Facile synthesis of [1,2,4]triazino[4,3-b][1,2,4,5]tetrazepin derivatives by a one-pot reactions using 4-amino-3-hydrazinyl-6-methyl-1,2,4-triazin-5 (4H)-one

<正>4-Amino-3-mercapto-6-methyl-l,2,4-triazin-5(4H)-one 1 converted to 4-amino-6-methy-3-(methylthio)-1,2,4-triazin-5(4H)-one by methylation with methyl iodide.Controlled hydrazination of the resulting compound afforded 4-amino-3-hydrazinyl-6- methyl-l,2,4-triazin-5(4H)-one 2 as a building block,to the synthesis of some novel derivatives of[1,2,4]triazino- [4,3,b][1,2,4,5]tetrazepine 3-6,by the reaction with 3-chloropentane-2,4-dione,chloro acetonitrile,1,3-dichloroacetone,and methyl bromoacetate.This general synthetic procedure can be extended to the preparation of wide variety of tetrazepines using 1,2- bielectrophiles derivatives.     

The role of triplet state keto-enol tautomerism in the photodeamination of metamitron

Substituted 4-amino-1,2,4-triazin-5-ones undergo photodeamination through cleavage of the N-NH(2) bond in the presence of oxygen and water. To elucidate the mechanism of this reaction, we investigated the photolysis of metamitron (4-amino-6-phenyl-3-methyl-1,2,4-triazin-5-one) by nanosecond laser flash photolysis, steady-state irradiation, and ab initio calculations. Upon pulsed laser excitation of deoxygenated aqueous metamitron, two transient species are clearly detected. The predictions of ab initio results are consistent with experimental results: (i) it is proposed here that the transient species are, respectively, the keto and diradical forms of the metamitron keto-enol tautomerism in the triplet state, and (ii) in water, the activation free energy barrier of enolization is drastically decreased. Thus, the formation of the diradical triplet is enabled in aqueous solvent. A detailed analysis of the intermediate structures that lead to the final products (HNO(2) and deaminometamitron) is provided.     

Synthesis of C-nucleoside isosteres of 9-(2-hydroxyethoxymethyl)guanine (acyclovir)

Syntheses of 2-amino-7-(2-hydroxyethoxymethyl)imidazo[5,1-f]-1,2,4-triazin-4(3H)-one ( 2 ) and 6-amino-3-(2-hydroxyethoxymethyl)-1,2,4-triazolo[3,4-f]-1,2,4-triazin-8(7H)-one ( 3 ), novel isosteres of the antiviral agent acyclovir, are reported.     

A Novel Rearrangement Cyclization of 3-Amino-2-benzyl-6-hydrazino-1,2,4-triazin-5-one

A facile ring closure reaction with the N-l nitrogen of the 1,2,4-triazine ring occurs when 3-amino-6-hydrazino-1,2,4-triazin-5-one(1) is refluxed in either acid, orthoester/dimethylformamide, carbon disulfide, cyanogen bromide or nitrous acid. 3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5-one(2), containing the benzyl group on the 2-position of 1, can not be cyclized under the above reaction conditions except refluxed with carbon disulfide in pyridine-water(1:1), which will pass through a novel rearrangement cyclization to afford a bicycloheterocyclic compound,6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][l,2,4]triazin-8(7H)-one(3). The mechanisms of their ring closure and rearrangement cyclization will be presented in detail.     

The difference between the reactivities of azomethine bonds in metamitron in electrochemical and chemical reductions

Electrochemical reduction of a herbicide metamitron (4-amino-3-mefhyl-6-phenyl-1,2,4-triazin-5(4H)-one) in buffered aqueous solutions occurs on the protonated 1,6-carbon-nitrogen double bond. The 2,3-double bond in the resulting 1,6-dihydrometamitron is electrochemically reduced at considerably more negative potentials. In reaction with borohydride the 2,3-double bond is reduced first. Reduction of the 1,6-double bond is very little influenced by replacing the 2,3-double bond by the -NHCH- grouping in 2,3-dihydrometamitron.     

