Preparation method of 1,3,5-trisubstituted benzene compounds

Abstract

The invention discloses a method for preparing a 1,3,5-trisubstituted benzene compound, the method comprising the following steps: reacting a nickel catalyst, a phosphorus ligand, zinc powder, a zinc halide, and a terminal acetylene compound shown in formula (1) in an organic solvent under an inert atmosphere to prepare the 1,3,5-trisubstituted benzene compound; the 1,3,5-trisubstituted benzene compound has a structure as shown in formula (2). The present invention uses a terminal acetylene compound as a raw material and a cheap and stable divalent nickel source as a catalyst to efficiently and regioselectively prepare the 1,3,5-trisubstituted benzene compound shown in formula (2). The present invention overcomes the shortcomings of the catalyst in the prior art, such as the complex structure and difficulty in synthesis, the low selectivity and yield of the product; it has the characteristics of being simple, mild, efficient and having good functional group compatibility, and has good application value, providing a basis for realizing industrialized production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound preparation, and relates to a method for preparing 1,3,5-trisubstituted benzene compounds, in particular to a method for preparing 1,3,5-trisubstituted benzene compounds by nickel-catalyzed terminal alkyne cyclotrimerization. Background Art

[0002] 1,3,5-trisubstituted benzene structures are widely used in biology and materials science due to their symmetry and uniformity. Compared with traditional transformation methods, transition metal-catalyzed alkyne cyclotrimerization is atom-economical and can directly construct trisubstituted benzene derivatives, so it has always been a hot topic in green chemistry research. Since Reppe et al. first reported the nickel-catalyzed cyclotrimerization of acetylene to benzene in 1948, a large number of transition metal catalysts have shown catalytic activity in the cyclotrimerization of terminal alkynes.

[0003] Since the product of terminal alkyne cyclotrimerization is usually a mixture of 1,2,4-trisubstituted benzene and 1,3,5-trisubstituted benzene, among the reported catalysts, the catalysts that can catalyze the regioselective preparation of 1,3,5-trisubstituted benzene from terminal alkynes are usually complex in structure, such as mononuclear iron and cobalt complexes and dinuclear rhodium, niobium, and chromium complexes. Moreover, the efficiency, selectivity, and functional group compatibility of these synthetic strategies are relatively poor. These shortcomings limit their wide application, making them difficult to meet the requirements of large-scale or productive preparation and not practical. Therefore, the efficient and regioselective synthesis of 1,3,5-trisubstituted benzene is still a huge challenge.

[0004] In summary, 1,3,5-trisubstituted benzene compounds have a wide range of biological and material application values. The existing synthesis methods have disadvantages such as complex catalyst and ligand structures, poor yield and regioselectivity. In short, the existing synthesis methods need to be further improved, and the development of new methods for efficient, convenient and regioselective synthesis of 1,3,5-trisubstituted benzene compounds is still a meaningful research and development work. Summary of the invention

[0005] The purpose of the present invention is to solve the problems existing in the prior art of preparing 1,3,5-trisubstituted benzene compounds, such as complex catalyst structure and difficulty in synthesis, low selectivity and yield of products, and to provide a method for preparing 1,3,5-trisubstituted benzene compounds by nickel-catalyzed terminal alkyne cyclotrimerization, which has simple reaction conditions, high efficiency and is easy to prepare on a large scale.

[0006] The technical solution of the present invention is as follows:

[0007] A method for preparing a 1,3,5-trisubstituted benzene compound, the method comprising the following steps:

[0008] Under an inert atmosphere, a nickel catalyst, a phosphorus ligand, zinc powder, a zinc halide, and a terminal acetylene compound represented by formula (1) are reacted in an organic solvent to prepare the 1,3,5-trisubstituted benzene compound; the 1,3,5-trisubstituted benzene compound has a structure represented by formula (2):

[0009]

[0010] R1 is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 1-20 Alkyl, C 6-20 Aryl, 5-20 membered aromatic heterocyclic group, C 3-20 Cycloalkyl, -SiR2R3R4;

[0011] R a Selected from C 1-20 Alkyl, halogen, -NR5R6;

[0012] R2, R3, R4, R5, R6 are the same or different and are independently selected from H, C 1-20 alkyl.

[0013] According to an embodiment of the present invention, the halogen is F, Cl, Br or I.

[0014] According to an embodiment of the present invention, R1 is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 1-12 Alkyl, C 6-12 Aryl, 5-12 membered aromatic heterocyclic group, C 3-10 Cycloalkyl, -SiR2R3R4.

[0015] According to an embodiment of the present invention, R a Selected from C 1-12 Alkyl, halogen, -NR5R6; for example, R a It is F, Br, -NH2, -N(CH3)3.

