Synthetic method of quinoxaline-2 (1H)-ketone derivative containing SF5 group

Abstract

The invention discloses a synthesis method of a quinoxaline-2 (1H)-ketone derivative containing an SF5 group, which comprises the following specific synthesis steps: taking a quinoxaline-2 (1H)-ketone compound 1 and a styrene compound 2 as reaction raw materials, taking SF5Cl as a pentafluorosulfenyl reagent, taking a halogenated hydrocarbon solvent as a reaction solvent, and reacting under blue light irradiation and argon atmosphere to obtain the quinoxaline-2 (1H)-ketone derivative containing the SF5 group. The quinoxaline-2 (1H)-ketone derivative 3 containing the SF5 group is obtained. The method is simple to operate, mild in condition, good in functional group tolerance and high in yield, and the quinoxaline-2 (1H)-ketone derivative containing the SF5 group can be conveniently obtained.

Description

Technical Field

[0002] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for synthesizing quinoxaline-2(1H)-one derivatives containing SF5 groups. Background Technology

[0004] Pentafluorosulfonyl (-SF5) is also known as "super CF3" due to its strong electronegativity, large steric hindrance, good lipophilicity and stability, and its potential as a... t The prominent properties of Bu or CF3 groups, such as their potential (bio)electron isosteres, have led to their widespread application in various fields, including medicine, agrochemicals, and materials science. Therefore, developing efficient and practical organic synthesis methods to construct functional pentafluorosulfur compounds is of great significance.

[0005] Quinoxaline-2(1H)-one is an important N-heteroaromatic hydrocarbon, and due to its significant biological activities, such as antifungal and anticancer properties, it has prominent applications in medicinal chemistry. This invention utilizes a three-component coupling strategy involving the bifunctionalization of olefins to disclose for the first time a general method for preparing this structure via the direct C5-fluorosulfonation reaction of styrene with SF5Cl and quinoxaline-2(1H)-one. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing quinoxaline-2(1H)-one derivatives containing SF5 groups. This method has the advantages of simple operation, mild reaction conditions, short reaction time, and easy implementation, and provides methodological support for further screening of highly bioactive alkyl pentafluorosulfur compounds.

[0008] To achieve the above objectives, this invention employs the following technical solution to synthesize a quinoxaline-2(1H)-one derivative 3 containing an SF5 group. The specific synthesis steps are as follows: using quinoxaline-2(1H)-one compound 1 and styrene compound 2 as reactants, SF5Cl as a pentafluorosulfurizing reagent, and a haloalkane solvent as the reaction solvent, the reaction is carried out under blue light irradiation and an argon atmosphere to obtain the target product, a quinoxaline-2(1H)-one derivative 3 containing an SF5 group. The reaction equation for the synthesis process is as follows:

[0009]

[0010] The structural formula of quinoxaline-2(1H)-ketone compound 1 is as follows:

[0011]

[0012] The structural formula of styrene compound 2 is:

[0013]

[0014] The structural formula of quinoxaline-2(1H)-one derivative 3 containing the SF5 group is as follows:

[0015]

[0016]

[0017] Furthermore, the halohydrocarbon solvent is specifically dichloromethane.

[0018] Furthermore, the molar ratio of the quinoxaline-2(1H)-one compound 1, the styrene compound 2, and SF5Cl is 1:3:3.

[0019] Furthermore, the synthesis process was carried out at room temperature (approximately 25°C).

[0020] Furthermore, the reaction process was detected using conventional detection methods in the art (such as TLC, NMR or HPLC), and the reaction endpoint was generally defined as the absence of starting material points detected by TLC, with a reaction time of 5 hours.

