阅读说明：本技术 一种芳巯基二唑类衍生物的合成方法 (Synthetic method of aromatic mercapto-diazole derivative ) 是由 戴立言 安宇 王晓钟 陈英奇 于 2019-09-20 设计创作，主要内容包括：本发明公开了一种芳巯基二唑类衍生物的合成方法,该方法以各类含有巯基的2,5-二取代恶二唑和噻二唑为原料,将其溶在一定量的有机溶剂中,加入氟化剂,形成原料体系,反应装置密闭并用N<Sub>2</Sub>充分置换后,升温到回流并用注射器加入苯炔前体,反应5-6h,反应完毕,经过后处理得到所述的芳巯基二唑类衍生物。本发明反应方法操作简单,节省原料和反应时间,反应的转化率和选择性较为理想,与现有的技术相比,环境污染小,操作安全,是一种新型的杂环化合物巯基芳基化反应方法。本方法应用于各类恶二唑和噻二唑环上巯基的芳基化反应,但不局限于芳巯基恶二唑和噻二唑的制备。(The invention discloses a synthesis method of aromatic mercapto-diazole derivatives, which takes various 2, 5-disubstituted oxadiazole and thiadiazole containing mercapto as raw materials, dissolves the raw materials in a certain amount of organic solvent, adds a fluorinating agent to form a raw material system, seals a reaction device and uses N 2 And after full replacement, heating to reflux, adding a benzyne precursor by using an injector, reacting for 5-6h, and after the reaction is finished, carrying out post-treatment to obtain the aromatic mercapto-diazole derivative. The reaction method has the advantages of simple operation, raw material and reaction time saving, ideal conversion rate and selectivity of the reaction, small environmental pollution and safe operation compared with the prior art, and is a novel heterocyclic compound sulfydryl arylation reaction method. The method is applied to the arylation reaction of sulfydryl on various oxadiazoles and thiadiazole rings, but is not limited to the preparation of arylsulfydryl oxadiazoles and thiadiazole.)

1. A synthetic method of aromatic mercapto-diazole derivatives is characterized by comprising the following steps:

under the action of fluoride, reacting a 2-mercapto-diazole compound with a benzyne precursor in an organic solvent, and carrying out post-treatment after the reaction is finished to obtain the aromatic mercapto-diazole derivative;

the structure of the 2-mercapto-diazole compound is shown as the formula (II):

the structure of the aromatic mercapto-diazole derivative is shown as the formula (I):

in the formulas (I) to (II), Y is S or O, and R is substituted or unsubstituted phenyl, alkyl or halogen;

the substituent on the phenyl is selected from C₁～C₄Alkyl or halogen.

2. The method for synthesizing an arylmercapto-diazole derivative according to claim 1, wherein R is methyl, phenyl, p-methylphenyl, p-methoxyphenyl or p-chlorophenyl.

3. The method for synthesizing the arylmercapto-diazole derivative according to claim 1, wherein the reaction feeding manner is as follows:

under the protection of inert gas, the 2-mercapto-diazole compound and fluoride are firstly added into the organic solvent, then the temperature is raised to a reflux state, and the benzyne precursor is added for reaction.

4. The method for synthesizing aromatic mercapto-diazole derivatives according to claim 1, wherein said fluoride is cesium fluoride or tetrabutylammonium fluoride.

5. The method for synthesizing aromatic mercapto-diazole derivatives according to claim 1, wherein said organic solvent is acetonitrile or tetrahydrofuran.

6. The method for synthesizing aromatic mercapto-diazole derivatives according to claim 1, wherein said phenylalkyne precursor is 2-trimethylsilyltrifluoromethanesulfonic acid phenyl ester.

7. The method for synthesizing aromatic mercapto-diazole derivatives according to claim 1, wherein the reaction time is 5-6 h.

8. The method for synthesizing the aromatic mercapto-diazole derivative according to claim 1, wherein the molar ratio of the 2-mercapto-diazole compound, the benzyne precursor and the fluoride is 1:1.2: 2.4.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of an aromatic mercapto-diazole derivative, and more particularly relates to a reaction method for arylation of mercapto groups on oxadiazole and thiadiazole rings.

