A method for synthesizing tetrahydroquinoline compounds using pinacol diboronate as a reducing agent.

Abstract

This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 2,9-dimethyl-1,2,3,4-tetrahydro-1,10-phenanthroline. The method includes: using 2,9-dimethyl-1,10-phenanthroline as a raw material, under a normal pressure carbon dioxide atmosphere, using pinacol diborate as a reducing agent and N,N-dimethylacetamide as an organic solvent, mixing the above components and carrying out a reductive hydrogenation reaction to produce 2,9-dimethyl-1,2,3,4-tetrahydro-1,10-phenanthroline as shown in formula (2). This invention provides a novel method for synthesizing tetrahydroquinoline compounds using pinacol diborate as a reducing agent under normal pressure carbon dioxide conditions. This method has advantages such as mild reaction conditions, no metal residue, environmental friendliness, high reaction selectivity, and a short synthesis procedure, making it suitable for the efficient preparation of target compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing tetrahydroquinoline compounds by using pinacol diboronate as a reducing agent through a reductive hydrogenation reaction. Background Technology

[0002] Tetrahydroquinoline compounds, as core structural units and key synthetic precursors of many alkaloids, are widely used in drug molecule design and synthesis, and are important research objects in the fields of organic synthesis and medicinal chemistry. For example, Galipinine (Formula A) is a naturally derived tetrahydroquinoline antimalarial drug. Its mechanism of action mainly involves interfering with the metabolic processes of Plasmodium, inhibiting the growth and proliferation of Plasmodium, and has a significant preventive and therapeutic effect on malaria. Kairine (Formula B) is an early synthesized tetrahydroquinoline antipyretic and analgesic. It exerts its antipyretic effect by inhibiting the synthesis of central prostaglandins and was once used for the symptomatic treatment of infectious fever such as typhoid fever. Nicanoprol (Formula C) is a tetrahydroquinoline antiarrhythmic drug. As a sodium channel blocker, it is used to treat supraventricular and ventricular arrhythmias by inhibiting the influx of sodium ions into myocardial cells, slowing conduction velocity, and prolonging the effective refractory period. Salsolinol (formula D) is an endogenous tetrahydroisoquinoline neuroactive substance that participates in the pathogenesis of neurodegenerative diseases such as Parkinson's disease by regulating dopaminergic neuronal signaling pathways and autophagy. It also exhibits potential neuroprotective effects at low concentrations. Overall, tetrahydroquinolines possess diverse structures and broad-spectrum biological activities, combining the structural advantages of natural product skeletons with the flexibility of artificial modification. Therefore, developing efficient and controllable reductive hydrogenation methods for the synthesis of tetrahydroquinolines has significant research value and practical implications in organic synthesis and drug development.

[0003]

[0004] Summary of the Invention

[0005] This invention provides a method for preparing tetrahydroquinoline compounds by reductive hydrogenation of 2,9-dimethyl-1,10-phenanthroline under ambient carbon dioxide conditions. Tetrahydroquinoline compounds have shown significant application potential in drug development and pesticide manufacturing, primarily due to their unique nitrogen-containing heterocyclic skeleton, which endows these molecules with excellent biological activity and good structural modifiability. Based on these characteristics, the method described in this invention has significant application value and broad development prospects in organic synthesis, heterocyclic chemistry, and green catalysis.

[0006] The specific plan is as follows:

[0007]

[0008] A method for synthesizing tetrahydroquinoline compounds by reductive hydrogenation involves using 2,9-dimethyl-1,10-phenanthroline (Formula 1) in a mixture with an organic solvent under normal pressure and the action of carbon dioxide and a reducing agent to synthesize tetrahydroquinoline compounds (Formula 2).

[0009] The method described in this invention enables the one-step synthesis of tetrahydroquinoline compounds. The reaction process is simple, the reaction conditions are mild and easy to control, and the operation is convenient. Furthermore, this method significantly reduces the environmental burden during the reaction process, exhibiting green and environmentally friendly characteristics. Moreover, the reaction system leaves no metal residue, avoiding potential contamination of the product by metal catalysts. This makes it suitable for applications in the pharmaceutical and fine chemical industries where metal residue requirements are high.

[0010] Preferably, the synthesis takes place under normal pressure in the presence of carbon dioxide, a reducing agent, and an organic solvent.

[0011] Preferably, the atmospheric pressure of carbon dioxide is 1 atm, that is, the pressure of carbon dioxide at one atmosphere.

[0012] Preferably, the reducing agent is pinacol diboronate.

[0013] Preferably, the organic solvent is N,N-dimethylacetamide.

[0014] Preferably, the reaction temperature is 80°C.

[0015] Preferably, the molar ratio of 2,9-dimethyl-1,10-phenanthroline and pinacol diboronic acid ester shown in Formula 1 in the reaction is 1:2.

[0016] Preferably, using the method of the present invention, tetrahydroquinoline compounds with the following structures can be synthesized:

[0017]

[0018] This invention describes the reductive hydrogenation reaction of 2,9-dimethyl-1,10-phenanthroline in N,N-dimethylacetamide solvent under normal pressure and carbon dioxide atmosphere, using pinacol diboronate as a reducing agent, to finally obtain tetrahydroquinoline compounds.

