A thiophosphonamide derivative and a three-component electrochemical synthesis method thereof

Abstract

The present application relates to the field of chemical synthesis, in particular to a kind of thiophosphoramide derivative and its three-component electrochemical synthesis method;The present application constructs three valence phosphine hydrogen compound, primary amine or secondary amine, three-component electrochemical oxidation reaction system of sulfur element, and synthesizes thiophosphoramide derivative through cascade reaction one step.The reaction operation is simple and safe, the method is simple and efficient, the raw material is easy to obtain, the reaction condition is mild, there is no by-product, the functional group tolerance of compound is high, and the post-treatment is convenient, the yield is generally very high, the use of highly toxic trichloro phosphorus sulfide, uncommercialized three valence phosphine thiophosphate derivative can be avoided, substrate applicability is wide, operation is simple, and it is suitable for mass synthesis.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a thiophosphoramide derivative and its three-component electrochemical synthesis method. Background Technology

[0002] Organophosphorus compounds are widely used in industry, agriculture, materials science, organocatalysis, and biomedicine. Among them, phosphoramides are small molecules with significant biological value and have been a research focus in recent years. Thiophosphoramides, as homologues of phosphoramides, theoretically possess similar biological activities and can be studied in depth. Currently, the main methods for synthesizing thiophosphoramide compounds are: 1) using trichlorophosphorus as a starting material and reacting it with different or the same alcohols to generate monochloro-substituted thiophosphoric esters, which then undergo nucleophilic substitution reactions with amine nucleophiles to generate a variety of thiophosphoramide esters. However, the high toxicity of trichlorophosphorus limits its widespread use; 2) using thiolated trivalent phosphorus derivatives as starting materials for synthesis, however, these derivatives have not been commercialized; 3) using phosphoramides as starting materials and reacting them with thioreagents such as Lawson's reagent to generate the corresponding thiophosphoramide compounds, but thioreagents often have a foul odor. Phosphoramides are typically synthesized through the following methods: 1) using various phosphorus halides (P(O)Cl3, PCl3, RPCl2, R2PCl, R2P(O)Cl) as substrates; 2) using phosphoric acid compounds as phosphorus sources and synthesizing phosphoramides via aminolysis or dehydration reactions; and 3) synthesizing phosphoramides through the reaction of phosphate hydrides with amines, diazo compounds, azo compounds, azido compounds, hydroxylamines, or haloamines. Among these methods, the synthesis of phosphoramides using phosphate hydrides as substrates has received widespread attention because it avoids the formation of chloride byproducts and the use of excessive dehydrating agents.

[0003] Using P(O)-H compounds as starting materials, the Atherton-Todd type reaction (Org. Biomol. Chem. 2021, 19, 5098-5107; Tetrahedron Lett. 2011, 52, 2367-2369; Tetrahedron Lett. 2015, 56, 6364-6367.) or the cross-coupling reaction involving peroxides (Org. Lett. 2013, 15, 6062-6065; Chem. Eur. J. 2020, 26, 881-887; J. Org. Chem. 2019, 84, 14949-14956.) is an important means of constructing phosphoramides; however, this type of reaction is not green enough. Encouragingly, the recently emerging strategy of electrochemical oxidation cross-coupling reactions (GreenChem. 2017, 19, 4769-4773; Org. Lett. 2020, 22, 3062-3066; Chem. Eur. J. 2021, 27, 14931-14935; Org. Biomol. Chem. 2021, 19, 5342-5347.) provides a unique perspective for the green synthesis of phosphoramide derivatives. Although diarylphosphine hydrogen has been applied to electrochemical oxidation cross-coupling reactions involving nitrogen-containing nucleophiles, only products with unoxidized phosphorus (Chem. Sci. 2022, 13, 3002-3008) and products with phosphorus oxidized to phosphine oxyphosphate (Chem. Eur. J. 2021, 27, 14931-14935) have been obtained, while phosphorus-containing products oxidized by elemental sulfur have not yet been reported. Based on this, a mild, green, and efficient three-component electrochemical synthesis route was developed to achieve the dehydrogenation cross-coupling reaction of phosphine hydrogen compounds with nitrogen-containing nucleophiles, which can facilitate the acquisition of less studied thiophosphoramide compounds. Summary of the Invention

[0004] The main objective of this invention is to provide a three-component electrochemical synthesis method for thiophosphoramides and to apply this method to the derivatization of drug molecules.

