Process for the synthesis of aryl substituted 1,3,4-oxadiazole derivatives

Abstract

The present application relates to a kind of synthesis method of aryl-substituted 1,3,4-oxadiazole derivative, comprising the following steps: under the condition of containing Mn catalyst and blue light, 1,3,4-oxadiazole derivative is coupled with aryl-substituted diazonium tetrafluoroborate salt;The containing Mn catalyst is selected from one or more of Mn2(CO) 10 ,CpMn(CO)3 and Mn(CO)5Br.The method reaction condition is mild, atomic utilization is high, product yield is high, and the containing Mn catalyst used is cheap and easy to obtain, avoids the cost of noble metal palladium and phosphine ligand catalyst, greatly reduces the synthesis cost;In addition, operation is safe, environment-friendly, simple and easy to operate, suitable for amplification production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic compound synthesis, and particularly relates to a synthesis method of aryl-substituted 1,3,4-oxadiazole derivatives. BACKGROUND

[0002] 1,3,4-oxadiazole is a widely used five-membered heterocyclic molecule, and due to the enhanced hydrolysis and metabolic stability of the oxadiazole ring, 1,3,4-oxadiazole has good pharmacokinetic properties, and is used for synthesizing various drug molecules, such as Raltegravir for inhibiting HIV, Isentress for an antiretroviral drug, Nesapidil for an antihypertensive drug, Furamizole for an antibiotic, and DGAT-1 inhibitor AZD 3988 for treating obesity and diabetes. In addition, aryl-substituted 1,3,4-oxadiazole derivatives can also be used for electroluminescence, preparation of OLED materials and the like.

[0003] At present, the general method for constructing 1,3,4-oxadiazole heterocycle mainly adopts dehydration ring closure of hydrazide and carboxylic acid, aldehyde ketone, amino urea, thiourea or carbon disulfide and other carbonyl compounds to obtain substituted 1,3,4-oxadiazole heterocycle containing corresponding functional groups. For example, a 2,5-asymmetric disubstituted 1,3,4-oxadiazole derivative synthesized by substituted formyl hydrazine and substituted alpha-carbonyl carboxylic acid under the action of graphite-platinum electrode power has been reported; or aryl-substituted 1,3,4-oxadiazole sulfide compounds are synthesized by using 2,4-dichlorobenzoic acid as a starting material to synthesize 2,4-dichlorobenzoyl hydrazine and then reacting with carbon disulfide. In addition, it is also reported that aryl-substituted 1,3,4-oxadiazole lipid compounds are synthesized by benzaldehyde and pre-prepared diazonium trivalent iodine reagent under light irradiation. There are few reports on a scheme for directly synthesizing aryl-substituted 1,3,4-oxadiazole derivatives by substituting 1,3,4-oxadiazole heterocycle in situ.

[0004] The current known scheme for directly synthesizing aryl 1,3,4-oxadiazole derivatives by substituting 1,3,4-oxadiazole heterocycle in situ is as follows: 1,3,4-oxadiazole heterocycle is made into a Zn complex of the oxadiazole heterocycle by using TMP2Zn·2LiCl reagent, and then aryl iodide is coupled to synthesize aryl-substituted 1,3,4-oxadiazole derivatives, wherein the coupling reaction uses palladium and phosphine ligand as catalyst. Since palladium is a noble metal and the phosphine ligand is also relatively expensive, the production cost of the reaction is very high. In addition, TMP2Zn·2LiCl reagent is highly flammable, the reaction is relatively dangerous, and it is difficult to realize scale-up production. SUMMARY

[0005] Based on this, the application provides a synthesis method of aryl-substituted 1,3,4-oxadiazole derivatives, which is suitable for industrial production, and has the advantages of easy availability of raw materials, mild reaction conditions, high atomic utilization rate, high product yield and low cost.

[0006] The technical scheme is as follows:

[0007] The synthesis method of aryl-substituted 1,3,4-oxadiazole derivatives comprises the following steps:

[0008] The 1,3,4-oxadiazole derivative is coupled with aryl-substituted diazonium tetrafluoroborate under the condition of a Mn-containing catalyst and blue light.

[0009] The Mn-containing catalyst is selected from one or more of Mn2(CO) 10 , CpMn(CO)3 and Mn(CO)5Br.

[0010] In one embodiment, the 1,3,4-oxadiazole derivative has the structure shown in the following formula (I):

[0011]

[0012] Each R1 is independently selected from an alkyl group or an aryl group substituted or unsubstituted by R;

[0013] r is selected from any integer from 0 to 2;

[0014] Each R is independently selected from halogen, cyano, amino, hydroxyl, an alkyl group, an alkoxy group or a halogenated alkyl group.

[0015] In one embodiment, each R1 is independently selected from a C1-C10 alkyl group or an aryl group having 6 to 30 ring atoms, which is substituted or unsubstituted by R.

[0016] In one embodiment, each R is independently selected from halogen, cyano, amino, hydroxyl, a C1-C20 linear alkyl group, a C3-C20 branched alkyl group, a C3-C20 cyclic alkyl group, a C1-C20 linear alkoxy group, a C3-C20 branched alkoxy group, a C3-C20 cyclic alkoxy group, a halogenated C1-C20 linear alkyl group, a halogenated C3-C20 branched alkyl group, a halogenated C3-C20 cyclic alkyl group.

[0017] In one embodiment, the aryl-substituted diazonium tetrafluoroborate has the structure shown in the following formula (II):

[0018]

[0019] Each R2 is independently selected from an alkyl group, an alkoxy group, a fluorinated alkyl group or halogen.

[0020] m is selected from any integer from 0 to 5.

[0021] In one embodiment, R2is ortho or para to the diazonium group.

[0022] In one embodiment, each R2is independently selected from C1-C10 alkyl, C1-C10 alkoxy, C1-C10 fluoroalkyl, or halogen.

[0023] In one embodiment, the molar ratio of the 1,3,4-oxadiazole derivative to the aryl-substituted diazonium tetrafluoroborate salt is 1:(1-2.5).

[0024] In one embodiment, the molar ratio of the Mn-containing catalyst to the 1,3,4-oxadiazole derivative is (1-10):100.

[0025] In one embodiment, the temperature of the coupling reaction is 5-40°C and the time is 0.5-10 hours.

[0026] In one embodiment, the solvent used in the coupling reaction is a mixture of one or both of dimethyl sulfoxide and N,N-dimethylformamide.

[0027] In one embodiment, the method for preparing the aryl-substituted diazonium tetrafluoroborate salt comprises the following steps:

[0028] mixing a primary amine-substituted aryl derivative with an aqueous solution of tetrafluoroboric acid in a solvent to form a tetrafluoroborate salt;

[0029] subjecting the tetrafluoroborate salt to diazotization with a nitrous acid compound and adding a precipitant to precipitate the aryl-substituted diazonium tetrafluoroborate salt.

[0030] In one embodiment, the solvent is an alcohol solvent.

[0031] In one embodiment, the nitrous acid compound is tert-butyl nitrite.

[0032] In one embodiment, the precipitant is methyl tert-butyl ether.

[0033] In one embodiment, the temperature of the diazotization reaction is 0±5°C and the time is 0.5-2 hours.

[0034] The present application has at least the following beneficial effects:

[0035] The application adopts a manganese-containing compound as a catalyst, and under the action of blue light, can effectively catalyze the coupling reaction of 1,3,4-oxadiazole derivatives and aryl-substituted tetrafluoroboric acid diazonium salt to prepare aryl-substituted 1,3,4-oxadiazole derivatives, and the reaction condition is mild, the atomic utilization rate is high, and the product yield is high. In addition, it also has the following advantages:

[0036] (1) The Mn-containing catalyst used in the reaction is cheap and easy to obtain, which avoids the high-cost noble metal palladium and phosphine ligand catalyst, and the aryl tetrafluoroboric acid diazonium salt is easy to prepare and stable, which greatly reduces the synthesis cost;

[0037] (2) Directly synthesize aryl-substituted 1,3,4-oxadiazole derivatives by in-situ substitution of 1,3,4-oxadiazole heterocycle, less steps, high production efficiency;

[0038] (3) The reaction condition is mild, safe to operate, friendly to the environment, simple and easy to operate, and suitable for large-scale production. DETAILED DESCRIPTION

[0039] The application will be further described in detail below in combination with specific embodiments. The application can be realized in many different forms, and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the application more thorough and comprehensive.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application belongs. The terms used in the specification of the application herein are only for the purpose of describing the specific embodiments and are not intended to limit the application. The term "and / or" as used herein includes any and all combinations of one or more related listed items.

