CN111304685A - Method for preparing 1,2,4-thiadiazole framework and fused rings thereof through electrocatalysis - Google Patents

Abstract

The invention discloses a 1,2,4-thiadiazole framework and a preparation method of a condensed ring thereof. The method comprises the steps of dissolving amidine or o-amino nitrogen heterocyclic compounds and isothiocyanate in a solvent, adding electrolyte into an air system at room temperature, and reacting for 4-6 hours under an electrocatalysis condition to directly generate a 1,2,4-thiadiazole framework and condensed rings thereof. The molar ratio of the amidine or o-amino nitrogen heterocyclic compound to the isothiocyanate is 1: 1-1: 1.5; the molar ratio of the electrolyte to the amidine or the o-amino nitrogen heterocyclic compound is 0.05: 1-0.25: 1. The method overcomes the defects of the prior art that a metal catalyst, an expensive or toxic chemical oxidant, oxygen which is easy to support combustion and the like are needed, and has the following advantages: 1) the electrochemical synthesis method is adopted, so that the use of expensive and toxic chemical oxidants and oxygen which is easy to support combustion is avoided; 2) no transition metal catalyst is used, so that heavy metal ions are prevented from remaining in the product; 3) one step directly produces 1,2,4-thiadiazole skeleton and its condensed rings. The synthetic method disclosed by the invention plays an important role in preparing 1,2,4-thiadiazole skeletons and condensed rings thereof, particularly in the application of 1,2,4-thiadiazole as a pharmacophore in the field of medicinal chemistry.

Description

A method for electrocatalytic preparation of 1,2,4-thiadiazole skeleton and its fused ring

technical field

The invention relates to a preparation method of a 1,2,4-thiadiazole skeleton and a fused ring thereof, in particular to an amidine or an o-amino nitrogen heterocyclic compound and an isothiocyanate added to an electrolyte, at room temperature A method for directly generating 1,2,4-thiadiazole skeleton and its fused ring by constructing a new N-S bond under electrocatalytic conditions in an air reaction.

Background technique

1,2,4-Thiadiazoles are an important class of heterocyclic skeletons and are the basic components of many biologically active compounds, such as central nervous system drugs, G-protein coupled receptor modulators, anti-inflammatory drugs, cardiac Vascular system drugs or antibacterial drugs, etc. The synthesis of 1,2,4-thiadiazoles mainly adopts the method of direct oxidative cyclization. For example, Wehn et al. cited a palladium-catalyzed Suzuki-Miyaura coupling reaction to give 3-amino-1,2,4-thiadiazole (Wehn PM, Harrington PE, Eksterowicz J E. Facile synthesis of substituted 5-amino-and 3-amino-1,2,4-thiadiazoles from a common precursor[J].Organic letters, 2009,11(24):5666-5669.), Khosropour et al. in the presence of (NH ₄ ) ₂ S and TCT-DMSO 1,2,4-thiadiazoles from aryl nitriles (Noei J, Khosropour AR. A novel process for the synthesis of 3,5-diaryl-1,2,4-thiadiazoles from aryl nitriles[J] . Tetrahedron Letters, 2013, 54(1): 9-11.), Kim et al. developed the formation of intramolecular oxidative SN bonds under the catalysis of copper (Kim HY, Kwak SH, Lee GH, et al. Copper-catalyzed synthesis of 3-substituted-5-amino-1,2,4-thiadiazoles viaintramolecular N–S bond formation[J]. Tetrahedron, 2014, 70(45):8737-8743.), Muthusubramanian et al developed a double (Trifluoroacetic acid) phenyl iodide (III)-catalyzed oxidative cyclization to synthesize 3,5-disubstituted 1,2,4-thiadiazoles (Mariappan A, Rajaguru K, Merukan Chola N, et al. Hypervalent Iodine (III) ) Mediated Synthesis of 3-Substituted 5-Amino-1,2,4-thiadiazolesthrough Intramolecular Oxidative S–N Bond Formation[J].The Journal of organicchemistry, 2016,81(15):6573-6579.). However, such traditional oxidation strategies often require the use of equivalent or excess oxidants, which inevitably leads to waste of raw materials, generation of more by-products, or cumbersome post-processing. Although the successful development of copper catalysis avoids the above problems, it also creates the problem of metal residues.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a 1,2,4-thiadiazole skeleton and a method for preparing the condensed ring thereof with easy-to-obtain raw materials, simple process and green.