[0005] The specific technical solution of the present invention is as follows:

[0006] A thiophosphoramide derivative, the structural formula of which is shown in Figure I.

[0007]

[0008] Where: R 1 Or R 2 It is one of C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, benzyl, and C2-C10 heterocyclic groups;

[0009] R3 Or R 4 It is any one of hydrogen, C1-C20 alkyl, C1-C20 perfluoroalkyl, C6-C12 aryl, benzyl, C2-C8 alkenyl substituent, C2-C8 alkynyl substituent, or C2-C10 heterocyclic group.

[0010] A three-component electrochemical synthesis method for a thiophosphoramide derivative is shown in the following formula:

[0011]

[0012] In the formula, the preparation steps of compound I are as follows:

[0013] S1. Place compound II, compound III, elemental sulfur, electrolyte and additives in an organic solvent, load them into the anode and cathode, seal the reaction vessel and pass a constant direct current through it to react.

[0014] S2. After compound III has completely disappeared, remove the organic solvent from the reaction mixture under reduced pressure.

[0015] S3. Compound I was obtained by elution using silica gel column chromatography.

[0016] The molar ratio of compound II, compound III and elemental sulfur is II:III:IV = 1.5-3.0:1.0:3.0-5.0.

[0017] The anode is an electrode made of graphite sheet, graphite rod, mesh glassy carbon, glassy carbon, graphite felt, foamed carbon, platinum sheet, platinum wire, or stainless steel.

[0018] The cathode is an electrode made of graphite sheet, graphite rod, mesh glassy carbon, glassy carbon, foamed carbon, platinum sheet, nickel, iron, copper, stainless steel, aluminum, zinc, titanium, or lead.

[0019] The electrolyte includes one or more of the following: tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium hydroxide, tetrabutylammonium iodide, tetrabutylammonium bromide, 1,3-dimethylimidazolium iodide, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphate, tetraethylammonium p-toluenesulfonate, tetrabutylammonium tetrafluoroborate, tetramethylammonium acetate, tetrabutylammonium hydrogen sulfate, tetrabutylammonium acetate, or tetraethylammonium perchlorate.

[0020] The additives include one or two of the following: 2,6-di-tert-butylphenol, tetramethylpiperidine oxide, zinc iodide, hydroiodic acid, methanesulfonic acid, trifluoroethanol, hexafluoroisopropanol, acetic acid, propionic acid, n-butyric acid, isobutyric acid, or tervastatin.

[0021] The organic solvent includes any one or at least two combinations of ethyl acetate, acetonitrile, dichloromethane, dichloroethane, N,N-dimethylpropenylurea, N-methylpyrrolidone, dimethylformamide, or dimethylacetamide.

[0022] The eluent used in the column chromatography was a mixture of petroleum ether and ethyl acetate, with a volume ratio of V / L. 石油醚 :V 乙酸乙酯 =40:1 to 2:1.

[0023] The beneficial effects of the present invention are as follows: (1) The present invention provides an electrochemical synthesis method for thiophosphoramide.

[0024] (2) The preparation method of the present invention uses current as an oxidant without leaving traces. The reaction does not require catalyst or inert gas protection, is simple and safe to operate, has few reaction steps, readily available raw materials, mild reaction conditions, no by-products, a wide range of substrates, high tolerance for compound functional groups, and the product yield can reach 88%.