[0041] Terminology

[0042] Unless otherwise stated or contradictory, the terms or phrases used herein have the following meanings:

[0043] The selection range of the terms "and / or", "or / and", "and / or" used in the present application includes any one of two or more related listed items, and also includes any and all combinations of the related listed items, which includes any two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", "and / or", it should be understood that in the present application, the technical solution undoubtedly includes the technical solution connected by "logical and", and also undoubtedly includes the technical solution connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C and D (i.e. the technical solution connected by "logical or"), and also includes any and all combinations of A, B, C and D, i.e. includes the combination of any two or any three of A, B, C and D, and also includes the four-item combination of A, B, C and D (i.e. the technical solution connected by "logical and").

[0044] In the present application, the meaning of "multiple" is at least two, such as two, three, etc., and the meaning of "multiple layers" is at least two layers, such as two layers, three layers, etc., unless otherwise explicitly and specifically limited. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise explicitly and specifically limited.

[0045] If not specifically stated, all steps of the present application can be performed in sequence or randomly. For example, the method includes steps (a) and (b), which means that the method can include steps (a) and (b) performed in sequence, or steps (b) and (a) performed in sequence. For example, the method is mentioned to further include step (c), which means that step (c) can be added to the method in any order, for example, the method can include steps (a), (b) and (c), or steps (a), (c) and (b), or steps (c), (a) and (b), etc.

[0046] In the present application, "preferably", "more preferably", "even more preferably" and the like are only used to describe the embodiments or examples with better effects, and it should be understood that they do not constitute a limitation on the protection scope of the present application.

[0047] In the present application, "further", "even further", "in particular" and the like are used for description purposes, indicating differences in content, but should not be understood as a limitation on the protection scope of the present application.

[0048] In the present application, the technical features described in an open form include both a closed technical solution consisting of the listed features and an open technical solution including the listed features.

[0049] In the present application, with respect to a numerical interval (i.e., a numerical range), unless otherwise specified, the optional numerical distribution within the numerical interval is considered to be continuous, and includes both numerical end points (i.e., the minimum value and the maximum value) of the numerical range and every numerical value between the two numerical end points. Unless otherwise specified, when a numerical interval refers only to integers within the numerical interval, both end point integers of the numerical range and every integer between the two end points are included. In addition, when multiple ranges are provided to describe a feature or a property, the ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein are understood to include any and all sub-ranges encompassed therein.

[0050] In the present application, the number of atoms described using a numerical range includes both the two integer end points of the numerical range and every integer in the two end points. For example, "C1-C10 alkyl" means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0051] In the present application, "the number of ring atoms" means the number of atoms among the atoms constituting a ring itself of a structural compound obtained by bonding atoms into a ring (e.g., a monocyclic compound, a fused ring compound, a crosslinked compound, a carbocyclic compound, a heterocyclic compound). When the ring is substituted with a substituent, the atoms included in the substituent are not included in the ring-forming atoms. The same applies to "the number of ring atoms" described below, unless otherwise specified. For example, the number of ring atoms of a benzene ring is 6, and the number of ring atoms of a naphthalene ring is 10.

[0052] In the present application, represents the connection site of the non-limiting substituent R.

[0053] In the present application, "halogen" or "halo" means F, Cl, Br, or I.

[0054] In the present application, the term "alkyl" refers to a saturated hydrocarbon radical of a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which loses one hydrogen atom to form a monovalent radical. Phrases containing this term, for example, "Ci-Cio alkyl" means an alkyl group containing from 1 to 10 carbon atoms, each occurrence of which can be independently Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or Cio alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).

[0055] In the present application, "haloalkyl" means an alkyl group substituted with one or more halogen (chlorine, fluorine, bromine or iodine) atoms. Polyhaloalkyl groups have the same or mixed types of halogen atoms. "Perhaloalkyl" means that every hydrogen atom in the alkyl group is replaced with a halogen atom. A haloalkyl group in which a certain carbon atom is "perhalo" means that every hydrogen atom attached to that carbon is replaced with a halogen atom. Representative mono-, di-, and trihaloalkyl groups include chloromethyl, chloroethyl, bromomethyl, bromoethyl, iodomethyl, iodoethyl, chloropropyl, bromopropyl, iodopropyl, 1,1-dichloromethyl, 1,1-dibromomethyl, 1,1-dichloropropyl, 1,2-dibromopropyl, 2,3-dibromopropyl, 1-chloro-2-bromoethyl, 2-chloro-3-bromopropyl, trifluoromethyl, trichloromethyl, and the like. Understandably, "fluoroalkyl" means an alkyl group substituted with one or more fluorine atoms.

[0056] In the present application, "cycloalkyl" means a non-aromatic hydrocarbon containing ring carbon atoms, which can be a monocycloalkyl group, or a spirocycloalkyl group, or a bridged cycloalkyl group. Phrases containing this term, such as "C3-C10 cycloalkyl", mean a cycloalkyl group containing 3 to 10 carbon atoms, each occurrence of which can independently be a C3 cycloalkyl group, a C4 cycloalkyl group, a C5 cycloalkyl group, a C6 cycloalkyl group, a C7 cycloalkyl group, a C8 cycloalkyl group, a C9 cycloalkyl group, or a C10 cycloalkyl group. Suitable examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Additionally, "cycloalkyl" can also contain one or more double bonds. Representative examples of cycloalkyl groups containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutadienyl.

[0057] In the present application, "substituted" means that a hydrogen atom in a substituent is replaced with a substituent.

[0058] In the present application, "substituted or unsubstituted" means that the defined group can be substituted or unsubstituted. When the defined group is substituted, it is understood that the defined group can be substituted with one or more substituents R selected from, but not limited to, a deuterium atom, a cyano group, an isocyano group, a nitro group, or a halogen, an alkyl group containing 1 to 9 C atoms, a cycloalkyl group containing 3 to 9 C atoms, -NR'R", a silyl group, a carbonyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carbamoyl group, a halogenformyl group, a formyl group, an isocyanate group, a thiocyanate group, an isothiocyanate group, a hydroxyl group, a trifluoromethyl group, and the above groups can be further substituted with a substituent acceptable in the art; and it is understood that R' and R" in -NR'R" are each independently selected from, but not limited to, H, a deuterium atom, a cyano group, an isocyano group, a nitro group, or a halogen, an alkyl group containing 1 to 9 C atoms, a cycloalkyl group containing 3 to 9 C atoms.

[0059] In the present invention, "aromatic group" or "aryl" refers to a hydrocarbon group comprising at least one aromatic ring, including monocyclic groups and polycyclic ring systems. These polycyclic rings can have two or more rings, wherein two carbon atoms are shared by two adjacent rings, i.e. fused rings. Of these polycyclic rings, at least one is aromatic or heteroaromatic. For the purposes of the present invention, aromatic groups or aryl groups include not only aromatic systems, but also, wherein multiple aromatic groups can be interrupted by short non-aromatic units (e.g. C atoms). Thus, for example, systems such as 9,9'-spirobifluorene, 9,9-diaromatic fluorene, etc. are also considered aromatic groups for the purposes of the present invention.

[0060] Specific examples of aromatic groups are benzene, naphthalene, anthracene, phenanthrene, rylenes, tetracene, chrysene, fluorene, and derivatives of these aromatic groups.

[0061] The temperature parameters in the present invention, if not specifically limited, allow not only constant temperature treatment, but also fluctuations within a certain temperature range. It should be understood that the constant temperature treatment allows fluctuations within the accuracy range controlled by the instrument. Fluctuations within the range of, for example, ±5°C, ±4°C, ±3°C, ±2°C, ±1°C are allowed.