The method for synthesizing the 1,2,4-thiadiazole skeleton and its fused ring provided by the present invention comprises the following steps: using amidine or o-amino nitrogen heterocyclic compound as raw material, dissolving the raw material and isothiocyanate in In a solvent, in an air system at room temperature, an electrolyte is added, and the reaction is carried out under electrocatalytic conditions for 4 to 6 hours to construct a new N-S bond to directly generate a 1,2,4-thiadiazole skeleton and its fused ring. The molar ratio of the amidine or o-amino nitrogen heterocyclic compound to isothiocyanate is 1:1 to 1:1.5; the molar ratio of the electrolyte to the amidine or o-amino nitrogen heterocyclic compound is 0.05: 1 to 0.25:1.

In the above method, the amidine is the compound represented by the formula II, the o-amino nitrogen heterocyclic compound is the compound represented by the formula III, and the isothiocyanate is the compound represented by the formula IV;

R is aryl, alkyl, alkenyl;

R ¹ -R ² are hydrogen, aryl;

R ³ -R ⁶ are hydrogen, alkyl, alkoxy, halogen, benzo[5,6];

wherein aryl includes substituted phenyl and naphthyl;

Wherein the substituent of the substituted phenyl group is selected from: halogen, alkyl, alkoxy, nitro, trifluoromethyl;

The solvent in the above method is acetonitrile, water, methanol.

The electrolyte in the above method is tetrabutylammonium iodide, tetrabutylammonium bromide, ammonium iodide, sodium iodide, potassium iodide, tetrabutylammonium tetrafluoroborate.

The present invention is characterized in that: the readily available amidine (compound represented by formula II) or o-amino nitrogen heterocyclic compound (compound represented by formula III) and isothiocyanate (compound represented by formula IV) are dissolved in a solvent , in the air reaction at room temperature, adding an electrolyte, and constructing a new N-S bond under electrocatalytic conditions directly generates the 1,2,4-thiadiazole skeleton and its fused ring (the compound shown in formula I), which overcomes the Some deficiencies in the prior art, such as traditional oxidation strategies often require the use of equivalent or excess oxidants, inevitably lead to waste of raw materials, generation of more by-products or the need for troublesome post-processing. Although the successful development of copper catalysis avoids the above problems, it also creates the problem of metal residues.

The present invention will be described in further detail below in conjunction with specific examples.

Detailed ways

The methods used in the following examples are conventional methods unless otherwise specified.

Example 1. Using 2-aminopyridine and phenyl isothiocyanate to construct a new N-S bond under electrocatalytic conditions to directly generate 1,2,4-thiadiazole compounds as an example to illustrate the reaction operation and detect the reaction of different electrolyte pairs Impact.

2-Aminopyridine (0.2 mmol), phenyl isothiocyanate (0.2 mmol), different electrolytes (0.2 mmol) (tetrabutylamine iodide, tetrabutylammonium bromide, amine iodide, sodium iodide, Potassium iodide and tetrabutylammonium tetrafluoroborate) were successively added into the three-necked reaction flask, and a Pt(+)Pt(-) electrode was used to react at room temperature for 6 hours under the condition of 5mA current. The target product (the compound shown in formula I-1) was isolated from the reaction solution by silica gel column chromatography, and the calculated separation yield was shown in Table 1, wherein the yield of the target product I-1 in tetrabutylamine iodide was obtained The highest value, 86%, identified the best electrolyte as tetrabutylamine iodide.

