阅读说明：本技术 1,3,4-恶二唑杂环化合物的合成方法 (Synthesis method of 1,3, 4-oxadiazole heterocyclic compound ) 是由 李剑 高旭 杜晓刚 侯国权 刘莉 于 2021-01-18 设计创作，主要内容包括：本发明属于有机合成及药物技术领域,具体涉及一种1,3,4-恶二唑杂环化合物的合成方法。本发明是以苯甲醛衍生物和重氮三价碘试剂作为原料,光照下,无任何催化剂,二氯甲烷为溶剂,室温发生反应,得到1,3,4-恶二唑杂环化合物。使用本发明提出的方法,在室温条件下,反应10-15小时,一步法即可得到1,3,4-恶二唑杂环衍生物,产率为48～89％。本反应用简单易得的原料,在光照条件下,一步简便快速地合成了1,3,4-恶二唑杂环类衍生物,为合成1,3,4-恶二唑杂环类衍生物提供了一条简单高效,温和的合成新方法。(The invention belongs to the technical field of organic synthesis and medicines, and particularly relates to a synthesis method of a 1,3, 4-oxadiazole heterocyclic compound. The invention takes benzaldehyde derivatives and diazo trivalent iodine reagent as raw materials, under the illumination, no catalyst is needed, methylene dichloride is taken as solvent, and the reaction is carried out at room temperature, so as to obtain the 1,3, 4-oxadiazole heterocyclic compound. By using the method provided by the invention, the 1,3, 4-oxadiazole heterocyclic derivative can be obtained by a one-step method at room temperature for 10-15 hours, and the yield is 48-89%. The reaction uses simple and easily obtained raw materials, and under the condition of illumination, the 1,3, 4-oxadiazole heterocyclic derivative is simply, conveniently and quickly synthesized in one step, so that a simple, high-efficiency and mild new synthesis method is provided for synthesizing the 1,3, 4-oxadiazole heterocyclic derivative.)

1. A synthetic method of a 1,3, 4-oxadiazole heterocyclic compound is characterized in that benzaldehyde derivatives and trivalent iodine reagents are used as raw materials, and the raw materials are added into a solvent to be stirred and react to generate the 1,3, 4-oxadiazole heterocyclic derivatives; the stirring reaction conditions are as follows: reacting at room temperature under the condition of illumination, wherein the reaction time is 10-15 hours.

2. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound according to claim 1, wherein the solvent is dichloromethane, chloroform, acetonitrile, or methanol.

3. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound of claim 1, wherein the molar ratio of the benzaldehyde derivative to the trivalent iodine reagent is 1: 1.5.

4. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound according to claim 1, wherein the benzaldehyde derivative is: benzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-methylbenzaldehyde, 4-methoxybenzaldehyde, 4-tert-butylbenzaldehyde 3-methoxybenzaldehyde, 2-cyanobenzaldehyde, 2, 4-dimethoxybenzaldehyde, 2, 6-dichlorobenzaldehyde, 2, 4-dichlorobenzaldehyde, 2, 3-dimethylbenzaldehyde, 3, 4-dimethylbenzaldehyde, 2,4, 6-trimethylbenzaldehyde.

5. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound according to claim 1, wherein the trivalent iodine has a structure represented by the following formula,

wherein R is¹＝COOEt，COOMe，COOCH₂Ph。

Technical Field

The invention belongs to the technical field of organic synthesis and pharmaceutical synthesis, and particularly relates to a synthesis method of a 1,3, 4-oxadiazole heterocyclic compound.

Background

1,3, 4-oxadiazole heterocycles are widely present in drug molecules due to their good biological and pharmacological activities, and also can be used as intermediates in synthetic chemistry, and are widely used in organic synthesis, and are attracted to and studied by many scientists (a) Sharma, s.; sharma, p.k.; kumar, n.; dudhee, r.pharma.chemica.,2010,2,253.(b) Khalilullah, h.; ahsan, m.j.; hedaitullah, m.; khan, s.; ahmed, b.mini-rev.med.chem.,2012,12,789 ]. The polycyclic compound with 1,3, 4-oxadiazole as a mother nucleus has good biological activity in the aspects of pain relieving, anticonvulsant efficacy, antifungal, insecticidal and the like, and a plurality of medicaments sold in the market, including an anti-AIDS medicament, namely Latiravir, an antihypertensive medicament, namely Nexadil and docetaxel with an anti-cancer effect, all contain the 1,3, 4-oxadiazole heterocyclic mother nucleus.