[0062] The traditional method of constructing 1,3,4-oxadiazole heterocycle requires the prior preparation of hydrazine containing the target oxadiazole heterocycle substituent or diazonium trivalent iodine reagent, and then the synthesis of substituted 1,3,4-oxadiazole heterocycle containing the corresponding functional group through ring closure. There are almost no reports of reactions directly involving 1,3,4-oxadiazole heterocycle, and such techniques cannot solve the re-arylation reaction of 1,3,4-oxadiazole heterocycle derivatives.

[0063] Currently, there have been reports of aryl substitution reactions directly involving 1,3,4-oxadiazole heterocycle, but this reaction requires the use of noble metal palladium and expensive phosphine ligand as catalyst, and the TMP2Zn·2LiCl reagent is highly flammable, the reaction is relatively dangerous, and it is difficult to realize large-scale production.

[0064] The present invention provides a method for synthesizing aryl-substituted 1,3,4-oxadiazole derivatives, which is suitable for industrial production, with easily available raw materials, mild reaction conditions, high atom utilization rate, high product yield, and low cost.

[0065] The technical solution is as follows:

[0066] A method for synthesizing aryl-substituted 1,3,4-oxadiazole derivatives, comprising the following steps:

[0067] Under blue light conditions and in the presence of a Mn-containing catalyst, 1,3,4-oxadiazole derivatives are coupled with aryl-substituted diazonium tetrafluoroborate salt;

[0068] The Mn-containing catalyst is selected from Mn2(CO)10 one or more of CpMn(CO)3 and Mn(CO)5Br.

[0069] The Mn-containing catalyst is inexpensive and readily available, and under the action of blue light, can effectively catalyze the coupling reaction of 1,3,4-oxadiazole derivatives and aryl-substituted tetrafluoroboric acid diazonium salt to prepare aryl-substituted 1,3,4-oxadiazole derivatives, and the reaction conditions are mild, the atomic utilization rate is high, and the product yield is high.

[0070] In one of the embodiments, the Mn-containing catalyst is CpMn(CO)3.

[0071] In one of the embodiments, the wavelength of the blue light is 450 nm to 500 nm.

[0072] In one of the embodiments, the 1,3,4-oxadiazole derivative has the structure shown in the following formula (I):

[0073]

[0074] Each R1 is independently selected from an alkyl group, or an aryl group substituted or unsubstituted by R;

[0075] r is selected from any integer from 0 to 2;

[0076] Each R is independently selected from halogen, cyano, amino, hydroxyl, alkyl, alkoxy, or haloalkyl.

[0077] Further, each R is independently selected from halogen, cyano, amino, hydroxyl, C1-C20 linear alkyl, C3-C20 branched alkyl, C3-C20 cyclic alkyl, C1-C20 linear alkoxy, C3-C20 branched alkoxy, C3-C20 cyclic alkoxy, halo-C1-C20 linear alkyl, halo-C3-C20 branched alkyl, halo-C3-C20 cyclic alkyl. Further, each R is independently selected from F, Cl, Br, I, cyano, amino, C1-C10 linear alkyl, C3-C10 branched alkyl, C3-C10 cyclic alkyl, C1-C10 linear alkoxy, C3-C10 branched alkoxy, C3-C10 cyclic alkoxy, fluoro-C1-C10 linear alkyl, fluoro-C3-C10 branched alkyl, fluoro-C3-C20 cyclic alkyl.

[0078] Further, each R1is independently selected from the group consisting of C1-C10 alkyl, or an aryl group having 6 to 30 ring atoms which is substituted or unsubstituted. Further, the aryl group having 6 to 30 ring atoms is selected from the group consisting of phenyl, naphthyl, phenanthryl, anthryl, benzophenanthryl, biphenyl, terphenyl. Further, each R1is independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, phenyl, trifluoromethylphenyl, methoxyphenyl, halophenyl, alkylphenyl, or cyano phenyl. Further, each R1is independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, phenyl, trifluoromethylphenyl, methoxyphenyl, fluorophenyl, alkylphenyl, or cyano phenyl.

[0079] It is understood that r is selected from any integer between 0 and 2, including but not limited to 0, 1, and 2.

[0080] In one embodiment, the 1,3,4-oxadiazole derivative is selected from the group consisting of

[0081] In one embodiment, the aryl-substituted tetrafluoroborate diazonium salt has the following structure shown in Formula (II):

[0082]

[0083] each R2is independently selected from the group consisting of alkyl, alkoxy, fluoroalkyl, or halogen;

[0084] m is selected from any integer between 0 and 5.

[0085] Further, each R2is independently selected from the group consisting of C1-C10 alkyl, C1-C10 alkoxy, C1-C10 fluoroalkyl, or halogen. Further, each R2is independently selected from the group consisting of methyl, methoxy, trifluoromethyl, or halogen.

[0086] It is understood that m is selected from any integer between 0 and 5, including but not limited to 0, 1, 2, 3, 4, and 5, preferably 0, 1, or 2.

[0087] In one embodiment, the R2is ortho or para substituted with respect to the diazonium group.

[0088] In one embodiment, the aryl-substituted tetrafluoroborate diazonium salt is selected from the group consisting of phenyl tetrafluoroborate diazonium salt, 4- trifluoromethylphenyl tetrafluoroborate diazonium salt, 4-methoxyphenyl tetrafluoroborate diazonium salt, or 2,4-dichlorophenyl tetrafluoroborate diazonium salt.

[0089] In one embodiment, the aryl-substituted 1,3,4-oxadiazole derivative has the following structure shown in Formula (III):

[0090]

[0091] p is 1, r-p is 0 or 1;

[0092] p is 2, r-p is 0.

[0093] A synthetic route of the aryl-substituted 1,3,4-oxadiazole derivative having a structure shown in the following formula (III) is as follows:

[0094]

[0095] In one embodiment, the method for preparing the aryl-substituted diazonium tetrafluoroborate salt comprises the following steps:

[0096] mixing and reacting a primary amine-substituted aryl derivative with an aqueous solution of tetrafluoroboric acid in a solvent to generate a tetrafluoroborate salt;

[0097] subjecting the tetrafluoroborate salt to a diazotization reaction with a nitrous compound, and adding a precipitant to precipitate the aryl-substituted diazonium tetrafluoroborate salt.

[0098] In one embodiment, the solvent is an alcohol solvent. Alternatively, the solvent is methanol and / or ethanol.

[0099] In one embodiment, the nitrous compound is tert-butyl nitrite.

[0100] In one embodiment, the precipitant is methyl tert-butyl ether.

[0101] In one embodiment, the diazotization reaction is performed at a temperature of 0°C ± 5°C, including but not limited to -5°C, -2°C, 0°C, 1°C, 2°C, 3°C, 4°C, and 5°C.

[0102] In one embodiment, the diazotization reaction is performed for a time period of 0.5 h to 2 h, including but not limited to 0.5 h, 1 h, 1.5 h, and 2 h.

[0103] In one embodiment, the molar ratio of the 1,3,4-oxadiazole derivative to the aryl-substituted diazonium tetrafluoroborate salt is 1:(1-2.5), including but not limited to 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2.0, 1:2.2, and 1:2.5.

[0104] In one embodiment, the molar ratio of the Mn-containing catalyst to the 1,3,4-oxadiazole derivative is (1-10):100, including but not limited to 1:100, 2:100, 3:100, 5:100, 6:100, and 10:100.

[0105] In one embodiment, the temperature of the coupling reaction is 5°C to 40°C, including but not limited to 5°C, 10°C, 15°C, 20°C, 22°C, 23°C, 25°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C and 40°C.

[0106] In one embodiment, the time of the coupling reaction is 0.5h to 10h, including but not limited to 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 9h and 10h.

[0107] In one embodiment, the solvent used in the coupling reaction is a mixture of one or both of dimethyl sulfoxide and N,N-dimethylformamide.

[0108] In one embodiment, the method for preparing the aryl-substituted tetrafluoroboric acid diazonium salt further comprises the following steps:

[0109] purifying the aryl-substituted tetrafluoroboric acid diazonium salt.

