Electrochemical synthesis of a methanethiol pyrazole derivative

Abstract

This invention discloses an electrochemical synthesis method for methylthiopyrazole derivatives, comprising the following steps: The electrochemical synthesis method for methylthiopyrazole derivatives provided by this invention is a novel electrochemical synthesis method for constructing C-H methylthiolation of pyrazole derivatives using potassium thiocyanate as the sulfiding reagent and alcohol as the methylating reagent. Compared with traditional preparation methods, thiocyanate as the sulfiding reagent is not only simple and readily available, but also avoids the addition of external electrolytes. Simultaneously, the electrochemical conditions are milder and more sustainable, requiring no metal catalysts or oxidants, avoiding the use of highly toxic sulfur reagents, and exhibiting green and efficient characteristics.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and more specifically, relates to an electrochemical synthesis method for methylthiopyrazole derivatives. Background Technology

[0002] Pyrazoles are highly valuable aromatic N-heterocyclic compounds with various pharmacological and biological activities, mainly distributed in natural compounds and synthetic drugs. Sulfur-containing pyrazole organic molecules are important structural motifs in organic synthesis, organic materials, agrochemicals, nanotechnology, and pharmaceutically significant compounds; their unique properties stem from the enhanced physical and chemical characteristics of sulfur atoms. Organic electrochemical synthesis, as a powerful and practical tool for constructing new chemical bonds in synthetic chemistry, has attracted much attention due to its environmental friendliness, high efficiency, and sustainability. Electrochemistry, which uses electric current to replace redox reagents, will reduce waste generation and improve atom utilization efficiency.

[0003] In 2018, Jiang's group reported a highly efficient palladium-catalyzed three-component cross-coupled methylthiolation scheme for aromatic rings, combining a green inorganic sulfur source and a methylating agent. However, these reactions require high temperatures and the presence of strong bases (Org. Lett., 2018, 20, 6193).

[0004]

[0005] In 2020, Zhao et al. reported an electrochemical cross-coupling scheme between aryl thiocyanate and methanol. Using a magnesium plate as a sacrificial anode and tetrabutylammonium tetrafluoroborate as the electrolyte, the cross-coupling reaction was achieved under air-isolated conditions, yielding the desired product in good yield (Green Chem., 2020, 22, 4906–4911).

[0006]

[0007] In 2023, Yao's research group proposed a three-component tandem reaction of electrochemical oxidation of arylhydrazine, 1,3-dione, and ammonium thiocyanate to construct 4-thiocyanate-1H-pyrazole. Lithium tetrafluoroborate was also added as a supporting electrolyte in this reaction (Eur. J. Org. Chem., 2023, 26, e202201278(1 of 5)).

[0008]

[0009] In summary, current literature on the synthesis of methylthiolated compounds either utilizes transition metal catalysts or only produces thiocyanate derivatives. This not only increases reaction costs but also imposes an environmental burden. Therefore, inventing a metal-free, multi-component, one-pot, green chemistry method for the synthesis of methylthiopyrazole derivatives is of paramount importance. Summary of the Invention

[0010] The purpose of this invention is to provide an electrochemical synthesis method for methylthiopyrazole derivatives.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] In a first aspect, the present invention provides an electrochemical synthesis method for pyrazole methylthioides derivatives, comprising the following steps:

[0013]

[0014] R1 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens (fluorine, chlorine, bromine, iodine);

[0015] R2 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens (fluorine, chlorine, bromine, iodine);

[0016] R3 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens (fluorine, chlorine, bromine, iodine);

[0017] R4 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens (fluorine, chlorine, bromine, iodine);

[0018] R5 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens (fluorine, chlorine, bromine, iodine);

[0019] R6 is selected from C1-C20 alkyl groups. C3~C8 cycloalkyl;

[0020] R7 is selected from C1-C20 alkyl groups. C3~C8 cycloalkyl;

[0021] R 11 Selected from hydrogen and C1-C20 alkyl groups;

[0022] R 12 Selected from hydrogen and C1-C20 alkyl groups;

[0023] R 13 Selected from hydrogen and C1-C20 alkyl groups;