Yellow solid, mp104-106℃.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J=7.2 Hz, 1H), 7.40 (t, J=7.7 Hz, 2H), 7.24-7.09 (m, 4H), 7.06 (d, J= 9.5Hz, 1H), 6.47 (t, J=6.7Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ )δ159.15, 151.55, 148.50, 133.29, 129.51, 126.02, 124.22, 121.00, 119.38, 109.58, 77.30, 76.9 ,76.67.

Table 1 Effects of different electrolytes on the reaction

Example 2. Influence of the ratio of electrolyte to 2-aminopyridine on the electrochemical reaction of the present invention

Except for the different molar ratios of electrolyte and 2-aminopyridine (0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1), other reaction conditions were the same as in Example 1. Influence of molar ratio of aminopyridine ratio on electrochemical reaction yield. After the reaction, the measurement results of the separation yield of the target product I-1 are shown in Table 2, which shows that with the change of the molar ratio of the electrolyte and 2-aminopyridine, the yield of the electrochemical reaction has an optimum value. The optimum molar ratio with 2-aminopyridine was set at 0.2:1.

Table 2 The effect of the molar ratio of electrolyte and 2-aminopyridine on the electrochemical reaction

Electrolyte to 2-aminopyridine ratio (mol/mol) 0.05 0.1 0.15 0.2 0.25 Separation yield (%) trace 30 70 86 86

Embodiment 3, the influence of reaction current on the electrochemical reaction of the present invention

Except for different currents (2mA, 3mA, 4mA, 5mA, 6mA, 10mA), other reaction conditions were the same as in Example 1, and the effect of reaction current on the yield of electrochemical reaction was detected. After the reaction, the measurement results of the separation yield of the target product I-1 are shown in Table 3, indicating that with the change of the reaction current, the yield of the electrochemical reaction has an optimal value, and the optimal reaction current is set as 5mA.

Table 3 Effects of different currents on electrochemical reactions

Reaction current (mA) 2 3 4 5 6 10 Separation yield (%) 70 79 84 86 78 trace

Embodiment 4, the influence of different solvents (volume ratio) on the electrochemical reaction of the present invention

Different solvent removals { _CH3CN :CH3OH (1:1), _CH3CN :CH3OH ( ₁ : ₂ ), _CH3CN :CH3OH ( ₂ : ₁ ), _CH3CN , CH3OH , CH ₃ CN:H ₂ O (1:1), CH ₃ OH:H ₂ O (1:1)}, other reaction conditions were the same as in Example 1, and the types and ratios of different solvents were detected on the electrochemical reaction yield. rate impact. After the reaction, the measurement results of the separation yield of the target product I-1 are shown in Table 4, indicating that acetonitrile: methanol volume ratio of 1:1 is the best.

Table 4 Effects of different solvent types and volume ratios on electrochemical reactions

Embodiment 5, the ratio of phenyl isothiocyanate and 2-aminopyridine to the influence of the electrochemical reaction of the present invention

Except for the different molar ratios of phenyl isothiocyanate and 2-aminopyridine (1:1, 1.2:1, 1.5:1), other reaction conditions are the same as those in Example 1. - Influence of the molar ratio of aminopyridine on the yield of the electrochemical reaction. After the reaction, the measurement results of the separation yield of the target product I-1 are shown in Table 5, indicating that with the change of the molar ratio of phenyl isothiocyanate and 2-aminopyridine, the yield of the electrochemical reaction has a maximum. The optimum molar ratio of phenyl isothiocyanate to 2-aminopyridine was set as 1.2:1.

