A method for synthesizing 2-(3,3-dimethylbutyl)pyridine

Abstract

The application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 2-(3,3-dimethylbutyl)pyridine. 2-vinylpyridine, brominated tertiary butane, a mixed solution of dimethyl ether and isopropyl ether as a reaction system solvent, nickel iodide as a nickel salt, bipyridine as a ligand, dicyclohexylmethylamine as a base in the system, 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine as a reducing agent, a photocatalyst 2,4,5,6-tetrakis(9 ‑ Carbazole) - m-phenylenedinitrile, under the condition of room temperature and nitrogen atmosphere, a reduction cross-coupling reaction is used to synthesize 2-(3,3-dimethylbutyl)pyridine. The application uses inexpensive nickel metal as a catalyst, constructs a cross-coupling reaction of carbon-carbon bond, and has the advantages of mild reaction condition, high economy and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing 2-(3,3-dimethylbutyl)pyridine. Background Technology

[0002] Pyridine compounds are widely found among the most common heterocyclic compounds in natural products, biopharmaceuticals, and organic synthesis. Some natural alkaloids can be prepared from pyridine compounds, such as (+)-dihydropinene, (-)-epidialdihydropinene, and (-)-pinenetanone, which have a piperidine skeleton. Many pyridine derivatives are key components of some drugs; for example, celidipine, with a 1,4-dihydropyridine skeleton similar to NADH, is a common blood pressure regulator. Some chiral cyclic pyridine structures are used to treat HIV, and some methylphenidate structures are used for ADHD and other diseases. In addition, pyridine compounds can also participate in chemical reactions as ligands. The nitrogen atom on the pyridine ring can interact with transition metals to modulate their electronic effects and fix the three-dimensional configuration of metal-ligand complexes for transition metal-catalyzed organic reactions. Given the importance of pyridine compounds and their derivatives, finding green, mild, and simple methods to synthesize pyridine compounds and their derivatives is an important research area in organic chemistry.

[0003] Traditional methods for the direct synthesis of chiral pyridine compounds and their derivatives include asymmetric hydrogenation of heteroaryl hydrocarbons, allylation of 2-benzylpyridine, and cross-coupling reactions of heteroaryl halides. While these methods have yielded significant progress, they still have limitations, such as the potential use of expensive metal catalysts or complex starting materials. In contrast, asymmetric cross-coupling reactions using nickel / visible light synergistic catalysis have seen considerable development in recent years due to their mild reaction conditions and simple operation. Summary of the Invention

[0004] This invention provides a nickel-catalyzed reduction-cross coupling reaction of 2-vinylpyridine with tert-butane bromide to obtain 2-(3,3-dimethylbutyl)pyridine with pharmaceutical value. This method is a direct and easy-to-operate way to synthesize 2-(3,3-dimethylbutyl)pyridine, and the synthesis method is simple and efficient.

[0005] The specific plan is as follows:

[0006]

[0007] A method for synthesizing 2-(3,3-dimethylbutyl)pyridine is disclosed, comprising: using 2-vinylpyridine as shown in Formula 1; tert-butane bromide as shown in Formula 2; and a mixed solution of dimethyl ether and isopropyl ether as the solvent in the reaction system; nickel iodide as the nickel salt; bipyridine as the ligand; dicyclohexylmethylamine as the base in the system; 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine as the reducing agent; and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile as the photocatalyst; and reacting at room temperature for 24 hours to carry out a cross-coupling reaction to synthesize 2-(3,3-dimethylbutyl)pyridine as shown in Formula 3.

[0008] The method of this invention can realize the reductive cross-coupling reaction of nickel-catalyzed 2-vinylpyridine with tert-butane bromide to generate 2-(3,3-dimethylbutyl)pyridine with excellent yield; the raw materials used in the synthesis method are simple and economical.

[0009] Preferably, the reaction is carried out under the protection of the inert gas nitrogen.

[0010] Preferably, the synthesis occurs in the presence of a transition metal catalyst, an achiral nitrogen ligand, a Brønsted base, a photocatalyst, a reducing agent, and an organic solvent.

[0011] Preferably, the transition metal catalyst is a nickel catalyst; the nitrogen ligand is bipyridine; the Brønsted base is dicyclohexylmethylamine; and the photocatalyst is 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile.

[0012] Preferably, the nickel catalyst is nickel iodide.

[0013] Preferably, the organic solvent is dimethyl ether and isopropyl ether.

[0014] Preferably, the molar ratio of 2-vinylpyridine (Formula 1), tert-butane (Formula 2), nickel catalyst, and photocatalyst in the reaction is 1:3:0.1:0.08; and the reaction temperature is 25°C.

