1.2.4.5- Tetrazines tautomerism

Cycloaddition of azirines 5 to 1.2,4,5-tetrazines 6 is followed by loss of nitrogen and ring enlargement to yield 5//-1,2,4-triazepines 7, which tautomerize spontaneously by a [1,51-hydrogen shift to the 2/7-1,2,4-triazepines 8. The triazepinesare accompanied by variable amounts of pyrimidines and pyrazoles.335 - 338... 

Only those compounds which do not have tautomeric aromatic triazole structures will be considered here, the others having been treated as triazoles. The triazolines are unstable and have been subjected to little study. Compounds which are disubstituted at the C(3) or C(5) atom are more stable than the mono- or unsubstituted analogues. The equilibrium has been observed by NMR spectroscopy between the six-membered tetrazine (75) and the triazolinethione (76) via the open-chain form, thus mirroring monosaccharide equilibria (Scheme 12) <90TL3927>. 

Methyl hydrazones of a wide range of aldehydes and ketones (380) undergo addition-cyclization to give 1,2,4,5-tetrazines (382) via 381 (216-219). Substituent effects on the ring-chain tautomerism between 381 and 382 were studied by NMR spectroscopy. 

There are manifold possibilities for tautomerism in partially saturated derivatives. As an example, dihydro-1,2,4,5-tetrazines have been formulated in the 1,2-, 1,4-, 1,6- and 3,6-dihydro structures, but the 1,4-dihydro structure is probably the most stable (see also Section 3.2.2.3.2). 

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). 

This procedure is also efficient for the synthesis of other fused tetrazoles, such as ethyl l,5-dihydro-5-oxo-7-phcnyl-8-(phenylsulfonyl)tetrazolo[ 1,5- pyridine-6-carboxy late <2000J(P1)3686>. At the same time, the unexpected azido-tetrazolo tautomerization and reversible tetrazolo transformation of 3,6-diazido-l,2,4,5-tetrazine are remarkable compared to all other polyazido heteroaromatic high-nitrogen C-N compounds <2005JA12537>. 

Synthesis and ring-chain tautomerism of hexahydro-1,2,4,5-tetrazine-3-thiones 93KGS991. 

There are many possibilities for tautomerism in partially-saturated derivatives. Dihydropyridines can exist in several tautomeric forms, e.g., 37 and 38, of which the 1,4-dihydro isomers are usually the most stable. Similarly, dihydro-1,2,4,5-tetrazines have been formulated as the 1,2-, 1,4-, 1,6- and 3,6-dihydro structures but the 1,4-dihydro structure is probably the most stable. In contrast, 2/7-pyrans, e.g., 67, are more stable than 4/7-pyrans, e.g., 68. Of the five possible dihydropyrimidines most known derivatives have 1,2-, 1,4-, or 1,6-dihydro structures of which the 1,2-structure is calculated to be the most stable <1985AHC(38)1>. 

Tautomerism of tetrazines was investigated by ID 15N INADEQUATE.85 Dimethyl dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate can exist either in 1,2- (8) or... 

More complex tautomeric equilibria have been observed for compound 21 involving the l,2,4,5-tetrazin-3-thione G. The equilibrium is strongly shifted toward the isoxazoline form A in solvents such as pyridine, acetone, dimethyl-sulfoxide (DMSO), and dimethylformamide (DMF), whereas the pyrazoline form D does not exceed 5-10% (Scheme 3) <2002CHE730>. The presence of the above tautomeric species has been demonstrated by NMR. 5-Hydroxy-3,3,5-trimethylisoxazolidine showed a similar behavior <2003CHE1257>. The presence of a CF3 group such as in 22 affects considerably the stmcture of these compounds, which exist only in the cyclic isoxazoline form <2000RCB1910>. 

Unexpected azido-tetrazolo tautomerizations and irreversible tetrazolo transformation have been studied in a report dealing with 3,6-diazido-l,2,4,5-tetrazine (DiAT) for which an improved synthesis pathway is also provided. DiAT undergoes azido-tetrazolo equilibria in CD3OD, (CD3)2C0 and CD3CN and transforms to tetrazolo isomer 53 in DMSO. The... 

Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with 6-methoxy-l,2,3,4-tetrahy-dropyridine gives dimethyl l,2,3,4-tetrahydropyrido[2,3-<5f]pyridazine-5,8-dicarboxylate. Apparently the lactim ether is in tautomeric equilibrium with the corresponding cyclic ketene A,O-acetal, which acts as the dienophile, the final step being the elimination of methanol.73 For a related synthesis, see ref 74. 

Comparison of the electronic spectra of l,2,4,5-tetrazine-3,6-diol (4), 3,6-dimethoxy-l,2,4,5-tetrazine (le), and 6-mcthoxy-2-methyl-1,2,4,5-tetrazin-3(2/7)-onc (5) shows26 that in solution 4 exists as a mixture of the two tautomeric forms 4 and 4. ... 

An attempted preparation of the condensed pentazine 8 involved treatment of 6-chloro-3-methyl-l,2,4,5-tetrazino[6,l-a]isoindole (6) with sodium azide. It was thought that valence tautomerization of the azide 7 should lead to the pentazine 8. The product isolated from this reaction, however, was 2-(6-methy]-1,2,4,5-tetrazin-3-yl)benzonitrile (9), whose formation may be explained by the intermediate formation of 8.3... 

Much more is known about tetrahydro-l,2,4-tetrazines which can form tautomeric structures with more than one double bond in the ring. These include the tetrahydro-oxo(thioxo)-1,2,4-triazines and tetrahydro-dioxo(thioxo)-l,2,4-triazines, which, in the absence of a principal group of higher priority, are more usually named as dihydro-1,2,4-triazinones and dihydro-1,2,4-tri-azinethiones. Still better known are the tetrahydro-dioxo-l,2,4-triazines and their mono- and di-thiooxo analogues, because the 3,5-isomers [l,2,4-triazine-3,5(2//,4//)-diones, 1,2,4-triazine-3,5(2/7,4//)-dithiones, and dihydro-3/5-thioxo-l,2,4-triazin-5/3-ones] are aza-uracil derivatives. 

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. 

Ghosez et al. have recently prepared so-called push-pull dienes (Scheme 6-II).7 These dienes are sufficiently electrophilic to react at relatively low temperatures with unactivated, electron-rich nitriles, affording initial [4 + 2] adducts which tautomerize to 2-aminopyridines. This method would seem to offer a potentially efficient approach to synthesis of certain substituted pyridines. An s-tetrazine dicarboxylate is also a sufficiently electrophilic diene to combine with an N-substituted cyana-mide to afford a triazene in good yield [Eq. (5)].8... 

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