1.3.4.6- Tetrahydro-1,2,4-triazine 4-oxides

Cyclization of the quinoline (242) to give the tetrahydro compound (245) occurred in refluxing AcOH or by treatment of the quinoline (242) with NaOMe in ethanol in the presence of air. Oxidation to yield the dihydro derivative (187) from compound (245) was achieved using LTA <74JMC244>. In a later study, the elaborated quinoline (242) was refluxed in methanolic HC1 to deliver the tetrahydro triazin-3-one (245) (95%). Alternatively, cyclization in refluxing ethanol gave the tetrahydro compound (245) (77%) <76JHC60i>. 

In this connection the possibility of oxidation of these substances to the tetrahydro derivatives should be mentioned. It was made use of by Thiele and Bailey for the preparation of 6-methyl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine (6-azathymine) (46) and only recently by Grundman et al. for that of 6-azauracil (42). 

Oxidation of the hexahydro to tetrahydro derivatives was mentioned in connection with the synthesis of 3,5-dioxo-l,2,4-triazines (e.g., Section II,B,2,a). The reverse procedure, hydrogenation of the tetrahydro derivatives, was used with 6-azauracil, 6-azathymine, and their iV-methyl derivatives. With all these compounds hydrogenation proceeds smoothly in the presence of Adams catalyst. Only the hydrogenation of l-methyl-6-azathymine was not successful. ... 

Ring-chain tautomerism was observed in a series of l,2,3,6-tetrahydro-l,2, 4-triazine 4-oxides 5 in nonpolar solvents (e.g., CCI4) by NMR spectroscopy. Depending on the nature of substituents R and R, the ratios of the cyclic form of 1,2,4-triazine 5a to the open-chain form of hydrazone 5b were found to be up to 45 55 (77ZOR2617). 

Hydrazino-3-methylbutan-2-one oxime reacts with aldehydes and ketones, resulting in l,3,4,6-tetrahydro-l,2,4-triazine 4-oxides 155 (77ZOR2617). 

The 1,2,4-triazine 4-oxides 55 were synthesized by the reaction of nitrones 158 (generated from a-hydroxylamino ketones and aldehydes) with an excess of hydrazine, followed by the oxidation of the intermediate 4-hydroxy-2,3,4,5-tetrahydro-l,2,4-triazines 159 with lead(TV) oxide (73KGS134). 

Chemical reduction of azine //-oxides, depending on substrate structure, reductant and reaction conditions can proceed both with or without deoxygenation of the N-atom. Thus, 1,2,3-triazine 1-oxide (337) with NaBH4 gives 2,5-dihydro-1,2,3-triazine (336), suggesting that the N-oxide moiety back-donates electrons to the triazine ring. On the other hand, on reduction of the isomeric 2-oxide leading to tetrahydro derivatives (338) and (339) the N-oxide function is not touched (82H(17)317). 

Data on the structures of monocyclic dihydro- or hexahydro-1,2,3-triazines, on 1,2,3-triazine tV-oxides and 1,2,3-triazinones are not yet available. From studies on the one-electron reduction of the tetrahydro-l,2,3-triazinium salts (7) it was concluded that the heterocyclic ring is flexible and not planar (80LA285). No detailed information on the structure of 3-benzyl-l,5-diphenyl-l,2-dihydro-l,2,3-triazine-4,6(3//,5f/)-dione (8) or of the 6-hydroxy-4-oxo-l,4-dihydro-l,2,3-triazinium hydroxide inner salts (9) seems to be available. 

The tetrahydro-l,2,4-triazine 4-oxides (49a) in tetrachloromethane exist in equilibrium with the open-chain structures (49b) (77ZOR2617), and equilibria between triazinones (50a) and the open-chain form (50b) were also observed (80ZOR2297). Ring-chain tautomerism was also found with the aldehydes (51a 51b) here the triazine ring is present throughout (77CB1492). 

Aromatic aldazines when treated in boiling toluene with potassium r-butoxide, furnished 3,5,6-triaryl-l,2,4-triazines (632) and their 2,5-dihydro (633) and 1,2,5,6-tetrahydro derivatives (634), besides triazoles, which were the major products (76JCS(Pl)207). The formation of the triazines is best explained by a [4+2] cycloaddition or a two-step process via the carbanion (631) and elimination of benzalimine to give (633), which can be oxidized to (632 Scheme 21). TTie formation of (634) is still in doubt. 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

Neither of these systems has been prepared in the fully conjugated state. The tetrahydro-isoxazolo[4,3-e][l,2,4]triazine (145) is prepared by cyclization of the benzylidene triazinone (144) with hydroxylamine (Equation (18)) <82iJC(B)ii5>. Manganese dioxide oxidation of the isoxazole (146) forms the isoxazolo[4,5-e]triazine derivative (147) (Equation (19)) <86JHC1795>. 

All the recorded derivatives of these systems have the sulfur atom in the fully oxidized state, the N—S02—N grouping being introduced by the use of sulfamide or a substituted derivative. The 3-unsubstituted 2,2-dioxopyrazolo[3,4-c][l,2,6]triazines (176) and (177 R = H) are formed by heating with sulfamide. With the substituted sulfamides, cyclization of the intermediate is achieved with either alcoholic sodium hydroxide or trifluoracetic acid in moderate yields (Scheme 17) <85S190>. In a similar synthesis (Equation (25)) the tetrahydro-2,2-dioxopyrazolo[4,3-c][l,2,6]thiadiazine (179) is formed from the aminopyrazole (178) <76IJC(B)766>. 

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