PEG-400催化含硫醚乙酰胺结构1,3,4-噁二唑的合成及抗真菌活性研究

为寻找具有较高活性新型1,3,4-噁二唑类杂环化合物,利用3,4,5-三甲氧基苯甲酰肼和二硫化碳环合生成的5-芳基-1,3,4-噁二唑-2-硫酮为活性基团,超声波辐射聚乙二醇-400相转移催化条件下,与(取代)N-氯乙酰基苯胺反应制备得到硫代乙酰胺修饰的1,3,4-噁二唑衍生物(3a~3f),合成收率为80~88%,其结构经IR、1HNMR和元素分析等测试技术加以确证;初步的活性测试结果表明,目标产物对白色念珠菌和黑曲霉等有较显著的抗菌活性。     

2,5-二芳基取代基-1,3,4-噁二唑类衍生物的合成与表征

以双酰肼环合法合成了含1,3,4-噁二唑结构单元的溴代芳卤,然后通过Sonogash ira钯催化偶联作用与不同单取代炔反应合成了3个新的2,5-二取代-1,3,4-噁二唑类小分子衍生物,其结构经DSC,1H NMR,IR和元素分析表征。     

新型1,3,4-噁二唑-2-硫酮衍生物的合成及其抗肿瘤活性

以手性氨基酸和间甲基苯甲酸(或苯乙酸)为原料,经酯化、缩合、肼解和环合反应合成了12个新型的1,3,4-噁二唑-2-硫酮衍生物(6a~6f或7a~7f),其结构经1H NMR,FT-IR和ESI-MS表征。用MTT法研究了6和7的抗肿瘤活性。结果表明:(2S)-5-(3-甲基苯甲酰胺基)苯乙基-1,3,4-噁二唑-2-硫酮(6f)和(2S)-5-(2-羟基-苯乙酰胺基)乙基-1,3,4-噁二唑-2-硫酮(7b)对红白血病细胞(K562)抑制活性较好。     

含1,8-萘啶环和噻吩环的1,3,4-噁二唑的合成及抗菌活性研究

以2-氨基吡啶-3-甲醛和取代乙酰乙酸乙酯Friedlander缩合反应生成1,8-萘啶-3-基甲酸乙酯,经肼解反应得到1,8-萘啶-3-基甲酰肼为原料,对甲苯磺酸催化芳酰肼与噻吩-2-基甲醛缩合反应形成N-酰基腙中间体;该中间体不需要分离,二氯二氰基苯醌氧化条件下环合反应制备得到新型1,3,4-噁二唑衍生物,合成收率为83~91%,化合物结构经IR、~1HNMR、MS和元素分析等测试技术加以确证;初步的活性测试结果表明,目标产物对大肠杆菌、金黄色葡萄球菌和枯草杆菌等有一定的抗菌活性。     

微波作用下2,5-二取代-1,3,4-噁二唑的合成

2 ,5 二取代 1 ,3 ,4 二唑可用作药品 ,光敏物质 ,闪烁体 ,激光材料 ,高分子液晶单体等[1- 5] 。一种是以芳香酸与水合肼作为原料用多聚磷酸作为脱水环合剂来合成此类化合物[6 ] ,另一种是由芳香酸转变为芳香酰氯或酯 ,再与水合肼反应得到单酰肼或二酰肼 ,最后用三氯氧磷[7] ,五氧化二磷和五氯化磷[8] ,一氯三甲硅[9] 脱水环合 ;此外 ,用水合肼和尿素合成得到的氨基脲代替水合肼 ,与芳香酸缩合合成二唑[10 ] ,这些方法共同的缺陷是 :环合时间较长 ,少者 4～ 5ｈ ,多则 8ｈ。近年来 ,微波技术在有机合成及其杂环化合物的合成中得到了广…     

对称双-1,3,4-噁二唑化合物的合成及性质

首先以苯氧乙酰肼和二酰氯为原料反应得到对称双酰肼化合物,再以POCl3合环得到系列对称双-1,3,4-噁二唑化合物。考察了该系列化合物的紫外-可见吸收光谱,其中,间苯双-1,3,4-噁二唑化合物在250nm附近有明显的最大吸收峰,对苯双-1,3,4-噁二唑化合物的最大吸收峰则红移至290nm附近;而脂肪族双-1,3,4-噁二唑化合物没有明显的最大吸收峰,说明没有大的共轭体系,与结构相符合。所有化合物的结构均经元素分析、IR、1H NMR和MS确证。     

脂肪族二酸二烷基双去氢枞基双噁二唑的合成及除草活性

以去氢枞酸为原料,制备去氢枞酸酰氯.以脂肪族二酸为原料,经过脂肪族二酸二乙酯得到脂肪族二酸二酰肼.脂肪族二酸二酰肼与去氧枞酸酰氯在相转移催化下反应得到N,N＇-二去氢枞酰基取代脂肪族二酸二酰肼,再脱水环合,得到5个标题化合物脂肪族二酸二烷基双去氢枞基双噁二唑.通过元素分析,IR,MS,1H NMR和13C NMR对所合成的新化合物进行了结构表征.初步的除草活性测试表明,化合物6b～6e在100 μg/mL浓度下对油菜的胚根生长具有良好的抑制作用,抑制率均超过80％.     

