Preparation method of c3-thioquinoline derivative under green reaction system

Abstract

The application discloses a kind of preparation method of C3-thioquinoline derivative under green reaction system belonging to the technical field of organic synthesis.The method is as follows: into reactor, the molar ratio of substituted benzoxazinone substance and substituted diphenyl disulfide compound is 1:3, tetraethylammonium hexafluorophosphate is added as electrolyte, nitromethane is added as solvent, and the reaction is promoted by electrocatalytic strategy;After the reaction is completed, the crude product is concentrated using a rotary evaporator, and then the target product is separated by silica gel column chromatography.The synthesis method of C3-thioquinoline derivative provided by the application is scientific and reasonable, has the characteristics of green and environmental protection, does not need metal catalyst;The reaction temperature is room temperature, instead of high temperature reaction condition;Synthesis method is simple;Product is easy to purify and the like.The reaction equation is as follows:

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing C3-thioquinoline derivatives in a green reaction system. Background Technology

[0002] C3-thioquinoline compounds are widely found in natural compounds, drugs, and bioactive molecules. For example, 3-phenylthioquinoline derivatives have CB2 agonist activity and therapeutic effects on osteoporosis, inflammation, pain relief, and cancer treatment. Bioorg. Med. Chem. 2011, 19 (939-950.) Furthermore, certain N-alkyl-3-phenylthioquinoline salts exhibit enhanced activity against AIDS-associated fungal pathogens. Eur. J. Med. Chem. 2011, 46 (1789-1797.) The research group of Qiu Renhua at Hunan University reported a method for synthesizing C3-thioquinoline derivatives: the C3-thioquinoline derivatives were synthesized through the selective thioetherification of quinoline with disulfide under nickel catalysis. ACS Catal. 2023, 13 (9753-9765.) The reaction formula is shown in Equation I:

[0003] Formula I The above methods have obvious drawbacks, such as multi-step reactions, the use of metal catalysts and chemical oxidants. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies for synthesizing C3-thioquinoline derivatives, this invention provides a method for preparing C3-thioquinoline derivatives via electrocatalysis in a green reaction system.

[0005] Electrocatalytic synthesis reactions have many significant advantages: they can avoid the use of toxic or difficult-to-handle catalysts, electrons are green reagents, the reaction products are highly pure and easy to separate, and they cause almost no pollution to the environment; in electrocatalytic reactions, the reaction rate can be controlled by changing the electrode voltage or current to avoid the occurrence of side reactions, thereby improving the selectivity and yield of the target product.

[0006] A method for preparing C3-thioquinoline derivatives in a green reaction system is characterized by the following steps: A substituted benzoxazinone compound and a substituted diphenyl disulfide compound are added to a reactor in a molar ratio of 1:3; tetraethylammonium hexafluorophosphate is added as an electrolyte; nitromethane is added as a solvent; and the reaction is promoted by an electrocatalytic strategy. After the reaction is complete, the crude product is concentrated using a rotary evaporator, and then separated by silica gel column chromatography to obtain the target product. The chemical process is shown in reaction formula II.

[0007] Formula II R 1 The substituent group is selected from hydrogen, methyl, fluorine and R 2 Selected from phenyl and R 3 Selected from phenyl; or R 1 Selected from hydrogen and R 2 Selected from p-methoxyphenyl, tert-butyl, n-butyl and R 3 Selected from phenyl; R 1 The substituent group is selected from hydrogen and R 2 Selected from phenyl and R 3 Selected from methyl, methoxy, fluorine, and chlorine.

[0008] The preparation method described above uses a current of 16 mA, graphite felt as the positive and negative electrode materials, room temperature, and a reaction time of 4.5 h.

