2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds and methods for their preparation

Abstract

The application discloses a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound and a preparation method thereof, and belongs to the technical field of organic synthesis. The application realizes remote heteroaromatic reaction of an amide alkyl carbon hydrogen bond and a 1,3,4-oxadiazole heterocyclic compound through a free radical reaction process by using a cheap copper catalytic system, and provides a synthesis method of the 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound with high efficiency and high selectivity. The method avoids using expensive transition metal catalysts, and the reaction substrate is easy to obtain, avoids using a pre-functionalized substrate, and directly synthesizes the 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound through a double carbon hydrogen bond activation strategy. The preparation method is easy to operate, the reaction condition is mild, the post-treatment is simple, the reaction efficiency is high, the regioselectivity is good, and the substrate has wide practicality.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound and a preparation method thereof. BACKGROUND

[0002] 1,3,4-oxadiazole is an important nitrogen-containing five-membered heterocyclic compound. Due to its unique structure, it has a wide range of applications in the fields of medicine and material science. In addition, these (1,3,4-oxadiazole) skeletons are components of various biologically active molecules and often have an impact during drug development. For example, raltegravir shows anti-retroviral properties. Therefore, it is extremely important to explore new synthetic methods for 1,3,4-oxadiazoles. Although significant progress has been made in recent years, from the perspective of step economy and atom economy, direct functionalization of the C(sp 2 )-H bond is a convenient synthesis method. For example, Miura used aryl iodides or aryl silicon compounds to perform arylation with 1,3,4-oxadiazoles under the action of copper catalysts ((a) Org. Lett., 2009, 11, 3072-3075; Angew. Chem. Int. Ed., 2010, 49, 2202-2205.). In 2021, Liu Xinyuan used anion ligands to realize the alkylation of alkyl bromides with 1,3,4-oxadiazole compounds under copper catalysis ((a) Angew. Chem. Int. Ed., 2021, 60, 380-384; (b) Tetrahedron, 2021, 89, 132152.). In 2022, Feng reported a palladium-catalyzed intermolecular cross-coupling reaction between unactivated alkyl C-H bonds and 1,3,4-oxadiazoles using bromides as traceless directing groups (Chem. Commun. 2022, 58, 6661-6664.). Therefore, developing a method for the region-selective cross-coupling reaction based on the dual activation of unactivated alkyl C-H bonds and 1,3,4-oxadiazole C-H bonds is still of great significance for the construction of 2-alkyl-substituted 1,3,4-oxadiazoles. SUMMARY

[0003] The purpose of the present application is to provide a synthesis method for 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compounds. By using a cheap copper catalyst system, a remote heteroaromatic reaction of amide alkyl C-H bonds and 1,3,4-oxadiazole heterocyclic compounds is realized through a free radical reaction process, providing a synthesis method for 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compounds with high efficiency and high selectivity.

[0004] To achieve the above technical purposes, the technical scheme adopted by the present application is:

[0005] A preparation method of 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds, comprising the following steps: under a nitrogen atmosphere, 1,3,4-oxadiazole compounds, catalyst, base, ligand compounds and reaction solvent are added to the reaction container respectively, then N-fluorobenzamide compounds are added to the mixture, the reaction mixture is stirred under magnetic force at 60℃ for 20-24h, after the reaction is completed, the precipitate is removed by filtration, and washed with dichloromethane, the filtrate is evaporated, and the residue is purified by silica gel column chromatography to obtain the final product 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds.

[0006] Preferably, the 1,3,4-oxadiazole compounds have the following structure:

[0007] , wherein Ar is one of phenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-naphthyl or 2-furyl.

[0008] Preferably, the catalyst is one of cuprous iodide, cuprous chloride, cuprous bromide, cuprous acetate, and copper thiophene-2-carboxylate.

[0009] Preferably, the ligand compound is one of 2,2-bipyridine, 1,10-phenanthroline, L1, L2, L3, wherein L1, L2, L3 have the following structure: .

[0010] Preferably, the base is one of potassium tert-butoxide, sodium ethoxide, and sodium tert-butoxide.

[0011] Preferably, the solvent is one of tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, and 1,2-dichloroethane.

[0012] Preferably, the N-fluorobenzamide compound has the structure shown in the following formula: ; wherein,

[0013] R1 is one of hydrogen atom, 2-methyl, 3-methyl, 4-methyl, 5-methyl, and 5-bromosubstituent;

[0014] R2 is tert-butyl or tert-octyl;

[0015] R3 is hydrogen atom or methyl.

[0016] Preferably, the molar ratio of the 1,3,4-oxadiazole compound, the catalyst, the base, the ligand compound, and the N-fluorobenzamide compound is 1.5:0.1:2:0.1:1; and the ratio of the solvent to the N-fluorobenzamide compound is 1ml:0.2mmol.

