Regioselectivity of cyclization of 3-allyl(propargyl)sulfanyl-5<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indoles

The interaction of 3-allylsulfanyl-5H-[1,2,4]triazino[5,6-b]indole with iodine led to 1-iodomethyl-1,2-dihydro[1,3]thiazolo[2',3':3,4][1,2,4]triazino[5,6-b]indol-11-ium pentaiodide with an angular structure, on the basis of which 1-iodomethyl-1,2-dihydro[1,3]thiazolo-, 1-methylidene-1,2-di-hydro[1,3]thiazolo, and 1-methyl[1,3]thiazolo derivatives were obtained. The intramolecular cyclization of 3-propargyl(allyl)sulfanyl-5H-[1,2,4]triazino[5,6-b]indoles under the influence of concentrated sulfuric acid led to linear annelated products:3-methyl[1,3]thiazolo[3',2':2,3][1,2,4]tri-azino[5,6-b]indole or its 2,3-dihydro derivative.     

Synthesis of 3-substituted bicyclic imidazo[1,2-d][1,2,4]thiadiazoles and tricyclic benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles

A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent S(N)Ar substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.     

C–H Arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Synthesis of a series of new 3,6-diaryl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles(5a–o) was achieved by phophine free, C–H arylative cross-coupling of 6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles(4a–o)with suitably substituted iodoanilines using 1-(2-naphthoyl)-3-(4-bromophenyl)thiourea as a ligand.The requisite triazolothiadiazoles(4a–o) were obtained by the condensation of 4-amino-1,2,4-triazole-3-thiol(3) with suitably substituted aromatic acids in the presence of phosphoryl chloride.     

含吡唑1,2,4-三唑噻二嗪衍生物的合成及抑菌活性

1-苯基-3-甲基-5-氯-4-吡唑甲醛与4-氨基-5-取代苯基-1,2,4-三唑-3-硫酮缩合生成4-(1-苯基-3-甲基-5-氯吡唑次甲亚胺基)-5-(取代苯基)-2H-1,2,4-三唑-3(4H)-硫酮,再烷基加成化为新型含吡唑基5,6-2H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪衍生物。 化合物结构经¹H NMR、IR以及元素分析确认。 初步生物活性测试结果表明,在100 mg/L浓度下,化合物8a(3-(2-甲基苯基)-6-(5-氯-2-甲基-4-苯基吡唑)-7-(4-硝基苯基)-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪)对黄瓜炭疽病的抑制率达90%。     

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.     

Synthesis of new condensed derivatives of pyrano[4,3-<Emphasis Type="Italic">b</Emphasis>]thieno[3,2-<Emphasis Type="Italic">e</Emphasis>]pyridine and pyrido[3',2':4,5]thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]pyrimidine

The reactions of 2-methyl (propyl) substituted 8,8-dimethyl-7,10-dihydro-4H,8H-pyrano[3",4":5',6']pyrido[3',2':4,5]thieno[3,2-d][1,3]oxazines with primary amines give 2-methyl (propyl) substituted 8,8-di- methyl-7,10-dihydro-8H-pyrano[3",4":5',6']pyrido[3',2':4,5]thieno[3,2-d][1,3]pyrimidin-4(3H)-ones or 3-acetyl-N-alkyl- and N-alkyl-3-butyrylamino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]- pyridine-2-carboxamides depending on steric hindrance in the amines.     

Reaction of 3-acetonyl-5-cyano-1,2,4-thiadiazole with phenylhydrazine hydrochlorides: indolization and phenylpyrazolation

Treatment of 3-acetonyl-5-cyano-1,2,4-thiadiazole (1) with 4-methyl or 4-methoxyphenylhydrazine hydrochloride provided 5-cyano-3-(2,5-dimethylindol-3-yl)-1,2,4-thiadiazole (2) or 5-cyano-3-(5-methoxy-2-methylindol-3-yl)-1,2,4-thiadiazole (3) as the sole product, respectively. In contrast, treatment of 1 with phenylhydrazine hydrochloride resulted in the formation of 5-cyano-3-(2-methylindol-3-yl)-1,2,4-thiadiazole (4) and the unexpected 5-cyano-3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-1,2,4-thiadiazole (5). In a similar manner, when 1 was treated with 4-chlorophenylhydrazine hydrochloride, indolization was suppressed by phenylpyrazolation giving rise to 5-cyano-3-(5-chloro-2-methylindol-3-yl)-1,2,4-thiadiazole (6) and 5-cyano-3-[1-(4-chlorophenyl)-3,5-dimethylpyrazol-4-yl]-1,2,4-thia diazole (7). The reaction mechanism is discussed. Compounds 4, 5 and 6 exhibited weak antimicrobial activity against Helicobacter pylori.     

