1,2,4-Triazines 2,3,4,5-tetrahydro— from

Some condensed tetrahydro-l,2,4-triazines, derived from the Af,f-A M tandem reactions, can he oxidized into the corresponding aromatic systems, and these oxidation products are regarded as products of the tandem reactions . For instance, aromatization of 3a,4,7,7a-tetrahydrothiazolo[4,5-< ]-l,2,4-triazines with potassium permanganate in acetone proceeds smoothly at room temperature, and the oxidation process is accompanied by elimination of the W-acetyl group (Scheme 78). 

According to the triazine nomenclature, 5-azauracil is 2,4-dioxo-l,2,3,4-tetrahydro-l,3,5-triazine (2). The subject index of Chemical Abstracts prefers s-triazine-2,4(lH,3H)-dione. Furthermore, some authors use a name derived from the lactim structure, 2,4-dihydroxy-s-triazine (3). The numbering of the substituents is the same for all these types of nomenclature. 

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). 

Most of the reported triazinothiadiazines have been prepared from 1,2,4-triazine derivatives. Treatment of amino-1,2,4-triazine 28 with chloroacetyl chloride in dioxane in the presence of triethylamine at 10 °C resulted in the formation of 6-methyl-4-(A -chloroacetamido)-3-thioxo-5-oxo-2,3,4,5-tetrahydro-l,2,4-triazine 29 and 3-methyl-4,7-dioxo-4,6,7,8-tetrahydro-l,2,4-triazino[3,4-A][l,3,4]thiadiazine 15 (Scheme 1) <2005JHC935>. 

Hydrazination of 4-aryl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine (66) also affords a rearranged product, 4-amino-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (81JHC953). This replacement of the A-aryl group by the N-amino group requires the intermediacy of the ring-opened compound 67. This intermediate could be isolated under mild conditions and its structure was proven by an independent synthesis. From this structure it can be concluded unequivocally that the ring transformation involves initial addition of the hydrazine at C-5 and not at C-3 (Scheme III.37). 

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. 

Hydroxy-l-nitrohydrazones (809) react with primary amines and formaldehyde to give 2,3,4,5-tetrahydro-l,2,4-triazines (810) (64MI21901), and similar compounds (812) can be obtained from the reaction of aldehyde hydrazones (811) with primary amines and aldehydes (74KGS425, 75KGS1290, 74UKZ1220). 

Diphenyl-3-[3-(2-phenylimidazol-l-yl)propyl]-l,2,4-triazine (70) underwent thermal intramolecular addition (with loss of nitrogen) to give the tricyclic intermediate (71) and thence (by loss of benzonitrile) 2,3-diphenyl-5,6,7,8-tetrahydro-l,5-naphthyridine (72) [substrate, antioxidant (2,6-di-terf-butyl-4-methylphenol), l,3,5-Pr 3C6H3, reflux, 3 h 92%] that could be aromatized to 2,3-diphenyl-1,5-naphthyridine (73) (l,3,5-Pr 3C6H3, reflux, air, 24h 91%) the latter product (73) was also made directly from the triazine (70) (neat substrate, Se, 330°C, 10 h 85%) analogs likewise.137,522... 

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>. 

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>. 

An attempt to isolate the tetrahydro (246) or dihydro (247) derivatives of the pyrido[3,4-e]-1,2,4-triazine ring system from the cyclization of the pyridine (248) failed in that the only isolable product was the aminoimidazolone (249). This product (249), however, is postulated to be derived from the desired compound (246) via an intramolecular reaction (Scheme 20) <76JHC60l>. 

Phenyl-2,3,5,6-tetrahydroimidazo[2,1 -b Jselenazole (selenotetramizole 97) is prepared by a three-step reaction sequence shown in Scheme 42. The biological activity of the (-)-isomer is comparable with that of (- )-tetramizole (78JMC496). The selenazolo[3,2-6][l,2,4]triazine system (98) is accessible from 6-substituted 3-selenoxo-2,3,4,5-tetrahydro-l,2,4-triazin-5-one by reaction with bromoacetic acid followed by treatment with acetic anhydride (Scheme 43) (71JHC1011). 

Aza-l,3-dienes react with diazenedicarboxylates and 4-phenyl-3ff-l,2,4-triazole-3,5(4//)-dione to afford in good yield, l,2,3,6-tetrahydro-l,2,4-triazines 14 and 15, respectively. The relative configuration of the substituents at C-3 and C-6 of one product derived from diethyl diazenedicarboxylate was ascertained by X-ray analysis32. 

Representatives (100) of the selenazolo[3,2-h][l,2,4]triazine system are accessible from 6-substituted 2,3,4,5-tetrahydro-a.s-triazin-5-one-3-selenone (98) by reaction with bromoacetic acid and ring closure of the intermediate products (99) with acetic anhydride [Eq. (26)]. 

Tricyclic furo[2,3-e]pyrido[l,2-fr][l,2,4]triazinium salt 612 underwent ring transformation by reaction with carbon nucleophiles. Thus, the sodium salt of 1 generated from reaction of 1 and sodium hydride in acetonitrile, was treated with 612 to give 7-benzoyl-8,9,10,ll-tetrahydro-9,9-dimethylindenoll,2-eJpyrido[l,2-frJl,2,4-triazin-ll-one (94CB1799), which because of the enhanced delocalization of the n electronic system, it existed in two equilibrium forms 613 and 614 (Scheme 132). 

Syntheses of this type are from urea, thiourea, and amidine and guanidine derivatives. Ureas give tetrahydro-l,3,5-triazin-2-ones on reaction with a primary amine (1 equiv.) and aqueous formaldehyde (2-30 equiv.). In general, alkyl and aryl amines, unsaturated amines, amino alcohols, and a-amino esters form triazinone derivatives (Equation (43)). Methyl and benzyl have proven to be the most useful urea substituents with respect to high yields and product solubility. N,N -Dicyclohexyl- and A,A -diphenyl-urea gave poor yields of triazinone <90TL2109>. 

The [l,2,4]triazino[4,3-h][l,2,4,5]tetrazines reported <8872249, 89JCS(Pl)247> have been prepared from 4-amino-6-methyl-3(l-methylhydrazino)-5-oxo-4,5-dihydro[l,2,4]triazine (4). The cyclocondensation of triazine (4) with carbonyl compounds such as aldehydes, ketones and 1,2-dicarbonyl compounds in ethanol at reflux temperature gave the corresponding 1,2,3,4-tetrahydro [l,2,4]triazino[4,3-h][l,2,4,5]tetrazines (5) (Scheme 1). The benzene solutions of these compounds on heating in presence of DDQ, gave the corresponding l,4-dihydro[l,2,4]triazino[4,3-h][l,2,4,5]... 

This compound (166) has not been reported. Tetrasubstituted derivatives have been prepared, in low yields, by Ullmann couplings of the corresponding iodotriazines (82NKK1425), while a tetrahydro derivative has been reported to result from the electrochemical reduction of 1,3,5-triazine (86JES2509). 

For 1,2,3-triazine 1 and 1,2,3-benzotriazine 2, N-2 as the preferred site of protonation has been predicted from theoretical investigations (see Section 9.01.2.12). The preparation of stable 4- and 5-phenyl-l,2,3-triazin-2-ium tetrafluoroborates and their spectral characterization have been described <2003S413>. Regarding the protonation of the acid-sensitive l,4,5,6-tetrahydro-l,2,3-triazine 11, see Section 9.01.2.15. 

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