Dihydropyridazines, aromatization

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... 

Chlorination of 6-(4-chloro-3-methylphenyl) -(3,5-dimethyl-l//-pyrazol-l-yl), 5-dihydropyridazin-3(2//)-one 116 with a mixture of phosphorus pentachloride and phosphorus oxychloride is followed by an elimination of 3,5-dimethyl-177-pyrazole giving the aromatized 3-chloro-6-(4-chloro-3-methylphenyl)pyridazine 117 (Scheme 25) <2005CJC251>. 

Intramolecular nucleophilic aromatic substitution on 243 allowed l,4-dihydropyridazin-3(2//)-one ring construction (Equation 58) . Similarly, a tetrahydropyridazine unit could be constructed starting from 244 (Equation 59) . 

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). 

Dihydropyridazines (117) result from Diels-Alder addition of. v-tetrazines (115) with electron-rich alkenes (e.g. 116). Frequently the products aromatize, as in (117) — (118) (see also Section 3.2.1.10.2.iv). 

We have devoted three papers explicitly to the relationships between aromaticity and tautomerism the first to the tautomerism of 1,2,3-triazole (30) and benzotria-zole (31) [46], If, in the first case, the relative stabilities are determined by the lone-pair/lone-pair repulsion of the adjacent lone pairs that destabilize 30a, in the second case this is partly compensated by the greater aromaticity of the benzenoid structure 31a. In the second paper, we discuss the aromaticity of formal 47i-electron antiaromatic 17/-2-azirine (32), 671-electron aromatic l,27/-3-diazetine (33), pyrrole (34), and 1,2-dihydropyridazine (35) [47], Compounds 33 and 35 are not planar and not aromatic. 

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],... 

In 1975 Carlson, Sheppard and Webster showed that the products of an old, known reaction between dienes and aromatic diazonium salts are not coupling products, but rather, they are dihydropyridazines. A detailed investigation of this reaction, in particular with electron-rich dienes, revealed the cycloaddition is concerted, and 3,6-dihydropyridazines 19 are formed first. They are transformed further into either 1,6-dihydropyri-dazines 20 or pyridazinium ions (84TL57). 

Dihydropyridazine-3,6-diones have reactive methylene groups, and they react with aromatic aldehydes to give 4,5-bis-arylidene derivatives (86JPR932 87JPR525). Pyridazines have been shown to undergo 1,3-dipolar cycloaddition with diazomethane [82H(I8)I75 88HI43I],... 

Cycloadditions of l,r-bicyclohexenyl (34) with acylazo compounds have given high yields of the tetrahydropyridazines 35 and 36. - ° No attempts have been made to aromatize such compounds, but it is found that alkaline hydrolysis of 36 is accompanied by decarboxyation to the unstable 37, which is oxidized by air back to l.l -bicyclohexenyl with loss of nitrogen, presumably via the dihydropyridazine 38. ... 

Pyridazinium salts or 1,6-dihydropyridazines have been obtained in cycloaddition reactions between aromatic and heterocyclic diazo compounds and dienes [Eq. (10)]. Diazoheterocycles usually cycloadd as 1,3- poles. 

Aromatic diazonium salts undergo cycloaddition to dienes to produce N-substituted 1,6-dihydropyridazines 53 [Eq. (8)]. 

Eq. (14)].122 Similarly, the addition of phenyl Grignard to 6-oxo-3-phenyl-1,4,5,6-tetrahydropyridazine gives the aromatic 3,6-diphenylpyridazine, presumably through the intermediacy of the dihydropyridazine.123,124... 

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. 

Cyclization between a carboxamide function and an adjacent styryl group by heating 1-(2-chlorophenyl)-5-cyano-6-oxo-4-styryl-1,6-dihydropyridazine-3-carboxamide at 230-240 °C gives 5.115 The final aromatization apparently occurs by air oxidation. 

While dihydropyridazines which can be oxidized to the aromatic system usually react rapidly with oxygen in solution to give pyridazines, presumably by addition of oxygen, hydroperoxide... 

Investigations to elucidate the stereochemistry of the tetrazine cycloadditions are rendered more difficult because the initially formed Diels-Alder adduct is not isolable, but loses nitrogen extremely rapidly (Scheme 5) and the 4,5-dihydropyridazine derivative formed undergoes either a rapid tautomerization to the 1,4-dihydro isomer or a )6-elimination reaction to form aromatic compounds (Scheme 6). In both cases the stereochemical centers, by which the stereochemical course of the reaction could be followed, are destroyed. 

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. ... 

Tetrazines are utilized as the key reagents (dipolarophiles) in synthetically useful cycloaddition-cycloreversion reactions. In such cases, the tetrazine first undergoes a [4+2] cycloaddition to the isolated double bond of a suitable Diels-Alder adduct. The so-formed dihydropyridazine intermediate undergoes aromatization via elimination of the pyridazine system. An example of a tetrazine-based cycloaddition-cycloreversion reaction cascade is the application... 

Two pathways for the preparation of 1,4-dihydropyridazine derivatives were envisaged. According to the first, dimethyl 3-oxopentane-l,5-dioate (dimethyl acetone-1,3-dicarboxylate) (1) was treated in ethanol and sodium acetate at 0 °C with acidic aqueous diazonium salts, prepared from aromatic or heteroaromatic amines, to give hydrazones 69 in 35-94% yields. They were next treated with DMFDMA in dichloromethane at room temperature to form the (dimethylamino) methylidene derivatives 70 as intermediates, which immediately cyclized into dimethyl 1 -(hetero)aryl-4-oxo-l, 4-dihydropyridazine-3,5-dicarboxy-lates 71 in 72-94% yields, except for 71 (R=lH-l,2,4-triazol-3-yl), which was obtained in 35% yield (08ZN(63b)407) (Scheme 23). 

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). 

---