[0110] In one embodiment, purifying the aryl-substituted tetrafluoroboric acid diazonium salt comprises:

[0111] Ethyl acetate and water are added to the reaction solution to extract and separate the liquid, the organic phase is washed with saturated brine for 3 times, then dried and filtered, and a mixture of n-hexane and ethyl acetate (v:v is 1:(1-20)) is used as an eluent to separate the product through a column.

[0112] The application is further described in detail below in combination with specific embodiments.

[0113] In the following examples and comparative examples, room temperature refers to 25°C±5°C.

[0114] In the following examples and comparative examples, the catalyst is:

[0115] C1: Mn2(CO) 10 ; C2: CpMn(CO)3; C3: Mn(CO)5Br.

[0116] (3) Synthesis of 1,3,4-oxadiazole derivatives:

[0117] ① S1: 1,3,4-oxadiazole synthesis:

[0118] After replacing Ar three times in a flask, add 108 g of polyphosphoric acid, heat to 100°C, then add phosphorus pentoxide (12 g, 42 mmol), stir for 15 minutes, then add N, N'-dimethylhydrazine (12 g, 136 mmol), and stir for 4 h. Pour the reaction solution into 100 g of ice to quench, neutralize with solid sodium bicarbonate, then extract three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and rotary evaporate to obtain the product 2.86 g, with a yield of 30%.

[0119] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0120] 1 H NMR (CDCI3, 400 MHz): δ = 8.51 (2H).

[0121] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 1.3.4-oxadiazole is synthesized.

[0122] 2, 2, 2-trifluoroacetohydrazide Synthesis:

[0123] Connect a distillation device to a flask, add 2, 2, 2-trifluoroacetohydrazide (8.80 g, 76.0 mmol), trimethyl orthoformate (12.5 mL, 114 mmol), and p-toluenesulfonic acid hydrate (217 mg, 1.14 mmol) to the reaction flask, heat and control the temperature to 80-120°C for 2 h, remove methanol by distillation during the reaction, and obtain a light yellow liquid 6.58 g by distillation under reduced pressure after the reaction is completed, with a yield of 69%.

[0124] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0125] 1 H NMR (CDCI3, 400 MHz): δ = 8.51 (2H).

[0126] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-tert-butyl-1, 3, 4-oxadiazole is synthesized.

[0127] Example 1:

[0128] The present embodiment provides a synthesis method of 2-phenyl-1, 3, 4-oxadiazole , which is specifically as follows:

[0129] (1) Synthesis of phenyl diazonium tetrafluoroborate

[0130] ​Aniline (9.3 g, 0.1 mol) and aqueous solution of tetrafluoroboric acid (35.2 g, mass fraction of 50% tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, purity of 90%, 0.2 mol) was slowly added dropwise. After the temperature was restored to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl tetrafluoroborate diazonium salt 16.3 g, with a yield of 85%.

[0131] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0132] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0133] According to the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound phenyl tetrafluoroborate diazonium salt is synthesized.

[0134] (2): 2-phenyl-1,3,4-oxadiazole Synthesis:

[0135] Under Ar atmosphere, phenyl tetrafluoroborate diazonium salt (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C1 (0.39 g, 2% mol of S1) and 20 mL of DMSO were added into a reaction bottle, and 1 h of reaction was carried out under the condition of 24 W blue light illumination and 25°C. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and the clean product 3.6 g was obtained by column separation using a mixed solvent of n-hexane and ethyl acetate (v:v is 1:5) as an eluent, with a yield of 49%.

[0136] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0137] 1 H NMR (CDCI 3, 400MHz) δ 8.48 (1H), δ 8.11-8.05 (2H), δ 7.57-7.49 (3H).

[0138] According to the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-phenyl-1,3,4-oxadiazole is synthesized, which is represented by P1.

[0139] Example 2: Synthesis of 2-phenyl-1,3,4-oxadiazole

[0140] The present example provides a synthesis method of 2-phenyl-1,3,4-oxadiazole , which is specifically as follows:

[0141] (1) phenyl tetrafluoroborate diazonium salt Synthesis of

[0142] Aniline (9.3 g, 0.1 mol) and aqueous solution of tetrafluoroboric acid (35.2 g, mass fraction of 50% tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, purity of 90%, 0.2 mol) was slowly added dropwise. After the temperature was restored to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl tetrafluoroborate diazonium salt (16.3 g, yield 85%).

[0143] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0144] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0145] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyl tetrafluoroborate diazonium salt was synthesized.

[0146] (2) 2-phenyl-1,3,4-oxadiazole Synthesis:

[0147] Under Ar atmosphere, phenyl tetrafluoroborate diazonium salt (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C2 (0.21 g, 2% mol of S1) and 20 mL of DMSO were added to a reaction bottle, and 6.2 g of clean product was obtained by column separation using a mixture of n-hexane and ethyl acetate (v:v 1:5) as eluent under the condition of 24 W blue light illumination at 25°C for 1 h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried and filtered, and the clean product was obtained by column separation using a mixture of n-hexane and ethyl acetate (v:v 1:5) as eluent, with a yield of 85%.

[0148] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0149] 1 H NMR (CDCI 3, ) δ 8.48 (1H), δ 8.11-8.05 (2H), δ 7.57-7.49 (3H).

[0150] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-phenyl-1,3,4-oxadiazole was synthesized, which is represented by P1.

[0151] Example 3:

[0152] The present example provides a synthesis method of 2-phenyl-1,3,4-oxadiazole , which is as follows:

[0153] (1) Synthesis of phenyl diazonium tetrafluoroborate

[0154] Aniline (9.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After the temperature was restored to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl diazonium tetrafluoroborate 16.3 g, with a yield of 85%.

[0155] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0156] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0157] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyl diazonium tetrafluoroborate was synthesized.

[0158] (2) Synthesis of 2-phenyl-1,3,4-oxadiazole

[0159] Under Ar atmosphere, phenyl diazonium tetrafluoroborate (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C3 (0.27 g, 2% mol of S1), and 20 mL of DMSO were added into a reaction bottle, and 1 h of reaction was performed under the condition of 24 W blue light illumination at 25°C. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and column separation was performed using a mixed solvent of n-hexane and ethyl acetate (v:v is 1:5) as an eluent to obtain the clean product 4.6 g, with a yield of 63%.

[0160] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0161] 1 H NMR (CDCI 3, ) δ 8.48 (1H), δ 8.11-8.05 (2H), δ 7.57-7.49 (3H).

[0162] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-phenyl-1,3,4-oxadiazole, represented by P1, was synthesized.

[0163] Example 4:

[0164] The present example provides a synthesis method of 2-phenyl-1,3,4-oxadiazole , which is specifically as follows: ​

[0165] (1) Synthesis of phenyl diazonium tetrafluoroborate

[0166] Aniline (9.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After the temperature was restored to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl diazonium tetrafluoroborate 16.3 g, with a yield of 85%.

[0167] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0168] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0169] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyl diazonium tetrafluoroborate was synthesized.

[0170] (2) Synthesis of 2-phenyl-1,3,4-oxadiazole

[0171] Under Ar atmosphere, phenyl diazonium tetrafluoroborate (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C2 (0.11 g, 1% mol of S1), and 20 mL of DMSO were added into a reaction bottle, and 1 h of reaction was performed under the condition of 24 W blue light illumination at 25°C. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and column separation was performed using a mixed solvent of n-hexane and ethyl acetate (v:v is 1:5) as an eluent to obtain the clean product 3.8 g, with a yield of 52%.

[0172] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0173] 1 H NMR (CDCI 3, ) δ 8.48 (1H), δ 8.11-8.05 (2H), δ 7.57-7.49 (3H).

[0174] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-phenyl-1,3,4-oxadiazole, represented by P1, was synthesized.

[0175] Example 5:

[0176] The present example provides a synthesis method of 2-phenyl-1,3,4-oxadiazole , which is specifically as follows:​​

[0177] (1) Phenylacetic tetrafluoroborate diazonium salt Synthesis:

[0178] Aniline (9.3 g, 0.1 mol) and an aqueous solution of tetrafluoroboric acid (35.2 g, 50% tetrafluoroboric acid, 0.2 mol) were added to 100 mL of ethanol and stirred for 10 min. The mixture was then cooled to 0 °C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After returning to room temperature, the mixture was stirred for 1 h. 500 mL of methyl ether was added, and the mixture was filtered, washed with methyl ether, and the filter cake was collected to obtain 16.3 g of the product, phenyl tetrafluoroboric acid diazonium salt, with a yield of 85%.