The current methods for the synthesis of 1,3, 4-oxadiazole heterocycles mainly involve the cyclisation of the hydrazide [ (a) Chu, w.j.; yang, y.; chen, c.f.org.lett.2010,12,3156; (b) dolman, S.J; gosselin F, O' shear, p.d.; davies, i.e.j.org.chem.2006; 71:9548.], C-H cross-oxidation of N-phenylhydrazide [ Zhang, L.; zhao, x.; sting, X.; zhang, x.; lu, S.; luo, l.; jia, x.tetrahedron lett.2016,57,5669] and the acid-catalyzed tandem cyclization of hydrazides with nitroalkanes (Aksenov, a.v.; Khamraev, v.; Aksenov, n.a.; Kirilov, n.k.; Domenyuk, d.a.; Zelensky, v.a.; Rubin, m.rsc Advances 2019,9, 6636). However, these methods have disadvantages in that a metal catalyst, an external oxidizing agent, and severe reaction conditions are required. Therefore, the development of a novel simple and efficient synthesis method of the 1,3, 4-oxadiazole heterocyclic derivative is of great significance.

Disclosure of Invention

The technical problem solved by the invention is as follows: in order to expand the universality of a substrate, the simple and easily obtained substrate and an environment-friendly solvent are used, the reaction steps are simplified, and the method for simply, conveniently and efficiently synthesizing the 1,3, 4-oxadiazole derivative by taking the benzaldehyde derivative and the trivalent iodine reagent as raw materials and reacting in one step without adding any catalyst under the illumination condition is provided.

The invention provides a method for synthesizing 1,3, 4-oxadiazole, which takes benzaldehyde derivatives and trivalent iodine reagents as raw materials, adds organic solvent, and reacts under the condition of illumination to generate 1,3, 4-oxadiazole heterocyclic derivatives.

The reaction conditions are as follows: reacting at room temperature under the condition of illumination, wherein the reaction time is 10-15 hours.

The organic solvent is dichloromethane, trichloromethane, acetonitrile or methanol.

The molar ratio of the raw materials is 1:1.5 of benzaldehyde derivatives and trivalent iodine reagents.

The benzaldehyde as raw material may be benzaldehyde, 4-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-methylbenzaldehyde, 4-tert-butylbenzaldehyde, 4-methoxybenzaldehyde, 3-methylbenzaldehyde, 2-cyanobenzaldehyde, 2-methoxybenzaldehyde, 2, 4-dimethoxybenzaldehyde, 2, 3-dimethylbenzaldehyde, 3, 4-dimethylbenzaldehyde, 2, 4-dichlorobenzaldehyde, 2, 6-dichlorobenzaldehyde, 2,4, 6-trimethylbenzaldehyde.

The structural formula of the raw material trivalent iodine is shown as the following formula,

wherein R is¹The radical being R¹＝COOEt，COOMe，COOCH₂Ph can smoothly react to obtain the corresponding 1,3, 4-oxadiazole heterocyclic derivative.

The diazo trivalence iodine reagent is synthesized by the following steps:

1-methoxy-1, 2-benziodoyl 3(1H) one (4.0g,14.4mmol,1equiv), trimethylsilyl trifluoromethanesulfonate (2.6mL,14.4mmol,1equiv) and dichloromethane (25mL) were added to a 100mL round-bottomed flask at room temperature. After stirring for 30 minutes at room temperature, ethyl diazoacetate (31.8mmol,2.2equiv) is slowly added, stirring is carried out for 3 hours, the filtrate is dried in a rotary manner after the reaction is finished, and the crude product is recrystallized by diethyl ether/dichloromethane (5:1) under a low-temperature pump to obtain pure diazo trivalent iodine reagent which is stored at low temperature.

Preparation of 1,3, 4-oxadiazole derivative: under the condition of illumination, adding a benzaldehyde derivative (1equiv), a diazo trivalent iodine reagent (1.5equiv) and an organic solvent into a 10mL reaction tube, stirring at room temperature for 10-15 hours, performing TLC (thin layer chromatography) plate tracking reaction, then spin-drying the filtrate, and further separating and purifying the crude product by silica gel column chromatography to obtain the 1,3, 4-oxadiazole.

The post-reaction treatment is simple and convenient, and the pure substituted 1,3, 4-oxadiazole derivative can be obtained by using a mixed solvent of petroleum ether and ethyl acetate as an eluent by a simple column chromatography separation method.