[0016] According to an embodiment of the present invention, R2, R3, R4, R5, and R6 are the same or different and are independently selected from H, C 1-12 Alkyl groups are, for example, independently selected from H, -CH3.

[0017] According to an embodiment of the present invention, R1 is selected from 4-methylphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-bromophenyl, n-butyl, trimethylsilyl, cyclopropyl, 3-methylphenyl or 2-fluorophenyl.

[0018] According to an embodiment of the present invention, the nickel catalyst is at least one of Ni(PPh3)2Cl2, Ni(dppm)Cl2, Ni(dppe)Cl2, Ni(dppp)Cl2, Ni(dppb)Cl2, etc., preferably Ni(PPh3)2Cl2.

[0019] According to an embodiment of the present invention, the phosphorus ligand is at least one of PPh3, DPPM, DPPE, DPPP, DPPB, DPPF, XPhos, etc., preferably DPPM.

[0020] According to an embodiment of the present invention, the terminal acetylene compound represented by formula (1) is selected from p-methylphenylacetylene, p-aminophenylacetylene, 4-ethynyl-N,N-dimethylaniline, p-bromophenylacetylene, 1-hexyne, trimethylsilylacetylene, ethynylcyclopropane, 1-ethynyl-3-methylbenzene or 1-ethynyl-2-fluorobenzene, but is not limited to the above compounds.

[0021] According to an embodiment of the present invention, the molar ratio of the nickel catalyst, the phosphorus ligand and the terminal alkyne compound represented by formula (1) is (0.01-1):(0.01-1):1; preferably (0.05-1):(0.05-1):1, and exemplarily 0.1:0.1:1.

[0022] According to an embodiment of the present invention, the organic solvent is at least one of tetrahydrofuran, dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetonitrile, toluene, etc., preferably acetonitrile.

[0023] According to an embodiment of the present invention, the molar ratio of the nickel catalyst to the zinc powder is 1:(1-5); illustratively 1:1, 1:2, 1:3, 1:4 or 1:5.

[0024] According to an embodiment of the present invention, the zinc halide is one of ZnCl2, ZnBr2, ZnI2, etc., preferably ZnI2.

[0025] According to an embodiment of the present invention, the molar ratio of the nickel catalyst to the zinc halide is 1:(1-4), illustratively 1:1, 1:2, 1:3 or 1:4.

[0026] According to an embodiment of the present invention, the reaction temperature is 30-110°C; illustratively 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C or 110°C.

[0027] According to an embodiment of the present invention, the reaction time is 1-12 hours.

[0028] According to an embodiment of the present invention, the reaction is carried out under an inert atmosphere, for example, under a nitrogen atmosphere.

[0029] According to an embodiment of the present invention, the method further comprises purifying the prepared product, illustratively, removing the organic solvent in the reaction product, separating impurities, and preparing a purified 1,3,5-trisubstituted benzene compound of formula (2); illustratively, after filtering the reaction product, removing the organic solvent by vacuum distillation, and separating and purifying the mixture in the reaction solution by column chromatography.

[0030] Illustratively, the 1,3,5-trisubstituted benzene compound shown in formula (2) is selected from one of the following compounds: 1,3,5-tri(4-methylphenyl)benzene, 1,3,5-tri(4-aminophenyl)benzene, 1,3,5-tri(4-dimethylaminophenyl)benzene, 1,3,5-tri(4-bromophenyl)benzene, 1,3,5-tributylbenzene, 1,3,5-tri(trimethylsilyl)benzene, 1,3,5-tricyclopropylbenzene, 1,3,5-tri(3-methylphenyl)benzene, and 1,3,5-tri(2-fluorophenyl)benzene.

[0031] As a preferred embodiment of the present invention, the preparation method of the 1,3,5-trisubstituted benzene compound comprises the following steps:

[0032] A nickel catalyst, a phosphorus ligand, zinc powder and anhydrous zinc halide are sequentially added to a reaction tube; the reaction tube is first evacuated and then nitrogen is introduced, and this operation is repeated three times, and then a terminal acetylene compound represented by formula (1) dissolved in an organic solvent is added to the reaction tube through a syringe; the reaction is carried out at 30-110° C. for 1-12 hours, and after the reaction is completed, the mixture is cooled to room temperature; the organic solvent is evaporated under reduced pressure after filtering, and the mixture in the reaction solution is separated and purified by column chromatography to obtain a 1,3,5-trisubstituted benzene compound.

[0033] Beneficial effects of the present invention:

[0034] The present invention uses terminal acetylene compounds as raw materials and a cheap and stable divalent nickel source as a catalyst to efficiently and regioselectively prepare 1,3,5-trisubstituted benzene compounds shown in formula (2). The present invention overcomes the shortcomings of the catalysts in the prior art, such as complex structures and difficulty in synthesis, low selectivity and yield of the products; it has the characteristics of simplicity, mildness, high efficiency and good functional group compatibility, has good application value, and provides a basis for realizing industrial production.