3-N-丙酰基-2-芳基-5-(2-碘苯基)-1,3,4-噁唑啉类化合物的合成

2-碘苯甲酰肼与芳醛反应得到相应的酰腙(1),1再与丙酸酐脱水环化合成了3-N-丙酰基-2-芳基-5-(2-碘苯基)-1,3,4-噁唑啉类化合物,其结构经1H NMR,IR,MS和元素分析表征。     

2-[1-(1,2,4-三唑)甲基]-3-乙酰基-2,5-二取代芳基-1,3,4-噁二唑啉类化合物的合成

在冰醋酸存在下, 4-取代苯乙酮和溴素容易进行溴代反应, 得到α-溴-4-取代苯乙酮; 将其和1,2,4-三唑在丙酮中反应, 得到α-(1,2,4-三唑-1-基)-4-取代苯乙酮2; 在冰醋酸催化下, 2和4-取代苯甲酰肼1进行缩合, 得到相应酰腙衍生物3; 化合物3在乙酸酐的作用下环化生成一系列2-[1-(1,2,4-三唑)甲基]-3-乙酰基-2,5-二取代芳基-1,3,4-噁二唑啉4. 化合物4的结构经IR, 1H NMR, MS, 元素分析和单晶衍射确证.     

含1,3,4-噁二唑和1,3,4-噻二唑的硫醚类化合物的合成

在KOH作用下,芳甲酰肼1a～1e与CS2环化生成5-芳基-2-巯基-1,3,4-噁二唑(2a～2e);将2a～2e与氯乙酸乙酯反应,生成2-(5-芳基-1,3,4-噁二唑)硫基乙酸乙酯(3a～3e);3a～3e肼解得2-(5-苯基-1,3,4-噁二唑-2-硫基)乙酰肼(4a～4e);4a～4e与芳酰基异硫氰酸酯5a～5d反应得到双酰基氨基硫脲衍生物A1～A19;A1～A19在H2SO4催化下环合得到目标化合物B1～B19;目标化合物的结构经IR,1H NMR,MS,HRMS确证.     

Propylphosphonic anhydride (T3P): an efficient reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles

Propylphosphonic anhydride (T3P^®) has been demonstrated to be an efficient and mild reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles from carboxylic acids.     

Mild and convenient one-pot synthesis of 1,3,4-oxadiazoles

A mild, general, convenient, and efficient one-pot synthesis of 2-phenyl-5-substituted-1,3,4-oxadiazoles is described. Both (hetero)aryl and alkyl carboxylic acids were efficiently condensed with benzohydrazide in the presence of TBTU to give diacylhydrazine intermediates. The latter underwent a smooth TsCl-mediated cyclodehydration reaction to afford 2-phenyl-5-substituted-1,3,4-oxadiazoles in good to very good yields.     

Syntheses of diheterocyclic compounds based on 2-thioacetohydrazide-5,7-dimethyl-1,2,4-triazolo[1,5-a]- pyrimidine

The syntheses of some diheterocyclic compounds from 2-thioacetohydrazide- 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (1) are described. Compound 1 can be converted into triazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. The structures of the intermediates and the target compounds were confirmed by (1)H-NMR, MS and elemental analyses.     

The synthesis of bis(1,3,4-oxadiazol-2-yl-phenylmethyl) sulfides and other related 1,3,4-oxadiazoles from 1,1′-diphenylthiodiacetic acid dihydrazide and triethyl orthoesters

Reactions of symmetrical 1,1′-diphenylthiodiacetic acid dihydrazide and triethyl orthoesters in the presence of catalytic amount of glacial acetic acid resulted in the formation of three heterocyclic products: the appropriate bis(1,3,4-oxadiazol-2-yl-phenylmethyl) sulfides, 2-benzyl-1,3,4-oxadiazoles and 2-benzoyl-1,3,4-oxadiazoles. The presence of the latter two compounds is connected with carbon-sulfur fission in the molecule of the starting hydrazide. The identity of the unexpected fission products was confirmed by parallel syntheses of the model 1,3,4-oxadiazoles from phenylacetic acid hydrazide and 2-hydroxymethyl-1,3,4-oxadiazole derivatives.     