含1-[二-(4-氟苯)甲基]哌嗪均三氮唑环的Mannich碱的合成及表征

微波辐射下,在冰醋酸中,3-甲基-4-氨基-1,2,4-三氮唑-5-硫酮1与芳香醛经微波辐射制得相应的中间体Schiff碱2(a~j),然后中间体2与1-[二-(4-氟苯)甲基]哌嗪于室温反应制得10个新的Mannich碱3(a~j).合成的10个目标化合物通过熔点测定和质谱、红外光谱、核磁共振氢谱分析、元素分析对其结构进行确证。     

Synthesis of 4(pyrazol-3-yl)[1,2,4]triazolo[4,3-a]quinoxalines and tetrazolo analog

The transformation of 2-chloro-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 3 to 1-aryl-4-[5-(hydroxymethyl-1-phenylpyrazol-3-yl][1,2,4]triazolo[4,3-a]quinoxalines 4a-c has been achieved upon treatment with aroylhydrazines in boiling butanol. Compounds 4a-c were smoothly acetylated by acetic anhydride to give their acetyl derivatives 5a-c in good yield. 4-[5-(Acetoxymethyl)-1-phenylpyrazol-3-yl]-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline was prepared by ring closure of 2-hydrazino-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 6 by the action of acetic anhydride. The reaction of 6 with acetylacetone afforded 3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]-2-(3,5-dimethylpyrazol-1-yl)quinoxaline 8 . In addition, the reaction of 3 with sodium azide in boiling N, N-dimethylformamide yielded the fused tetrazolo[1,5-a]quinoxaline 9 .     

Synthesis and biological activity of fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines

In our lead finding program, 12 new fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines were prepared via a practical three-step procedure starting from (iso)nicotinic hydrazides. The fluorine substituted aryl fragment was introduced in the last step through cyclocondensation of N-(3-pyridyl-1,2,4-triazol-5-yl)guanidines and fluoro/trifluoromethyl substituted benzaldehydes. The structures of the compounds were confirmed by ¹H and ¹³C NMR spectral data. The tautomeric preferences for the compounds were established using 2D NOESY experiments. The antiproliferative activity of the synthesized 1,2,4-triazolo[1,5-a][1,3,5]triazines was evaluated against breast, colon and lung cancer cell lines. The highest antiproliferative activity in the series was found for 2-(pyridine-3-yl)-7-(4-trifluoromethylphenyl)-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amine. The lack of inhibitory activity against bovine dihydrofolate reductase (DHFR) indicated that the antiproliferative activity was realized via other mechanisms.     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.     

Recherches en série triazépine-1,2,4: II — Etude de la réaction de l'acétylacétate d'éthyle avec les diamino-3,4 oxo-5 dihydro-4,5 triazines-1,2,4

The reaction of 3,4-diamino-5-oxo-4,5-dihydro-l,2,4-triazine or its 6-methyl or 6-phenyl substituted derivatives and ethyl acetoacetate gave three compounds: 4,7-dioxo-9-methyl-1,4,6,7-tetrahydro-as-triazino[4,3-b]-1,2,4-triazepine in poor yield, isomeric 4,9-dioxo-7-methyl-1,4,8,9-tetrahydro-as -triazino[4,3-b]-1,2,4-triazepine and by competitive cyclisation, 2-methyl-7-oxo-3,7-dihydro-s-triazolo[3,2-c]-1,2,4-triazine. By condensation of 3-methylamino-4-amino-5-oxo-4,5-dihydro-1,2,4-triazine with ethyl acetoacetate, the formation of 4,9-dioxo-7,10-dimethyl-4,8,9,10-tetrahydro-as-triazino[4,3-b]-1,2,4-triazepine was strongly favored.     

Synthesis of new modified aza heterocycles on the basis of 5-(2-chloro-1-nitroalkyl)-3-phenyl-and 5-(2-chloro-1-nitroalkyl)-3-methyl-1,2,4-oxadiazoles

3-Phenyl-and 3-methyl-5-(2-chloro-1-nitroalkyl)-1,2,4-oxadiazoles reacted with piperidine, pyrrolidine, and morpholine to give the corresponding 5-(2-amino-1-nitroalkyl) derivatives, while their reactions with sodium p-toluenesulfinate led to the formation of 2-[3-methyl(or phenyl)-1,2,4-oxadiazol-5-yl]-2-nitroethyl p-tolyl sulfones.     

Novel One-Pot Multicomponent Synthesis of Substituted 2,3-Dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)phthalazine-1,4-diones and Substituted 3-[3-(N′-Benzylidene-hydrazino)-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-6-yl]-4-hydroxy-6-methyl-pyran-2-ones

A one-pot procedure has been developed for the synthesis of substituted 2,3-dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazin-3-yl)phthalazine-1,4-diones by reaction of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and phthalic anhydrides in acetic acid medium. Similarly, a one-pot, three-component synthetic procedure has been developed for substituted 3-[3-(N¹-benzylidene-hydrazino)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl]-4-hydroxy-6-methyl-pyran-2-ones from 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and various aromatic aldehydes in absolute ethanol and a few drops of glacial acetic acid.