[0035] Definition and explanation of terms

[0036] The term "C 1-20 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. For example, "C 1-12"Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0037] The term "C 6-20 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-12 The term "C 6-12 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-12 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0038] The term "5-20 membered aromatic heterocyclyl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-12 membered aromatic heterocyclyl". The term "5-12 membered aromatic heterocyclyl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition, in each case may be benzo-fused. In particular, the aromatic heterocyclic group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. When the 5-20 membered aromatic heterocyclic group is connected with other groups to form the compound of the present invention, the carbon atom on the 5-20 membered aromatic heterocyclic group ring may be connected with other groups, or the heteroatom on the 5-20 membered aromatic heterocyclic group ring may be connected with other groups. When the 5-20 membered aromatic heterocyclic group is substituted, it may be monosubstituted or polysubstituted. In addition, there is no restriction on the substitution site, for example, the hydrogen connected to the carbon atom on the aromatic heterocyclic group ring may be substituted, or the hydrogen connected to the heteroatom on the aromatic heterocyclic group ring may be substituted. When the aromatic heterocyclic group contains N atoms, the 5-20 membered aromatic heterocyclic group may also be oxidized to its nitrogen oxide.

[0039] The term "C 3-20 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or bridged cycloalkane having 3 to 20 carbon atoms, preferably "C 3-10 The term "Cycloalkyl" 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or a bridged cycloalkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as decalin. The cycloalkyl group may be a spiro ring, such as spiro [3,3] ring, spiro [3,4] ring, spiro [3,5] ring, spiro [4,4] ring, spiro [4,5] ring, spiro [5,5] ring. DETAILED DESCRIPTION

[0040] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0041] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0042] Example 1: Preparation of 1,3,5-tri(4-methylphenyl)benzene

[0043]

[0044] 0.066 g (0.1 mmol) Ni(PPh3)2Cl2, 0.039 g (0.1 mmol) DPPM, 0.013 g (0.2 mmol) zinc powder, and 0.064 g (0.2 mmol) zinc iodide were added to a 25-mL reaction tube in sequence; the reaction tube was first evacuated and then nitrogen was passed through, and this operation was repeated three times. 0.116 g (1 mmol) p-methylphenylacetylene was dissolved in 2 mL acetonitrile and added to the reaction tube with a syringe; the reaction was carried out at 40°C for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the organic solvent was evaporated under reduced pressure. The mixture in the reaction solution was separated and purified by column chromatography to obtain 0.105 g (yield 91%) of the target product 1,3,5-tri(4-methylphenyl)benzene.

[0045] Example 2: Preparation of 1,3,5-tris(4-aminophenyl)benzene

[0046]

[0047] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by p-aminophenylacetylene. Finally, 0.11 g of the target product was obtained (yield 94%, mass ratio of 1,3,5-tris(4-aminophenyl)benzene to 1,2,4-tris(4-aminophenyl)benzene greater than 20:1).

[0048] Example 3: Preparation of 1,3,5-tris(4-dimethylaminophenyl)benzene

[0049]

[0050] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by 4-ethynyl-N,N-dimethylaniline. Finally, 0.137 g of the target product was obtained (yield 92%).

[0051] Example 4: Preparation of 1,3,5-tri(4-bromophenyl)benzene

[0052]

[0053] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by p-bromophenylacetylene, and the reaction temperature was changed from 40° C. to 70° C. Finally, 0.154 g of the target product was obtained (yield 85%).

[0054] Example 5: Preparation of 1,3,5-tributylbenzene

[0055]

[0056] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by 1-hexyne, and the reaction temperature was changed from 40° C. to 70° C. Finally, 0.076 g of the target product was obtained (yield 93%).

[0057] Example 6: Preparation of 1,3,5-tris(trimethylsilyl)benzene

[0058]

[0059] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by trimethylsilylacetylene, and the reaction temperature was changed from 40° C. to 70° C. Finally, 0.09 g of the target product was obtained (yield 92%).

[0060] Example 7: Preparation of 1,3,5-tricyclopropylbenzene

[0061]

[0062] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by ethynylcyclopropane, and the reaction temperature was changed from 40° C. to 70° C. Finally, 0.064 g of the target product was obtained (yield 97%).

[0063] Example 8: Preparation of 1,3,5-tri(3-methylphenyl)benzene

[0064]

[0065] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by 1-ethynyl-3-methylbenzene, and the reaction temperature was changed from 40° C. to 70° C. Finally, 0.109 g of the target product was obtained (yield 94%).