[0021] The positive advancements and beneficial effects of this invention are as follows: Using inexpensive and readily available quinoxaline-2(1H)-one compounds and styrene compounds as raw materials, and utilizing SF5Cl as a pentafluorosulfurizing reagent, this invention synthesizes quinoxaline-2(1H)-one derivatives containing SF5 groups under very mild conditions and with excellent yields under blue light irradiation and an argon atmosphere. This provides a new and efficient strategy for the synthesis of pentafluorosulfur compounds. This invention is simple to operate, operates under mild conditions, exhibits good functional group tolerance, and achieves high yields, facilitating the preparation of quinoxaline-2(1H)-one compounds containing SF5 groups. Attached Figure Description

[0023] Figure 1 The above is the 1H NMR spectrum of compound 3a in Example 1.

[0024] Figure 2 The image shows the carbon NMR spectrum of compound 3a from Example 1.

[0025] Figure 3 The NMR fluorine spectrum of compound 3a in Example 1 is shown.

[0026] Figure 4 The above is the 1H NMR spectrum of compound 3b from Example 2.

[0027] Figure 5 The image shows the carbon NMR spectrum of compound 3b from Example 2.

[0028] Figure 6 The NMR fluorine spectrum of compound 3b in Example 2 is shown.

[0029] Figure 7 The above is the 1H NMR spectrum of compound 3c in Example 3.

[0030] Figure 8 The image shows the carbon NMR spectrum of compound 3c in Example 3.

[0031] Figure 9 The NMR fluorine spectrum of compound 3c in Example 3 is shown.

[0032] Figure 10 The image shows the 1H NMR spectrum of compound 3d in Example 4.

[0033] Figure 11 The image shows the carbon NMR spectrum of compound 3d in Example 4.

[0034] Figure 12 The NMR fluorine spectrum of compound 3d in Example 4 is shown.

[0035] Figure 13 The above is the 1H NMR spectrum of compound 3e in Example 5.

[0036] Figure 14 The image shows the carbon NMR spectrum of compound 3e from Example 5.

[0037] Figure 15 The NMR fluorine spectrum of compound 3e in Example 5 is shown. Detailed Implementation

[0039] The present invention will now be described in detail through specific embodiments, but this does not limit the invention to the scope of the embodiments described. In the following embodiments, experimental methods without specific conditions are performed according to conventional methods and conditions, or as selected according to the product instructions.

[0040] Example 1

[0041] Preparation of quinoxaline-2(1H)-one (3a) containing an SF5 group; the structural formulas of compounds 2a and 3a are as follows:

[0042]

[0043] Preparation method: Under an argon atmosphere, a 2 mL solution of DCM containing substrate 1 (0.2 mmol, 1.0 equiv, 32.0 mg) was placed in a 20 mL sealed tube. Substrate 2a (0.6 mmol, 3.0 equiv, 62.4 mg) and SF5Cl reagent (0.6 mmol, 3.0 equiv, 0.1 M n-hexane solution) were added. The reaction tube was then sealed, and the reaction mixture was stirred for 5 h at room temperature under blue LED irradiation (36 W, 450 nm, approximately 5 cm from the reaction tube). After the reaction was completed by TLC, 10 mL of water was added to terminate the reaction, and the reaction mixture was extracted three times with ethyl acetate (15 mL). The combined organic layers were washed with saturated NaCl aqueous solution and dried with anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1, V / V) to obtain product 3a, 62.5 mg, containing an SF5 group, with a yield of 80%. Its melting point, NMR, and high-resolution mass spectrometry information are as follows: mp: 142-144 ℃. 1 H NMR (400 MHz, CDCl3): δ 7.94(dd, J = 8.0, 1.6 Hz, 1H), 7.54 (td, J = 8.0, 1.2 Hz, 1H), 7.44 (d, J = 7.6Hz, 2H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 7.32-7.20 (m, 4H), 5.50 (d, J =10.0, 3.6 Hz, 1H), 5.21-5.08 (m, 1H), 4.12-3.98 (m, 1H), 3.63 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 157.3, 153.9, 137.9, 133.2, 132.2, 130.5, 130.2, 129.0,128.5, 127.9, 123.8, 113.7, 73.5 (p, J = 12.4 Hz), 44.0 (p, J = 3.7 Hz), 29.3; 19 F NMR (376 MHz, CDCl3): δ 85.3 (p, J = 144.0 Hz, 1F), 65.9 (d, J =144.0 Hz, 4F); HRMS (ESI): calcd for C 17 H 16 F5N2OS [M+H]+ : 391.0898, found:391.0889.