[0024] R 14 Selected from hydrogen and C1-C20 alkyl groups;

[0025] R 15 Selected from hydrogen and C1-C20 alkyl groups;

[0026] Compound II and Compound III, with a molar ratio of 1:0.5 to 2:1 to 10 (preferably 1:1:5, 1:1.2:5, or 1:0.83:4.1), are mixed with an electrolyte, and a solvent is added. The mixture is then reacted for 1 to 24 hours (preferably 16, 18, 18 mA) under different anodic and cathode conditions, with a direct current of 10 to 20 mA and a temperature of 20 to 50 °C (preferably 40 °C, 25 °C, or 50 °C) to obtain Compound I.

[0027] The anode is selected from carbon cloth electrode, platinum electrode, and glassy carbon electrode;

[0028] The cathode is selected from carbon cloth electrode, platinum electrode, and nickel electrode;

[0029] The electrolyte is selected from potassium thiocyanate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, and tetrabutylammonium perchlorate;

[0030] The solvent is selected from methanol, a mixture of methanol and water.

[0031] The volume ratio of methanol to water is selected from 9:1 and 8:2.

[0032] Preferably, in compound II,

[0033] R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine;

[0034] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine;

[0035] R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine;

[0036] R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine;

[0037] R5 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine.

[0038] Preferably, in compound III,

[0039] R6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl.

[0040]

[0041] R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl.

[0042]

[0043] Most preferably, compound II is selected from one of the following structures:

[0044]

[0045] Most preferably, compound III is selected from one of the following structures:

[0046]

[0047] Most preferably, the methylthiopyrazole derivative is selected from one of the following structures:

[0048]

[0049]

[0050] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0051] The electrochemical synthesis method for methylthiopyrazole derivatives provided by this invention is a novel electrochemical synthesis method for constructing CH methylthiolation of pyrazole derivatives using potassium thiocyanate as the sulfiding reagent and alcohol as the methylating reagent. Compared with traditional preparation methods, thiocyanate as the sulfiding reagent is not only simple and readily available, but also avoids the addition of external electrolytes. Furthermore, the electrochemical conditions are milder and more sustainable, requiring no metal catalysts or oxidants, thus avoiding the use of highly toxic sulfur reagents, and exhibiting green and efficient characteristics.

[0052] Patent application CN114149405A discloses a method and application for synthesizing aromatic sulfides via aromatic exchange bimetallic catalysis. This invention uses aryl halides or other aryl electrophilic reagents and aryl sulfide sources as raw materials, with palladium and nickel as bimetallic catalysts, and obtains aromatic sulfides at high temperature in the presence of a base and reducing agent under inert gas protection. This invention uses potassium thiocyanate as the sulfiding agent and methanol as the methylating agent, employing green electrochemistry as the oxidation driving force to construct methylthiolated pyrazole derivatives. Furthermore, it eliminates the need for metal catalysts and additives such as bases, offering significant advantages in terms of mild reaction and green economy. Moreover, this invention obtains the methylthiolated product at a lower temperature and in an air atmosphere, clearly demonstrating that the method provided by this invention is superior to the comparative example. Attached Figure Description

[0053] Figure 1 This is a schematic diagram of the proton NMR spectrum of compound I-1. Detailed Implementation

[0054] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0055] The specifications, purity, and manufacturers of the reagents used in this invention are shown in Table 1.

[0056] Table 1

[0057]

[0058]

[0059] The preparation method of compound II includes the following steps:

[0060]

[0061] A mixture of hydrazine hydrochloride (6 mmol) and potassium carbonate (8 mmol) was added to 20 mL of water and stirred at room temperature for one hour. The resulting mixture was extracted with ethyl acetate to separate the organic layer, followed by extraction of the aqueous layer with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give compound II.

[0062] Hydrazine hydrochloride compounds are selected from one of the following structures:

[0063]

[0064] Example 1

[0065]

[0066] Phenylehydrazine (compound II-1, 1.0 mmol, 1 equivalent), acetylacetone (compound III-1, 1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product compound I-1 as a yellow liquid, with a yield of 83%. Figure 1 This is a schematic diagram of the proton NMR spectrum of compound I-1. 1 H NMR(400MHz,DMSO-d6)δ7.53–7.48(m,4H),7.43–7.36(m,1H),2.35(s,3H),2.26(s,3H),2.17(s,3H).HRMS(ESI):calcdfor C 12 H 14 N2S[M+H] + :219.0950; found:219.0946.

