New approaches to synthesis of tris[1,2,4]triazolo[1,3,5]triazines

Thermal cyclization of 3-R-5-chloro-1,2,4-triazoles (R = Cl, Ph) afforded 2,6,10-tri-R- tris[1,2,4]triazolo[1,5-a:1′,5′c:1″,5″-e][1,3,5]triazines 5 (R = Ph) and 7 (R = Cl). These compounds are first representatives of this class of heterocycles, whose structures were unambiguously established. Treatment of these compounds with nucleophiles (H₂O/NaOH, NH₃) results in the triazine ring opening to give compounds consisting of three 1,2,4-triazole rings linked in a chain. For example, treatment of cyclic compound 5 with aqueous alkali affords 3-phenyl-1-3-phenyl-1-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,2,4-triazol-5-yl-1H-1,2,4-triazol-5-one. Treatment of 3,7,11-triphenyltris[1,2,4]triazolo[4,3-a:4′,3′c:4″,3″-e][1,3,5]triazine (2) with HCl/SbCl₅ leads to the triazine ring opening giving rise to 5-(3-chloro-5-phenyl-1,2,4-triazol-4-yl)-3-phenyl-4-(5-phenyl-1H-1,2,4-triazol-3-yl)-1,2,4-triazole. Thermal cyclization of the latter produces 3,7,10-triphenyltris[1,2,4]triazolo[1,5-a:4′,3′c:4″,3″-e][1,3,5]triazine (13). Thermolysis of both cyclic compound 2 and cyclic compound 13 is accompanied by the Dimroth rearrangement to yield 3,6,10-triphenyl-tris[1,2,4]triazolo[1,5-a:1′, 5′-c:4″,3″-e][1,3,5]triazine (14). Compounds 13 and 14 are the first representatives of cyclic compounds with this skeleton. ¹³C NMR spectroscopy allows the determination of the isomer type in a series of tris[1,2,4]triazolo[1,3,5]triazines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 706–712, March, 2005.     

Synthesis and Tautomeric Structure of 7-Arylhydrazono-7H-[1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazines

Two synthetic approaches were developed for the title compounds 8a-g via coupling of diazotized anilines with 7-acetyl-6-methyl-3-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine 7 , and reaction of N-aryl 2-oxopropanehydrazonoyl chlorides 9 with 4-amino-3-mercapto-5-phenyl-1,2,4-triazole 1 . The tautomeric structures of 8 were elucidated by their spectral analyses and correlation of their acid dissociation constants with Hammett equation.     

Synthesis and Antimicrobial Activities of Some 6-Methyl-3-Thioxo-2,3-Dihydro-1,2,4-Triazine Derivatives

Abstract

4-Arylidene-imidazole derivatives (4a,b) were readily prepared by reacting 4-am- ino-6-methyl-3–thioxo-2,3–dihydro[1,2,4]triazin-5(4H)-one (1) with 4-arylidene-2-phenyl- 4H-oxazol-5-one (2). Reaction of 1 with some aromatic aldehydes in presence of triethylphosphite exclusively afforded the corresponding aminophosphonates 5a-c. Reaction of 1 with 3-phenyl-1H-quinazoline-2,4-dione (6a) and/or 3-phenyl-2-thioxo-2,3-dihydro- 1H-quinazolin-4-one (6b) gave 2-(6-methyl-5-oxo-3-thioxo-2,5-dihydro-3H-[1,2,4]triazin-4-ylimino)-3-phenyl-2,3-dihydro-1H-quinazolin-4-one (7). Moreover, on treating 1 with 2-phenylbenzo[d][1,3]thiazine-4-thione (8), 6-methyl-4-(2-phenyl-4-thioxo-4H-quinazolin-3-yl)-3-thioxo-3,4-dihydro-2H-[1,2,4]triazine-5-one (9) was obtained in 65% yield. Reaction of 1 with 4-sulfonylaminoacetic acid derivatives (10a,b) afforded the corresponding sulfonamides (11a,b), respectively. Acid hydrolysis of 11a afforded 7-aminomethyl-3-methyl[1,3,4]thiadiazole[2,3-c][1,2,4]triazin-4-one (12). 4-Amino-6-methyl-3-(morpholine-4-ylsulfanyl)-4H-[1,2,4]triazin-5-one (14) was prepared by reacting compound 1 with morpholine in presence of KI/I₂, while 3,3′-bis(4-amino-6-methyl-5-oxo-triazinyl)disulfide (16) was obtained by oxidation of 1 with lead tetraacetate. The antimicrobial activity of the products was evaluated against Gram-positive and Gram-negative bacteria as well as the fungus Candida albicans.

