Pyridazines tautomerism

For further details and examples of prototropic tautomerism in pyridazines and condensed pyridazines, see (63AHC(1)339, B-76MI21200). 

The barriers to rotation in a series of (V,(V-dimethylformamidine derivatives of pyrido-[2,3-d]- and -[3,4-d]-pyridazines have been measured by an NMR method <78JHC1105), and NMR studies have also been used in a study of tautomerism in the latter system <75BSF702). 

There seems to have been no systematic study of tautomerism in the pyridopyridazines, but isolated observations in the pyrido[3,4-d]pyridazinedione (75BSF702, 69CPB2266) and pyrido[2,3-d]pyridazinedione (74JHC351) series have involved methylation studies. The pyrido[2,3-d]pyridazine-5,8-diones are believed to be enolized at the 8-position, from metal complexation results (67MI21500). 

Pyridazine-3-carboxamide, 1,6-dihydro-6-oxo-analysis, 3, 2 tautomerism, 3, 4 Pyridazinecarboxamides synthesis, 3, 33... 

S-N rearrangement, 3, 36 ionization constants, 3, 4 oxidation, 3, 37 quatemization, 3, 17 Pyridazine-3 (2 H) - thiones analysis, 3, 2 tautomerism, 3, 5 Pyridazinium betaine, 3-oxido-photolysis, 3, 11 Pyridazinium betaine, 5-oxido-photolysis, 3, 11 Pyridazinium dicyanomethylide photolysis, 3, 12... 

Pyridazino[4,5-d]pyridazine, hydroxy-IR spectra, 3, 333 methylation, 3, 343 tautomerism, 3, 333... 

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... 

TL5981>. The proposed mechanism involves the oxidation of the amine to an imine, tautomerization to an enamine, and a sequence of nucleophilic attacks on the pyridazine rings followed by oxidation steps. The oxidant of choice is (bispyridine)silver permanganate <1982TL1847>, which is easily prepared, mild in action, and is soluble in organic media. If R1 = H in the product 77, electrophilic substitution (e.g., bromination, nitration, Mannich, and Vilsmeier-Haack-Arnold reactions) occurs at this position. 

Pyrido[2,3-, pyridazine derivatives 48 have been synthesized by refluxing equimolar amounts of an appropriate 5-benzylidene-2,2-dimethyl-l,3-dioxane-4,6-dione 47 with 5-amino-6-phenylpyridazin-3(2/7)-one 46 in methanol or a methanol acetic acid mixture. The electron-poor carbon atom of the polarized carbon-carbon double bond of 47 is the electrophile attacking C-4 of the 5-aminopyridazinone 46. Imino-enamine tautomerization of the intermediate is followed by ring closure and subsequent loss of acetone and carbon dioxide affording the reaction products 48 as stable crystalline solids in 70-90% yield (Scheme 9) <2000T2473>. 

Imino-substituted pyridazine 68 reacted in the 5-position with the lithium enolate of ethyl 2-methylpropanoate 69 via an interesting cascade of nucleophilic addition, ring closure via addition-elimination and tautomerization (Scheme 13) <1996JHC1731>. 

The potential tautomerism of l,2,3,4-tetrahydro-5,7-dimethyl-6//-pyrrolo[3,4-i/ pyridazine-l,4-diones has been examined by AMI semi-empirical methods <1998JMT(434)7, 1998JMT(427)65, 1998JMT(430)85>. 

Amino-5-methoxypyrido[3,4-,7 pyridazine-l,4-(27/,37r)-dione could exist in different tautomeric forms 29-31 besides the dilactam form 32. The forms 29 and 30 are the preferred tautomers based on the chemical shift for the hydroxyl group which is consistent with the presence of intramolecular hydrogen bonding that could stabilize such lactim forms <1997T8225>. 

Tautomerism is also of interest in the case of the pyrimidine nucleoside analogue 20 <2003TL3387>, where the solid-state structure has been established crystallographically as the 57/ tautomer 20a, wherein the pyridazine ring is fully aromatic, rather than the 87/ tautomer 20b. 

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). 

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