The invention has the advantages that: 1,3, 4-oxadiazole is an important biological and pharmaceutical active molecule, and has wide application in the fields of medicine and pharmacology. The invention uses benzaldehyde and diazo trivalence iodine reagent derivatives as raw materials for the first time, does not need to add any catalyst under the condition of illumination, and obtains different substituted 1,3, 4-oxadiazole heterocyclic parent nucleus by one-step construction at room temperature, and the yield reaches 48-89%.

Detailed Description

The synthesis method of the diazo trivalent iodine reagent comprises the following steps: 1-methoxy-1, 2-benziodoyl 3(1H) one (4.0g,14.4mmol,1equiv), trimethylsilyl trifluoromethanesulfonate (2.6mL,14.4mmol,1equiv) and dichloromethane (25mL) were added to a 100mL round-bottomed flask at room temperature. After stirring for 30 minutes at room temperature, ethyl diazoacetate (31.8mmol,2.2equiv) is slowly added, stirring is carried out for 3 hours, the filtrate is dried in a rotary manner after the reaction is finished, and the crude product is recrystallized by diethyl ether/dichloromethane (5:1) under a low-temperature pump to obtain pure diazo trivalent iodine reagent which is stored at low temperature.

The synthesis reaction process of the 1,3, 4-oxadiazole derivative and the structural formula of the obtained product are shown in the specification

Example 1

Under the illumination condition, benzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 12 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the yield of the target compound 3a which is 85%.¹H NMR(400MHz,CDCl₃)δ8.10(d,J＝7.7Hz,2H),7.56-7.46(m,3H),4.48(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).

Example 2

Under the illumination condition, 4-fluorobenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 12 hours at room temperature, and the separation is carried out by silica gel column chromatographyThe yield of the objective compound 3b was 81%.¹H NMR(400MHz,CDCl₃)δ8.14-8.09(m,2H),7.20-7.17(m,2H),4.50(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).

Example 3

Under the illumination condition, 4-chlorobenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, and the reaction is carried out for 12 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3c with the yield of 84%.¹H NMR(400MHz,CDCl₃)δ8.04(d,J＝8.3Hz,2H),7.46(d,J＝8.3Hz,2H),4.49(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).

Example 4

Under the illumination condition, 4-methylbenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, and the mixture is reacted for 12 hours at room temperature and separated by silica gel column chromatography to obtain the target compound 3d with the yield of 87%.¹H NMR(300MHz,CDCl₃)δ8.02(d,J＝8.6Hz,2H),6.95(d,J＝8.6Hz,2H),4.47(q,J＝7.1Hz,2H),3.82(s,3H),1.40(t,J＝7.1Hz,3H).

Example 5

Under the illumination condition, 4-methoxybenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 12 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3e with the yield of 85%.¹H NMR(300MHz,CDCl₃)δ7.97(d,J＝8.7Hz,1H),6.60(dd,J＝8.7,2.3Hz,1H),6.56(d,J＝2.3Hz,1H),4.53(q,J＝7.2Hz,2H),3.97(s,3H),3.89(s,3H),1.47(t,J＝7.1Hz,3H).

Example 6

Under the illumination condition, 4-tert-butyl benzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 12 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3f with the yield of 89%.¹H NMR(400MHz,CDCl₃)δ8.09(d,J＝8.5Hz,2H),7.55(d,J＝8.5Hz,2H),4.55(q,J＝7.1Hz,2H),1.49(t,J＝7.1Hz,3H),1.36(s,9H).

Example 7

Under the condition of light, will3-methoxybenzaldehyde (1mmol), diazo trivalence iodine reagent 1(1.5mmol) and dichloromethane (2mL) were added to a 15mL test tube, reacted at room temperature for 12 hours, and separated by silica gel column chromatography to give the objective compound 3g in 79% yield.¹H NMR(400MHz,CDCl₃)δ7.73(d,J＝7.8Hz,1H),7.67(s,1H),7.44(t,J＝8.0Hz,1H),7.15(dd,J＝8.3,2.5Hz,1H),4.56(q,J＝7.1Hz,2H),3.89(s,3H),1.49(t,J＝7.1Hz,3H).

Example 8

Under the illumination condition, 2-cyanobenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound with the yield of 65 h.