[0067] Example 2

[0068]

[0069] Compound II-2 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-2, as a pale yellow liquid, with a yield of 33%. 1 H NMR (400MHz, DMSO-d6) δ7.39–7.34(m,2H),7.32–7.27(m,2H),2.35(s,3H),2.32(s,3H),2.25(s,3H),2.16(s,3H); 13 C NMR(151MHz,DMSO-d6)δ150.83,142.29,137.18,136.97,129.60,124.11,109.90,20.62,19.39,11.94,11.24.HRMS(ESI):calcd forC 13 H 17 N2S[M+H] + :233.1063; found:233.1118.

[0070] Example 3

[0071]

[0072] Compound II-3 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-3, as a pale yellow liquid, with a yield of 34%. 1 H NMR (400MHz, DMSO-d6) δ7.41–7.37(m,2H),7.32(d,J=8.4Hz,2H),2.66(q,J=7.5Hz,2H),2.33(s,3H),2.25(s,3H),2.17(s,3H),1.21(t,J=7.6Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ150.85,143.17,142.31,137.37,128.43,124.18,109.92,27.73,19.39,15.50,11.95,11.26.HRMS(ESI):calcd for C 14 H 19 N2S, [M+H] + :247.1263; found:247.1274.

[0073] Example 4

[0074]

[0075] Compound II-4 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 20 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-4, as a pale yellow liquid with a yield of 75%. 1H NMR (400MHz, DMSO-d6) δ7.09 (s, 2H), 7.01 (s, 1H), 2.32 (d, J = 8.2Hz, 9H), 2.24 (s, 3H), 2.16 (s, 3H); 13 C NMR(151MHz,DMSO-d6)δ150.74,142.21,139.45,138.44,128.77,128.76,121.81,109.95,20.76,19.36,11.88,11.87,11.30,11.28.HRMS(ESI):calcd forC 14 H 19 N2S, [M+H] + :247.1263; found:247.1272.

[0076] Example 5

[0077]

[0078] Compound II-5 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18.5 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-5, as a pale yellow liquid, with a yield of 53%. 1 H NMR (400MHz, DMSO-d6) δ7.69–7.63(m,2H),7.53–7.47(m,2H),2.38(s,3H),2.26(s,3H),2.18(s,3H); 13 C NMR (151MHz, DMSO-d6) δ151.55, 146.97 (d, J = 2.7Hz), 142.74, 138.48, 125.85, 121.86, 110.79, 19.28, 11.93, 11.30; 19 F NMR(376MHz,DMSO-d6)δ-56.96.HRMS(ESI):calcd for C 13 H 14 F3N2OS,[M+H] + :303.0773; found:303.0775.

[0079] Example 6

[0080]

[0081] Compound II-6 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-6, as a pale yellow liquid, with a yield of 42%. 1 H NMR (400MHz, DMSO-d6) δ7.88–7.83(m,2H),7.79–7.72(m,2H),2.41(s,3H),2.27(s,3H),2.18(s,3H); 13 C NMR (151MHz, DMSO-d6) δ151.93, 142.98, 140.08, 130.58, 127.66, 123.88 (dd, J = 7.55, 4.53Hz), 120.52 (q, J = 4.53Hz), 111.21, 19.26, 11.94, 11.36; 19 F NMR(376MHz,DMSO-d6)δ-61.22.HRMS(ESI):calcd for C 13 H 14 F3N2S,[M+H] + 309.0644; found: 309.0650.

[0082] Example 7

[0083]

[0084] Compound II-7 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-7, as a pale yellow liquid, with a yield of 45%. 1 H NMR (400MHz, DMSO-d6) δ7.58–7.52(m,2H),7.38–7.30(m,2H),2.33(s,3H),2.25(s,3H),2.17(s,3H).; 13 C NMR(151MHz,DMSO-d6)δ160.94(d,J=244.62Hz),151.09,142.57,135.97(d,J=1.5 1Hz),126.42,(d,J=9.06Hz),115.97(d,J=24.16Hz),110.15,19.32,11.90,11.14; 19 F NMR(376MHz,DMSO-d6)δ-114.53.HRMS(ESI):calcd forC 12 H 14 FN2S[M+H] + :237.0812; found:237.0860.