[0025] (3)(3) The present invention can avoid the use of commercially available P(S)-H compounds and can also prepare thiophosphoramide derivatives at the gram scale. Attached Figure Description

[0026] Figure 1 The nuclear magnetic resonance spectrum (H NMR spectrum) of product I-1 obtained in the embodiments of the present invention is shown below.

[0027] Figure 2 The nuclear magnetic resonance (carbon) spectrum of product I-1 obtained in the embodiments of the present invention is shown.

[0028] Figure 3 The nuclear magnetic resonance spectrum (H NMR spectrum) of product I-14 obtained in the embodiments of the present invention is shown below.

[0029] Figure 4 The NMR spectrum (phosphorus spectrum) of product I-14 obtained in the embodiments of the present invention is shown. Detailed Implementation

[0030] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments:

[0031] The following are preferred embodiments for the preparation of compounds according to the present invention. In all the following embodiments, NMR spectroscopy was performed using a Bruker 400, JEOL 400 instrument in CDCl3. δ values ​​are relative to internal standards (CHCl3 calibration δ 7.26). 1 H NMR and 77.16 13 10⁻¹⁵ C NMR. High-resolution mass spectrometry (HRMS) was obtained using a 4G quadrupole time-of-flight (QTof) mass spectrometer.

[0032] Example 1

[0033] The reaction formula of Example 1, specifically the compounds II-1, III-1, sulfur powder, and the structure of product I-1 are as follows. Experiments show that the preferred anode of this invention is a graphite sheet, the preferred cathode is a platinum sheet, the preferred electrolyte is tetrabutylammonium iodide, the preferred additive is hexafluoroisopropanol (HFIP), the preferred DC current is 6 mA, the preferred organic solvent is acetonitrile (MeCN), the highest yield of the reaction product is 88%, the best molar ratio of raw materials is the molar ratio of compound II to compound III is II:III = 2:1, where compound III should be an equivalent value, and the optimal concentration of the solution is 0.04M.

[0034]

[0035] The specific experimental procedure is as follows: In a 10 mL straight reaction tube, 22 mg (0.2 mmol, 1.0 equivalent) of compound III-1, 19 mg of sulfur powder (0.6 mmol, 3.0 equivalent), 74 mg of tetrabutylammonium iodide (0.2 mmol, 1.0 equivalent), and 0.5 mL of hexafluoroisopropanol were dissolved in 4.5 mL of acetonitrile. A graphite anode and platinum cathode were then placed inside, and the tube was purged with nitrogen. 74 mg (0.40 mmol, 2.0 equivalent) of compound II-1 was injected using a microsyringe. The reaction was carried out at room temperature for 8 hours under a direct current of 6 mA. After the reaction, the solvent was removed by rotary evaporation under reduced pressure using a water pump. The residue was eluent with 200-300 mesh silica gel (volume ratio V). 石油醚 :V 乙酸乙酯 The compound shown in I-1 was obtained by column chromatography with a ratio of 100:1 to 10:1. The product was identified by NMR (H1N, C1N, and N2N) and high-resolution mass spectrometry.

[0036] White solid,55mg,Yield=86%,R f =0.37 (PE / EA = 20:1). 1 H NMR (400MHz, CDCl3) δ8.06–8.02(m,2H),8.02–7.99(m,2H),7.54–7.50(m,2H),7.49–7.44 (m,4H),6.96(d,J=8.4Hz,2H),6.81(d,J=8.4Hz,2H),4.84(d,J=6.4Hz,1H),2.23(s,3H); 13C NMR (100MHz, CDCl3) δ137.52, 133.83 (d, J = 102.6Hz), 132.10 (d, J = 3.1Hz), 131.75 (d,J=11.3Hz),131.39,129.73,128.85(d,J=13.1Hz),119.08(d,J=6.8Hz),20.70; 31 P NMR (162MHz, CDCl3) δ53.27; HRMS (ESI) m / z: [M+H]+Calcd for C 19 H 19 NPS 324.0976; Found 324.0979.