[0179] The hydrogen nuclear magnetic resonance (NMR) spectrum data are as follows:

[0180] 1 H NMR(DMSO-d6)δ8.66(2H), δ8.26(1H), δ7.98(2H).

[0181] The above-mentioned proton NMR data show that the target compound, phenyltetrafluoroborate diazonium salt, was synthesized.

[0182] (2) 2-Phenylon-1,3,4-oxadiazole Synthesis:

[0183] Under an Ar atmosphere, 9.6 g (0.05 mol) of phenyltetrafluoroborate diazonium salt, 3.5 g (0.05 mol) of S1, 0.53 g (5% mol of S1), and 20 mL of DMSO were added to a reaction flask. The reaction was carried out at 25 °C for 1 h under 24 W blue light irradiation. After the reaction was completed, ethyl acetate and water were added for extraction and separation. The organic phase was washed three times with saturated brine, dried, and filtered. Column chromatography was performed using a mixed solvent of n-hexane and ethyl acetate (v:v = 1:5) as the eluent to obtain 6.4 g of clean product, with a yield of 88%.

[0184] The hydrogen nuclear magnetic resonance (NMR) spectrum data are as follows:

[0185] 1 H NMR (CDCl) 3, )δ8.48(1H), δ8.11–8.05(2H), δ7.57–7.49(3H).

[0186] The above 1H NMR data show that the target compound, 2-phenyl-1,3,4-oxadiazole, denoted as P1, was synthesized.

[0187] Example 6:

[0188] This embodiment provides a 2-tert-butyl-5-phenyl-1,3,4-oxadiazole The synthesis method of P2 is as follows:

[0189] (1) Synthesis of phenyl diazonium tetrafluoroborate:

[0190] Aniline (9.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and slowly added with tert-butyl nitrite (23 g, 90% purity, 0.2 mol). After the temperature was restored to room temperature, the mixture was stirred for 1 h. Then 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl diazonium tetrafluoroborate 16.3 g, with a yield of 85%.

[0191] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0192] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0193] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyl diazonium tetrafluoroborate was synthesized.

[0194] (2) Synthesis of 2-tert-butyl-5-phenyl-1,3,4-oxadiazole:

[0195] Under Ar atmosphere, phenyl diazonium tetrafluoroborate (9.6 g, 0.05 mol) and S2 (6.0 g, 0.05 mol), CpMn(CO)3 (0.21 g, 2% mol of S2), and 20 mL of DMSO were added into a reaction bottle, and the mixture was reacted under the condition of 24 W blue light illumination at 25°C for 1 h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and then separated by column chromatography using a mixed solvent of n-hexane and ethyl acetate (v:v=1:10) as the eluent to obtain the clean product 8.8 g, with a yield of 87%.

[0196] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0197] 1 H NMR (CDCI3): δ 8.06-8.03 (2H), δ 7.52-7.48 (3H), δ 1.49 (9H).

[0198] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-tert-butyl-5-phenyl-1,3,4-oxadiazole, denoted as P2, was synthesized.

[0199] Example 7:

[0200] ​​The embodiment provides a synthesis method of 2-(4-trifluoromethylphenyl)-1,3,4-oxadiazole , and specifically as follows:

[0201] (1) Synthesis of 4-trifluoromethylphenyl diazonium tetrafluoroborate:

[0202] 4-trifluoromethylphenylamine (16.1 g, 0.1 mol) and an aqueous solution of tetrafluoroboric acid (35.2 g, 50% by mass of tetrafluoroboric acid, 0.2 mol) are added into 100 mL of ethanol, stirred for 10 min, cooled to 0 DEG C, and slowly added with tert-butyl nitrite (23 g, 90% in purity, 0.2 mol), stirred for 1 h after the temperature is recovered to room temperature. 500 mL of methyl tert-butyl ether is added, filtered, washed with methyl tert-butyl ether, and the filter cake is collected to obtain the product 4-trifluoromethylphenyl diazonium tetrafluoroborate 24.7 g, with a yield of 95%.

[0203] Tested, the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0204] 1 H NMR (DMSO-d6) δ 8.90 (2H), δ 8.41 (2H).

[0205] From the nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 4-trifluoromethylphenyl diazonium tetrafluoroborate is synthesized.

[0206] (2) Synthesis of 2-(4-trifluoromethylphenyl)-1,3,4-oxadiazole:

[0207] Under Ar atmosphere, 4-trifluoromethylphenyl diazonium tetrafluoroborate (13 g, 0.05 mol) and 1,3,4-oxadiazole S1 (3.5 g, 0.05 mol), CpMn(CO)3 (0.21 g, 2% mol of S1) and 20 mL of DMSO are added into a reaction bottle, 1 h of reaction is carried out under the condition of 24 W blue light illumination and 25 DEG C. After the reaction is completed, ethyl acetate and water are added for extraction and separation, the organic phase is washed with saturated brine for three times, dried, filtered, and the mixture solvent (v:v is 1:10) of n-hexane and ethyl acetate is used as an eluent to separate the product through a column to obtain 7.0 g of clean product, with a yield of 79%.

[0208] Tested, the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0209] 1 H NMR (CDCl3) δ 8.55 (1H), δ 8.10 (2H), δ 7.68 (2H).

[0210] From the nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-(4-trifluoromethylphenyl)-1,3,4-oxadiazole is synthesized, which is represented as P3. ​

[0211] Example 8:

[0212] The present example provides a synthesis method of 2-(4-methoxyphenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0213] (1) Synthesis of 4-methoxyphenyl diazonium tetrafluoroborate :

[0214] Aminoanisole (12.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added to 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After recovering to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product 4-methoxyphenyl diazonium tetrafluoroborate 15.5 g, with a yield of 70%.

[0215] Tested, the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0216] 1 H NMR (DMSO-d6) δ 8.60 (2H), δ 7.48 (2H), δ 4.04 (3H).

[0217] From the above nuclear magnetic resonance hydrogen spectrum data, it can be seen that the target compound 4-methoxyphenyl diazonium tetrafluoroborate is synthesized.

[0218] (2) Synthesis of 2-(4-methoxyphenyl)-1,3,4-oxadiazole :

[0219] Under Ar atmosphere, 4-methoxyphenyl diazonium tetrafluoroborate (11.1 g, 0.05 mol) and 1,3,4-oxadiazole S1 (3.5 g, 0.05 mol), CpMn(CO)3 (0.21 g, 2% mol of S1), and 20 mL of DMSO were added to a reaction bottle, and 24 W blue light was irradiated under the condition of 25°C for 1 h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried and filtered, and a mixture of n-hexane and ethyl acetate (v:v=1:10) was used as an eluent to separate the product through column to obtain 9.8 g of clean product, with a yield of 92%.

[0220] Tested, the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0221] 1 H NMR (CDCl3) δ 8.41 (1H), δ 8.02 (2H), δ 7.02 (2H), δ 3.88 (3H).

[0222] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-(4-methoxyphenyl)-1,3,4-oxadiazole is synthesized, and P4 represents.

[0223] Example 9:

[0224] The present example provides a synthesis method of 2-(2,4-dichlorophenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0225] (1) Synthesis of 2,4-dichlorophenyl diazonium tetrafluoroborate:

[0226] 2,4-dichloroaniline (16.2 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% by mass of tetrafluoroboric acid, 0.2 mol) were added to 100 ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After recovering to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product 2,4-dichlorophenyl diazonium tetrafluoroborate 23.0 g, with a yield of 88%.

[0227] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0228] 1 H NMR (DMSO-d6) δ 8.64 (1H), δ 8.05 (1H), δ 7.66 (1H).

[0229] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2,4-dichlorophenyl diazonium tetrafluoroborate is synthesized.