[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.]     

Synthesis,anti-inflammatory and analgesic activity of 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid derivatives

The title compounds 3a–l have been synthesized by the reaction of thiocarbohydrazide with substituted phenoxy acetic acid to obtained substituted 1,2,4-triazoles (1). Compound 1 was treated with various substituted aromatic aldehydes which results in 4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-2H-1,2,4-triazol-3(4H)-thiones (2a–g), further 2a–g is converted to 2-[4-(substituted benzylideneamino)-5-(substituted phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3a–l) derivatives by the reaction with chloroacetic acid. All the newly synthesized compounds were evaluated for in vivo anti-inflammatory and analgesic activities. Among the series 2-[4-(2,4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3d), 2-[4-(4-dichlorobenzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl thio] acetic acid (3e), 2-[4-(2,4-dichlorobenzylideneamino)-5-[(2,4-dichlorophenoxy)methyl]-4H-1,2,4-triazol-3-yl thio] acetic acid (3j) and 2-[5-[(2,4-dichlorophenoxy)methyl)]-4-(4-chlorobenzylideneamino)-4H-1,2,4-triazol-3-yl thio] acetic acid (3k) showed significant anti-inflammatory activity with P < 0.001 (63.4%, 62.0%, 64.1% and 62.5% edema inhibition, respectively), as compared to the standard drug diclofenac (67.0%) after third hour respectively and also compounds 3j, 3k exhibited significant analgesic activity with P < 0.001 (55.9% and 54.9% protection, respectively) and less ulcerogenic activity as compared with standard drug aspirin (57.8%).     

Synthesis of Some 3-Substituted 1,2-Dihydroindoles

The reaction of 4-oxo-2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-1,3-thiazin-6-methyl carboxylate 2 with hydrazine hydrate in methanol gave 4-oxo-2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-1,3-thiazin-6-carbonylhydrazine 3. Furthermore, the reaction of 3 with carbon disulfide and then hydrazine hydrate afforded 3-[6-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-oxo-1,3-thiazin-2-yl] hydrazone-1,3-dihydroindol-2-one 5. the latest reacted with DMAD to give {6-hydroxy-3-[4-oxo-2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-1,3-thiazin-6yl]-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-ylidene}methoxycarbonylmethylene 6.     

Synthesis of 3-Alkyl-6-aryl(arylamino)-7H-[1,2,4]triazolo- [3,4-b][1,3,4]thiadiazines

Starting from 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols and substituted chloroacetanilides, the corresponding (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilides were synthesized. The products underwent intramolecular cyclization in boiling phosphoryl chloride to afford 3-alkyl-6-arylamino-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines. 3-Alkyl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hydrobromides were obtained by reaction of 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols with substituted phenacyl bromides.     

Reactions of 1,2,4-triazole derivatives with a “model” thiirane

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-2,4(1H,3H)-dione.     

Synthesis of 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one. Derivatives and their ring transformation into 5-benzamido-1,2,4-triazolidine-3,5-dione derivatives

Some 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one derivatives 6 and 9 have been synthesized in two ways. The expected thermal ring transformation into 2,5-disubstituted 1,3,4-oxadiazoles did not occur but, by acid hydrolysis of 5-aryl-3-[3-benzylidene-2-methyl(or phenyl)carbazoyl]-1,3,4-oxadiazol-2(3H)-ones 6 , a new ring transformation took place and the corresponding 4-benzamido-1-methyl(or phenyl)-1,2,4-triazolidine-3,5-dione derivatives 11 were formed. The 4-amino-1-phenyl-1,2,4-triazolidine-3,5-dione ( 19 ) has been prepared and its structure was confirmed by some reactions.     

2-{2-[3-(取代苯基)-3-氧代-2-1,2,4-三唑-1-基-丙基]-苯基}-2-甲氧亚氨基乙酸甲酯和乙酰甲胺类衍生物的合成与杀菌活性研究

以2-甲基苯甲酰甲酸甲酯为起始原料, 通过与甲氧基胺的盐酸盐、甲胺、N-溴代丁二酰亚胺(NBS)和1H-1,2,4-三氮唑钠反应合成了两个系列共计22个2-{2-[3-(取代苯基)-3-氧代-2-1,2,4-三唑-1-基-丙基]-苯基}-2-甲氧亚氨基乙酸甲酯和乙酰甲胺类的衍生物. 经IR, 1H NMR和MS对目标化合物进行了结构表征. 用浓度为 10 µg&#8226;mL－1的目标化合物进行了初步离体杀菌活性试验, 结果表明: Ha4, Ha5, Ha7对油菜菌核病有杀菌活性; Ha2, Hb8对小麦纹枯病有杀菌活性; Hb4对蔬菜灰霉病有杀菌活性; Hb4, Hb5对小麦赤霉病和小麦纹枯病均有杀菌活性.