Table 5 Effect of molar ratio of phenyl isothiocyanate to 2-aminopyridine on electrochemical reaction

Example 6. Influence of electrodes on the electrochemical reaction of the present invention

Except electrodes are different {Pt(+)Pt(-), C felt(+)Pt(-), C rod(+)Pt(-), Pt(+)Zn(-), Pt(+)Sn(-) } Except that, other reaction conditions are the same as in Example 5, and the influence of the electrode on the yield of the electrochemical reaction is detected. After the reaction, the measurement results of the separation yield of the target product I-1 are shown in Table 6, indicating that with the change of the positive and negative electrodes, the yield of the electrochemical reaction has an optimal value, and the electrode is set as Pt(+) Pt(-) is the best.

Table 6 Influence of electrode on electrochemical reaction

Example 7. Synthesis of compound I-2 represented by formula

4-Methyl-2-aminopyridine (0.2 mmol), phenyl isothiocyanate (0.24 mmol), tetrabutylamine iodide (0.20 mmol) and acetonitrile (1.5 mL), methanol (1.5 mL) were added sequentially In the three-necked reaction flask, use Pt(+)Pt(-) as the electrode, the current is 5mA, and place the reaction in the air at room temperature for 6 hours. The reaction solution is separated by silica gel column chromatography, and the yield is 93% .

Yellow solid, mp 94-96°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J=7.3 Hz, 1H), 7.38 (t, J=7.7 Hz, 2H), 7.12 (dd, J=15.8, 7.8 Hz, 3H), 6.81 (s, 1H), 6.30 (d, J=7.3Hz, 1H), 2.26 (s, 3H). ¹³ CNMR (101 MHz, CDCl ₃ ) δ 159.25, 151.86, 148.60, 144.83, 129.51, 124.94, 124.15, 121.12, 116.81 ,112.82,77.38,77.06,76.75,21.45.

Example 8. Synthesis of compound I-3 represented by formula

Except that 4-methyl-2-aminopyridine was 5-methyl-2-aminopyridine, other reaction conditions were the same as those in Example 7, and the yield was 92%.

Yellow solid, mp 75-76°C.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.39 (t, J=7.7Hz, 2H), 7.19-7.03 (m, 4H), 6.99 (d, J=9.5Hz, 1H) ,2.22(s,3H). ¹³ C NMR(101MHz, CDCl ₃ )δ159.48,151.20,148.78,136.88,129.55,124.10,122.75,121.06,119.37,118.65,77.38,77.06,76.74,76.630,1

Example 9. Synthesis of compound I-4 represented by formula

Except that 4-methyl-2-aminopyridine is p-3-methyl-2-aminopyridine, other reaction conditions are the same as in Example 7, and the yield is 94%.

Yellow solid, mp 90-91°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J=7.2 Hz, 1H), 7.41 (t, J=7.7 Hz, 2H), 7.15 (dd, J=17.2, 7.8 Hz, 3H), 7.04 (d, J=6.4Hz, 1H), 6.44 (t, J=6.8Hz, 1H), 2.37 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 159.89, 152.31, 148.69, 130.91, 129.54, 128.90 ,124.15,123.91,121.10,109.80,77.37,77.05,76.73,16.73.

Example 10. Synthesis of compound I-5 represented by formula

Except that 4-methyl-2-aminopyridine was 4-methoxy-2-aminopyridine, other reaction conditions were the same as those in Example 7, and the yield was 92%.

Yellow solid, mp 165-167°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J=7.6 Hz, 1H), 7.38 (t, J=7.7 Hz, 2H), 7.13 (d, J=8.0 Hz, 3H), 6.25 (d , J=10.0Hz, 2H), 3.84(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ163.85, 158.93, 152.80, 148.57, 129.49, 126.18, 124.16, 121.13, 106.71, 93.97, 77.34, 77.02, 76 ,55.86.

Example 11. Synthesis of compound I-6 represented by formula

Except that 4-methyl-2-aminopyridine is 5-bromo-2-aminopyridine, other reaction conditions are the same as in Example 7, and the yield is 78%.