Synthesis and molecular structure of 6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one

The title compound 6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]-triazin-8(7H)-one (4), molecular formula C(11)H(10)N(6)OS, was obtained by the reaction of 3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5(2H)-one (3) with carbon disulfide in a water/pyridine mixture. Compound 4 can also be synthesized by reacting 6-amino-3(2H)mercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one (7) with benzyl bromide in methanolic ammonia water. The compound crystallizes in the monoclinic space group P2(1)/c with a = 7.2926(15), b = 14.456(2), c = 11.436(2) A, beta = 105.30(2) degrees , V= 1162.9(4) A(3) and Z = 4, resulting in a density Dcalc of 1.567 g/cm(3). Molecules of 4 are linked by extensive intermolecular N-H...N and N-H...O hydrogen bonding [graph set R(2)(2 )(9)]. The structure is further stabilized by pi-pi stacking interactions.     

1,2,4-Triazines, 9. The synthesis of novel 4-amino-1,6-dihydro-1,2,4-triazinones

3-Alkylthio-4-amino-1,6-dihydro-1,2,4-triazin-5(4H)-ones were synthesized by the reduction of 3-thio-4-amino-1,2,4-triazine-3,5(2.H,4H)-diones and successive S-alkylation. The regiospecific alkylation on the N-1 position or the exo amino group leads to a variety of 1,6-dihydro-1,2,4-triazin-5(4H)-one derivatives. An alternative synthesis of 3-thio-4-amino-1,6-dihydro-1,2,4-triazine-3,5(2H,4H)-diones was accomplished through the cyclization of 1-thiocarbohydrazidoacetamide derivatives.     

Vibrational assignment, structure and intramolecular hydrogen bond study of 3-amino-1-phenyl-2-buten-1-one

Fourier transform infrared and Fourier transform Raman spectra of 3-amino-1-phenyl-2-buten-1-one and its deuterated analogue were recorded in the regions 400-4,000 and 150-4,000 cm(-1), respectively. Furthermore, the molecular structure and vibrational frequencies of title compound were investigated by a series of density functional theoretical, DFT, and ab initio calculations at the post-Hartree-Fock (MP2) level. Although, the calculated frequencies are generally in agreement with the observed spectra but the DFT results are in much better quantitative agreement with the observed spectra than the MP2 results. The observed wavenumbers were analyzed and assigned to different normal modes of vibration of the molecule. The calculated geometrical parameters show a strong intramolecular hydrogen bond with a N...O distance of 2.621-2.668 A. This bond length is shorter than that of its parent, 4-amino-3-penten-2-one (with two methyl groups in the beta-position), which is in agreement with spectroscopic results. The topological properties of the electron density contributions for intramolecular hydrogen bond in 3-amino-1-phenyl-2-buten-1-one and 4-amino-3-penten-2-one have been analyzed in term of the Bader theory of atoms in molecules (AIM). These results also support the stronger hydrogen bond in the title compound with respect to the parent molecule.     

Solvatochromism of Heteroaromatic Compounds: IX. Anions of 3-Nitro-1,2,4-triazol-5-ones

Solvatochromism of the long-wave band in the electronic absorption spectra of 3-nitro-1,2,4-triazol-5-one anions was studied and quantitatively described with the Kamlet-Taft solvent parameters. Azole anions are specifically solvated in amphiprotic solvents. The strength of the hydrogen bond in H complexes with amphiprotic solvents decreases in going to the Franck-Condon excited state. The UV and IR specrta show that 3-nitro-1,2,4-triazol-5-one anions, in contrast to nitroazole anions, are specifically solvated with participation of the carbonyl group. In highly polar organic solvents the 3-nitro-1,2,4-triazol-5-one anion mainly exists in the form of the 1H tautomer.     