[0009] The beneficial effects of this invention are as follows: The method for synthesizing C3-thioquinoline derivatives provided by this invention is scientific and reasonable, and provides a new route for synthesizing C3-thioquinoline derivatives. Through this method, C3-thioquinoline derivatives with multiple substituents are obtained. Its characteristics are: the synthesis route is green and environmentally friendly, requiring no metal catalyst; the reaction temperature is room temperature, replacing high-temperature reaction conditions; the synthesis method is simple; and the product is easy to purify. Attached Figure Description

[0010] Figure 1 The NMR spectrum of compound 3ba prepared in Example 2; Figure 2 The NMR spectrum of compound 3fa prepared in Example 6; Figure 3 The NMR spectrum of compound 3ad prepared in Example 9. Detailed Implementation

[0011] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments: Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0012] Example 1 Preparation of C3-thioquinoline derivative 3aa

[0013] 4-Phenylacetylbenzoxazinone 1a (0.2 mmol, 49.5 mg), diphenyl disulfide 2a (0.6 mmol, 131.0 mg), and tetraethylammonium hexafluorophosphate (0.4 mmol, 110.1 mg) were added to a 10 mL diaphragm-free electrolyzer. Both the cathode and anode electrodes were graphite felt electrodes (1 cm x 1 cm x 0.5 cm). The system was then purged with nitrogen, and nitromethane (5.0 mL) was added. Electrolysis was carried out at a constant current of 16 mA at room temperature for 4.5 h. After the reaction was complete, the solvent was removed using a rotary evaporator to obtain the crude product. The crude product was separated by column chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate = 20 / 1), and the solvent was removed again using a rotary evaporator to obtain the target product, C3-thioquinoline derivative 3aa, with a yield of 66%.

[0014] Spectral analysis data 3aa: 1 H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.72(dd, J = 7.7, 1.9 Hz, 2H), 7.66 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.59 – 7.55(m, 3H), 7.54 – 7.45 (m, 4H), 7.44 – 7.34 (m, 3H); 13 C NMR (125 MHz, CDCl3) δ159.2, 146.4, 140.6, 137.0, 135.8, 129.9, 129.4, 129.2, 129.0, 129.0, 128.9,128.7, 128.4, 128.2, 128.1, 126.8, 126.6.

[0015] Example 2 Replace 1a in Example 1 with 1b, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0016]

[0017] Spectral analysis data 3ba: 1 H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.6 Hz, 1H), 7.75 – 7.69 (m,3H), 7.51 – 7.43 (m, 4H), 7.40 – 7.30 (m, 6H), 2.49 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 157.9, 144.9, 140.1, 137.7, 136.0, 133.6, 133.2, 131.7, 131.2,129.6, 129.2, 129.0, 128.7, 128.3, 128.2, 127.7, 125.5, 22.1.

[0018] Example 3 Replace 1a in Example 1 with 1c, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0019]

[0020] Spectral analysis data 3ca: 1 H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 9.2, 5.3 Hz, 1H), 7.72 (d, J =5.7 Hz, 2H), 7.61 (s, 1H), 7.52 – 7.45 (m, 3H), 7.45 – 7.38 (m, 6H), 7.19(dd, J = 8.9, 2.8 Hz, 1H); 13 C NMR (125 MHz, CDCl3) δ 162.0, 159.5, 157.6,143.0, 139.3, 134.1, 133.9, 133.8, 133.6, 132.3, 132.2, 131.8, 131.7, 129.9,129.1, 129.0, 129.0, 128.4, 128.3, 125.4, 119.4, 119.1, 109.7, 109.5.

[0021] Example 4 Replace 1a in Example 1 with 1d, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0022]

[0023] Spectral analysis data 3da: 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 1H), 7.77 – 7.70 (m,3H), 7.67 – 7.56 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.42 – 7.34 (m, 5H), 7.05 – 6.99 (m, 2H), 3.88 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 160.2, 158.4, 146.2,135.9, 133.5, 133.3, 132.2, 131.5, 130.7, 129.7, 129.3, 129.2, 128.4, 127.5,126.7, 126.6, 113.6, 55.4.

[0024] Example 5 Replace 1a in Example 1 with 1e, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0025]

[0026] Spectral analysis data 3ea: 1 H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.65(ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.46 – 7.42 (m,1H), 7.36 (d, J = 4.3 Hz, 4H), 7.32 (q, J = 4.2 Hz, 1H), 3.14 – 3.08 (m, 2H), 1.85 – 1.76 (m, 2H), 1.47 (h, J = 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13CNMR (125 MHz, CDCl3) δ 8.04 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.65 (ddd, J =8.4, 6.8, 1.5 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.36(d, J = 4.3 Hz, 4H), 7.32 (q, J = 4.2 Hz, 1H), 3.14 – 3.08 (m, 2H), 1.85 –1.76 (m, 2H), 1.47 (h, J = 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0027] Example 6 Replace 1a in Example 1 with 1f, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0028]