Yellow solid, mp 132-134°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.40 (t, J=7.8 Hz, 2H), 7.23 (d, J=9.9 Hz, 1H), 7.14 (t, J=7.5 Hz) , 3H), 6.97 (d, J=9.9Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ )δ149.68, 136.76, 129.61, 125.86, 124.53, 120.99, 119.98, 104.10, 77.33, 77.01, 76.69.

Example 12. Synthesis of compound I-7 represented by formula

Except that 4-methyl-2-aminopyridine is 2-aminoquinoline, other reaction conditions are the same as in Example 7, and the yield is 71%.

Yellow solid, mp 127-129°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.89 (d, J=8.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.41 (t , J=7.9Hz, 2H), 7.39-7.35 (m, 2H), 7.14 (t, J=7.4Hz, 3H), 6.91 (d, J=9.7Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ )δ163.30,152.11,150.84,136.13,134.29,130.20,129.91,127.75,125.39,124.47,123.40,120.46,118.58,117.79,77.36,77.04,76.73.

Example 13. Synthesis of compound I-8 represented by formula

Except that the phenyl isothiocyanate is 4-methyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 88%.

Yellow solid, mp 138-140°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J=7.3 Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 6.80 (s , 1H), 6.29(d, J=7.3Hz, 1H), 2.34(s, 3H), 2.26(s, 3H). ¹³ C NMR(101MHz, CDCl ₃ )δ158.66,151.86,145.99,144.79,133.69,130.07 ,124.99,120.94,116.78,112.67,21.44,21.00.

Example 14. Synthesis of compound I-9 represented by formula

Except that the phenyl isothiocyanate is 3-methyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 90%.

Yellow solid, mp84-86℃

¹ H NMR (400MHz, CDCl ₃ ) δ 8.10 (d, J=7.3Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 7.00-6.89 (m, 3H), 6.80 (s, 1H) , 6.29(d, J=7.3Hz, 1H), 2.37(s, 3H), 2.26(s, 3H). ¹³ C NMR(101MHz, CDCl ₃ )δ159.08,151.85,148.60,144.80,139.38,129.32,125.00, 124.94,121.98,117.80,116.80,112.75,77.39,77.07,76.75,21.53,21.44.

Example 15. Synthesis of compound I-10 represented by formula

Except that the phenyl isothiocyanate is 2-methyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 89%.

Yellow solid, mp 128-130°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J=7.3 Hz, 1H), 7.22 (dd, J=18.3, 7.8 Hz, 2H), 7.03 (t, J=7.1 Hz, 2H), 6.81 (s, 1H), 6.31 (d, J=7.3Hz, 1H), 2.28 (d, J=2.2Hz, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 158.76, 152.01, 147.53, 144.75, 131.39, 130.91 ,126.91,124.92,124.22,117.85,116.90,112.76,77.34,77.03,76.71,21.46,17.87.

Example 16. Synthesis of compound I-11 represented by formula

Except that the phenyl isothiocyanate is 4-methoxyphenyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 89%.

Yellow solid, mp 144-145°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J=7.3 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 6.80 (s , 1H), 6.30(d, J=7.3Hz, 1H), 3.82(s, 3H), 2.27(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ158.06, 156.25, 151.88, 144.81, 141.72, 125.00 ,122.17,116.78,114.68,112.60,77.34,77.03,76.71,55.50,21.44.

Example 17. Synthesis of compound I-12 represented by formula

Except that the phenyl isothiocyanate is 3-methoxyphenyl isothiocyanate, other reaction conditions are the same as those in Example 7, and the yield is 90%.

Yellow solid, mp 66-67°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J=7.3 Hz, 1H), 7.28 (t, J=8.3 Hz, 1H), 6.81 (s, 1H), 6.77-6.65 (m, 3H) , 6.30(d, J=7.3Hz, 1H), 3.82(s, 3H), 2.26(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ160.71, 160.29, 159.61, 151.84, 150.04, 144.83, 139.17, 130.21, 129.72, 124.90, 116.80, 113.13, 112.87, 110.14, 109.19, 106.82, 77.39, 77.08, 76.76, 55.29, 52.30, 21.45.