Background

Oxadiazoles and thiadiazoles are two important classes of compounds among many heterocyclic compounds, and are of great interest because of their unique five-membered polyatomic ring structures. Many oxadiazole and thiadiazole derivatives have excellent antibacterial, insecticidal, plant growth regulating and antiviral activities, and can also play pharmacological roles of resisting infection, inflammation, depression, cancer and the like. The derivatives of oxadiazoles and thiadiazoles linked to a benzenethiol group have received attention in the fields of microbiology and pharmacology, and studies have shown that the antimicrobicity of benzenethiol thiadiazole is 100. mu.g/ml (Candida albicans), 50. mu.g/ml (Candida parapsilosis), 25. mu.g/ml (Candida tropicalis), 25. mu.g/ml (Cryptococcus neoformans), 12.5. mu.g/ml (Trichophyton), and similar compounds have similar bacteriostatic activity (Farmaco, Edizone scientific (1982),37(5), 298-. In addition, 20 kinds of mercaptothiadiazoles are synthesized and tested for bacteriostatic properties against four microorganisms such as Venturi inacalis, Bofrytis cinerea, Fusarium bulbigerenur and Cercospora melonis, and only thiadiazoles containing aromatic halogen groups are found to show fungal toxicity, and the cracking of Ph-S bonds occurring in bacteriostatic processes of these compounds may be related to nucleophilic attack by fungal cell components, indicating the importance of mercaptothiadiazoles derivatives from the viewpoint of practical value (M.PIANKA. journal of the Science of Food and Agriculture (1968),19, (9), 502-7). Thiol arylation has the same significance for oxadiazole rings, and studies have indicated that two phenylthiol oxadiazole-containing syntheses can be achieved by phenyl zinc halide and show effective inhibition of proliferation activity in breast cancer cells of the MCF-7 line relative to normal stromal cells of the MCF-10A line (Ivelina M. Yonova. J. org. chem.2014,79, 1947-1953). In addition, many studies have pointed out the broad spectrum of biological activities of arylsulfonyl oxadiazoles, and a large number of such oxadiazole derivatives having bactericidal, anti-pest, herbicidal, etc. effects can be obtained by oxidation of mercaptooxadiazole, and thus benzomercaptooxadiazole has the meaning of an intermediate in the synthesis of such substances (weimingxu. cn101812034 (a)).

The 2-benzene mercapto thiadiazole compound is synthesized by using iodobenzene and 2-mercapto thiadiazole in CuI and K₂CO₃Similar to the synthesis method of 2-benzene mercapto oxadiazole prepared by long-time high-temperature reaction in solvents such as DMF, DMSO and the like in the presence of other catalysts, the method is limited by the cost of organic iodides and cuprous salt catalysts (L.F. Niu et al/Tetrahedron 67(2011)2878-(ii) a Or diazotizing the 2-aminothiadiazole to obtain 2-halogenated thiadiazole, and then reacting with phenyl containing active hydrogen such as thiophenol to obtain the target product. The diazotization-halogenation reaction is catalyzed by cuprous salt, the diazonium salt has high temperature or explosion risk under impact, and the operation of the diazotization reaction and the product treatment have more problems and defects and need to be further improved (Alemagna, A.; Bacchetti, T.; Beltrame, P.tetrahedron1968,24,3209); other methods for introducing benzene sulfydryl and phenyl ether groups into oxadiazole and thiadiazole rings use Organic reagents with complicated preparation processes, high cost, and the like, such as Grignard reagents, Organic zinc reagents, and the like, and the conditions are too harsh to be suitable for popularization and application (Yonova, Ivelina M. journal of Organic Chemistry,79(5), 1947-1953; 2014). In summary, the benzene sulfhydrylation reaction of oxadiazole and thiadiazole compounds is also basically limited to the improvement of the traditional coupling synthesis method system, such as the development of catalysts and the application of new benzene sulfhydrylation reagents, and most of the synthesis methods can be completed under the conditions of high temperature and long time.

The method uses a reaction method of benzyne chemistry for reference, and adopts benzyne precursor 2-trimethylsilyl trifluoromethanesulfonic acid phenyl ester which is easy to synthesize to perform reflux reaction with oxadiazole and thiadiazole containing sulfydryl in solvent acetonitrile for 5-6h in the presence of cesium fluoride to obtain aromatic sulfydryl oxadiazole and thiadiazole with high selectivity and conversion rate.

Disclosure of Invention

The invention provides a synthesis method of aromatic mercapto-diazole derivatives, which has the advantages of easily obtained raw materials and higher reaction conversion rate and selectivity.