[0230] (2) Synthesis of 2-(2,4-dichlorophenyl)-1,3,4-oxadiazole

[0231] Under Ar atmosphere, 2,4-dichlorophenyl diazonium tetrafluoroborate (13.04 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C2 (0.21 g, 2% mol of S1) and 20 mL of DMSO were added to a reaction bottle, and 24 W blue light was irradiated under the condition of 25°C for 1 h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, then dried and filtered, and a mixture of n-hexane and ethyl acetate (v:v is 1:5) was used as an eluent to separate the product through column to obtain 9.6 g of clean product, with a yield of 89%.

[0232] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0233] 1 ​​H NMR (CDCI3) δ 8.57 (1 H), δ 7.96 (1 H), δ 7.58 (1 H), δ 7.41 (1 H).

[0234] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-(2,4-dichlorophenyl)-1,3,4-oxadiazole is synthesized, which is represented by P5.

[0235] Example 10:

[0236] The present example provides a synthesis method of 2-tert-butyl-5-(4-methoxyphenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0237] (1) Synthesis of 4-methoxyphenyl diazonium tetrafluoroborate

[0238] The p-aminoanisole (12.3 g, 0.1 mol) and the aqueous solution of tetrafluoroboric acid (35.2 g, mass fraction of tetrafluoroboric acid 50%, 0.2 mol) are added into 100 ethanol, stirred for 10 min, cooled to 0°C, and then the tert-butyl nitrite (23 g, purity 90%, 0.2 mol) is slowly added dropwise. After the room temperature is recovered, it is stirred for 1 h. Then 500 mL of methyl tert-butyl ether is added, filtered, washed with methyl tert-butyl ether, and the filter cake is collected to obtain the product 4-methoxyphenyl diazonium tetrafluoroborate 15.5 g, with a yield of 70%.

[0239] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0240] 1 H NMR (DMSO-d6, 300 MHz) δ 8.60 (2H), δ 7.48 (2H), δ 4.04 (3H).

[0241] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 4-methoxyphenyl diazonium tetrafluoroborate is synthesized.

[0242] (2) Synthesis of 2-tert-butyl-5-(4-methoxyphenyl)-1,3,4-oxadiazole

[0243] Under Ar atmosphere, the 4-methoxyphenyl diazonium tetrafluoroborate (11.1 g, 0.05 mol) and S2 (6.0 g, 0.05 mol), C2 (0.21 g, 2% mol of S2) and 20 mL of DMSO are added into a reaction bottle, and then the reaction is carried out under the condition of 24 W blue light illumination at 25°C for 1 h. After the reaction is completed, ethyl acetate and water are added for extraction and separation, the organic phase is washed with saturated brine for 3 times, dried, filtered, and then the mixture solvent of n-hexane and ethyl acetate (v:v is 1:10) is used as an eluent to separate the column to obtain the clean product 9.5 g, with a yield of 82%.​​

[0244] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0245] 1 H NMR (DMSO-d6) δ 7.92 (2H), δ 7.12 (2H), δ 3.84 (3H), δ 1.41 (9H).

[0246] It can be known from the above nuclear magnetic resonance hydrogen spectrum data that the target compound 2-tert-butyl-5-(4-methoxyphenyl)-1,3,4-oxadiazole is synthesized, which is denoted as P6.

[0247] Example 11:

[0248] The present example provides a synthesis method of 2-tert-butyl-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0249] (1) Synthesis of 4-trifluoromethylphenyl diazonium tetrafluoroborate :

[0250] 4-trifluoromethylphenylamine (16.1 g, 0.1 mol) and an aqueous solution of tetrafluoroboric acid (35.2 g, mass fraction of tetrafluoroboric acid 50%, 0.2 mol) are added into 100 ethanol, stirred for 10 min, cooled to 0°C, and slowly added with tert-butyl nitrite (23 g, purity 90%, 0.2 mol). After the temperature is recovered to room temperature, stirring is performed for 1 h. 500 mL of methyl tert-butyl ether is added, filtered, washed with methyl tert-butyl ether, and the filter cake is collected to obtain the product 4-trifluoromethylphenyl diazonium tetrafluoroborate 24.7 g, with a yield of 95%.

[0251] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0252] 1 H NMR (DMSO-d6, 300 MHz,) δ 8.90 (2H), δ 8.41 (2H).

[0253] It can be known from the above nuclear magnetic resonance hydrogen spectrum data that the target compound 4-trifluoromethylphenyl diazonium tetrafluoroborate is synthesized.

[0254] (2) Synthesis of 2-tert-butyl-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole :

[0255] Under Ar atmosphere, 4-trifluoromethylphenyl diazonium tetrafluoroborate (13 g, 0.05 mol) and S2 (6.0 g, 0.05 mol), C2 (0.21 g, 2% mol of S2) and 20 mL of DMSO were added into a reaction bottle, and 1 h of reaction was carried out under the condition of 24 W blue light illumination and 25°C. After the reaction was completed, ethyl acetate and water were added for extraction and separation, and the organic phase was washed with saturated brine for 3 times, dried, filtered, and separated by column chromatography using a mixed solvent of n-hexane and ethyl acetate (v:v = 1:10) as the eluent to obtain 12.7 g of pure product, with a yield of 93%.

[0256] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0257] 1 H NMR (DMSO-d6) δ 8.19 (1H), δ 7.93 (1H), δ 1.43 (4H).

[0258] According to the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-tert-butyl-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole is synthesized, which is denoted as P7.

[0259] Example 12:

[0260] The present example provides a synthesis method of 2-tert-butyl-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0261] (1) Synthesis of 2,4-dichlorophenyl diazonium tetrafluoroborate

[0262] 2,4-dichloroaniline (16.2 g, 0.1 mol) and an aqueous solution of tetrafluoroboric acid (35.2 g, 50% by mass of tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and slowly added with tert-butyl nitrite (23 g, 90% purity, 0.2 mol). After the temperature was recovered to room temperature, the mixture was stirred for 1 h. Then, 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain 23.0 g of the product 2,4-dichlorophenyl diazonium tetrafluoroborate, with a yield of 88%.

[0263] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0264] 1 H NMR (DMSO-d6, 300 mHz) δ 8.64 (1H), δ 8.05 (1H), δ 7.66 (1H).

[0265] According to the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2,4-dichlorophenyl diazonium tetrafluoroborate is synthesized. ​

[0266] (2) 2-tert-butyl-5-(2,4-dichlorophenyl) 1,3,4-oxadiazole Synthesis of:

[0267] Under Ar atmosphere, phenyl diazonium tetrafluoroborate (13 g, 0.05 mol) and S2 (6.0 g, 0.05 mol), C2 (0.21 g, 2% mol of S2) and 20 mL of DMSO were added into a reaction bottle, and 1 h of reaction was carried out under the condition of 24 W blue light illumination at 25°C. After the reaction was completed, ethyl acetate and water were added for extraction and separation, and the organic phase was washed with saturated brine for 3 times, then dried, filtered, and separated by column chromatography using a mixed solvent of n-hexane and ethyl acetate (v:v = 1:10) as the eluent to obtain 12.3 g of pure product, with a yield of 91%.

[0268] Tested, the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0269] 1 H NMR (DMSO-d6) δ 8.04 (1H), δ 7.93 (1H), δ 7.62 (1H) δ 1.42 (9H).

[0270] From the above nuclear magnetic resonance hydrogen spectrum data, it can be seen that the target compound 2-tert-butyl-5-(2,4-dichlorophenyl) 1,3,4-oxadiazole is synthesized, which is represented by P8.

[0271] Example 13:

[0272] The present embodiment provides a synthesis method of 2,5-diphenyl-1,3,4-oxadiazole , which is specifically as follows:

[0273] (1) Synthesis of phenyl diazonium tetrafluoroborate :

[0274] Aniline (9.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% by mass of tetrafluoroboric acid, 0.2 mol) were added into 100 ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After the temperature was restored to room temperature, stirring was carried out for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain 16.3 g of the product phenyl diazonium tetrafluoroborate, with a yield of 85%.

[0275] Tested, the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0276] 1 H NMR (DMSO-d6, 300 mHz) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0277] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound phenyl tetrafluoroboric acid diazonium salt is synthesized.