[0037] Example 2

[0038] Thiophosphoramide was synthesized using phenylhydrazine as a nitrogen source.

[0039]

[0040] The methods used in the examples of preparing other compounds of the present invention were the same as in Example 1, and the reaction conditions were as follows: In a 10 mL straight reaction tube, 22 mg (0.2 mmol, 1.0 equivalent) of compound III-1, 19 mg of sulfur powder (0.6 mmol, 3.0 equivalent), 74 mg of tetrabutylammonium iodide (0.2 mmol, 1.0 equivalent), and 0.5 mL of hexafluoroisopropanol were dissolved in 4.5 mL of acetonitrile. A graphite anode and a platinum cathode were placed inside, and the tube was purged with nitrogen. Then, 74 mg (0.40 mmol, 2.0 equivalent) of compound II-1 was injected using a microsyringe. The reaction was carried out at room temperature for 8 hours under a direct current of 6 mA. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure using a water pump. The residue was eluent with 200-300 mesh silica gel (volume ratio V). 石油醚 :V 乙酸乙酯 The compound shown in I-1 was obtained by column chromatography with a ratio of 100:1 to 10:1. The product was identified by NMR (1H, 1C, and 1P NMR) and high-resolution mass spectrometry as follows:

[0041] White solid,31mg,Yield=48%,R f =0.47 (PE / EA = 15:1). 11H NMR (400 MHz, CDCl3) δ 8.06–8.02 (m, 2H), 8.02–7.98 (m, 2H), 7.52–7.47 (m, 2H), 7.45–7.40 (m, 4H), 7.21–7.15 (m, 2H), 6.93 (dd, J = 8.0, 1.1 Hz, 2H), 6.84–6.80 (m, 1H), 5.76 (d, J = 4.0 Hz, 1H), 4.43 (d, J = 16.0 Hz, 1H); 31 31P NMR (162 MHz, CDCl3) δ 64.20; HRMS (ESI) m / z: [M+H]+ Calcd for C 18 H 18 N2PS 325.0928; Found 325.0924.

[0042] Compound I-1

[0043]

[0044] P,P-Diphenyl-N-(p-tolyl)phosphinothioic amide. (55 mg, Yield = 86%, Rf = 0.37 (PE / EA = 20:1)) was isolated as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 8.06–8.02 (m, 2H), 8.02–7.99 (m, 2H), 7.54–7.50 (m, 2H), 7.49–7.44 (m, 4H), 6.96 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.84 (d, J = 6.4 Hz, 1H), 2.23 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 137.52, 133.83 (d, J = 102.6 Hz), 132.10 (d, J = 3.1 Hz), 131.75 (d, J = 11.3 Hz), 131.39, 129.73, 128.85 (d, J = 13.1 Hz), 119.08 (d, J = 6.8 Hz), 20.70; 31 31P NMR (162 MHz, CDCl3) δ 53.27; HRMS (ESI) m / z: [M+H]+ Calcd for C 19 H 19 NPS 324.0976; Found 324.0979.

[0045] Compound I-2

[0046]

[0047] P,P-Diphenyl-N-(m-tolyl)phosphinothioic amide. (55 mg, Yield=86%, Rf=0.35(PE / EA=20:1)) was isolated as a white solid. 1 1H NMR (400 MHz, CDCl3) δ8.05–8.02 (m, 2H), 8.01–7.98 (m, 2H), 7.55–7.50 (m, 2H), 7.50–7.44 (m, 4H), 7.04–7.00 (m, 1H), 6.75–6.68 (m, 3H),, 4.88 (d, J=6.4 Hz, 1H), 2.21 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ140.11 (d, J=2.0 Hz), 139.13, 133.84 (d, J=102.6 Hz), 132.13 (d, J=3.1 Hz), 131.74 (d, J=11.5 Hz), 129.00, 128.87 (d, J=13.2 Hz), 122.81, 119.74 (d, J=7.0 Hz), 116.00 (d, J=6.6 Hz), 21.57; 31 31P NMR (162 MHz, CDCl3) δ53.07.

