Synthesis method of chiral 3-(1-aryl-2-alkyl) pyridine compound

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a chiral 3-(1-aryl-2-alkyl) pyridine compound. 2-methyl-5-vinylpyridine, 1-(4-bromophenyl) ethyl-1-ketone and 2-bromo-2-methylpropane are subjected to a reaction in the presence of a nickel catalyst (nickel diacetylacetonate) and a nitrogen ligand ((4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S, 4S In the presence of a blue LED (light-emitting diode), 4, 4 'S)-1, 1'-bis (3-tert-butylphenyl)-4, 4 ', 5, 5'-tetrahydro-4, 4 '-bis [(1S)-1-methylpropyl]-2, 2'-bis-4H-imidazole), a reducing agent (N, N-dicyclohexylmethylamine and a 1, 4-dihydropyridine derivative), a photocatalyst (1, 2, 3, 5-tetrakis (carbazole-9-yl)-4, 6-dicyanobenzene), and a catalyst (1, 2, 3, 5-tetrakis (carbazole-9-yl)-4, 6-dicyanobenzene), the blue LED (light-emitting diode) can be used for synthesizing the blue LED. And mixing with an organic solvent (ethylene glycol dimethyl ether and isopropyl ether (1: 1)), and carrying out asymmetric three-component cross-coupling reaction to synthesize (R)-1-(4-(3, 3-dimethyl-1-(6-methylpyridine-3-yl) butyl) phenyl) ethyl-1-ketone as shown in a formula 4. A reduction cross-coupling reaction of carbon-carbon bonds is constructed through a nickel / photooxidation reduction catalytic system, and the method has the advantages of being mild in reaction condition, high in economical efficiency, wide in application range, high in expansibility and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing chiral 3-(1-aryl-2-alkyl)pyridine compounds. Background Art

[0002] Pyridine compounds are important basic structural units in organic synthesis, so the research on this compound has attracted the attention of many scientific researchers. This structure exists in a large number of drug molecules. For example, chlorphenamine (Chlorphenamine Hydrogen Maleate) (Formula A) is a histamine H1 receptor antagonist. It can be used to relieve allergic reactions caused by various reasons by inhibiting the dilation of capillaries caused by histamine and reducing the permeability of capillaries. At the same time, omeprazole (Omeprazole) (Formula B) is a proton pump inhibitor that can specifically act on the site of the proton pump in gastric parietal cells to inhibit H + , K + -ATPase activity, thereby reducing gastric acid secretion. In addition, pyridine compounds also have important applications in the field of pesticides, and can be used as herbicides, insecticides and other multiple purposes. For example, Isoxapyrifop (Formula C) is a heterocyclic oxyphenylpropionic acid herbicide, which mainly inhibits the synthesis of fatty acids. The agent is absorbed by the leaves and conducted to the meristem, inhibiting the growth of the meristem, causing the young tissue to lose green necrosis. Imidacloprid (Formula D) is a neonicotinoid insecticide with broad spectrum, high efficiency, low toxicity, low residue, pests are not easy to develop resistance, and there are multiple effects such as contact killing, stomach poison and systemic absorption. In addition, chiral pyridine compounds play an important role in the field of asymmetric synthesis as ligand-controlled reactions in organic synthesis. Therefore, the synthesis of various pyridine compounds with potential application prospects is of great value in promoting research and practical applications in the field of organic synthesis.

[0003] Summary of the invention

[0004] The invention provides an asymmetric three-component cross-coupling reaction of 2-methyl-5-vinylpyridine, 1-(4-bromophenyl)ethan-1-one and 2-bromo-2-methylpropane under a nickel / light redox catalytic system, which can obtain chiral 3-(1-aryl-2-alkyl)pyridine compounds with biological and pharmacological activities and medicinal values, effectively avoids the use of prefabricated organometallic reagents, equal amounts of bases and stoichiometric oxidants, and synthesizes chiral 3-(1-aryl-2-alkyl)pyridine compounds in a direct and easy-to-operate method.

[0005] The specific plan is as follows:

[0006]

[0007] A method for synthesizing a chiral 3-(1-aryl-2-alkyl)pyridine compound comprises: using 2-methyl-5-vinylpyridine shown in formula 1, 1-(4-bromophenyl)ethan-1-one shown in formula 2, and 2-bromo-2-methylpropane shown in formula 3, and mixing with an organic solvent in the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, a photocatalyst, and a blue LED to carry out an asymmetric three-component cross-coupling reaction to synthesize (R)-1-(4-(3,3-dimethyl-1-(6-methylpyridin-3-yl)butyl)phenyl)ethan-1-one shown in formula 4;

[0008] The method of the invention can realize the one-pot method for generating chiral 3-(1-aryl-2-alkyl)pyridine compounds, reducing the reaction steps, thereby improving the product yield; the raw material acquisition pathways used in the synthesis method are diversified and have high economic benefits.