[0278] (2) 2,5-diphenyl-1,3,4-oxadiazole Synthesis:

[0279] Under Ar atmosphere, phenyl tetrafluoroboric acid diazonium salt (9.6 g, 0.05 mol) and P1 (10 g, 0.05 mol), C2 (0.21 g, 2% mol of P1) and 20 mL of DMSO are added to a reaction bottle, and 24W blue light is irradiated under the condition of 25°C for 1h. After the reaction is completed, ethyl acetate and water are added for extraction and separation, and the organic phase is washed with saturated brine for 3 times, then dried and filtered. The mixture solvent (v:v is 1:10) of n-hexane and ethyl acetate is used as eluent to separate the clean product 8.4 g by column, and the yield is 76%.

[0280] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0281] 1 H NMR (DMSO-d6) δ 8.15-8.08 (4H), δ 7.66-7.60 (6H).

[0282] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2,5-diphenyl-1,3,4-oxadiazole is synthesized, which is represented by P9.

[0283] Example 14:

[0284] The present embodiment provides a synthesis method of 2-phenyl-5-(4-methoxyphenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0285] (1) Synthesis of phenyl tetrafluoroboric acid diazonium salt :

[0286] Aniline (9.3 g, 0.1 mol) and aqueous solution of tetrafluoroboric acid (35.2 g, 50% of tetrafluoroboric acid by mass, 0.2 mol) are added to 100 ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) is slowly added dropwise. After the room temperature is restored, it is stirred for 1h. 500 mL of methyl tert-butyl ether is added, filtered, washed with methyl tert-butyl ether, and the filter cake is collected to obtain the product phenyl tetrafluoroboric acid diazonium salt 16.3 g, with a yield of 85%.

[0287] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0288] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0289] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound phenyl tetrafluoroboric acid diazonium salt is synthesized.

[0290] (2) 2-phenyl-5-(4-methoxyphenyl)-1,3,4-oxadiazole Synthesis:

[0291] Under Ar atmosphere, phenyl tetrafluoroboric acid diazonium salt (9.6 g, 0.05 mol) and P4 (10 g, 0.05 mol), C2 (0.21 g, 2% mol of P4) and 20 mL of DMSO are added to a reaction bottle, and 25°C is reacted for 1h under the condition of 24W blue light illumination. After the reaction is completed, ethyl acetate and water are added for extraction and separation, and the organic phase is washed with saturated brine for 3 times, then dried and filtered. The mixture solvent (v:v is 1:10) of n-hexane and ethyl acetate is used as eluent to separate the clean product 9.96 g by column, and the yield is 79%.

[0292] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0293] 1 H NMR (DMSO-d6) δ 8.15-8.11 (2H), δ 8.11-8.05 (2H), δ 7.54 (3H), δ 7.09-7.00 (2H), δ 3.90 (3H).

[0294] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-phenyl-5-(4-methoxyphenyl)-1,3,4-oxadiazole is synthesized, which is represented by P10.

[0295] Example 15:

[0296] The present embodiment provides a synthesis method of 2-phenyl-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0297] (1) Synthesis of phenyl tetrafluoroboric acid diazonium salt

[0298] Aniline (9.3 g, 0.1 mol) and aqueous solution of tetrafluoroboric acid (35.2 g, mass fraction of tetrafluoroboric acid is 50%, 0.2 mol) are added to 100 ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, purity is 90%, 0.2 mol) is slowly added dropwise. After the temperature is recovered to room temperature, it is stirred for 1h. 500 mL of methyl tert-butyl ether is added, filtered, washed with methyl tert-butyl ether, and the filter cake is collected to obtain the product phenyl tetrafluoroboric acid diazonium salt 16.3 g, and the yield is 85%.

[0299] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0300] ​1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0301] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound phenyl tetrafluoroboric acid diazonium salt is synthesized.

[0302] (2) 2-phenyl-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole Synthesis:

[0303] Under Ar atmosphere, phenyl tetrafluoroboric acid diazonium salt (9.6 g, 0.05 mol) and P3 (8.8 g, 0.05 mol), C2 (0.21 g, 2% mol of P3) and 20 mL of DMSO were added to the reaction bottle, and 24W blue light was irradiated under the condition of 25℃ for 1h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, and the organic phase was washed with saturated brine for 3 times, then dried and filtered. The mixture solvent of n-hexane and ethyl acetate (v:v is 1:10) was used as eluent to separate the column to obtain the pure product 10.0 g, with a yield of 69%.

[0304] After testing, the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0305] 1 H NMR (CDCI3) δ 8.41 (1H), δ 8.37 (1H), δ 8.20-8.16 (2H), δ 7.84 (1H), δ 7.71 (1H), δ 7.62-7.55 (3H).

[0306] From the above nuclear magnetic resonance hydrogen spectrum data, it can be known that the target compound 2-phenyl-5-(4-trifluoromethylphenyl)-1,3,4-oxadiazole is synthesized, which is represented by P11.

[0307] Example 16:

[0308] This embodiment provides a synthesis method of 2-phenyl-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole , which is specifically as follows:

[0309] (1) Synthesis of phenyl tetrafluoroboric acid diazonium salt

[0310] ​Aniline (9.3 g, 0.1 mol) and aqueous solution of tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and tert-butyl nitrite (23 g, 90% purity, 0.2 mol) was slowly added dropwise. After the temperature was restored to room temperature, it was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl tetrafluoroborate diazonium salt 16.3 g, with a yield of 85%.

[0311] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0312] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0313] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyl tetrafluoroborate diazonium salt was synthesized.

[0314] (2) 2-phenyl-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole Synthesis:

[0315] Under Ar atmosphere, phenyl tetrafluoroborate diazonium salt (9.6 g, 0.05 mol) and P5 (10.8 g, 0.05 mol), C2 (0.21 g, 2% mol of P5) and 20 mL of DMSO were added into a reaction bottle, and 1 h of reaction was carried out under the condition of 24 W blue light illumination at 25°C. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and the clean product 11.9 g was obtained by column separation using a mixed solvent of n-hexane and ethyl acetate (v:v 1:10) as the eluent, with a yield of 82%.

[0316] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0317] 1 H NMR (CDCl3) δ 8.24 (1H) δ 8.15-8.11 (2H) δ 7.91 (1H) δ 7.76 (1H) δ 7.64 (3H).

[0318] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-phenyl-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole, represented by P12, was synthesized.

[0319] Comparative Example 1:

[0320] This comparative example provides a synthesis method of 2-phenyl-1,3,4-oxadiazole , which is as follows:

[0321] (1) phenyldiazonium tetrafluoroborate Synthesis of phenyldiazonium tetrafluoroborate:

[0322] Phenylamine (9.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added to 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and slowly added with tert-butyl nitrite (23 g, 90% purity, 0.2 mol). After the temperature was restored to room temperature, the mixture was stirred for 1 h. 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyldiazonium tetrafluoroborate 16.3 g, with a yield of 85%.

[0323] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0324] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0325] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyldiazonium tetrafluoroborate was synthesized.

[0326] (2) 2-phenyl-1,3,4-oxadiazole Synthesis of 2-phenyl-1,3,4-oxadiazole:

[0327] Under Ar atmosphere, phenyldiazonium tetrafluoroborate (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C2 (0.21 g, 2% mol of S1), and 20 mL of DMSO were added to a reaction bottle, and the mixture was reacted under 24 W white light illumination at 25°C for 1 h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and separated by column chromatography using a mixed solvent of n-hexane and ethyl acetate (v:v = 1:5) as the eluent to obtain the clean product 2.6 g, with a yield of 36%.

[0328] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0329] 1 H NMR (CDCI 3, 400MHz) δ 8.48 (1H), δ 8.11-8.05 (2H), δ 7.57-7.49 (3H).

[0330] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-phenyl-1,3,4-oxadiazole, denoted as P1, was synthesized.