[0085] Example 8

[0086]

[0087] Compound II-8 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-8, as a pale yellow liquid, with a yield of 73%. 1H NMR (400MHz, DMSO-d6) δ7.57–7.50(m,1H),7.43–7.37(m,2H),7.28–7.22(m,1H),2.40(s,3H),2.26(s,3H),2.17(s,3H); 13 C NMR (151MHz, DMSO-d6) δ162.06 (d, J = 246.13Hz), 151.55, 142.74, 140.94 (d, J = 10.57Hz), 130.88 (d, J = 9.0 6Hz), 119.94 (d, J = 3.02Hz), 114.16 (d, J = 21.14Hz), 111.20 (d, J = 25.67Hz), 110.91, 19.26, 11.93, 11.38; 19 FNMR(376MHz,DMSO-d6)δ-111.52.HRMS(ESI):calcd for C 12 H 14 FN2S,[M+H] + :237.0812; found:237.0871.

[0088] Example 9

[0089]

[0090] Compound II-1 (1.0 mmol, 1 equivalent), compound III-2 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-9, as a yellow liquid, with a yield of 27%. 1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=3.9Hz,4H),7.44–7.38(m,1H),2.67(q,J=7.5Hz,2H),2.36(s,3H),2.18(s,3H),1.22(t,J=7.5Hz,3H); 13C NMR(151MHz,DMSO-d6)δ156.10,142.66,139.63,129.21,127.50,124.25,109.50,19.78,19.74,13.56,11.23.HRMS(ESI):calcd for C 13 H 17 N2S, [M+H] + :233.1107; found:233.1111.

[0091] Example 10

[0092]

[0093] Compound II-1 (1.0 mmol, 1 equivalent), compound III-3 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-10, as a pale yellow liquid, with a yield of 27%. 1 H NMR (400MHz, DMSO-d6) δ7.55–7.42(m,5H),2.77(q,J=7.6Hz,2H),2.68(q,J=7.6Hz,2H),2.20(s,3H),1.23(t,J=7.6Hz,3H),0.99(t,J=7.5Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ156.09,147.97,139.72,129.29,127.97,124.95,108.54,20.29,19.60,17.88,13.57,13.34.HRMS(ESI):calcd for C 14 H 19 N2S[M+H] + :246.1191; found:246.1141.

[0094] Example 11

[0095]

[0096] Compound II-1 (1.0 mmol, 1 equivalent), compound III-4 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 19 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-11, as a pale yellow liquid, with a yield of 67%. 1 H NMR (400MHz, DMSO-d6) δ7.57–7.46(m,4H),7.42–7.36(m,1H),2.22(d,J=2.3Hz,6H),1.99–1.88(m,1H),0.90–0.83(m,2H),0.79–0.66(m,2H); 13 C NMR(151MHz,DMSO)δ151.13,145.28,139.64,128.88,127.35,124.57,110.19,19.63,11.81,7.15,7.07.HRMS(ESI):calcd for C 14 H 17 N2S[M+H] + :245.1063; found:245.1114.

[0097] Example 12

[0098]

[0099] Compound II-1 (1.0 mmol, 1 equivalent), compound III-5 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. A platinum sheet electrode was used as both the anode and cathode. The reaction mixture was reacted for 18 hours at 40 °C with a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was then purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product, compound I-12, as a pale yellow liquid, with a yield of 23%. 1H NMR (400MHz, DMSO-d6) δ7.41–7.36(m,3H),7.35–7.23(m,5H),7.20–7.14(m,2H),2.36(s,3H),2.12(s,3H); 13 C NMR(151MHz,DMSO-d6)δ151.82,145.16,139.56,129.96,129.49,128.90,128.74,128.39,127.35,124.75,19.45,12.01.HRMS(ESI):calcd forC 17 H 17 N2S, [M+H] + :281.1059; found:281.1104.

