2-alkyl substituted 1, 3, 4-oxadiazole heterocyclic compound and preparation method thereof

Abstract

The invention 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. According to the present invention, the cheap copper catalysis system is adopted, the free radical reaction process is performed, the remote heteroaromatization reaction of the amide alkyl carbon-hydrogen bond and the 1, 3, 4-oxadiazole heterocyclic compound is achieved, and the efficient and high-selectivity 2-alkyl substituted 1, 3, 4-oxadiazole heterocyclic compound synthesis method is provided. According to the method, an expensive transition metal catalyst is not used, a reaction substrate is easy to obtain, a pre-functionalized substrate is not used, the 2-alkyl substituted 1, 3, 4-oxadiazole heterocyclic compound is directly synthesized through a double-carbon-hydrogen bond activation strategy, and the preparation method is easy to operate, mild in reaction condition, simple and convenient in post-treatment, high in reaction efficiency, good in regioselectivity and suitable for industrial production. The practical range of the substrate is wide.

Description

Technical Field

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

[0002] 1,3,4-oxadiazoles are an important class of nitrogen-containing five-membered heterocyclic compounds that have a wide range of applications in medicine and materials science due to their unique structure. In addition, these (1,3,4-oxadiazole) skeletons are building blocks of a variety of bioactive molecules and often have an impact in drug development. For example, raltegravir shows antiretroviral 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, the synthesis of C(sp 2 )-H bond for direct functionalization is a convenient synthetic method. For example, Miura used aryl iodide or aryl silicon compound to react with 1,3,4-oxadiazole in the presence of copper catalyzer ((a) Org. Lett., 2009, 11, 3072-3075; Angew. Chem. Int. Ed., 2010, 49, 2202-2205.). In 2021, Liu Xinyuan used anionic ligands to realize the alkylation reaction of alkyl bromide with 1,3,4-oxadiazole 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 bromide as a traceless directing group (Chem. Commun. 2022, 58, 6661-6664.). Therefore, the development of a regioselective cross-coupling reaction method based on 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 of the invention

[0003] The purpose of the present invention is to provide a method for synthesizing 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds. By using a cheap copper catalytic system and undergoing a free radical reaction process, a remote heteroaromatic reaction of an amidoalkyl carbon-hydrogen bond with a 1,3,4-oxadiazole heterocyclic compound is achieved, providing a highly efficient and highly selective method for synthesizing 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds.

[0004] In order to achieve the above technical objectives, the technical solution adopted by the present invention is: A method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound comprises the following steps: under a nitrogen atmosphere, a 1,3,4-oxadiazole compound, a catalyst, a base, a ligand compound and a reaction solvent are added to a reaction container respectively, and then an N-fluorobenzamide compound is added to the mixture, the reaction mixture is reacted at 60°C for 20-24 hours under magnetic stirring, after the reaction is completed, the precipitate is filtered out 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.

[0005] Preferably, the 1,3,4-oxadiazole compound has the structure shown below: , wherein Ar is one of phenyl, 3-tolyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-naphthyl or 2-furyl.

[0006] Preferably, the catalyst is one of cuprous iodide, cuprous chloride, cuprous bromide, cuprous acetate, and copper thiophene-2-carboxylate.

[0007] Preferably, the ligand compound is one of 2,2-bipyridine, 1,10-phenanthroline, L1, L2, and L3, wherein L1, L2, and L3 have the following structure: .

[0008] Preferably, the base is one of potassium tert-butoxide, sodium ethoxide and sodium tert-butoxide.

[0009] Preferably, the solvent is one of tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane.

[0010] Preferably, the N-fluorobenzamide compound has a structure as described below: ;in, R1 is a hydrogen atom, a 2-methyl, a 3-methyl, a 4-methyl, a 5-methyl, or a 5-bromo substituent; R2 is tert-butyl or tert-octyl; R3 is a hydrogen atom or a methyl group.

[0011] 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 amount ratio of the solvent to the N-fluorobenzamide compound is 1 ml:0.2 mmol.

[0012] Preferably, the eluent during the silica gel column chromatography purification is petroleum ether:ethyl acetate = 10:1~4:1.

[0013] A compound obtained by the above-mentioned method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound has the following general formula: ; Wherein R1 is a hydrogen atom, a 2-methyl, a 3-methyl, a 4-methyl, a 5-methyl, or a 5-bromo substituent; R2 is tert-butyl or tert-octyl; 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 or 2-furyl.