[0048] Compound I-3

[0049]

[0050] P,P-Diphenyl-N-(o-tolyl)phosphinothioic amide. (52 mg, Yield=81%, R f =0.52(PE / EA=15:1)) was isolated as a white solid. 1 1H NMR (400 MHz, CDCl3) δ8.05–8.02 (m, 2H), 8.01–7.98 (m, 2H), 7.55–7.50 (m, 2H), 7.49–7.44 (m, 4H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.96 (td, J=7.7, 1.7 Hz, 1H), 6.85 (td, J=7.6, 1.2 Hz, 1H), 4.73 (d, J=6.0 Hz, 1H), 2.25 (s, 3H); 1313C NMR (100 MHz, CDCl3) δ 138.61, 133.95 (d, J = 102.6 Hz), 132.16 (d, J = 3.3 Hz), 131.71 (d, J = 11.1 Hz), 130.72, 128.94 (d, J = 13.2 Hz), 126.81, 126.25 (d, J = 7.6 Hz), 122.05, 118.82 (d, J = 5.3 Hz), 17.95; 31 31P NMR (162 MHz, CDCl3) δ 53.32.

[0051] Compound I-4

[0052]

[0053] N,P,P-Triphenylphosphinothioic amide. (48 mg, Yield = 77%, Rf = 0.32 (PE / EA = 20:1)) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.06–8.02 (m, 2H), 8.01–7.98 (m, 2H) 7.56–7.44 (m, 6H), 7.18–7.12 (m, 2H), 6.95–6.88 (m, 3H), 4.91 (d, J = 6.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 140.20 (d, J = 1.4 Hz), 133.72 (d, J = 102.6 Hz) 132.20 (d, J = 2.9 Hz), 131.77 (d, J = 11.3 Hz) 129.23, 128.92 (d, J = 13.3 Hz), 121.91, 118.94 (d, J = 6.9 Hz); 31 31P NMR (162 MHz, CDCl3) δ 53.11.

[0054] 1 1H NMR (400 MHz, Chloroform-d) δ 8.06–8.02 (m, 2H), 8.02–7.99 (m, 2H), 7.53 (dd, J = 7.1, 1.9 Hz, 2H), 7.49 (dd, J = 7.4, 3.4 Hz, 4H), 7.16 (t, J = 7.9 Hz, 2H), 6.92 (t, J = 8.3 Hz, 3H), 4.91 (d, J = 6.2 Hz, 1H).

[0055] Compound I-5

[0056]

[0057] N-(4-(Tert-butyl)phenyl)-P,P-diphenylphosphinothioic amide. (43 mg, Yield=59%, R f =0.52(PE / EA=15:1)) was isolated as a white solid. 1 H NMR(400 MHz, CDCl3) δ8.07–8.03(m, 2H), 8.03–7.99(m, 2H), 7.54–7.50(m, 2H), 7.49–7.44(m, 4H), 7.17(d, J=8.4 Hz, 2H), 6.82(d, J=8.8 Hz, 2H), 4.84(d, J=6.0 Hz, 1H), 1.24(s, 9H); 13 C NMR(100 MHz, CDCl3) δ144.66, 137.45, 133.94(d, J=102.9 Hz), 132.12, 131.79(d, J=11.3 Hz), 128.88(d, J=13.3 Hz), 126.11, 118.56, 34.23, 32.26; 31 P NMR(162 MHz, CDCl3) δ47.24.