Example 18. Synthesis of compound I-13 represented by formula

Except that the phenyl isothiocyanate is 4-fluoroisothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 68%.

Yellow solid, mp 168-169°C.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.08 (d, J=7.3Hz, 1H), 7.11-7.03 (m, 4H), 6.82 (s, 1H), 6.31 (d, J=7.3Hz, 1H) _The ^_

Example 19. Synthesis of compound I-14 represented by formula

Except that the phenyl isothiocyanate is 4-chloroisothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 78%.

Yellow solid, mp 152-153°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J=7.3 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.5 Hz, 2H), 6.84 (s , 1H), 6.34(d, J=7.3Hz, 1H), 2.28(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ159.78, 147.12, 144.94, 129.52, 129.01, 124.84, 122.48, 116.83, 113.07, 77.34, 77.02, 76.71, 21.46.

Example 20. Synthesis of compound I-15 represented by formula

Except that the phenyl isothiocyanate is 4-trifluoromethyl phenyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 62%.

Yellow solid, mp 123-124°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J=7.3 Hz, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 6.85 (s , 1H), 6.35(d, J=7.3Hz, 1H), 2.28(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ160.75, 151.84, 151.63, 145.04, 126.71, 126.67, 124.77, 121.33, 116.84, 113.35, 77.36, 77.04, 76.72, 21.44.

Example 21. Synthesis of compound I-16 represented by formula

Except that the phenyl isothiocyanate is 3-chloroisothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 80%.

Yellow solid, mp 94-95°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J=8.8 Hz, 2H), 8.27 (d, J=8.8 Hz, 2H), 8.17 (d, J=7.4 Hz, 1H), 8.17 (d , J＝7.4Hz, 1H), 7.24(d, J＝8.8Hz, 2H), 7.24(d, J＝8.8Hz, 2H), 6.93(s, 1H), 6.45(d, J＝7.3Hz, 1H) ), 6.45(d, J=7.3Hz, 1H), 2.33(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ159.78, 151.88, 147.12, 144.94, 129.52, 129.01, 124.84, 122.48, 116.83, 113.07, 77.34, 77.02, 76.71, 21.46.

Example 22. Synthesis of compound I-17 represented by formula

Except that the phenyl isothiocyanate is 1-naphthalene isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 78%.

Yellow solid, mp 144-145°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=8.1 Hz, 1H), 8.31 (d, J=7.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.62 (d , J=8.2Hz, 1H), 7.48 (dd, J=14.3, 6.8Hz, 3H), 7.17 (d, J=7.3Hz, 1H), 6.85 (s, 1H), 6.36 (d, J=7.3Hz) ,1H),2.28(s,3H). ¹³ C NMR(101MHz, CDCl ₃ )δ159.52,151.86,145.09,144.85,134.60,128.99,127.85,126.39,125.17,125.36,125.01,124.17,123.68,1 112.98,77.36,77.04,76.73,21.49.

Example 23. Synthesis of compound I-18 represented by formula

Except that phenyl isothiocyanate is ethyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 82%.

Yellow solid, mp 96-97°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (d, J=7.3 Hz, 1H), 6.72 (s, 1H), 6.19 (d, J=7.3 Hz, 1H), 3.18 (q, J=7.2 Hz , 2H), 2.23(s, 3H), 1.33(t, J=7.2Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ158.81, 144.70, 124.80, 116.73, 111.96, 77.35, 77.03, 76.71, 49.23, 21.37, 15.53.

Example 24. Synthesis of compound I-19 represented by formula

Except that the phenyl isothiocyanate is allyl isothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 81%.

