Triazine rings

C. Reaction with Electi ophiles Directed to Atoms of the 1,2,4-Triazine Ring. 268... 

It is useful to compare the spectroscopic data of 1,2,4-triazine mono-A-oxides with the data for the corresponding 1,2,4-triazines. Introduction of an A-oxide group in the 1,2,4-triazine ring changes its physicochemical properties dramatically, and the analysis of these changes allows one to determine which of three nitrogens is oxidized. The most useful method in this case is NMR spectroscopy, including H, C, and N NMR. 

The presence of an TV-oxide group activates the 1,2,4-triazine ring toward electrophilic attack, for instance, in halogenation reactions. Thus, 3-methoxy- and 3-amino(alkylamino)-1,2,4-triazine 1-oxides 16 react easily with chlorine or bromine to form the corresponding 6-halo-1,2,4-triazine 1-oxides 17 (77JOC3498, 78JOC2514). 

The reaction of the fervenulin 1-oxides 100 with secondary amines results in contraction of the 1,2,4-triazine ring to form 2-amino-5,7-dimethylimidazo[4,5-e] pyrimidine-4,6(5/7,7//)-diones 101. The reaction of the same fervenulin 1-oxides 100 with ammonia leads to the 1,2,4-triazine ring cleavage product, 1,3-dimethyl-5-imino-6-isonitrosouracil 102 (94KGS1253). 

The highly 7r-deficient character of the 1,2,4-triazine ring increases the nucle-ophilicity of the methyl group in methyl-1,2,4-triazine A-oxides in reactions with electrophilic alkenes and aldehydes. Thus treatment of the 6-methyl-3-phenyl-1,2,4-triazine 4-oxide 113 with l-(dimethylamino)-l-ethoxyethylene leads to the... 

The reaction of 3-amino-1,2,4-triazine 1-oxide 1 with methyl iodide in the presence of sodium bicarbonate leads to the methylation of the amino group to afford 3-methylamino-l,2,4-tiiazine 1-oxide 123. This iV-oxide 123, under neutral conditions in the presence of Mel, undergoes methyl group migration to the N(2) atom of the 1,2,4-triazine ring, yielding 3-imino-2-methyl-1,2,4-triazine 1-oxide 124. The same product 124 was obtained by direct methylation of compound 1 under neutral conditions (84TL1677). 

Tiiazine A-oxides can be obtained by two general methods by direct oxidation of the parent 1,2,4-tiiazines with organic peracids, and by the formation of the A-oxide group of the 1,2,4-triazine ring by cyclization involving nitro, nitroso (isonitroso), or hydroxylamino groups. 

Triazine 4-oxides are readily available compounds that can be used successfully for the functionalization of the 1,2,4-triazine ring. The possibilities for the... 

Reaction of 2,3-dichlorobenzoyl chloride with cyanide ion leads to the corresponding benzoyl cyanide (141). Condensation of that reactive intermediate with aminoguanidine 142 leads to the hydrazone-like product 143. Treatment with base results in addition of one of the guanidine amino groups to the nitrile function and formation of the 1,2,4-triazine ring. The product, lamo-trigine (144), is described as an anticonvulsant agent [31]. 

The synthesis of this ring system was achieved by the reaction of the ketene aminal 79 with 3-morpholino-l-ethyl-l,2,4-triazinium tetrafluoro-borate 78 to give 80 (89IZV494). Cyclization of 78 with the bifunctional nucleophile 81 gave the pyrrolo[3,2-e][l,2,4]triazinones 82 (88TL1431). This reaction represents the first example of orthocyclization onto the 1,2,4-triazine ring by the addition of dienophiles at C-5,6 (Scheme 20). 

A facile ring closure at the N-l nitrogen of the 1,2,4-triazine ring occurs to afford triazolo[3,4-/][l, 2,4]triazinones 962 when 961 reacted with acids,... 

Coupling of the diazotetrazole with ethyl cyanoacetate gave 1034. Its cyclization in boiling acetic acid or pyridine afforded 1035 as the major product in addition to 1036. Mass spectral fragmentation of 1035 confirmed that the azole ring is more stable than the 1,2,4-triazine ring on electron impact [76JCS(P1) 1496] (Scheme 194). 