[0058] Compound I-6

[0059]

[0060] N-(4-Methoxyphenyl)-P,P-diphenylphosphinothioic amide. (58 mg, Yield=85%, R f =0.48(PE / EA=15:1)) was isolated as a white solid. H NMR(400 MHz, CDCl3) δ8.05–8.02(m, 2H), 8.02–7.99(m, 2H), 7.54–7.50(m, 2H), 7.49–7.44(m, 4H), 6.88–6.84(m, 2H), 6.73–6.69(m, 1H),, 4.70(d, J=5.6 Hz, 1H), 3.71(s, 3H); 1313C NMR (100 MHz, CDCl3) δ 155.13, 143.85 (d, J = 102.7 Hz), 133.16, 132.08 (d, J = 2.4 Hz), 131.79 (d, J = 11.1 Hz), 128.80 (d, J = 13.3 Hz), 121.06 (d, J = 6.5 Hz), 114.53, 55.54; 31 31P NMR (162 MHz, CDCl3) δ 54.15.

[0061] Compound I-7

[0062]

[0063] N-(4-Chlorophenyl)-P,P-diphenylphosphinothioic amide. (48 mg, Yield = 71%, R f = 0.43 (PE / EA = 15:1)) was isolated as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 8.04–8.00 (m, 2H), 8.00–7.95 (m, 2H), 7.57–7.52 (m, 2H), 7.51–7.45 (m, 4H), 7.13–7.08 (m, 2H), 6.87–6.83 (m, 2H), 4.94 (d, J = 6.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 138.83, 133.33 (d, J = 102.6 Hz), 132.37 (d, J = 2.8 Hz), 131.74 (d, J = 11.4 Hz), 129.14 (d, J = 14.8 Hz), 128.93, 127.14, 120.17 (d, J = 6.8 Hz); 31 31P NMR (162 MHz, CDCl3) δ 53.84.

[0064] Compound I-8

[0065]

[0066] N-(4-Fluorophenyl)-P,P-diphenylphosphinothioic amide. (54 mg, Yield = 83%, R f = 0.51 (PE / EA = 15:1)) was isolated as a white solid. 11H NMR (400 MHz, CDCl3) δ 8.05–8.01 (m, 2H), 8.01–7.97 (m, 2H), 7.56–7.51 (m, 2H), 7.50–7.45 (m, 4H), 6.91–6.82 (m, 4H), 4.84 (d, J = 6.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 158.42 (d, J = 239.6 Hz), 136.13, 133.53 (d, J = 102.6 Hz), 132.28 (d, J = 3.0 Hz), 131.78 (d, J = 11.3 Hz), 128.93 (d, J = 13.1 Hz), 120.65 (t, J = 7.3 Hz), 115.89 (d, J = 22.4 Hz); 31 31P NMR (162 MHz, CDCl3) δ 54.03; 19 19F NMR (376 MHz, CDCl3) δ –;

[0067] Compound I-9

[0068]

[0069] Ethyl 4-((diphenylphosphorothioyl)amino)benzoate. (45 mg, Yield = 59%, R f = 0.42 (PE / EA = 15:1)) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.04–7.99 (m, 2H), 7.99–7.96 (m, 1H), 7.87–7.81 (m, 2H), 7.57–7.52 (m, 2H), 7.52–7.44 (m, 3H), 6.94 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 5.25 (d, J = 7.2 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 1.38–1.31 (m, 3H); 13 13C NMR (100 MHz, CDCl3) δ 166.43, 144.67, 133.12 (d, J = 102.5 Hz), 132.46 (d, J = 3.1 Hz), 131.73 (d, J = 11.2 Hz), 131.08, 129.56 (d, J = 13.2 Hz), 123.71, 118.02 (d, J = 7.1 Hz, 1H), 60.77, 14.47; 31 31P NMR (162 MHz, CDCl3) δ 53.09.