[0044] Example 2

[0045] Preparation of quinoxaline-2(1H)-one (3b) containing an SF5 group; the structural formulas of compounds 2b and 3b are as follows:

[0046]

[0047] The preparation method was the same as in Example 1, except that the reactant amounts were modified as follows: compound 2b (0.6 mmol, 3.0 equiv, 70.8 mg). Other conditions were the same as in Example 1. The final product was compound 3b, 67.1 mg, with a yield of 83%. Its melting point, NMR, and high-resolution information are as follows: mp: 150-152 °C. 1 H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 8.0,1.2 Hz, 1H), 7.54 (td, J = 8.0, 1.2 Hz, 1H), 7.40-7.24 (m, 4H), 7.10 (d, J =8.0 Hz, 2H), 5.45 (dd, J = 10.0, 3.6 Hz, 1H), 5.17-5.10 (m, 1H), 4.10-4.00(m, 1H), 3.62 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 157.5, 153.9, 137.7, 134.9,133.2, 132.3, 130.4, 130.2, 129.7, 128.4, 123.8, 113.7, 73.6 (p, J = 12.4Hz), 43.7 (p, J = 3.6 Hz), 29.2, 21.1; 19 F NMR (376 MHz, CDCl3): δ 85.4 (p, J= 144.0 Hz, 1F), 65.9 (d, J = 144.0 Hz, 4F); HRMS (ESI): calcd forC 18 H 18 F5N2OS [M+H] + : 405.1055, found: 405.1047.

[0048] Example 3

[0049] Preparation of quinoxaline-2(1H)-one (3c) containing an SF5 group; the structural formulas of compounds 2c and 3c are as follows:

[0050]

[0051] The preparation method was the same as in Example 1, except that the reactant amounts were modified as follows: compound 2c (0.6 mmol, 3.0 equiv, 82.8 mg), and other conditions were the same as in Example 1. The final product was 3c, 75.0 mg, with a yield of 84%. Its melting point, NMR, and high-resolution information are as follows: mp: 155-157 °C. 1 H NMR (400 MHz, CDCl3): δ 7.94 (dd, J = 8.0, 1.2Hz, 1H), 7.54 (td, J = 8.4, 1.2 Hz, 1H), 7.39-7.25 (m, 6H), 5.48 (dd, J =10.4, 2.8 Hz, 1H), 5.24-5.12 (m, 1H), 4.10-3.97 (m, 1H), 3.64 (s, 3H), 1.25(s, 9H); 13 C NMR (101 MHz, CDCl3): δ 157.4, 154.0, 150.8, 134.8, 133.2, 132.3,130.4, 130.2, 128.1, 126.0, 123.8, 113.7, 73.5 (p, J = 12.4 Hz), 43.5 (p, J =3.6 Hz), 34.5, 31.3, 29.2; 19 F NMR (376 MHz, CDCl3): δ 85.5 (p, J = 144.0 Hz, 1F), 65.7 (d, J = 144.0 Hz, 4F); HRMS (ESI): calcd for C 21 H 24 F5N2OS [M+H] + :447.1524, found: 447.1522.

[0052] Example 4

[0053] Preparation of quinoxaline-2(1H)-one (3d) containing an SF5 group; the structural formulas of compounds 2d and 3d are as follows:

[0054]