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures, and tables.]     

Microwave Assisted Synthesis of 6-Aryl-3-substituted-5H-[1,2,4]-triazolo[4,3-b][1,2,4]triazoles: A Case for a Comparative Study

A simple and fast synthesis of 6-aryl-3-substituted-5H-[1,2,4]-triazolo[4,3-b][1,2,4]triazoles 4 in high yields has been developed by microwave assisted heterocyclization of N-(3-methylthio-5-substituted-4H-1,2,4-triazol-4-yl)benzenecarboximidamides 3 . The effectiveness of the microwave irradiation and conventional heating for the formation of compounds 4 has been investigated.     

5,6-2H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪衍生物的合成及抗癌活性测定

取代苯甲醛与4-氨基-5-(3,4,5-三甲氧基苯基)-1,2,4-三唑-3-硫酮(2)缩合生成5-(3,4,5-三甲氧基苯基)-4-取代苯基亚胺基-1,2,4-三唑-3-硫酮(3),再烷基加成化为新型5,6-2H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪衍生物4.化合物结构经1HNMR 13C NMR,IR以及元素分析确认.采用噻唑兰(MTT)比色法进行化合物抑制人体前列腺癌细胞(PC3)体外活性测试,结果表明所合成的化合物具有不同程度的抑制PC3活性,其中化合物4a在10μmol·L-1浓度下对PC3的抑制率为75.9%.     

Utilization of cleavage of the [1]benzofuro[2,3‐e][1,2,4]triazine ring for the synthesis of oxygen,nitrogen and sulfur derivatives of [1,2,4]triazine

A series of 6‐azacytosines 4a‐4k and 5a‐5c were prepared by nucleophilic cleavage of furan ring of [1]benzofuro[2,3‐e][1,2,4]triazine derivative 1 . Some of them were used for the preparation of derivatives of [1,2,4]triazolo[4,3‐d][1,2,4]triazine ( 6a‐6d ) and tetrazolo[1,5‐d][1,2,4]triazine (7). The reaction of 1 with hydrogen sulfide afforded the corresponding 6‐(2‐hydroxyphenyl)‐2‐phenyl‐5‐thioxo‐4,5‐dihydro‐1,2,4‐tri‐azin‐3(2H)‐one ( 8 ), while with hydrogen selenide 6‐(2‐hydroxyphenyl)‐2‐phenyl‐4,5‐dihydro‐1,2,4‐triazin‐3(2H)‐one ( 9 ) was formed. The prepared compounds were tested for biological activity.     

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.     

Revisiting the Synthesis of Functionally Substituted 1,4-Dihydrobenzo[e][1,2,4]triazines

A series of novel 1,4-dihydrobenzo[1,2,4][e]triazines bearing an acetyl or ester moiety as a functional group at the C(3) atom of the 1,2,4-triazine ring were synthesized. The synthetic protocol is based on an oxidative cyclization of functionally substituted amidrazones in the presence of DBU and Pd/C. It was found that the developed approach is suitable for the preparation of 1,4-dihydrobenzo[e][1,2,4]triazines, but the corresponding Blatter radicals were isolated only in few cases. In addition, a previously unknown dihydrobenzo[e][1,2,4]triazolo[3,4-c][1,2,4]triazine tricyclic open-shell derivative was prepared. Studies of thermal behavior of the synthesized 1,4-dihydrobenzo[1,2,4][e]triazines revealed their high thermal stability (up to 240–250 °C), which enables their application potential as components of functional organic materials.     

Unexpected Direction of Iodocyclization of 3-Allylthio-5-phenyl-4H-1,2,4-triazole

The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, and 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of the products obtained was established using ¹H NMR spectroscopy of their dehydriodination products.     