Direct introduction of heterocyclic units into porphyrin derivatives

In the reaction with quinazoline and 5-phenyl-1,2,4-triazin-5(2H)-one, 5,10,15,20-tetra(4-methoxyphenyl)porphyrin exhibits nucleophilic properties. In quinazoline excess, C—C coupling occurs at the C=N bond of azines and position 3 of the aryl ring to form 5,10,15,20-tetrakis(3-heteryl-4-methoxyphenyl)porphyrins. Monoheteryl-substituted porphyrin was obtained by the reaction of equimolar amounts of 5,10,15,20-tetra(4-methoxyphenyl)porphyrin and 5-phenyl-1,2,4-triazin-5(2H)-one.     

The synthesis of 5H-thiazolo[2,3-c][1,2,4]triazine derivatives and substituted 3-(2-acylvinylthio)-1,2,4-triazin-5-ones from 6-methyl-3-thioxo-1,2,4-triazin-5-one, 1-acyl-2-bromoacetylenes,and α-acetylenic ketones. X-ray study of 3-benzoyl-6-methyl-5H-thiazolo[2,3-c][1,2,4]triazin-5-one

3-Acyl-6-methyl-5H-thiazolo[2,3-c][1,2,4]triazines were synthesized by reaction of 1-acyl-2-bromoacetylenes with 6-methyl-3-thioxo-1,2,4-triazin-5-one in methanol in the presence of triethylamine at 20 °C. The structure of 3-benzoyl-6-methyl-5H-thiazolo[2,3-c][1,2,4]triazine was established by X-ray structural analysis. Substituted 3-(2-acetylvinylthio)1,2,4-triazin-5-ones were obtained by the reaction of -acetylenic ketones with 6-methyl-3-thioxo-1,2,4-triazin-5-one under the same conditions. The structures of the new compounds were confirmed by IR,¹H, and¹³C NMR spectroscopy.Deceased.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2971–2975, December, 1996.     

Reaction of Acetone Cyanohydrin with Thiosemicarbazide

We have established that when acetone cyanohydrin is heated with thiosemicarbazide in aqueous medium, 3-mercapto-6,6-dimethyl-1,2,4-triazin-5-one and 2-methyl-2-thiosemicarbazidopropanoic acid are formed. Cyclization of the latter in dioxane in the presence of H₃BO₃ leads to 2-amino-5,5-dimethyl-1,3,4-thiadiazin-6-one.     

New Synthesis of [1,3,4] Thiadiazolo [2,3-C][1,2,4] Triazinone; Transfer of Active Electron by Microwaves

Reaction of various aromatic aldehydes with 4-amino-6-methyl-1,2,4-triazin-5-one supported on to montmorillonite-K10 in the presence of nitrobenzene under microwaves irradiation, afforded the corresponding [1,3,4] thiadiazole [2,3-c][1,2,4]-triazinones.     

1,2,4-Triazines. 8. Reduction of 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride. Regioselective preparation of dihydro-1,2,4-triazin-5(4H)-ones

Reduction of 3-methylthio-1,2,4-triazin-5(4H)-one ( 1a ) with sodium borohydride afforded 3-methylthio-1,6-dihydrotriazin-5(4H)-one ( 2b ) selectively. 3-Methylthio-6-t-butyl-1,2,4-triazin-5(4H)-one ( 1d ) reacted with sodium borohydride to give mainly 6-t-butyl-2,3-dihydro-1,2,4-triazin-5(4H)-one ( 3d ). The reaction of various 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride and the influence of bulkiness and electronic effect of the substituents at the 3- and 6-positions upon the product ratio, are also discussed.     

Acid-Base Properties and Prototropic Tautomerism of Isomeric 1,2,4-Triazin-3- and -5-ones

The acidity and basicity constants of isomeric phenyl(aryl)-1,2,4-triazin-3- and -5-ones in aqueous solution were determined by spectrophotometry: pK _a = 7.3–6.2; pK _BH+= 0.1 to –2.2. 1,2,4-Triazin-3-ones are weaker bases than the corresponding 1,2,4-triazin-5-ones. According to the AM1 calculations, the most thermodynamically favorable tautomer in the gas phase is the oxo form: namely, 2H-tautomers of the neutral bases and 2,4-H,H ⁺-tautomers of the conjugate acids.     