The Reaction of 5-Aryl(hetaryl)-2-aroylmethylthio-1,3,4-oxadiazoles with Aryldiazonium Tetrafluoroborates

5-Aryl(hetaryl)-2-aroylmethylthio-1,3,4-oxadiazoles behave as CH acids and readily react with aryldiazonium tetrafluoroborates at the active methylene group to give azo coupling products. The spectroscopic properties of the compounds synthesized have been studied.     

Synthesis and study of poly (1, 3, 4-oxadiazoles)

Various conditions for synthesizing poly (1,3,4-oxadiazoles) from carboxylic acids, their hydrazides, and polyhydrazides, are investigated. Methods of cyclodehydration of polyhydrazides using phosphorus oxychloride, sulfuric acid, and certain other reagents are not of general utility for synthesizing poly (1,3,4-oxadiazoles). Vacuum-heating polyhydrazides gives crosslinked polymers. A new method of preparing poly (1,3,4-oxadiazoles) is offered. It is the reaction of hydrazine sulfate or dihydrazides of acids with dicarboxylic acids in oleum solution. Some chemical properties of the compounds synthesized are investigated.     

Design and synthesis of novel quinoline derivatives bearing oxadiazole,isoxazoline, triazolothiadiazole,triazolothiadiazine, and piperazine moieties

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1 , which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4 , 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c , respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7 . Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c . Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 , 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c . Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.     

Structural modification studies of 3-piperonylsydnone I. synthesis of piperonyl-substituted pyrazoles,isoxazoles, triazoles,oxadiazoles and thiadiazoles

As a structural modification study of the antimalarial compound 3-piperonylsydnone, a number of pyrazoles, isoxazoles, 1,2,4-triazoles, ψ-1,2,4-triazoles, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and their intermediates all of which contain the piperonyl moiety have been synthesized. The antimalarial activity of these compounds was found to be less than that of the original sydnone. With the exception of 2,4-diamino-5-piperonylpyrimidine, among the compounds tested, those which showed survival time of eleven days or over all possess a N-N linkage.     

2-Phenyl-5-(trichloromethyl)-1,3,4-oxadiazoles,A new class of antimalarial substances

An investigation of hybrids of 2,5-dimethyl-1,3,4-oxadiazole (I) and α,α,α,α',α',α'-hexachloro-p-xylene (Hetol®) (II) as potential antimalarial agents led to the synthesis of representative 2-phenyI-5-(trichloromethyl)-1,3,4-oxadiazoles (VIa-f, VIII-X) and related trichloromethyl 1,2,4-oxadiazole, 1,3,4-oxadiazoles, and 1,3,4-thiadiazole (VII, XIII-XV). Treatment of the appropriately substituted benzoic: acid hydrazides (IVa-f) with trichloroacetic anhydride afforded the intermediate 1-benzoyl-2-(triehloroacetyl)hydrazines (Va-f) which were cyclized to the desired 5-(chlorophenyl, tolyl, or α,α,α-trifluorotolyl)-2-(trichloromethyl)-1,3,4-oxadiazoles (VIa-f) (44–66%) in situ utilizing phosphorous oxychloride. Chlorination of the 5-tolyl-2-(trichloromethyl)-1,3,4-oxadiazoles (VId-f) afforded 2-(trichloromethyl)-5-(α,α,α-trichloro-m- and p-tolyl)-1,3,4-oxadiazole (VIII and IX) and 2-(α,α,α,α',α',α'-hexachloro-3,5-xylyl)-5-(trichloromethyl)-1,3,4-oxadiazole (X) in 23–56% yield. Each of the 2-phenyl-5-(trichloromethyl)-1,3,4-oxadiazoles (VIa-f, VIII-X) was active against Plasmodium berghei in mice when administered in single 160 or 640 mg./kg. subcutaneous doses or given orally by drug-diet for 6 days at doses of 29–336 mg./kg./day. The 2-(trichloromethyl)-5-(α,α,α-trichlorotolyl)-1,3,4-oxadiazoles (VIII-X) were the most active compounds prepared and exhibited activity against P. berghei comparable with Hetol®. Structure-activity relationships are discussed.     

Synthesis and properties of furan derivatives. 4. Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles containing furan fragments

The condensation of hydrochloride sats of iminoesters of furan acids with hydrazides of carboxylic acids gives 2,5-disubstituted 1,3,4-oxadiazoles containing furan fragments. Such compounds are also formed in the condensation of hydrazides of 5-R-furan-2-carboxylic acids with hydrocloride salts of carboxylic acid iminoesters. The reaction of furan acids with hydrazine dihydrochloride in polyphosphoric acid gave symmetrically disubstituted 1,3,4-oxadiazoles containing furan fragments.Communication 3, see ref. [1].I. M. Gubkin State Petroleum and Natural Gas Institute, 117917, Moscow. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 238–249, February, 1995. Original article submitted January 24, 1995.