1,2,4-Triazinones

In the research laboratories of the Bayer AG the attention of Westphal and his coworkers was turned to this new group of compounds. Owing to their similarity to nucleic acids a series of 1,2,4-triazinone compounds were synthesised and tested for biological activity. This led to the recognition of the herbicidal activity of the group (Westphal et al.. 1966). 

Of this group the compound of highest activity and at the same time highest selectivity is metribuzin, 4-amino-6-t-butyl-3-methylthio-l,2,4-triazin-5-one (1) (Draber et al., 1968). 

Metribuzin is a crystalline compound, very slightly soluble in water. Of the organic solvents it is relatively soluble in methanol. 

The industrial synthesis of metribuzin proceeds by the reaction of thiocarbohy-drazide with 2-oxo-3,3-dimethylbutyric acid, yielding 4-amino-6-t-butyl-3-thio- 

The reason of the selectivity of metribuzin is that the mechanism of the absorption, translocation and detoxification are different in the sensitive and tolerant plants. Hargroder and Rogers (1974) showed in tracer experiments, in 

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H-Cyclohepta[e][l,2,4]triazine, 3-phenyl-synthesis, 3, 449 Cyclohepta[e][ 1,2,4]triazines synthesis, 3, 453 Cyclohepta[e][l,2,4]triazinone reactions... 

In the literature, various other types of resin preparation procedures are described, e.g. yielding uron structures [20-22] or triazinone rings in the resins [23,24]. The last ones are formed by the reaction of urea and an excess of formaldehyde under basic conditions in the presence of ammonia or an amine, respectively. These resins are used to enhance the wet strength of paper. 

Synthesis, properties, and applications of nonsymmetric triazinones 99MI26. Transformations of 1,2,4-triazines by the action of C-nucleophiles 98ZOR327. 1,2,4-Triazine A -oxides and their annelated derivatives 98UK707. 

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 regioselective synthesis of 2-amino[l, 2,4]triazinones 708 was reported (82JHC1583 83JHC1671) by reaction of 706 with 0-(2,4-dinitrophenyl)-hydroxylamine 707 as an amino transfer agent. Subsequent reaction of 708 with ammonia or amines, followed by ring closure with formic acid, provided 709. 

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,... 

Compound 961 has been converted into 3-amino-6-azido-5(2//)[ 1,2,4]tri-azinone 1041, which was employed in a study of azide-tetrazole equilibrium affording 6-amino-8(5//)tetrazolo[5,1-/][1,2,4]triazinone 1042 (79JHC555) (Scheme 196). 

Die Reduktion kann bis zum 3-Oxo(Thiono)-5,6-diphenyl-hexahydro-l,2,4-triazin weitergeftihrt werden, dabei wird jedoch beim 3-Oxo-tetrahydro-Derivat in Acetonitril bei pH — 1 (-1,0 V) unter Ringverengung das 2-Hydroxy-4,5-diphenyl-imidazol (50% d.Th. F 318°) gebildet. Zur Reduktion der N-Alkyl-l,2,4-triazinone s, S. 613. 

Some 1,2,4-triazines having a 1,2,4-triazinone substituent, and some 1,2,4-triazolo[4,3-fc]-1,2,4-triazinones have been shown to have in vitro anti-HIV and anticancer activity < 95MI04 96CA(124)86961 >. 

Engelhard G, W Ziegler, PR Wallnofer, HJ Jarcszyk, L Oehhnann (1982) Degradation of the triazinone herbicide metamitron by Arthrobacter sp. DSM 20389. J Agric Food Chem 30 278-282. 

The mass spectra of the derivatives of 17 typified by 26a, 26b, and 26c <2001IJB475> possessed the fragmentation peaks shown below along with the molecular ion peaks. The mass spectra of thiazino-triazinones 26a, 26b, and 26c were in conformity with the assigned stmcture. Similarly, the compound 21 <1998JHC293> showed a molecular ion peak at ml z = 273 (M+) and a fragmentation peak at m/z = 230 (M+-CONH) due to loss of-CONH group from the molecular ion. 

Thus, heating under reflux a mixture of 10 and 12 in pyridine afforded, in each case, one product whose H NMR spectrum showed the absence of the methylthio (6 2.55-2.65) and amino (6 5.0-5.03) proton signals present in the spectra of the respective 4-amino-3-methylthio-l,2,4-triazinones 12. Instead, the spectra of the products isolated revealed in each case a characteristic one proton singlet (N-H) in the region S 9.0-9.4. These findings indicate that route A seems to be the most plausible mechanism for the studied reactions of 10 with either 8 or 12 <2000JPR342>. 