[0017] Preferably, the eluent used in the silica gel column chromatography is petroleum ether: ethyl acetate = 10:1~4:1.

[0018] A 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound prepared by the above method, having the following general formula: ; wherein R1 is one of a hydrogen atom, 2-methyl, 3-methyl, 4-methyl, 5-methyl, and 5-bromosubstituent;

[0019] R2 is a tert-butyl group or a tert-octyl group;

[0020] R3 is a hydrogen atom or a methyl group;

[0021] Ar is one of a phenyl group, a 3-tolyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenyl group, a 2-naphthyl group, and a 2-furyl group.

[0022] The synthetic route of the present application is as follows:

[0023]

[0024] The 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compounds prepared by the above method are all first disclosed synthesis, and the structural formula and yield of some of the products are shown in the following figure:

[0025]

[0026]

[0027] Compared with the prior art, the present application has the following beneficial effects: the copper catalyst used in the present application is inexpensive and easy to obtain, avoiding the use of expensive transition metal catalysts; and the two reaction substrates are easy to obtain, avoiding the use of pre-functionalized substrates, and directly synthesizing 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compounds through a double carbon-hydrogen bond activation strategy. The preparation method is easy to operate, the reaction conditions are mild, the post-treatment is simple, the reaction efficiency is high, the regioselectivity is good, the substrate has a wide range of practicality, and has good industrial application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figures 1-2 The nuclear magnetic resonance spectrum of the product obtained in Example 1 of the present application;

[0029] Figures 3-4NMR spectrum of the product obtained in Example 2 of the present application;

[0030] Figures 5-6 NMR spectrum of the product obtained in Example 3 of the present application. DETAILED DESCRIPTION

[0031] The technical solutions of the present application are further described below in conjunction with specific examples, but are not limited thereto.

[0032] Example 1

[0033] Under argon atmosphere, a Schlenk reactor equipped with magnetic stirring was charged with 0.3 mmol of 2-phenyl-1,3,4-oxadiazole compound, 0.02 mmol of cuprous cyanide, 0.4 mmol of potassium tert-butoxide, 0.02 mmol of 1,10-phenanthroline and 1 ml of anhydrous trifluorotoluene (C6H5CF3). Then, 0.20 mmol of N-fluoro-N-tert-butyl-2-methylbenzamide compound was added to the mixture, and then the reaction mixture was stirred at 60°C for 22 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the precipitate was removed by filtration and washed with dichloromethane (DCM), and the filtrate was evaporated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to obtain the desired 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound with a yield of 76%, and its structural formula is as follows:

[0034] . 1 H NMR (400 MHz, CDCl3) δ 8.05-7.98 (m, 2H), 7.52-7.44 (m, 4H), 7.39-7.29 (m, 3H), 6.08 (s, 1H), 4.51 (s, 2H), 1.41 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 168.9, 165.8, 164.9, 137.9, 131.7, 130.7, 130.2, 129.0, 127.8, 127.6, 126.9, 123.9, 52.1, 29.4, 28.7; HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 22 N3O2336.1707; found 336.1705.

[0035] The structural formula of 2-phenyl-1,3,4-oxadiazole is as follows: ; N-fluoro-N-tert-butyl-2-methylbenzamide has the following structure: .

[0036] Example 2

[0037] A Schlenk reaction tube equipped with magnetic stirring was charged with 0.3 mmol of 2-(α-furyl)-1,3,4-oxadiazole compound, 0.02 mmol of cuprous cyanide, 0.4 mmol of potassium tert-butoxide, 0.02 mmol of 1,10-phenanthroline, and 1 ml of tetrahydrofuran (THF) under an argon atmosphere. Then, 0.20 mmol of N-fluoro-N-tert-butyl-2-methylbenzamide was added to the mixture, and the reaction mixture was stirred at 60°C for 22 hours. Upon completion of the reaction (monitored by thin layer chromatography (TLC)), the precipitate was removed by filtration and washed with dichloromethane (DCM). The filtrate was evaporated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6:1) to obtain the desired 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound in a yield of 85%, which has the following structure: . 1 H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 1.7, 0.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.38-7.27 (m,3H), 7.12-7.08 (m, 1H), 6.55 (dd, J = 3.5, 1.7 Hz, 1H), 6.03 (s, 1H), 4.47 (s,2H), 1.38 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 168.9, 165.2, 157.9, 145.6, 139.4,137.9, 131.5, 130.8, 130.3, 128.0, 127.6, 114.0, 112.2, 52.1, 29.3, 28.7; HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 20 N3O3326.1499; found 326.1497.