[0070] Compound I-10

[0071]

[0072] N-(4-Bromophenyl)-P,P-diphenylphosphinothioic amide. (56mg, Yield=73%, R f =0.43(PE / EA=15:1)) was isolated as a white solid. 1 H NMR(400MHz, CDCl3) δ8.03–7.99(m, 2H), 7.98–7.96(m, 2H), 7.56–7.52(m, 2H), 7.50–7.46(m, 4H), 7.27–7.23(m, 2H) 6.82–6.78(m, 2H), 4.94(d, J=6.8Hz, 1H); 13 C NMR(100MHz, CDCl3) δ139.38, 133.33(d, J=2.8Hz), 133.31(d, J=102.7Hz),, 132.38(d, J=3.1Hz), 132.12, 131.73(d, J=11.4Hz), 130.17(d, J=274.2Hz), 129.00(d, J=13.1Hz), 120.56(d, J=7.0Hz), 116.85, 114.55; 31 P NMR(162MHz, CDCl3) δ53.43.

[0073] Compound I-11

[0074]

[0075] P,P-Diphenyl-N-(4-(trifluoromethyl)phenyl)phosphinothioic amide. (63mg, Yield=84%, R f =0.52(PE / EA=10:1)) was isolated as a white solid. Compound 3 1 H NMR(400MHz, CDCl3) δ8.04–8.00(m, 2H), 8.00–7.97(m, 2H), 7.59–7.54(m, 2H), 7.53–7.47(m, 4H), 7.40(d, J=8.4Hz, 2H), 6.98(d, J=8.4Hz, 2H), 5.19(s, 1H); 1313C NMR (101 MHz, CDCl3) δ; 31 31P NMR (162 MHz, CDCl3) δ 53.31.

[0076] Compound I-12

[0077]

[0078] N-(Furan-2-ylmethyl)-P,P-diphenylphosphinothioic amide. (32 mg, Yield = 51%, R f = 0.45 (PE / EA = 10:1)) was isolated as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 8.04–8.00 (m, 2H), 8.00–7.97 (m, 2H), 7.51–7.41 (m, 6H), 7.36 (dd, J = 1.6, 0.8 Hz, 1H), 6.28 (dd, J = 3.2, 2.0 Hz, 1H), 6.17 (dd, J = 3.2, 0.8 Hz, 1H), 4.11 (dd, J = 8.8, 6.8 Hz, 2H), 2.74 (s, 1H); 13 13C NMR (100 MHz, CDCl3) δ 152.45 (d, J = 11.9 Hz), 142.41, 133.75 (d, J = 102.1 Hz), 131.93 (d, J = 3.2 Hz), 131.76 (d, J = 11.1 Hz), 128.64 (d, J = 12.9 Hz), 110.52, 107.73, 38.26; 31 31P NMR (162 MHz, CDCl3) δ 60.56.

[0079] Compound I-13

[0080]

[0081] P,P-Diphenyl-N-(4-(trifluoromethoxy)phenyl)phosphinothioic amide. (53 mg, Yield = 67%, R f = 0.53 (PE / EA = 10:1)) was isolated as a white solid. 11H NMR (400 MHz, CDCl3) δ 8.04–8.01 (m, 2H), 8.01–7.97 (m, 2H), 7.57–7.53 (m, 2H), 7.51–7.46 (m, 4H), 7.02 (d, J = 8.4 Hz, 3H), 6.94–6.87 (m, 2H), 4.97 (d, J = 6.4 Hz, 1H); 31 31P NMR (162 MHz, CDCl3) δ 53.62.

[0082] Compound I-14

[0083]

[0084] diphenyl(4-phenylpiperazin-1-yl)phosphine sulfide. (41 mg, Yield = 51%, R f = 0.4 (PE / EA = 10:1)) was isolated as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.82-7.77 (m, 2H), δ 7.65-7.51 (m, 5H), δ 7.28-7.21 (m, 4H), δ 6.92-6.83 (m, 4H), δ 3.27-3.20 (m, 4H), δ 3.21-3.13 (m, 4H); 31 31P NMR (162 MHz, CDCl3) δ 61.56.