[0055] The preparation method was the same as in Example 1, except that the reactant amounts were modified as follows: compound 2d (0.6 mmol, 3.0 equiv, 70.8 mg), with other conditions identical to Example 1. The final product was 3d, 65.5 mg, with a yield of 73%. Its melting point, NMR, and high-resolution information are as follows: mp: 169-172 °C. 1 H NMR (400 MHz, CDCl3): δ 8.00-7.93 (m, 4H), 7.58(td, J = 8.0, 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.40 (td, J = 8.0, 0.8Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.54 (dd, J = 9.2, 4.4 Hz, 1H), 5.16-5.04(m, 1H), 4.16-4.04 (m, 1H), 3.88 (s, 3H), 3.65 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 166.6, 156.7, 153.8, 142.9, 133.2, 132.2, 130.7, 130.3, 130.2, 129.7, 128.6, 124.0, 113.8, 73.2 (p, J = 12.4 Hz), 52.2, 44.0 (p, J = 3.7Hz), 29.3; 19 F NMR (376 MHz, CDCl3): δ 84.9 (p, J = 144.0 Hz, 1F), 66.2 (d, J= 144.0 Hz, 4F); HRMS (ESI): calcd for C 19 H 18 F5N2O3S [M+H] + : 449.0953, found:449.0944.

[0056] Example 5

[0057] Preparation of quinoxaline-2(1H)-one (3e) containing an SF5 group; the structural formulas of compounds 2e and 3e are as follows:

[0058]

[0059] The preparation method was the same as in Example 1, except that the reactant amounts were modified as follows: compound 2e (0.6 mmol, 3.0 equiv, 65.2 mg), and other conditions were the same as in Example 1. The final product was 3e, 65.5 mg, with a yield of 81%. Its melting point, NMR, and high-resolution information are as follows: mp: 143-145 °C. 1 H NMR (400 MHz, CDCl3): δ 7.95 (dd, J = 8.4, 1.2 Hz,1H), 7.56 (td, J = 7.6, 1.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30-7.15 (m,4H), 7.05 (d, J = 7.2 Hz, 1H), 5.45 (dd, J = 10.4, 3.2 Hz, 1H), 5.21-5.13 (m,1H), 4.09-3.98 (m, 1H), 3.64 (s, 3H), 2.30 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 157.3, 153.9, 138.8, 137.8, 133.2, 132.3, 130.4, 130.2, 129.2, 128.9,128.7, 125.5, 123.8, 113.7, 73.5 (p, J = 11.7 Hz), 44.0 (p, J = 3.7 Hz), 29.2, 21.4; 19 F NMR (376 MHz, CDCl3): δ 85.4 (p, J = 144.0 Hz, 1F), 65.8 (d, J= 144.0 Hz, 4F); HRMS (ESI): calcd for C 18 H 18 F5N2OS [M+H] + : 405.1055, found:405.1049.

[0060] The foregoing has shown and described the basic principles, main features and advantages of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit and scope thereof, and all such changes and modifications fall within the scope of the present invention as claimed.

Claims

1. A method for synthesizing a quinoxaline-2(1H)-one derivative containing an SF5 group, characterized in that... The specific synthetic steps are as follows: using quinoxaline-2(1H)-one compound 1 and styrene compound 2 as reactants, SF5Cl as the pentafluorosulfurizing agent, and a haloalkane solvent as the reaction solvent, the reaction is carried out under blue light irradiation and an argon atmosphere to obtain quinoxaline-2(1H)-one derivative 3 containing the SF5 group. The reaction equation for the synthetic process is as follows: The structural formula of quinoxaline-2(1H)-ketone compound 1 is as follows: The structural formula of styrene compound 2 is: The structural formula of quinoxaline-2(1H)-one derivative 3 containing the SF5 group is as follows: .

2. The method for synthesizing the quinoxaline-2(1H)-one derivative containing the SF5 group according to claim 1, characterized in that: The halohydrocarbon solvent is specifically dichloromethane.

3. The method for synthesizing the quinoxaline-2(1H)-one derivative containing the SF5 group according to claim 1, characterized in that: The molar ratio of the quinoxaline-2(1H)-one compound 1, the styrene compound 2, and SF5Cl is 1:3:

3.

4. The method for synthesizing the quinoxaline-2(1H)-one derivative containing the SF5 group according to claim 1, characterized in that: The synthesis process was carried out at room temperature for 5 hours.

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