[0029] Spectral analysis data 3fa: 1 H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.64(ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.54 (dt, J = 7.3, 1.9 Hz, 2H), 7.43 (d, J =7.2 Hz, 2H), 7.30 (d, J = 4.2 Hz, 3H), 1.67 (s, 9H); 13 C NMR (125 MHz, CDCl3) δ8.03 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.64 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H),7.54 (dt, J = 7.3, 1.9 Hz, 2H), 7.43 (d, J= 7.2 Hz, 2H), 7.30 (d, J = 4.2Hz, 3H), 1.67 (s, 9H).

[0030] Example 7 Replace 2a in Example 1 with 2b, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0031]

[0032] Spectral analysis data 3ab: 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.2Hz, 2H), 7.67 – 7.56 (m, 3H), 7.54 – 7.43 (m, 4H), 7.34 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 2.39 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 158.3,145.9, 139.7, 139.0, 134.5, 134.2, 132.7, 130.6, 129.3, 129.1, 129.0, 129.0,128.8, 128.2, 127.7, 126.8, 126.5, 21.3.

[0033] Example 8 Replace 2a in Example 1 with 2c, and keep the other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0034]

[0035] Spectral analysis data 3ac: 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 7.79 – 7.74 (m,2H), 7.62 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.56 (dd, J= 8.2, 1.4 Hz, 1H),7.55 – 7.39 (m, 7H), 6.98 – 6.92 (m, 2H), 3.85 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 160.6, 157.7, 145.7, 139.6, 136.9, 134.0, 133.1, 129.3, 129.2,129.1, 128.9, 128.4, 127.8, 126.9, 126.6, 122.3, 115.6, 55.5.

[0036] Example 9 Replace 2a in Example 1 with 2d, and keep the other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0037]

[0038] Spectral analysis data 3ad: 1 H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H), 7.73 – 7.69 (m,3H), 7.68 – 7.59 (m, 2H), 7.55 – 7.43 (m, 4H), 7.42 – 7.33 (m, 2H), 7.10 –7.02 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 164.0, 162.3, 158.4, 146.1, 139.5,136.2, 136.2, 135.2, 132.1, 129.5, 129.4, 129.2, 129.1, 128.4, 128.1, 128.1,127.7, 127.2, 126.7.

[0039] Example 10 Replace 2a in Example 1 with 2e, and keep other conditions the same as in Example 1. The experimental results are shown in Table 1.

[0040]

[0041] Spectral analysis data 3ae: 1 H NMR (500 MHz, CDCl3) δ 8.13 (d, J= 8.5 Hz, 1H), 7.85 (s, 1H), 7.71– 7.64 (m, 4H), 7.54 – 7.45 (m, 4H), 7.32 – 7.25 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ 159.0, 146.4, 139.6, 136.7, 134.6, 134.4, 132.2, 130.7, 129.9, 129.7, 129.5, 129.2, 129.0, 128.3, 127.7, 127.2, 126.8.

[0042] Table 1

[0043]

Claims

1. A method for preparing C3-thioquinoline derivatives in a green reaction system, characterized in that, A substituted benzoxazinone compound and a substituted diphenyl disulfide compound were added to a reactor in a molar ratio of 1:

3. Tetraethyl hexafluorophosphate was added as an electrolyte and nitromethane was added as a solvent. The reaction was promoted by an electrocatalytic strategy. After the reaction was completed, the crude product was concentrated by a rotary evaporator and then separated by silica gel column chromatography to obtain the target product. The chemical process is shown in the reaction equation: ； R 1 The substituent group is selected from hydrogen, methyl, fluorine and R 2 Selected from phenyl and R 3 Selected from phenyl; or R 1 Selected from hydrogen and R 2 Selected from p-methoxyphenyl, tert-butyl, n-butyl and R 3 Selected from phenyl; or R 1 The substituent group is selected from hydrogen and R 2 Selected from phenyl and R 3 Selected from methyl, methoxy, fluorine, and chlorine.

2. The preparation method according to claim 1, characterized in that: The current was 16 mA, the positive and negative electrode materials for electrocatalysis were graphite felt, the reaction temperature was room temperature, and the reaction time was 4.5 h.

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