[0066] Example 9: Preparation of 1,3,5-tri(2-fluorophenyl)benzene

[0067]

[0068] The method and steps of Example 1 were followed, except that p-methylphenylacetylene was replaced by 1-ethynyl-2-fluorobenzene, and the reaction temperature was changed from 40° C. to 70° C. Finally, 0.108 g of the target product was obtained (yield 90%).

[0069] Examples 10-14

[0070] The preparation methods of Examples 10-14 are the same as those of Example 1, except that acetonitrile is replaced by the solvents listed in Table 1 below.

[0071] Table 1

[0072] Solvents Target product yield Example 10 THF 41％ Embodiment 11 Dioxane 26％ Example 12 DMF 29％ Embodiment 13 DMA 30％ Embodiment 14 Toluene 65％

[0073] It can be seen from the data in Table 1 that replacing acetonitrile with other solvents will lead to a decrease in the yield of the reaction. Acetonitrile has a higher conversion rate, so acetonitrile is the preferred solvent.

[0074] The above is an exemplary description of the embodiments of the present invention. However, the protection scope of the present invention is not limited to the above embodiments. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a 1,3,5-trisubstituted benzene compound, characterized in that: The method comprises the following steps: Under an inert atmosphere, a nickel catalyst, a phosphorus ligand, zinc powder, a zinc halide, and a terminal alkyne compound represented by formula (1) are reacted in an organic solvent to prepare the 1,3,5-trisubstituted benzene compound; the 1,3,5-trisubstituted benzene compound has a structure represented by formula (2): R1 is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 1-20 Alkyl, C 6-20 Aryl, 5-20 membered aromatic heterocyclic group, C 3-20 Cycloalkyl, -SiR2R3R4; R a Selected from C 1-20 Alkyl, halogen, -NR5R6; R2, R3, R4, R5, R6 are the same or different and are independently selected from H, C 1-20 alkyl; The nickel catalyst is at least one of Ni(PPh3)2Cl2, Ni(dppm)Cl2, Ni(dppe)Cl2, Ni(dppp)Cl2, and Ni(dppb)Cl2; The phosphorus ligand is at least one of PPh3, DPPM, DPPE, DPPP, DPPB, DPPF, and XPhos.

2. The method according to claim 1, characterized in that The halogen is F, Cl, Br or I.

3. The method according to claim 1, characterized in that: R1 is selected from unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 1-12 Alkyl, C 6-12 Aryl, 5-12 membered aromatic heterocyclic group, C 3-10 Cycloalkyl, -SiR2R3R4.

4. The method according to claim 1, characterized in that R a Selected from C 1-12 Alkyl, halogen, -NR5R6.

5. The method according to claim 1, characterized in that R2, R3, R4, R5, R6 are the same or different and are independently selected from H, C 1-12 alkyl.

6. The method according to claim 1, characterized in that R1 is selected from 4-methylphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-bromophenyl, n-butyl, trimethylsilyl, cyclopropyl, 3-methylphenyl or 2-fluorophenyl.

7. The method according to claim 1, characterized in that The terminal acetylene compound represented by formula (1) is selected from p-methylphenylacetylene, p-aminophenylacetylene, 4-ethynyl-N,N-dimethylaniline, p-bromophenylacetylene, 1-hexyne, trimethylsilylacetylene, ethynylcyclopropane, 1-ethynyl-3-methylbenzene or 1-ethynyl-2-fluorobenzene.

8. The method according to claim 1, characterized in that The molar ratio of the nickel catalyst, the phosphorus ligand and the terminal alkyne compound represented by formula (1) is (0.01-1):(0.01-1):

1.

9. The method according to claim 1, characterized in that: The organic solvent is at least one of tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and toluene.

10. The method according to claim 1, characterized in that The molar ratio of the nickel catalyst to the zinc powder is 1:(1-5).

11. The method according to claim 1, characterized in that: The zinc halide is one of ZnCl2, ZnBr2 and ZnI2.

12. The method according to claim 1, characterized in that The molar ratio of the nickel catalyst to the zinc halide is 1:(1-4).

13. The method according to claim 1, characterized in that The reaction temperature is 30-110° C.; the reaction time is 1-12 hours.

14. The method according to claim 1, characterized in that The 1,3,5-trisubstituted benzene compound shown in formula (2) is selected from one of the following compounds: 1,3,5-tri(4-methylphenyl)benzene, 1,3,5-tri(4-aminophenyl)benzene, 1,3,5-tri(4-dimethylaminophenyl)benzene, 1,3,5-tri(4-bromophenyl)benzene, 1,3,5-tributylbenzene, 1,3,5-tri(trimethylsilyl)benzene, 1,3,5-tricyclopropylbenzene, 1,3,5-tri(3-methylphenyl)benzene, and 1,3,5-tri(2-fluorophenyl)benzene.

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