[0015] Preferably, the method of the present invention can be used to synthesize 2-(3,3-dimethylbutyl)pyridine containing the following structure:

[0016]

[0017] Under the action of transition metal catalyst nickel iodide and nitrogen ligand bipyridine, 2-vinylpyridine undergoes a cross-coupling reaction with tert-butane bromide to finally prepare 2-(3,3-dimethylbutyl)pyridine.

[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 this invention are all inexpensive and readily available;

[0020] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and increases the yield of the product due to fewer reaction steps.

[0021] The operation steps required by this invention are relatively simple, without the need for extreme heating or cooling, and the reaction can be carried out at room temperature and pressure, making it safe and convenient; Attached Figure Description

[0022] Figure 1A The proton NMR spectrum of the product obtained in Example 1;

[0023] Figure 1B The image shows the carbon NMR spectrum of the product obtained in Example 1. Detailed Implementation

[0024] To facilitate understanding by those skilled in the art, the concept of the present invention is further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All chemical reagents and pharmaceuticals used in this chapter were purchased commercially. For example, anhydrous dimethyl ether and isopropyl ether were purchased from J&K Corporation, and other reagents were purchased from companies such as Bailingwei, Xins, Energie, and Aladdin. The NMR spectra of the samples were obtained using a Jeol 400MHz NMR spectrometer. The gas chromatograph was a Shimadzu 2010Plus. The high-performance liquid chromatograph was an Agilent 1260. Infrared data were obtained from a Thermo Fisher IS10 FT-IR spectrometer. The KBr window used for infrared testing was purchased from an IS10 FT-IR spectrometer (Thermo Fisher). High-resolution mass spectrometry (HRMS) data were measured on a Waters-LC-TOF mass spectrometer (Xevo G2-XS QTof). In the experiment, a 450-455nm, 20W LED was used as the light source for the photoreaction.

[0025] Experimental Example 1

[0026] In a pre-dried Shrek tube equipped with a magnetic stir bar, nickel iodide (3.1 mg, 0.01 mmol), bipyridine (1.7 mg, 0.011 mmol), dicyclohexylmethylamine (58.5 mg, 0.3 mmol), 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine (76.0 mg, 0.3 mmol), and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (6.4 mg, 0.008 mmol) were added sequentially. The reaction flask was transferred to a nitrogen-protected glove box, and 1.0 mL of the reaction solvent was added. The mixture was stirred at room temperature for 30 minutes. Then, 1.0 mL of a dimethyl ether solution of 2-vinylpyridine (10.5 mg, 0.1 mmol) and tert-butyl bromide (41.1 mg, 0.3 mmol) was added. The flask was sealed and removed from the glove box. The reaction was carried out at room temperature for 24 hours under blue LED illumination. The crude product was separated by silica gel column chromatography using petroleum ether (PE) and ethyl acetate (EA) to obtain the target product, 2-(3,3-dimethylbutyl)pyridine (14.6 mg, 90% yield). The proton and carbon NMR spectra of the product were as follows: Figure 1A and Figure 1B The spectral data is as follows: 1 H NMR (400MHz, CDCl3) δ8.53-8.48 (m, 1H), 7.59-7.54 (m, 1H), 7.14 (d, J=7.8Hz, 1H), 7.10-7.05(m, 1H), 2.79-2.70(m, 2H), 1.62-1.57(m, 2H), 0.96(s, 9H)ppm. 13 C NMR (101MHz, CDCl3) δ163.2, 149.2, 136.3, 122.6, 120.8, 44.3, 33.9, 30.5, 29.3ppm.

[0027] The first group of experiments is Example 1, and the corresponding NMR spectrum of the product is as follows: Figure 1A and Figure 1B .

[0028] The table lists the structural formulas of the products in Example 1, and the last column lists the yields of the products in Example 1.

[0029]

Claims

1. A method for synthesizing 2-(3,3-dimethylbutyl)pyridine, characterized in that: 2-(3,3-dimethylbutyl)pyridine of Formula 3 was synthesized by cross-coupling reaction of vinylpyridine of Formula 1 and tert-butane of Formula 2 under room temperature conditions with nickel catalyst, nitrogen ligand, base, reducing agent, photocatalyst, and organic solvent. The nickel catalyst is nickel iodide; the nitrogen ligand is bipyridine; the base is dicyclohexylmethylamine; the reducing agent is 2,6-dimethyl-3,5-diethyl-1,4-dihydropyridine; and the photocatalyst is 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile.

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

3. The synthesis method according to claim 1, characterized in that, The organic solvents mentioned are dimethyl ether and isopropyl ether.

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