[0331] Comparative Example 2

[0332] The present comparative example provides a synthesis method of 2-phenyl-1,3,4-oxadiazole , and the specific process is as follows:

[0333] (1) Synthesis of phenyl diazonium tetrafluoroborate:

[0334] Aniline (9.3 g, 0.1 mol) and aqueous tetrafluoroboric acid (35.2 g, 50% mass fraction of tetrafluoroboric acid, 0.2 mol) were added into 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and slowly added with tert-butyl nitrite (23 g, 90% purity, 0.2 mol). After the temperature was restored to room temperature, the mixture was stirred for 1 h. Then 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl diazonium tetrafluoroborate 16.3 g, 85%.

[0335] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0336] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0337] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound phenyl diazonium tetrafluoroborate was synthesized.

[0338] (2) Synthesis of 2-phenyl-1,3,4-oxadiazole:

[0339] Under Ar atmosphere, phenyl diazonium tetrafluoroborate (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C2 (0.21 g, 2% mol of S1), and 20 mL of DMSO were added into a reaction bottle, and the mixture was reacted under the condition of 24 W red light illumination at 25°C for 1 h. After the reaction was completed, ethyl acetate and water were added for extraction and separation, the organic phase was washed with saturated brine for 3 times, dried, filtered, and separated by column chromatography using a mixed solvent of n-hexane and ethyl acetate (v:v is 1:5) as an eluent to obtain the clean product 0.4 g, with a yield of 5%.

[0340] The tested nuclear magnetic resonance hydrogen spectrum data are as follows:

[0341] 1 H NMR (CDCI 3, ) δ 8.48 (1H), δ 8.11-8.05 (2H), δ 7.57-7.49 (3H).

[0342] According to the above nuclear magnetic resonance hydrogen spectrum data, the target compound 2-phenyl-1,3,4-oxadiazole, represented by P1, was synthesized.

[0343] Comparative Example 3:

[0344] This comparative example provides a 2-phenyl-1,3,4-oxadiazole ​​The synthesis method of the compound is as follows:

[0345] (1) phenyl diazonium tetrafluoroborate The synthesis of the compound is as follows:

[0346] Aniline (9.3 g, 0.1 mol) and an aqueous solution of tetrafluoroboric acid (35.2 g, mass fraction of tetrafluoroboric acid 50%, 0.2 mol) were added to 100 mL of ethanol, stirred for 10 min, cooled to 0°C, and slowly added with tert-butyl nitrite (23 g, purity 90%, 0.2 mol). After the temperature was restored to room temperature, the mixture was stirred for 1 h. Then 500 mL of methyl tert-butyl ether was added, filtered, washed with methyl tert-butyl ether, and the filter cake was collected to obtain the product phenyl diazonium tetrafluoroborate 16.3 g, with a yield of 85%.

[0347] The test results of the hydrogen nuclear magnetic resonance spectrum are as follows:

[0348] 1 H NMR (DMSO-d6) δ 8.66 (2H), δ 8.26 (1H), δ 7.98 (2H).

[0349] According to the hydrogen nuclear magnetic resonance spectrum data, the target compound phenyl diazonium tetrafluoroborate was synthesized.

[0350] (2) 2-phenyl-1,3,4-oxadiazole The synthesis of the compound is as follows:

[0351] Under an argon atmosphere, phenyl diazonium tetrafluoroborate (9.6 g, 0.05 mol) and S1 (3.5 g, 0.05 mol), C2 (0.21 g, 2% mol of S1), and 20 mL of DMSO were added to a reaction bottle, and the mixture was reacted in the dark at 25°C for 1 h. After the reaction was completed, no product was detected.

[0352] The yield and yield of each example and comparative example are shown in Table 1:

[0353] Table 1

[0354]

[0355]

[0356] As can be seen from Table 1, compared with Comparative Examples 1 to 3, Examples 1 to 16 couple 1,3,4-oxadiazole derivatives with aryl-substituted diazonium tetrafluoroborate under the conditions of containing Mn catalyst and blue light to prepare aryl-substituted 1,3,4-oxadiazole derivatives, the reaction conditions are mild, the atom utilization rate is high, the product yield is high, and the catalytic effect of CpMn(CO)3 is better.

[0357] Any combination of the technical features in the above-described embodiments can be made, and for the sake of brevity, not all possible combinations of the technical features in the above-described embodiments are described, however, as long as the combination of the technical features does not exist in contradiction, it should be considered as within the scope of the present disclosure.

[0358] The above-described embodiments only express several implementation manners of the present application, facilitate specific and detailed understanding of the technical solutions of the present application, but cannot be understood as a limitation on the patent protection scope of the present application. It should be noted that, for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. It should be understood that, on the basis of the technical solutions provided by the present application, the technical solutions obtained by logical analysis, reasoning or limited experiments by ordinary skilled persons in the art all belong to the protection scope of the appended claims of the present application. Therefore, the patent protection scope of the present application should be subject to the contents of the appended claims, and the description can be used to explain the contents of the claims.

Claims

1. A method for synthesizing aryl-substituted 1,3,4-oxadiazole derivatives, characterized by, The method comprises the following steps: under the condition of a Mn-containing catalyst and blue light, coupling a 1,3,4-oxadiazole derivative with an aryl-substituted diazonium tetrafluoroborate; said Mn-containing catalyst is selected from one or more of Mn2(CO) 10 , CpMn(CO)3, and Mn(CO)5Br; the aryl-substituted diazonium tetrafluoroborate has the following structure shown in formula (II): each R2 is independently selected from alkyl, alkoxy, fluoroalkyl or halogen; m is selected from any integer between 0 and 5; the aryl-substituted 1,3,4-oxadiazole derivative has the following structure shown in formula (III): each R1 is independently selected from alkyl, or aryl substituted or unsubstituted by R; each R is independently selected from halogen, cyano, amino, hydroxyl, alkyl, alkoxy or haloalkyl; p is 1, and r-p is 0 or 1; or p is 2, and r-p is 0.

2. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives according to claim 1, characterized in that, the 1,3,4-oxadiazole derivative has the following structure shown in formula (I): r is selected from any integer between 1 and 2.

3. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives as claimed in claim 2 wherein, each R1 is independently selected from C1-C10 alkyl, or aryl with 6-30 ring atoms substituted or unsubstituted by R.

4. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives as claimed in claim 2, wherein, each R is independently selected from halogen, cyano, amino, hydroxyl, C1-C20 linear alkyl, C3-C20 branched alkyl, C3-C20 cyclic alkyl, C1-C20 linear alkoxy, C3-C20 branched alkoxy, C3-C20 cyclic alkoxy, halo C1-C20 linear alkyl, halo C3-C20 branched alkyl, halo C3-C20 cyclic alkyl.

5. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives as claimed in claim 1, wherein, the R2 is ortho or para substituted with a diazonium group; and / or each R2 is independently selected from C1-C10 alkyl, C1-C10 alkoxy, C1-C10 fluoroalkyl or halogen.

6. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives according to any one of claims 1 to 5, characterized in that, the molar ratio of the 1,3,4-oxadiazole derivative to the aryl-substituted diazonium tetrafluoroborate is 1:(1-2.5); and / or the molar ratio of the Mn-containing catalyst to the 1,3,4-oxadiazole derivative is (1-10):100; and / or the temperature of the coupling reaction is 5-40℃, and the time is 0.5-10h.

7. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives according to any one of claims 1 to 5, characterized in that, the solvent used in the coupling reaction is a mixture of one or both of dimethyl sulfoxide and N,N-dimethylformamide.

8. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives according to any one of claims 1 to 5, characterized in that, The method for preparing the aryl-substituted diazonium tetrafluoroborate comprises the following steps: mixing a primary amine-substituted aryl derivative with an aqueous tetrafluoroboric acid solution in a solvent to generate a tetrafluoroborate salt; carrying out diazotization reaction of the tetrafluoroborate salt with a nitrous acid compound, and adding a precipitant to precipitate the aryl-substituted diazonium tetrafluoroborate.

9. The method of synthesis of aryl substituted 1,3,4-oxadiazole derivatives as claimed in claim 8, wherein, the solvent is an alcohol solvent; and / or the nitrous acid compound is tert-butyl nitrite; and / or the precipitant is methyl tert-butyl ether; and / or the temperature of the diazotization reaction is 0±5℃, and the time is 0.5-2h.

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