[0014] The synthetic route diagram of the present invention is as follows: The 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compounds prepared by the above method are all publicly synthesized for the first time, and the structural formulas and yields of some of the obtained products are shown in the following figure: Compared with the prior art, the present invention has the following beneficial effects: the copper catalyst used in the present invention is cheap and readily available, avoiding the use of expensive transition metal catalysts; and the two reaction substrates are readily available, 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, has mild reaction conditions, simple post-treatment, high reaction efficiency, good regioselectivity, a wide range of substrate practicality, and has good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1-2 This is the NMR spectrum of the product obtained in Example 1 of the present invention; Figure 3-4 This is the NMR spectrum of the product obtained in Example 2 of the present invention; Figure 5-6 This is the NMR spectrum of the product obtained in Example 3 of the present invention. DETAILED DESCRIPTION

[0016] The technical solution of the present invention is further described below in conjunction with specific embodiments, but is not limited thereto.

[0017] Example 1 Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: 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 in sequence, and the reaction mixture was stirred at 60°C for 22 hours. When the reaction was completed (monitored by thin layer chromatography (TLC)), the precipitate was filtered out and washed with dichloromethane (DCM). After evaporation of the filtrate, 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%. Its structural formula is shown below: . 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 N3O2 336.1707; found 336.1705. The structural formula of 2-phenyl-1,3,4-oxadiazole is as follows: ; The structural formula of N-fluoro-N-tert-butyl-2-methylbenzamide is as follows: .

[0018] Example 2 Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: 0.3 mmol of 2-(α-furanyl) 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). Then, 0.20 mmol of N-fluoro-N-tert-butyl-2-methylbenzamide was added to the mixture in sequence, and the reaction mixture was stirred at 60°C for 22 hours. When the reaction was completed (monitored by thin layer chromatography (TLC)), the precipitate was filtered off and washed with dichloromethane (DCM). After evaporation of the filtrate, 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 with a yield of 85%, and its structural formula is shown below: . 1 H NMR (400MHz, 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. The structural formula of 2-(α-furanyl)-1,3,4-oxadiazole is as follows: ; N-Fluoro-N-tert-butyl-2-methylbenzamide .

[0019] Example 3 Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: 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 dichloromethane (CH2Cl2). Then, 0.20 mmol of N-fluoro-N-tert-octyl-2-methylbenzamide was added to the mixture in sequence, and the reaction mixture was stirred at 60°C for 22 hours. When the reaction was completed (monitored by thin layer chromatography (TLC)), the precipitate was filtered off and washed with dichloromethane (DCM). After evaporation of the filtrate, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4: 1) to obtain the desired 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound with a yield of 79%, and its structural formula is shown below: . 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 N3O2 378.2176; found 378.2186. The structural formula of 2-phenyl-1,3,4-oxadiazole compound is as follows: ; The structural formula of N-fluoro-N-tert-octyl-2-methylbenzamide is as follows: .

[0020] Other compounds can be synthesized by referring to the above method to obtain the target final product. It should be noted that the above embodiments are only partial embodiments of the preferred methods of implementing the present invention, rather than all embodiments. Obviously, any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound, characterized in that: The method comprises the following steps: under nitrogen atmosphere, 1,3,4-oxadiazole compounds, catalysts, bases, ligand compounds and reaction solvents are added into a reaction container respectively, and then N-fluorobenzamide compounds are added into the mixture, the reaction mixture is reacted at 60°C for 20-24 hours under magnetic stirring, after the reaction is finished, the precipitate is filtered out 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.

2. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: 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-furyl.

3. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: The catalyst is one of cuprous iodide, cuprous chloride, cuprous bromide, cuprous acetate and copper thiophene-2-carboxylate.

4. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: 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: .

5. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: The base is one of potassium tert-butoxide, sodium ethoxide and sodium tert-butoxide.

6. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: The solvent is one of tetrahydrofuran, 1,4-dioxane, toluene or halogenated toluene, dichloromethane and 1,2-dichloroethane.

7. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: The N-fluorobenzamide compound has the following structure: ;in, R1 is a hydrogen atom, a 2-methyl, a 3-methyl, a 4-methyl, a 5-methyl, or a 5-bromo substituent; R2 is tert-butyl or tert-octyl; R3 is a hydrogen atom or a methyl group.

8. The method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to claim 1, characterized in that: 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; the usage ratio of the solvent to the N-fluorobenzamide compound is 1 ml:0.2 mmol.

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

1.

10. A compound obtained by the method for preparing a 2-alkyl substituted 1,3,4-oxadiazole heterocyclic compound according to any one of claims 1 to 9, which has the following general formula: ; Wherein R1 is a hydrogen atom, one of a 2-methyl, 3-methyl, 4-methyl, 5-methyl, and 5-bromo substituent; R2 is tert-butyl or tert-octyl; 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 or 2-furyl.

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