Synthetic and spectroscopic study of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones

5-Amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 can be synthesized from 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) via a selective acylation with an acid anhydride in pyridine. The ¹H nmr spectral characteristics of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 is in particular, compared with 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) and 5-amino-2-alkyl-1,2,4-thiadiazolin-3-ones 1–2, 1–3 . The 5-amino group of 2–1 appeared as two peaks in its ¹H nmr spectrum, which merged to a single peak at a higher temperature, while those of compound 1–1, 1–2 and 1–3 appear only as a single peak. The restricted rotation of the C(5)-N(5) (at amino) bond of 5-amino-2-acetyl-1,2,4-thiadiazolin-3-one (2a-1) is about 14.5 Kcal/mol.     

Synthesis,reactions and biological evaluation of some 1,2,4-triazine derivatives

6-Substituted benzyl-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-5-ones 3a-d were prepared and converted into their corresponding 3-methylthio derivatives 4a-d . Reaction of compounds 4a-d with hydrazine hydrate gave the corresponding 4-amino-3-anilino-4,5-dihydro-1,2,4-triazin-5-ones 5a-d . 6-Substituted benzyl-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 9a-c were synthesized and allowed to react with hydrazine hydrate to give the corresponding 6-substituted benzyl-4-amino-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 10a-c . The biological evaluation of some of these triazines is described. All compounds were screened for antiviral, antibacterial, antimycobacterial, antifungal and antiyeast activity. No important biological activity was found.     

Synthesis of 4-Amino-6-R-4,5-dihydro-3-phenacylthio-1,2,4-triazin-5-ones and 8H-3-R-7-Aryl-1,2,4-triazino[3,4-b][1,3,4]thiadiazin-4-ones

A study was carried out on the reaction of 4-amino-6-R-2,3,4,5-tetrahydro-3-thioxo-1,2,4-triazin-5-ones with halo ketones in alkaline media to yield 4-amino-6-R-4,5-dihydro-3-phenacylthio-1,2,4-triazin-5-ones, which then convert to 8H-3-R-7-aryl-1,2,4-triazino[3,4-b][1,3,4]thiadiazin-4-ones.     

Synthesis and anticancer activity of some new s-glycosyl and s-alkyl 1,2,4-triazinone derivatives

A series of S-glycosyl and S-alkyl derivatives of 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (1) were synthesized using different halo compounds such as preacetylated sugar bromide, 4-bromobutylacetate, 2-acetoxyethoxy-methyl bromide, 3-chloropropanol, 1,3-dichloro-2-propanol, epichlorohydrin, allyl bromide, propargyl bromide, phthalic and succinic acids in POCl3. The structures of the synthesized compounds have been deduced from their elemental analysis and spectral (IR, 1H-NMR, and 13C-NMR) data. Some of the synthesized compounds were screened as anticancer agents. Significant anticancer activities were observed in vitro for some members of the series, and compounds 4-Amino-3-(3-hydroxypropylthio)-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (12) and 3-(4-Oxo-3-(2-(2-thienyl)vinyl)-4H-[1,3,4]thiadiazolo-[2,3-c][1,2,4]tr-iazin-7-yl)propanoic acid (18) are active cytotoxic agents against different cancer cell lines.     

Interaction of aminoazoles with Meldrum’s acid and dialkyl ketones or cyclohexanone

Interaction of 3-amino-5-methylpyrazole, 3-amino-5-methylthio-, and 3,5-diamino-1,2,4-triazole with Meldrum’s acid, acetone, ethyl methyl ketone, and cyclohexanone leads to alkyl-substituted pyrazolo[3,4-b]pyridin-6-ones and 1,2,4-triazolo[1,5-a]pyrimidin-7-ones respectively. The structure of 5,5-dimethyl-2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-7-one was demonstrated by an X-ray structural investigation. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 595–601, April, 2007.