[0100] Table 2

[0101]

[0102] Examples 13-16

[0103] Screening of working electrode materials

[0104] Compound II-1 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate, i.e., compound IV (5.0 mmol, 5 equivalent), were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. Carbon cloth electrode and platinum electrode (Example 13), platinum electrode and nickel electrode (Example 14), platinum electrode and carbon cloth electrode (Example 15), and glassy carbon electrode and platinum electrode (Example 16) were used as anode and cathode, respectively. The reaction was carried out for 18 hours under a direct current of 15 mA and at 40 °C. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried with anhydrous sodium sulfate, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product compound I-1, a pale yellow liquid, with corresponding yields of 43% (Example 13), 37% (Example 14), 36% (Example 15), and 20% (Example 16). The above results, compared with those of Example 1, show that the yield is optimal when platinum electrode is used as both the anode and cathode material.

[0105] Examples 17-19

[0106] Solvent selection

[0107] Compound II-1 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. Then, 9 mL of methanol (Example 17), 8 mL of methanol and 2 mL of water (Example 18), and 9 mL of acetonitrile and 1 mL of water (Example 19) were added as solvents, respectively. Using platinum electrodes as anode and cathode, the reaction was carried out for 18 hours under a direct current of 15 mA and at 40°C. The reaction mixture was extracted with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the pale yellow liquid target product compound I-1, with corresponding yields of 10% (Example 17), 30% (Example 18), and 0% (Example 19), respectively. These results, compared with Example 1, indicate that the optimal yield was achieved using 9 mL of methanol and 1 mL of water as solvents.

[0108] Examples 20-22

[0109] Electrolyte selection

[0110] Compound II-1 (1.0 mmol, 1 equivalent) and Compound III-1 (1.0 mmol, 1 equivalent) were placed in a 50 mL three-necked flask. 1.0 mmol of tetrabutylammonium tetrafluoroborate (Example 20), tetrabutylammonium hexafluorophosphate (Example 21), and tetrabutylammonium perchlorate (Example 22) were added as electrolytes, respectively. Then, 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. Using platinum electrodes as anode and cathode, the reaction was carried out for 18 hours at 40°C and a direct current of 15 mA. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product compound I-1, a pale yellow liquid, with corresponding yields of 38% (Example 20), 27% (Example 21), and 38% (Example 22), respectively. The above results, compared with those of Example 1, show that the yield is optimal when potassium thiocyanate is used as the electrolyte.

[0111] Examples 23-24

[0112] Screening of operating current

[0113] Compound II-1 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. Using platinum electrodes as anode and cathode, the reaction was carried out under direct current of 18 mA (Example 23), 12 mA (Example 24), and 40 °C for 18 hours, respectively. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the pale yellow liquid target product, compound I-1, with yields of 55% (Example 23) and 59% (Example 24), respectively. Comparison with Example 1 shows that the optimal yield was achieved with a working current of 15 mA.

[0114] Examples 25-26

[0115] Screening of reaction temperature

[0116] Compound II-1 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalents) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. Using platinum electrodes as both anode and cathode, a direct current of 15 mA was applied, and the reaction was carried out at temperatures of 50 °C (Example 25) and 25 °C (Example 26) for 18 hours, respectively. The reaction mixture was extracted with dichloromethane and water, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the pale yellow liquid target product, compound I-1, with yields of 49% (Example 25) and 40% (Example 26), respectively. These results, compared with Example 1, indicate that the optimal yield was achieved at a reaction temperature of 40 °C.

[0117] Examples 27-28

[0118] Screening of reaction time

[0119] Compound II-1 (1.0 mmol, 1 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate (compound IV, 5.0 mmol, 5 equivalent) were placed in a 50 mL three-necked flask. 9 mL of methanol (CH3OH) and 1 mL of water (H2O) were added as solvents. Using platinum electrodes as anode and cathode, the reaction was carried out at 15 mA DC and 40 °C for 20 hours (Example 27) and 16 hours (Example 28), respectively. The reaction mixture was extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the pale yellow liquid target product, compound I-1, with yields of 38% (Example 27) and 56% (Example 28), respectively. Comparison with Example 1 shows that an optimal yield was achieved with a reaction time of 18 hours.