[0009] Preferably, the reaction is carried out under the protection of an inert gas, argon, which has a good protection effect.

[0010] Preferably, the synthesis occurs in the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, a photocatalyst, and a blue LED.

[0011] Preferably, the transition metal catalyst is a nickel catalyst; the nitrogen ligand is (4S,4'S)-1,1'-bis(3-tert-butylphenyl)-4,4',5,5'-tetrahydro-4,4'-bis[(1S)-1-methylpropyl]-2,2'-bis-4H-imidazole; the reducing agent is N,N-dicyclohexylmethylamine and 1,4-dihydropyridine derivatives (Hantzsch esters); and the photocatalyst is 1,2,3,5-tetrakis(carbazole-9-yl)-4,6-dicyanobenzene.

[0012] Preferably, the nickel catalyst is nickel diacetylacetonate having high catalytic activity.

[0013] Preferably, the organic solvent is a mixed solvent of ethylene glycol dimethyl ether and isopropyl ether (1:1).

[0014] Preferably, in the reaction, the molar ratio of 2-methyl-5-vinylpyridine shown in Formula 1, 1-(4-bromophenyl)ethan-1-one shown in Formula 2, 2-bromo-2-methylpropane shown in Formula 3, the transition metal catalyst and the photocatalyst is: 1-2: 1-2: 1-2: 0.05-0.2: 0.004-0.02; and the reaction temperature is 25°C.

[0015] Preferably, the method of the present invention can generate R-configuration 3-(1-aryl-2-alkyl)pyridine compounds with the following structure:

[0016]

[0017] In the presence of transition metal catalyst nickel diacetylacetonate and nitrogen ligand (4S,4'S)-1,1'-bis(3-tert-butylphenyl)-4,4',5,5'-tetrahydro-4,4'-bis[(1S)-1-methylpropyl]-2,2'-bis-4H-imidazole, styrene, p-bromoacetophenone and tert-butyl bromide underwent a three-component cross-coupling reaction to prepare a chiral 3-(1-aryl-2-alkyl)pyridine compound (R)-1-(4-(3,3-dimethyl-1-(6-methylpyridin-3-yl)butyl)phenyl)ethan-1-one.

[0018] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0019] The raw materials used in the synthesis method of the present invention are all cheap and can be obtained in a variety of ways, thus having high economic benefits;

[0020] The present invention adopts a one-pot synthesis method, which has fewer reaction steps, reduces the loss of raw materials and saves reaction time, thereby improving product yield and reaction efficiency;

[0021] The operation steps required by the present invention are relatively simple, and no extreme heating or cooling is required. The reaction can be performed under normal pressure, which is safe, convenient and low in energy consumption. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The accompanying drawings are hydrogen and carbon nuclear magnetic resonance spectra of the products of each embodiment. The serial numbers of the accompanying drawings correspond to the serial numbers of the embodiments. Figure A is a hydrogen nuclear magnetic resonance spectrum, and Figure B is a carbon nuclear magnetic resonance spectrum. Figure 1A is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1, Figure 1B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 1 is shown in FIG. Specific embodiments

[0024] In order to facilitate the understanding of those skilled in the art, the concept of the present invention is further described below in conjunction with the embodiments. The specific description of the following embodiments is not a limitation of the present invention, but is only for the convenience of those skilled in the art to understand the technical solution. Various raw materials involved in the specification are purchased from the market, or through simple synthesis, other drugs are purchased from Anaiji, Bi De, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K., and the nuclear magnetic resonance spectrometer model is Bruker 400M.