Example 9

Under the illumination condition, 2-methoxybenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3i with the yield of 70%.¹H NMR(400MHz,CDCl₃)δ8.05-8.03(m,1H),7.60-7.55(m,1H),7.13-7.08(m,2H),4.56(q,J＝7.1Hz,2H),4.01(s,3H),1.49(t,J＝7.1Hz,3H).

Example 10

Under the illumination condition, 2, 4-dimethoxybenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, and the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3j with the yield of 64%.¹H NMR(500MHz,CDCl₃)δ7.97(d,J＝8.8Hz,1H),6.60(dd,J＝8.8,2.3Hz,1H),6.55(d,J＝2.3Hz,1H),4.54(q,J＝7.1Hz,2H),3.97(s,3H),3.89(s,3H),1.47(t,J＝7.1Hz,3H).

Example 11

Under the illumination condition, 2, 6-dichlorobenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3k with the yield of 65%.¹H NMR(400MHz,CDCl₃)δ7.49(t,J＝4.1Hz,3H),4.58(q,J＝7.1Hz,2H),1.50(t,J＝7.1Hz,2H).

Example 12

Under the illumination condition, 2, 4-dichlorobenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3l with the yield of 56%.¹H NMR(400MHz,CDCl₃)δ8.04(d,J＝8.5Hz,1H),7.61(d,J＝1.9Hz,1H),7.44(dd,J＝8.5,1.5Hz,1H),4.56(q,J＝7.1Hz,2H),1.48(t,J＝7.1Hz,3H).

Example 13

Under the illumination condition, 2, 3-dimethylbenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, and the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound with the yield of 3m being 57%.¹H NMR(400MHz,CDCl₃)δ7.80(d,J＝7.8Hz,1H),7.36(d,J＝7.4Hz,1H),7.24(d,J＝7.8Hz,1H),4.55(q,J＝7.1Hz,2H),2.62(s,3H),2.38(s,3H),1.48(t,J＝7.1Hz,3H).

Example 14

Under the illumination condition, 3, 4-dimethylbenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3n with the yield of 65%.¹H NMR(400MHz,CDCl₃)δ7.95(s,1H),7.89-7.87(m,1H),7.24(d,J＝7.8Hz,1H),4.55(q,J＝7.1Hz,2H),2.62(s,3H),2.38(s,3H),1.48(t,J＝7.1Hz,3H).

Example 15

Under the illumination condition, 2,4, 6-trimethylbenzaldehyde (1mmol), diazo trivalent iodine reagent 1(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out to obtain the target compound 3o with the yield of 48%.¹H NMR(400MHz,CDCl₃)δ6.97(s,2H),4.54(q,J＝7.1Hz,2H),2.34(s,3H),2.27(s,6H),1.48(t,J＝7.1Hz,3H).

Example 16

Under the illumination condition, adding 3-methoxybenzaldehyde (1mmol), diazo trivalent iodine reagent 2(1.5mmol) and dichloromethane (2mL) into a 15mL test tube, reacting at room temperature for 15 hours, and separating by silica gel column chromatography to obtainThe yield to the target compound 3p was 87%.¹H NMR(400MHz,CDCl₃)δ8.05(d,J＝8.8Hz,2H),6.99(d,J＝8.8Hz,2H),4.06(s,3H),3.86(s,3H).

Example 17

Under the illumination condition, 3-methoxybenzaldehyde (1mmol), diazo trivalent iodine reagent 3(1.5mmol) and dichloromethane (2mL) are added into a 15mL test tube, the reaction is carried out for 15 hours at room temperature, and silica gel column chromatography separation is carried out, so that the yield of the target compound 3q is 78%.¹H NMR(400MHz,CDCl₃)δ¹H NMR(500MHz,CDCl₃)δ8.01(d,J＝6.9Hz,2H),7.43-7.41(m,2H),7.33-7.31(m,3H),6.93(d,J＝6.9Hz,2H),5.42(s,2H),3.81(s,3H).

Comparative example 1

Benzaldehyde (1mmol), a diazo trivalent iodine reagent (1.2mmol) and dichloromethane (2mL) are added into a 15mL test tube under the condition of keeping out of the light, and the reaction is carried out for 12 hours at room temperature, so that the target compound cannot be obtained.

Comparative example 2

Under the illumination condition, benzaldehyde (1mmol), a photocatalyst rhodamine B (10% mmol), a diazo trivalent iodine reagent 1(1.2mmol) and dichloromethane (2mL) are added into a 15mL test tube and react for 12 hours at room temperature to obtain the target compound 3a with the yield of 72%.