5- dihydropyridazine tautomerism

In this work the possibility of the existence of 1,2-dihydro isomer with the core structure 42 was not considered. Recently, however, it was shown that 1,2-dihydropyridazines could be prepared by careful electroreduction of the corresponding pyridazines, and that their stability depends significantly on the ring substitutions. Thus, dimethyl l,2-dihydropyridazine-3,6-dicarboxylate 43a (R = H) is reasonably stable and rearranges into the 1,4-dihydro tautomer 43b only at a more negative potential, while the tautomerization in its tetrasubstituted analog 43a (R = COOMe) occurs more readily (Scheme 14) [00TL647]. 

A derivative of 5-(indol-2 -yl)dihydropyridazine 44 (R = H) exists in DMSO-iig solution exclusively as tautomer 44a (within the limits of 400-MHz H NMR detection). However, the introduction of methyl groups both into the indole ring and into the pyridazine ring favors a shift of the tautomeric equilibrium... 

The reduction of a number of pyridazines was treated in Part I1 later electrochemical investigations296 confirmed that the initial reduction consumed two electrons and the primary product was suggested to be 1,2-dihydropyridazine, which tautomerized to the 1,4-dihydro derivative hydrolysis with ring opening followed. 

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). 

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. 

Pyridazines are polarographically reducible [306, 307], often stepwise. The first reduction generally yields a dihydropyridazine, which can exist in different tautomeric forms, the most stable forms usually being the 1,4- and 4,5-dihydropyridazines [306]. The further reduction is complicated by the fact that the different tautomeric forms may be reduced differently and at different potentials and that the rate of transformation of a given tautomer to the most easily reducible one may or may not be fast compared to the further reduction. 

A similar type of tautomerism was found in a series of dihydropyridazines (see Section IV,C) and dihydropyrimidines (see Section V,C,2). For example, on the basis of NMR measurements in CDC13, it has been shown that 3,6-diphenyl-4,5-dihydropyridazine (28a) exists in tautomeric equilibrium with the corresponding 1,4-dihydro compound (28b) in the ratio 1 8. 

An unexpected example of the less common N—N bond formation in the preparation of pyridazines is provided by the reaction of 3-methyl-1,2-benzisoxazoles with strong base in the absence of an electrophile (Scheme 122). The reaction, which is postulated to proceed via an o-hydroxyphenyl-azirine, gives about 40% yields of the dihydropyridazines (159) which are very labile with respect to oxidation and tautomerization, but manganese dioxide oxidation without purification of the crude intermediate (159, R = OH) gives a 61 % yield of 3,5-bis(2,6-dihydroxyphenyl)pyridazine (160, R = OH) <89JOC4970>. 

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. 

Sol 16. (i) 3,6-Diphenyl-l,2,4,5-tetrazine (I) undergoes Diels—Alder reaction with acrylonitrile to give a bicyclic product (II), which undergoes retro Diels—Alder reaction generating a 4,5-dihydropyridazine (III), which on tautomerization gives a 1,4-dihydropyridazine (IV). 

---