Aromatization pyridazines

On the basis of H NMR, nuclear Overhauser effect (NOE) experiments, and X-ray diffraction Guard and Steel showed that earlier reported benzylidene-4,5-dihydropyridazines should be represented as aromatic pyridazine... 

Aromatization of tetrahydropyridazines is another method of synthesizing the aromatic pyridazine ring, althou this route is sometimes met with difficulty. Ravina and co-workers reported that the oxidation of tetrahydropyridazine 123 produced 124 in 45% yield in the course of the preparation of a series of 5-substituted pyridazines <99JHC985>. The synthetically useful bromo derivative 125 was prepared either from aromatic alcohol 124 or in a single step from 123. 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

Eeduction with sodium and ethanol has been used in the synthesis of hexahydropyridazine which is obtained together with 1,4-diaminobutane. Similarly, reduction of 3-(p-tolyl)-pyridazine gave besides the corresponding hexahydropyridazine also a substituted pyrrolidine. 3,6-Dimethylpyridazine, when reduced in this way, can give its dihydro or hexahydro analog.In all other cases of pyridazine reductions, no dihydro- and tetrahydropyridazines have been isolated, probably on account of their more ready reduc-ibility compared to aromatic pyridazines. 

Reaction with POCI3 in the way we have seen for pyridine gives the undoubtedly aromatic pyridazine dichloride. 

Dihydropyridazines have also been produced by the reduction of aromatic pyridazines. For instance, the action of lithium aluminum hydride on the diethyl ester of 3,6-dimethylpyridazine-4,5-dicarboxylic acid produces 74 in addition to other compounds [Eq. (18)].128... 

The chemical properties of dihydropyridazines were not studied systematically until now, and information about these compounds is almost completely absent. The only known property of most of the N-unsubstituted dihydropyridazines is that they can be easily oxidized (very often spontaneously in air) to the corresponding aromatic pyridazines. 

A common method for the synthesis of pyridazines involves a 1,4-dicarbonyl compound reacting with hydrazine unless the four-carbon component is unsaturated, a hnal oxidative step is needed to give an aromatic pyridazine. 

The compound actually prefers to exist as the second tautomer, which is more aromatic . Reaction with POCI3 in the way we have seen for pyridine gives the undoubtedly aromatic pyridazine dichloride. 

Saturated 1,4-diketones can suffer in this approach from the disadvantage that they can react with hydrazine in two ways, giving mixtures of the desired dihydropyridazine and an A -aminopyrrole this complication does not arise when unsaturated 1,4-diketones are employed.Synthons for unsaturated 1,4-diketones are available as cyclic acetals from the oxidation of furans (section 15.1.4), and react with hydrazines to give the fully aromatic pyridazines directly. ... 

The compound actually prefers to exist as the second tautomer (in the green frame). Reaction with POCI3 in the way we have seen for pyridine gives the undoubtedly aromatic pyridazine dichloride. Now we come to the point. Each of these chlorides can be displaced in turn with an oxygen or nitrogen nucleophile. Only one chloride is displaced in the first reaction, if that is required, and then the second can be displaced with a different nucleophile. 

In 2(X)8, two groups independently reported on the reactivity of 1,2,4,5-tetrazines with strained olefins including rrani-cyclooctene and norbornene [81, 82]. In the course of the reaction, the initially formed highly strained bicyclic adduct rapidly converts to the 4,5-dihydropyridazine. The final prototropic isomerization leads to the corresponding 1,4-dihydro product that can be further oxidized (external oxidants are usually required) to the fiilly aromatic pyridazine. A molecule of nitrogen is produced by the reaction as the only by-product (Fig. 15). 

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