Investigation of routes to indeno[2,1-f] -2H-1,2,4-triazepinediones

The synthesis of a number of 3-(substituted thiosemiearbazido)-2-(a]koxycarbonyl)indones (1) from 2-alkoxycarbonyl-1, 3-indandiones and substituted thiosemicarbazides is described. Cyeliza-tion of compounds 1 in the presence of a variety of catalysts gave substituted Δ²-1,2,4-triazoline-5-thiones (³) and (⁴), instead of the expected substituted 3(4H)-thioxoindeno[2,1-f]-2H-1,2,4-triazepine-5(5aH),6-diones (2). The preparation of 4-(2-methyl-1,3-dioxo-2-indanylmethyl)semi-carbazide ( 9 ) is reported. Cyelization of 9 gave 5,5a-dihydro-5a-methylindeno[2,1-f]-2H-1,2,4-triazepine-3(4H),6-dione ( 10 ). Structure assignments of these compounds are discussed.     

Reaction of 2-Aryl-5-R-5,6-dihydro-7H-[1,2,4]-triazolo[5,1-<Emphasis Type="Italic">b</Emphasis>][1,3]thiazin-7-ones with Aryl Bromomethyl Ketones and Benzyl Bromide

The products of the reaction of 2-aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones with aryl bromomethyl ketones are 2-aryl-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones and aryl methyl ketones or 2,5-diaryl[1,3]thiazolo[3,2-b][1,2,4]triazoles and 3-phenyl-2-propenoic acid, depending on the structure of R. The reaction of 2-aryl-5-R-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones with benzyl bromide yields 5-aryl-3-benzylthio-4H-1,2,4-triazoles and 3-aryl-2-propenoyl bromide. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 905–909, June, 2005.     

新型2-氧代-1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂类稠杂环的合成

将取代色满酮(1)与芳肼反应生成的腙与HNCO发生[3+2]环加成反应,加成产物(2)经氧化得到偕偶氮异氰酸酯(3).化合物3在HBF4的催化下发生环化-重排反应,得到新颖的三环系2-氧代-1,2,4-三唑并[3,2-d][1,5]苯并氧氮杂化合物5a～5g.     

新型2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮的超声辅助一锅法合成及乙酰胆碱酯酶抑制活性研究

以取代苯甲醛、溴乙腈和6-苄基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮为起始原料,在超声辅助下,一锅合成了9个新型6-苄基-2-亚苄基-2H-噻唑[3,2-b][1,2,4]三嗪-3,7-二酮类化合物,结构经_¹H NMR,_¹³C NMR和MS（ESI）表征并对其合成机理进行了初步研究。测试了目标化合物(4a~4i)的体外乙酰胆碱酯酶的抑制活性,其中4a和4d抑制活性最好,有进一步研究的价值。     

Synthesis of Certain S-Triazole and s-Triazolo[3,4-B] 1,3,4-Thiadiazole Derivatives of Expected Pharmacological Activity

Reaction of the newly prepared 3-(2-thienyl)-4-amino-s-triazole-5-thione (I) with different alkyl kalides and aromatic aldehydes afforded the corresponding thioethers and arylidene derivatives (II and III), respectively. Attempt ring closure of (I) with acetic anhydride produced the unexpected triacetyl derivative (IV). The synthesis of certain 3-(2-thienyl)-6-substituted-s-triazolo[3,4-b] 1,3,4-thiadiazoles (V and VII) was described. IR, NMR and mass spectral analyses of the prepared compounds were discussed.     

1,2,4-triazines. 7. Regioselective n2-amination of 3-methylthio-1,2,4-triazin-5(2H)-ones.A novel synthesis of [1,2,4]triazolo[2,3-b][1,2,4]triazinones and -triazine

A regioselective synthesis of 2-aminotriazinones 6a-d is reported, by reaction of 3-methylthio-1,2,4-triazinones 5a-d with O-(2,4-dinitrophenyl)hydroxylamine (2) as an amino-transfer agent. A spectroscopic study and an unequivocal synthesis of 2-amino-4-methyl-6-phenyl-1,2,4-triazinedione ( 11a ) has shown the site of amination to be N2 of the 1,2,4-triazinone ring. Subsequent reaction of 2-amino-1,2,4-triazinones 6a-b with amines, followed by ring closure with aliphatic acids provided [1,2,4]triazolo[2,3-b][1,2,4]triazine-7(1H)ones 13a-e. Conversion of [1,2,4]triazolo[2,3-b][1,2,4]triazinone 13c to unsubstituted [1,2,4]triazolo[2,3-6][1,2,4]triazine (15) was attained.     