In addition to the synthesis of industrially important azo dyes using heteroaromatic diazo components, intramolecular azo coupling reactions of heterocyclic diazonium ions also have interesting synthetic uses, because they lead to new fused-ring heterocycles, as shown by the diazotization of 2-amino-3-arylbenzimidazoles (12.7) in which, without isolation of the diazonium ion, a 1,2,4-triazine ring is formed (Kolodyazhnaya et al., 1973). Further examples of intramolecular azo couplings were reviewed by Tisler and Stanovnik (1980), and very extensively (403 references ) by Kishimoto et al. (1990). 

As mentioned in Section II,D,l,a, the presence of a r-butyl or phenyl group at position 5 of the 1,2,4-triazine ring does not prevent addition of the amide ion to that position. Therefore, it becomes of interest to investigate whether in the amino-dehalogenation of two annelated 3-chloro-l,2,4-triazines, i.e., 3-chloro-l,2,4-benzotriazine (123) and 3-chlorophenanthro[9,10-e]l,2,4-triazine (125), using potassium amide/liquid ammonia, the Sn(ANRORC) process would be involved. Both compounds... 

The 1,2,3-triazine ring was constructed from o-aminophenyl oximes in the conditions of nitrosation (NaN02/HCl) , while hydrazinooximes were used for the synthesis of the 1,2,4-triazine ring Thus, cyclization of a-hydrazinooxime 342 with Pb304 in the presence of acetic acid afforded 1,2,4-triazines 343 in 44-54% yields (equation 149) . Interaction of oxime 344 with hydrazine leads to the spiro compound product 345 in 73% yield (equation 150) °. 

The 1,2,4-triazine ring is an ambident electrophile, and reacts with enamine-type nucleophiles. For example, addition of enamine 78 to a solution of triazine 77 in acetic anhydride furnished the pyrrolotriazine 31 (Equation 24) <2003TL2421>. 

The 1,2,4-triazine ring of 3,4-dihydro-2-methyl-1,2,4-triazino[3,2-6]-quinazoline-3,10-dione (622) was formed when 3-amino-2-(substituted amino)quinazolin-4-one (621) was cyclized with ethyl pyruvate in acetic acid (86JHC833). 

When the 3-methylthio-1,2,4-triazine (625) was cyclocondensed with anthranilic acid, it afforded the 1,2,4-triazino[3,4-6]quinazoline (626) (84CB1077) cyclization with N-4 of the 1,2,4-triazine ring was possible as a result of blocking N-2. 

Cyclization of the urido-l,2,4-trizine derivatives (634) to the 1,2,4-triazino[2,3-c]quinazoline (635) by heating with polyphosphoric acid has already been discussed (see Section XVI.B.7) (74JHC747). However, pyrolytic cyclization of 634 by heating at 200° afforded the 1,2,4-triazino[4,3-c]quinazoline (638) as a result of eliminative cyclization between the urido function and N-4 of the 1,2,4-triazine ring (74JHC747). The structure of 638 was confirmed by an unequivocal synthesis from 2-oxo-4-thioxoquinazoline (639) (74JHC747). 

The most reactive position of the 1,2,4-triazine ring is position 5, where nucleophiles can attack very easily. Very often nucleophilic attack at position 5 is followed by an electrophilic attack at 4 (or 2). 

The 1,2,4-triazine ring is even less stable toward bases than toward acids. Although many with acidic functionality can be dissolved in bases and reprecipitated unchanged many others are destroyed, especially on prolonged treatment. The half-life of the parent 1,2,4-... 

Alkylation and acylation of the different 1,2,4-triazine systems have also been extensively studied. Alkylation of 1,2,4-triazines (172) with methyl iodide gave mainly 1-methyl-1,2,4-triazinium iodides (173), which are red, and in a few cases the colourless 2-methyl isomers (174). The best results were obtained when nitromethane was used as the solvent for the alkylation. The formation of (173) or (174) depends on the substituents on the 1,2,4-triazine ring (63JCS1628). 

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