A synthetic method of aromatic mercapto-diazole derivatives comprises the following steps:

under the action of fluoride, reacting a 2-mercapto-diazole compound with a benzyne precursor in an organic solvent, and carrying out post-treatment after the reaction is finished to obtain the aromatic mercapto-diazole derivative;

the structure of the 2-mercapto-diazole compound is shown as the formula (II):

the structure of the aromatic mercapto-diazole derivative is shown as the formula (I):

in the formulas (I) to (II), Y is S or O, and R is substituted or unsubstituted phenyl, alkyl or halogen;

the substituent on the phenyl is selected from C₁～C₄Alkyl or halogen.

According to the invention, the arylation of sulfydryl on oxadiazole and thiadiazole is realized by using the phenyl 2-trimethylsilyl trifluoromethanesulfonate as the benzyne precursor, the method is simple to operate, raw materials and reaction time are saved, the conversion rate and selectivity of the reaction are ideal, and compared with the prior art, the method is small in environmental pollution and safe to operate, and is a novel sulfydryl arylation reaction method for heterocyclic compounds.

The reaction formula of the invention is as follows:

preferably, R is methyl, phenyl, p-methylphenyl, p-methoxyphenyl or p-chlorophenyl.

Preferably, the reaction feeding mode is as follows:

under the protection of inert gas, the 2-mercapto-diazole compound and fluoride are firstly added into the organic solvent, then the temperature is raised to a reflux state, and the benzyne precursor is added for reaction.

The kind of fluoride and organic solvent may have a great influence on the reaction result, wherein the fluoride may be organic fluoride or inorganic fluoride salt, and preferably, the fluoride is cesium fluoride or tetrabutylammonium fluoride.

Preferably, the organic solvent is acetonitrile or tetrahydrofuran, and the weight ratio of the organic solvent to the phenylalkyne precursor is 23.7: 1.

Preferably, the reaction time is 5 to 6 hours.

Preferably, the molar ratio of the 2-mercaptodiazole compound, the benzyne precursor and the inorganic fluoride salt is 1:1.2: 2.4.

In the present invention, the separation and purification process may be performed according to a conventional method in the art. The method comprises the following specific steps: after the reaction is finished, adding water with the volume about 5-6 times of that of acetonitrile serving as a reaction solvent for quenching, extracting by using ethyl acetate serving as an organic solvent, washing by using a saturated NaCl solution, and carrying out anhydrous MgSO (MgSO)₄Drying, concentrating, and separating by column chromatography to obtain aromatic mercapto oxadiazole or aromatic mercapto thiadiazole.

The used phenylalkyne precursor is 2-trimethylsilyl trifluoromethanesulfonic acid phenyl ester, and the molar ratio of the phenylalkyne precursor to a substrate oxadiazole or thiadiazole is 1.2: 1.

The reaction process can be monitored by thin-layer chromatography analysis in the reaction, and the reaction end point is determined; the reaction products are subjected to melting point measurement and nuclear magnetic resonance hydrogen spectrum (¹H-NMR) and nuclear magnetic resonance carbon Spectroscopy (C¹³C-NMR) to determine the structure.

Compared with the traditional arylation reaction method of sulfydryl on oxadiazole and thiadiazole rings, the method has the following advantages that:

(1) the reaction condition is relatively mild, the time is saved, and the purity and the yield of the product are high;

(2) simple operation, no use of highly toxic or explosive organic reagents, safety and environmental protection.

Drawings

FIG. 1 is the NMR spectrum of 5-methyl-2-benzenemercapto-1, 3, 4-oxadiazole obtained in example 1 of the present invention,¹H NMR(500MHz,Chloroform-d)δ7.69–7.54(m,2H),7.41(qd,J＝5.0,1.6Hz,3H),2.49(s,3H).

FIG. 2 is the NMR carbon spectrum of 5-methyl-2-benzenemercapto-1, 3, 4-oxadiazole obtained in example 1 of the present invention,¹³C NMR(126MHz,Chloroform-d)δ165.64,163.04,133.67,129.79,129.73,127.11,11.19.

both sets of data are consistent with the NMR data and the carbon spectrum data reported in the literature for 5-methyl-2-phenylmercapto-1, 3, 4-oxadiazole (Tetrahedron 67(2011) 2878-.

Detailed Description