[0038] 2-(α-furyl)-1,3,4-oxadiazole has the following structure: ; N-fluoro-N-tert-butyl-2-methylbenzamide .

[0039] Example 3

[0040] A Schlenk tube equipped with magnetic stirring was charged with 0.3 mmol of 2-phenyl-1,3,4-oxadiazole compound, 0.02 mmol of copper cyanide, 0.4 mmol of potassium tert-butoxide, 0.02 mmol of 1,10-phenanthroline and 1 ml of anhydrous dichloromethane (CH2Cl2) under argon atmosphere. Then, 0.20 mmol of N-fluoro-N-tert-octyl-2-methylbenzamide was added to the mixture, and the reaction mixture was stirred at 60 °C for 22 hours. Upon completion of the reaction (monitored by thin layer chromatography (TLC)), the precipitate was removed by filtration and washed with dichloromethane (DCM). The filtrate was evaporated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4: 1) to give the desired 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound in 79% yield, whose structural formula is shown as follows: . 1 H NMR (400 MHz, CDCl3) δ 8.04-7.99 (m, 2H), 7.76-7.71 (m, 2H), 7.53 -7.47 (m, 3H), 7.45-7.37 (m, 3H), 6.48 (s, 1H), 2.98 (s, 2H), 2.05 (s, 2H), 1.58 (s, 6H), 1.18 (s, 6H); 13 C NMR (101 MHz, CDCl3) δ 167.3, 165.5, 164.8, 136.0, 131.7, 131.2, 129.1, 128.6, 126.9, 126.9, 124.0, 55.4, 49.4, 38.6, 35.3, 29.7, 29.2; HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 28 N3O2378.2176; found 378.2186.

[0041] The structural formula of the 2-phenyl-1,3,4-oxadiazole compound is as follows: ; the structural formula of the N-fluoro-N-tert-octyl-2-methylbenzamide is as follows: .

[0042] Other compounds can be synthesized according to the above method to obtain the target end product.

[0043] It should be noted that the above-mentioned embodiments are only some of the preferred modes of implementing the present application, but not all. Obviously, any changes, modifications, replacements, combinations, simplifications made without departing from the spirit and principles of the present application should be equivalent replacements, and should be included in the protection scope of the present application.

Claims

1. A method for preparing a 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound, characterized in that: It comprises the following steps: under a nitrogen atmosphere, 1,3,4-oxadiazole compound, catalyst, base, ligand compound and reaction solvent are added into a reaction container respectively, then N-fluorobenzamide compound is added into the mixture, the reaction mixture is stirred under magnetic stirring at 60℃ for 20-24h, after the reaction is completed, the precipitate is removed by filtration, and washed with dichloromethane, the filtrate is evaporated, and the residue is purified by silica gel column chromatography to obtain the final product 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound; The 1,3,4-oxadiazole compound has the following structure: wherein Ar is one of phenyl, 3-tolyl, 4-fluorophenyl, 4-chlorophenyl, 4- bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-naphthyl, or 2- furanyl; The catalyst is one of cuprous iodide, cuprous chloride, cuprous bromide, cuprous acetate and copper thiophene-2-carboxylate; The ligand compound is one of 2,2-bipyridine, 1,10-phenanthroline, L1, L2 and L3, wherein L1, L2 and L3 have the following structures: the base is one of potassium tert-butoxide, sodium ethoxide, sodium tert-butoxide; The N-fluorobenzamide compound has a structure as described by the following formula: Wherein, R1 is one of hydrogen atom, 2-methyl, 3-methyl, 4-methyl, 5-methyl and 5-bromosubstituent; R2 is a tert-butyl group; R3 is a hydrogen atom or a methyl group.

2. The method for producing 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds according to claim 1, characterized by, The solvent is one of tetrahydrofuran, 1,4-dioxane, toluene or halogenated toluene, dichloromethane and 1,2-dichloroethane.

3. The method of producing 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds according to claim 1, characterized by, The molar ratio of the 1,3,4-oxadiazole compound, catalyst, base, ligand compound and N-fluorobenzamide compound is 1.5:0.1:2:0.1:1; the ratio of the amount of the solvent to N-fluorobenzamide compound is 1ml:0.2mmol.

4. The method for preparing a 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, wherein: The eluent for silica gel column chromatography purification is petroleum ether: ethyl acetate = 10:1-4:

1.

5. The method for preparing a 2-alkyl-substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, wherein: The compounds have the general formula: wherein R1 is one of a hydrogen atom, 2-methyl, 3-methyl, 4-methyl, 5-methyl, 5-bromo substituent; R2 is a tert-butyl group; R3 is a hydrogen atom or a methyl group. Ar is one of phenyl, 3-tolyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-naphthyl and 2-furyl.

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