[0085] Compound I-15

[0086]

[0087] N',P,P-Triphenylphosphinothioic hydrazide. (31 mg, Yield = 48%, R f = 0.47 (PE / EA = 15:1)) was isolated as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 8.06–8.02 (m, 2H), 8.02–7.98 (m, 2H), 7.52–7.47 (m, 2H), 7.45–7.40 (m, 4H), 7.21–7.15 (m, 2H), 6.93 (dd, J = 8.0, 1.1 Hz, 2H), 6.84–6.80 (m, 1H), 5.76 (d, J = 4.0 Hz, 1H), 4.43 (d, J = 16.0 Hz, 1H); 31PNMR (162 MHz, CDCl3) δ 64.20; HRMS (ESI) m / z: [M+H]+ Calcd for C 18 H 18 N2PS 325.0928; Found 325.0924.

[0088] Compound I-16

[0089]

[0090] P,P-di-o-tolyl-N-(p-tolyl)phosphinothioic amide. (44 mg, Yield = 63%, R f = 0.5 (PE / EA = 10:1)) was isolated as a white solid. 1 1H NMR (400 MHz, Chloroform-d) δ 7.92–7.81 (m, 2H), 7.45–7.39 (m, 2H), 7.29–7.27 (m, 2H), 7.25–7.23 (m, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.82–6.75 (m, 2H), 4.88 (d, J = 6.5 Hz, 1H), 2.53 (s, 6H), 2.22 (s, 3H); 31 31P NMR (162 MHz, CDCl3) δ 53.59.

[0091] Compound I-17

[0092]

[0093] P,P-bis(3,5-dimethylphenyl)-N-(p-tolyl)phosphinothioic amide. (43 mg, Yield = 56%, R f = 0.4 (PE / EA = 10:1)) was isolated as a white solid. 1 1H NMR (400 MHz, Chloroform-d) δ 7.63 (s, 2H), 7.59 (s, 2H), 7.14 (s, 2H), 6.96 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.3 Hz, 2H), 4.76 (d, J = 5.7 Hz, 1H), 2.34 (s, 12H), 2.23 (s, 3H); 31 31P NMR (162 MHz, CDCl3) δ 54.34.

[0094] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0095] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A three-component electrochemical synthesis method for thiophosphoramide derivatives, the structural formula of which is shown in Figure I. Formula I in: R 1 Or R 2 It is one of C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, benzyl, and C2-C10 heterocyclic groups; R 3 Or R 4 It is any one of hydrogen, C1-C20 alkyl, C1-C20 perfluoroalkyl, C6-C12 aryl, benzyl, C2-C8 alkenyl-containing substituent, C2-C8 alkynyl-containing substituent, or C2-C10 heterocyclic group; characterized in that the synthesis method is shown in the following formula: Formula II In the formula, the preparation steps of compound I are as follows: S1. Place compound II, compound III, elemental sulfur, electrolyte and additives in an organic solvent, load them into the anode and cathode, seal the reaction vessel and pass a constant direct current through it to react. S2. After compound III has completely disappeared, remove the organic solvent from the reaction mixture under reduced pressure. S3. The compound was obtained by elution using silica gel column chromatography; The anode is a graphite sheet, the cathode is a platinum sheet, the electrolyte is tetrabutylammonium iodide, the additive is hexafluoroisopropanol (HFIP), the DC current is 6 mA, the organic solvent is acetonitrile, the molar ratio of compound II to compound III is II:III = 2:1, where compound III should be an equivalent value, and the concentration of the solution is 0.04 M.

2. The three-component electrochemical synthesis method for a thiophosphoramide derivative according to claim 1, characterized in that: The eluent used in the column chromatography was a mixture of petroleum ether and ethyl acetate, with a volume ratio of V / L. 石油醚 :V 乙酸乙酯 =100:1~10:1.

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