The first case of the use of amino acids as chiral auxiliaries in nucleophilic addition to triazinones was employed in the reaction of C-nucleophiles with 3-aryl-l,2,4-triazin-5(4 )-ones 16 and A-protected amino acids 17, to form l-acyl-6-Nu-3-aryl-l,6-dihydro-l,2,4-triazin-5(4A)-ones 18 in high diastereomeric excess <06TL7485>. 

Dioxane solutions of 4(5)-aminoimidazole (64) have been treated with several reagents [92JCS(P1)2789], Imidazo[l,5-a]-l,3,5-triazines (65 R = Ph, Me SMe) were obtained by reaction with methyl N-cyanobenzimidate (57 R = Ph), ethyl N-cyanoacetimidate (58 R = Me), and dimethyl yV-cyanodithioiminocarbonate (59 R = SMe). The uncy-clized product (68 R = H) (73%), obtained by condensation with ethyl N-cyanoformimidate (58 R = H), underwent facile cyclization to give the imidazo[l,5-a]-l,3,5-triazine (65 R = H). Likewise, the condensation adduct (69 R = H) (78%) was obtained using ethoxy methyleneurethane (60 R = H) and this underwent base-catalyzed cyclization to give the imidazo[ 1,5-a]-1,3,5-triazinone (67). Imidazo[l, 5-a]pyrimidines (66 R = H, Me) were obtained from the condensation of 4(5)-aminoimidazole... 

When the diamino salt 9 was treated with the 2,3-furandione 10, it gave the pyrido[l,2,-6][l,2,4]triazinone 11, whose reaction with base gave the respective monobenzoyl derivative (89CB1935). Cyclocondensation of 1,6-diaminopyridines 12 with diacetyl gave [73KGS1266 90JCR(S)186] pyridolf 1,2 b] 1,2,4]triazines 13. On the other hand, reaction with benzil was unsuccessful. 

A series of the benzo derivatives 194 was prepared (86JHC721) by treatment of the corresponding triazinone 194 (R = OH) with phosphorus oxychloride to give the chloro derivatives, whose reaction with nucleophiles gave the respective hydrazino, azido, and amino derivatives. 

Butynylthio)[l,2,4]triazin-5-ones 504 participate in competitive intramolecular Diels-Alder and intramolecular coplanar cycloamination processes to provide triazinones 505, and pyridinones 506. In relatively inert aromatic solvent systems, their ratios are markedly dependent on the electronic disposition of the substituent at C-6 of 504 (84H1225 88JOC5093). 

Reaction of hydrazonoyl halides 40 with 4-amino-23-dihydro-6-substituted-3-thioxo-1,2,4-triazinones 39 gives l,2,4-triazino[43-h][l,2,4,5]tetrazine derivatives 41 <00JPR96>. 

Pyrrolo[l,2-rf [l,2,4]triazinones 21 were synthesized from methyl ester of /ra j-4-hydroxy-L-proline 72. The synthetic route involved formation of hydrazones followed by cyclisation with orthoesters <1998BMC349>. Similar reactions have been developed with 3-benzylindole-2-carbohydrazides 73 in reaction with triethyl orthoformate, giving the corresponding ring systems indolo[l,2-r][ 1,2,4]triazin-4-oncs 74 <2004JHC7>. 

The pyrrolo[l,2-4][l,2,4]triazinone skeleton 76 was also accessible in quantitative yield through a triflic acid-catalyzed heterocyclization of trisilylated diacylhydrazines 75 derived from pyroglutamic acid (Equation 10) <1996JHC1073>. 

An Iranian group described the synthesis of some [l,3,4]thiadiazolo[2,3-c][l,2,4]triazinones 88 <2002PS2399> and in the course of the synthetic pathway the dihydro derivative 87 was first obtained. These authors found that microwave irradiation of 87 on montmorillonite in the presence of nitrobenzene allowed to accomplish the final oxidative step and yielded the fully conjugated end-product in good yields (50-62%). The reaction as proceeding was interpreted by electron transfer to 89 caused by the microwave irradiation followed by the formation of the intermediate radical 90. 

Transformations of [l,3,4]thiadiazolylazomethines to thiadiazolo[3,2-tf][l,3,5]triazinones are demonstrated in Scheme 32. The azomethines 161 containing various aryl groups were treated with different aryl isothiocyanates... 

Two other results should be reviewed here, too. The substituted thiadiazolo[3,2-trifluoromethyl groups) was described by Sokolov and Aksinenko <2003IZV2053> 2-amino-5-methyl[l,3,4]thiadiazole 165 was heated with iV-ethoxycarbonyl-bis-trifluoroacetone imine in DMF in the presence of />-toluenesulfonic acid to yield the cyclized product 166 in good yield (77%). 

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