the nucleus of certain pyridine carboxylic acids, e.g. picolinic acid — (271), probably by a similar mechanism. 

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in V-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

With the iV-oxidation of the pyridazine ring profound changes in properties and chemical reactivity result. Many reactions, otherwise difficult to carry out with pyridazines, are accomplished easily with their iV-oxides. Since the oxygen atom of the V-oxide group is removable, new routes to otherwise inaccessible substituted pyridazines are available. 

Two isomeric V-oxides are expected to result from V-oxidation of unsymmetrically substituted pyridazines. So far, only mono-V-oxides are known in the pyridazine series, in contrast to cinnolines which also form 1,2-dioxides. " ... 

Pyridazine iV -oxide is formed in 89% yield when pyridazine is treated with hydrogen peroxide in glacial acetic acid. 3-Methyl-pyridazine similarly gives a mono-i -oxide for which the 2-oxide structure (109) has been ascribed. Ogata and Kano ° repeated this V-oxidation and were able to isolate the 2-oxide (109) and 1-oxide (110) in a ratio of 3 1. Likewise, 4-methylpyridazine yielded the corresponding 2-oxide and 1-oxide in a ratio of about 4 1. The... 

Treatment with phosphorus trichloride removes the /V-oxide function of 8-methylpyrido[2,3-phosphoryl chloride produced is not sufficient to convert the 5-oxo group into a chloro substituent. If, alternatively, phosphoryl chloride is added after the deoxygenation step, 5-chloro-8-methylpyrido[2,3-rf]pyridazine (2) results in 66% yield.56... 

For structure elucidation, the removal of. V-oxide oxygen with concomitant introduction of chlorine into the adjacent carbon is accomplished by treatment with phosphoryl chloride. Thus, pyrido[3,4-rf]pyridazine 2-oxide gives l-chloropyrido[2,3-fi ]pyridazinc, and the 3-oxide gives 4-chloropyrido[2,3-fi ]pyridazine in unspecified yield.163... 

V-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 iV-oxide undergoing first, electrophilic... 

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