[0025] Example 1

[0026] In a pre-dried photoreaction bottle with a magnet, nickel diacetylacetonate (2.6 mg, 10 mol%), (4S, 4'S)-1,1'-bis(3-tert-butylphenyl)-4,4',5,5'-tetrahydro-4,4'-bis[(1S)-1-methylpropyl]-2,2'-bis-4H-imidazole (5.6 mg, 0.011 mmol), N,N-dicyclohexylmethylamine (58.5 mg, 0.3 mmol), 1,4-dihydropyridine derivative (76.0 mg, 0.2 mmol) and 1,2,3,5-tetrakis(carbazole-9-yl)-4,6-dicyanobenzene (6.4 mg, 8 mol%) were added in sequence, the reaction bottle was transferred to an argon-protected glove box, 1.0 mL of ethylene glycol dimethyl ether and 1.0 mL of isopropyl ether were added thereto, and the mixture was stirred at room temperature for 30 minutes. 1.0 mL of DME solution mixed with 2-methyl-5-vinylpyridine (11.9 mg, 0.1 mmol), 1-(4-bromophenyl)ethan-1-one (39.8 mg, 0.2 mmol), and 2-bromo-2-methylpropane (41.1 mg, 0.3 mmol) was added thereto. The bottle was sealed and taken out of the glove box. The reaction was carried out at room temperature for 24 h under blue LED irradiation. The crude product was separated by silica gel column chromatography using petroleum ether (PE) and ethyl acetate (EA) (petroleum ether: ethyl acetate = 15:1) to obtain the target product (R)-1-(4-(3,3-dimethyl-1-(6-methylpyridin-3-yl)butyl)phenyl)ethan-1-one (27.2 mg, 92% yield, 85% enantiomeric excess). The hydrogen and carbon nuclear magnetic resonance spectra of the product are respectively Figure 1A and Figure 1B , the spectrum data is: 1 H NMR (400MHz, CDCl3) δ: 8.36 (d, J=2.3Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.35 (dd, J=7.8, 2.6Hz, 1H), 7.10 (d, J=8.0Hz , 1H), 4.21 (dd, J=7.5, 5.7Hz, 1H), 2.52 (s, 3H), 2.41 (dd, J=14.0, 7.5Hz, 1H), 2.24 (s, 3H), 1.98 (dd, J=14.0, 5.7Hz, 1H), 0.80 (s, 9H)ppm. 13 C NMR (101MHz, CDCl3) δ: 197.8, 160.9, 151.5, 149.6, 137.2, 135.1, 130.7, 128.6, 128.0, 122.2, 50.1, 48.4, 31.4, 30.0, 26.5, 18.0ppm.

Claims

1. A method for synthesizing a chiral 3-(1-aryl-2-alkyl)pyridine compound, characterized in that: A method for synthesizing a chiral 3-(1-aryl-2-alkyl)pyridine compound comprises: using 2-methyl-5-vinylpyridine shown in Formula 1, 1-(4-bromophenyl)ethan-1-one shown in Formula 2, and 2-bromo-2-methylpropane shown in FIG. 3, and mixing them with an organic solvent in the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, a photocatalyst, and a blue LED to carry out an asymmetric three-component cross-coupling reaction to synthesize (R)-1-(4-(3,3-dimethyl-1-(6-methylpyridin-3-yl)butyl)phenyl)ethan-1-one shown in Formula 4.

2. The synthesis method according to claim 1, characterized in that The synthesis occurs under the conditions of the presence of a transition metal catalyst, a nitrogen ligand, a reducing agent, a photocatalyst, a blue LED and an organic solvent.

3. The synthesis method according to claim 2, characterized in that The transition metal catalyst is a nickel catalyst.

4. The synthesis method according to claim 3, characterized in that The nickel catalyst is nickel diacetylacetonate.

5. The synthesis method according to claim 1, characterized in that The reaction was carried out under the protection of inert gas argon.

6. The synthesis method according to claim 1, characterized in that The nitrogen ligand is (4S, 4'S)-1,1'-bis(3-tert-butylphenyl)-4,4',5,5'-tetrahydro-4,4'-bis[(1S)-1-methylpropyl]-2,2'-bis-4H-imidazole.

7. The synthesis method according to claim 1, characterized in that The organic solvent is a mixed solvent of ethylene glycol dimethyl ether and isopropyl ether (1:1).

8. The synthesis method according to claim 1, characterized in that The photocatalyst is 1,2,3,5-tetrakis(carbazole-9-yl)-4,6-dicyanobenzene.

9. The synthesis method according to claim 1, characterized in that In the reaction, the molar ratio of 2-methyl-5-vinylpyridine shown in formula 1, 1-(4-bromophenyl)ethan-1-one shown in formula 2, 2-bromo-2-methylpropane shown in formula 3, transition metal catalyst and photocatalyst is: 1-2: 1-2: 1-2: 0.05-0.2: 0.004-0.02; and the reaction temperature is 25°C.

10. The synthesis method according to claim 1, characterized in that The 2-methyl-5-vinylpyridine, 1-(4-bromophenyl)ethan-1-one, 2-bromo-2-methylpropane and the product chiral 3-(1-aryl-2-alkyl)pyridine compound are as follows: The invention discloses a method for synthesizing chiral 3-(1-aryl-2-alkyl)pyridine compounds, and belongs to the field of organic synthesis. The present invention uses 2-methyl-5-vinylpyridine shown in Formula 1, 1-(4-bromophenyl)ethan-1-one shown in Formula 2 and 2-bromo-2-methylpropane shown in Formula 3 to mix with an organic solvent in the presence of a transition metal catalyst, a nitrogen ligand and a reducing agent to carry out a reduction cross-coupling reaction to synthesize a chiral 3-(1-aryl-2-alkyl)pyridine compound shown in Formula 4. The synthesis method of the present invention is simple and easy to operate, and is of great significance for synthesizing chiral 3-(1-aryl-2-alkyl)pyridine compounds.

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