[0019] By adopting the technical solution of the present invention, the following beneficial effects can be achieved:

[0020] The raw materials used in the synthesis method of this invention are widely available and inexpensive, resulting in good economic benefits and making it suitable for large-scale production applications.

[0021] This invention employs a one-pot reaction, with only one synthesis step, making it simple to operate and highly efficient in utilizing raw materials. This helps to improve the yield of the target product and reduce material losses caused by intermediate processing steps.

[0022] The reducing agent used in this invention, pinacol diboronate, has a relatively low cost and low toxicity. Compared with traditional reducing agents such as metal hydrides, it has better operational safety and environmental compatibility.

[0023] This invention is simple to operate, with mild reaction conditions. It can be carried out smoothly under normal pressure carbon dioxide conditions without the need for high-pressure equipment or special gas devices. It is safe and convenient, and the reaction process has little environmental pollution, which is in line with the development concept of green chemistry. Attached Figure Description

[0025] The attached figures are the proton and carbon NMR spectra of the products of each embodiment. The figures are numbered according to the embodiment numbers. Figure 1 This is the proton NMR spectrum. Figure 2 This is a carbon NMR spectrum. like Figure 1 The above is the proton NMR spectrum of the product obtained in Example 1. Figure 2 The image shows the carbon NMR spectrum of the product obtained in Example 1. Specific Implementation

[0026] To facilitate understanding by those skilled in the art, the concept of the present invention will be 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 raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bidex, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta, or J&K. The NMR spectra of the samples were obtained using a Jeol 400MHz NMR spectrometer.

[0027] Example 1

[0028] In a pre-dried Shrek tube equipped with a magnetic dome, 2,9-dimethyl-1,10-phenanthroline (125 mg, 0.6 mmol) and pinacol diborate (304.7 mg, 1.2 mmol) were added sequentially. Carbon dioxide gas was then introduced into the Shrek tube, followed by the addition of 1.2 mL of N,N-dimethylacetamide. The reaction was heated for 24 h. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the target product 2,9-dimethyl-1,2,3,4-tetrahydro-1,10-phenanthroline (90% yield). The proton and carbon NMR spectra of the product were obtained as follows. Figure 1 and Figure 2 The spectral data is as follows: 1 H NMR (400MHz, Chloroform-d) δ: 7.89 (d, J=8.4Hz, 1H), 7.17 (d, J=8.3Hz, 1H), 7.10 (d, J =8.2Hz, 1H), 6.94 (d, J = 8.2Hz, 1H), 5.85 (s, 1H), 3.58 (m, J = 9.4, 6.3, 2.8Hz, 1H), 3.00 ( m, J=16.7, 11.0, 5.8Hz, 1H), 2.86 (m, J=16.6, 5.4, 3.7Hz, 1H), 2.68 (s, 3H), 2.04 (m, J=1 2.7, 6.0, 3.1Hz, 1H), 1.72 (m, J=12.7, 10.8, 9.6, 5.4Hz, 1H), 1.38 (d, J=6.3Hz, 4H)ppm. 13 C NMR (101MHz, Chloroform-d) δ: 156.73, 141.00, 137.72, 136.96, 128.77, 126.25, 122.23, 117.57, 114.22, 47.56, 30.98, 27.61, 26.13, 23.46ppm.

Claims

1. A method for synthesizing tetrahydroquinoline compounds by quinoline reduction hydrogenation, characterized in that: 2,9-dimethyl-1,10-phenanthroline (Formula 2) was synthesized by reductive hydrogenation of 2,9-dimethyl-1,2,3,4-tetrahydro-1,10-phenanthroline (Formula 2) in the presence of carbon dioxide and a reducing agent and an organic solvent.

2. The synthesis method according to claim 1, characterized in that, The synthesis is carried out under normal pressure in the presence of carbon dioxide, a reducing agent, and an organic solvent.

3. The synthesis method according to claim 1, characterized in that, The aforementioned atmospheric pressure carbon dioxide pressure is 1 atm, which is the pressure of carbon dioxide at one atmosphere.

4. The synthesis method according to claim 1, characterized in that, The reducing agent is pinacol diboronate.

5. The synthesis method according to claim 1, characterized in that, The organic solvent is N,N-dimethylacetamide.

6. The synthesis method according to claim 1, characterized in that, In the reaction, the molar ratio of 2,9-dimethyl-1,10-phenanthroline and pinacol diboronic acid ester shown in Formula 1 is 1:

2.

7. The synthesis method according to claim 1, characterized in that, The reaction temperature is 80℃.

8. The synthesis method according to claim 1, characterized in that, The 2,9-dimethyl-1,10-phenanthroline and its product 2,9-dimethyl-1,2,3,4-tetrahydro-1,10-phenanthroline are shown in the table below. This invention discloses a method for synthesizing tetrahydroquinoline compounds by quinoline reduction hydrogenation, belonging to the field of organic synthesis. This invention synthesizes 2,9-dimethyl-1,10-phenanthroline (Formula 1) by reductive hydrogenation with an organic solvent under the action of carbon dioxide and a reducing agent, as shown in Formula 1. The synthesis method is simple and convenient, and is of great significance for the efficient preparation of tetrahydroquinoline compounds.

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