[0120] Examples 29-30

[0121] Screening of raw material molar ratio

[0122] Compound II-1 (1.0 mmol, 1 equivalent), compound III-1 (1.2 mmol, 1.2 equivalent), compound II-1 (1.2 mmol, 1.2 equivalent), compound III-1 (1.0 mmol, 1 equivalent), and potassium thiocyanate, i.e., compound IV (5.0 mmol, 5 equivalent), were placed in 50 mL three-necked flasks, respectively. Then, 9 mL of methanol and 1 mL of water were added as solvents. Platinum electrodes were used as anodes and cathodes, and the reaction was carried out for 18 hours under a direct current of 15 mA and a temperature of 40 °C. The reaction mixture was extracted with dichloromethane and water, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 200 / 10) to obtain the target product compound I-1, which was a light yellow liquid with corresponding yields of 67% (Example 29) and 43% (Example 30). The above results, compared with those of Example 1, show that the yield is optimal when 1 equivalent of compound II-1 and 1 equivalent of compound III-1 are involved in the reaction.

[0123] Comparative Example 1

[0124]

[0125] Patent application CN114149405A reports a similar reaction involving a metal catalyst (palladium compound and nickel compound) and a reducing agent (zinc). In contrast, this invention requires no metal catalyst or additives, utilizes green electrochemistry as the oxidation driving force, and employs milder conditions and more economical raw materials. Therefore, the method provided by this invention is superior to the comparative example.

[0126] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An electrochemical synthesis method for a methylthiopyrazole derivative, characterized in that, Includes the following steps: R1 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens; R2 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens; R3 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens; R4 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens; R5 is selected from hydrogen, C1-C20 alkyl groups, CF3O, CF3, and halogens; R6 is selected from C1-C20 alkyl groups. C3~C8 cycloalkyl; R7 is selected from C1-C20 alkyl groups. C3~C8 cycloalkyl; R 11 Selected from hydrogen and C1-C20 alkyl groups; R 12 Selected from hydrogen and C1-C20 alkyl groups; R 13 Selected from hydrogen and C1-C20 alkyl groups; R 14 Selected from hydrogen and C1-C20 alkyl groups; R 15 Selected from hydrogen and C1-C20 alkyl groups; Compound II and Compound III, in a molar ratio of 1:0.5 to 2:1 to 10, were mixed with an electrolyte, and a solvent was added. The mixture was reacted for 1 to 24 hours under different anodic and cathode conditions, with a direct current of 10 to 20 mA and a temperature of 20 to 50 °C, to obtain Compound I. Platinum sheet electrode and platinum sheet electrode, carbon cloth electrode and platinum electrode, platinum electrode and nickel electrode, platinum electrode and carbon cloth electrode, and glassy carbon electrode and platinum electrode were used as anode and cathode, respectively; The electrolyte is selected from potassium thiocyanate, KSCN / n Bu4NBF4、KSCN / n Bu4NPF6、KSCN / n Bu4NClO4; The solvent is selected from methanol, a mixture of methanol and water.

2. The electrochemical synthesis method of methylthiopyrazole derivatives according to claim 1, characterized in that, The volume ratio of methanol to water is selected from 9:1 and 8:

2.

3. The electrochemical synthesis method of methylthiopyrazole derivatives according to claim 1, characterized in that, In compound II, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine; R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine; R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine; R5 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, CF3O, CF3, fluorine, chlorine, and bromine.

4. The electrochemical synthesis method of methylthiopyrazole derivatives according to claim 1, characterized in that, In compound III, R6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl. R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl.

5. The electrochemical synthesis method of methylthiopyrazole derivatives according to claim 1, characterized in that, Compound II is selected from one of the following structures:

6. The electrochemical synthesis method of methylthiopyrazole derivatives according to claim 1, characterized in that, Compound III is selected from one of the following structures:

7. The electrochemical synthesis method of methylthiopyrazole derivatives according to claim 1, characterized in that, The methylthiopyrazole derivative is selected from one of the following structures:

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