Regioselective Synthesis of 2-Substituted [1,2,4]Triazolo[5,1-b][1,3]thiazin-7-ones by Heteropolyacids

2-Substituted [1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones 3 were synthesized via regioselective cyclization of 4H-[1,2,4]triazol-3-ylsulfanyl-acrylic acids 2 in the presence of catalytic amounts of heteropolyacids at room temperature in very good yields and rates.     

2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones

A novel method for synthesis of 2-R-5-Ar(Het)-5,6-dihydro-7H-[1,2,4]triazolo[5,1-b][1,3]thiazin-7-ones by condensation of 3-R-4,5-dihydro-1H-1,2,4-triazole-5-thiones with 3-aryl(heteryl)-2-propenoyl chlorides is proposed.     

Synthesis and Reactions of 3‐Methylthiazolo[3,2‐a]Benzimidazole‐2‐Carboxylic Acid Hydrazide: Synthesis of Some New Pyrazole, 1,3‐Thiazoline, 1,2,4‐Triazole and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐Thiadiazine Derivatives Pendant to Thiazolo[3,2‐a]Benzimidazole Moiety

The reaction of 3‐methylthiazolo[3,2‐a]benzimidazole‐2‐carboxylic acid ethyl ester (1) with hydrazine hydrate gives the hydrazide 2 which reacts with CS₂/KOH to afford the potassium salt 3. Treatment of 3 with l‐aryl‐2‐bromoethanones 4a,b afforded the 1,3‐thiazoline derivatives 6a,b, respectively, while the reaction of 3 with hydrazine hydrate afforded 1,2,4‐triazole‐3‐thione derivative 9. The reaction of 9 with l‐aryl‐2‐bromoethanones 4a,b and with hydrazonyl chlorides 11a,b gave the 1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazine derivatives 10a,b and 12a,b, respectively. Treatment of hydrazide 2 with phenyl isothiocyanate in refluxing benzene gave the thiosemicarbazide derivative 16. The latter reaction gave 1,3,4‐oxadiazole derivative 17 when benzene was replaced by DMF. Cyclization of the thiosemicarbazide derivative 16 with NaOH resulted in the formation of the 1,2,4‐triazole‐3‐thione derivative 18.     

Differentiation between [1,2,4]triazolo[1,5‐a] pyrimidine and [1,2,4]triazolo[4,3‐a]‐ pyrimidine regioisomers by 1H?15N HMBC experiments

The condensation of malonoaldehyde derivatives with either a 3‐amino‐[1,2,4]‐triazole or a 3,5‐diamino‐[1,2,4]‐triazole precursor was studied. In agreement with previous reports, two different bicycles, namely, bearing the regioisomeric [1,2,4]triazolo[1,5‐a]pyrimidine ( 1 ) or[1,2,4] triazolo [4,3‐a]pyrimidine ( 2 ) structural surrogates, could be obtained. We found that, depending on the triazole precursor, only one regioisomer resulted, either of the 1 or 2 series. We also observed that these two structural surrogates could be unambiguously differentiated by indirectly measuring their ¹⁵N chemical shifts by ¹H? ¹⁵N HMBC experiments. The occasional conversion of [1,2,4]triazolo[4,3‐a]pyrimidines to the [1,2,4]triazolo[1,5‐a]pyrimidine counterparts could be unequivocally determined by ¹⁵N NMR data. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis,Antibacterial, and Antifungal Activities of Imidazo[2,1-c][1,2,4]triazoles and 1,2,4-Triazolo[4,3-a]pyrimidinones

A straightforward method has been developed for the synthesis of 1-phenyl-imidazo [2,1-c][1,2,4]triazole derivatives 5a–j and 1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidinones derivatives 6a–g starting from 5-amino-1-phenyl[1,2,4]triazole and p-toluenesulfonic acid (PTSA). This methodology affords a number of 1-phenyl-imidazo [2,1-c][1,2,4]triazoles 5a–j and 1-phenyl-[1,2,4]triazolo[4,3-a]pyrimidinones 6a–g in reasonable yields and short reaction times. The structures of all new compounds were elucidated using infrared, ¹H and ¹³C NMR, and high-resolution mass spectrometry. Some of the newly synthesized compounds were screened for their antimicrobial activity.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications ^® for the following free supplemental resource(s): Full experimental and spectral details.]