Yellow solid, mp 79-80°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J=7.3 Hz, 1H), 6.74 (s, 1H), 6.21 (d, J=7.3 Hz, 1H), 6.01 (dq, J=10.5, 5.5Hz, 1H), 5.34(d, J=17.1Hz, 1H), 5.18(d, J=10.2Hz, 1H), 3.85–3.75(m, 2H), 2.23(s, 3H). ¹³ C NMR( 101MHz, CDCl ₃ )δ160.16,152.53,144.74,134.70,124.79,116.74,116.13,112.18,77.37,77.05,76.73,56.57,21.40.

Example 25. Synthesis of compound I-20 represented by formula

Except that the phenyl isothiocyanate is 4-nitroisothiocyanate, other reaction conditions are the same as in Example 7, and the yield is 70%.

Yellow solid, mp 178-180°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J=8.8 Hz, 2H), 8.17 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.93 (s , 1H), 6.45(d, J=7.3Hz, 1H), 2.33(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ212.07, 145.23, 125.50, 124.73, 121.58, 116.93, 113.95, 29.70.

Example 25. Synthesis of compound I-21 represented by formula

Benzamidine hydrochloride (0.2 mmol), phenyl isothiocyanate (0.24 mmol), tetrabutylamine iodide (0.20 mmol), triethylamine (0.2 mmol) and acetonitrile (1.5 mL), methanol ( 1.5mL) was added into the three-necked reaction flask in turn, used Pt(+)Pt(-) as the electrode, the current was 5mA, placed in the air for 6 hours at room temperature, and the reaction solution was separated by silica gel column chromatography to separate the product . Yield 91%.

White solid, mp 175-177°C.

¹ H NMR(400MHz,DMSO)δ11.05(s,1H),8.25-8.11(m,2H),7.66(d,J=8.1Hz,2H),7.57-7.47(m,3H),7.44(t , J=7.7Hz, 2H), 7.11 (t, J=7.3Hz, 1H). ¹³ C NMR (101MHz, DMSO) δ179.59, 169.00, 140.34, 133.23, 130.63, 129.88, 129.23, 128.03, 123.38, 118.16, 40.63 ,40.42,40.21,40.01,39.80,39.59,39.38.

Example 26. Synthesis of compound I-22 represented by formula

Benzamidine hydrochloride (0.2 mmol), phenyl 4-methylisothiocyanate (0.24 mmol), tetrabutylamine iodide (0.20 mmol), triethylamine (0.2 mmol) and acetonitrile (1.5 mL) were combined ), methanol (1.5mL) were added into the three-necked reaction flask in turn, Pt(+)Pt(-) was used as the electrode, the current was 5mA, and the reaction was placed in the air for 6 hours at room temperature, and the reaction solution was passed through the silica gel column layer. The product was isolated by precipitation. Yield 82%.

White solid.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.24-8.15 (m, 2H), 7.71 (d, J=8.5Hz, 2H), 7.47-7.38 (m, 3H), 7.24 (d, J=8.6Hz, 2H), 2.37(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ183.35, 170.48, 137.87, 136.94, 132.93, 130.32, 130.25, 128.54, 128.14, 120.71, 77.34, 77.02, 76.70, 20.9

Example 27. Synthesis of compound I-23 represented by formula

N-phenylbenzamidine (0.2mmol), phenyl isothiocyanate (0.24mmol), tetrabutylamine iodide (0.20mmol) and acetonitrile (1.5mL), methanol (1.5mL) were added to the three-neck reaction in sequence In the bottle, Pt(+)Pt(-) was used as an electrode, the current was 5mA, and the reaction was placed in the air at room temperature for 6 hours, and the reaction solution was separated by silica gel column chromatography to separate the product. Yield 85%.

White solid, mp 116-118°C.

¹ H NMR (400MHz, CDCl ₃ ) δ 7.46-7.27 (m, 10H), 7.25-7.18 (m, 2H), 7.13-6.98 (m, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.43, 157.08 ,150.70,136.60,130.27,130.05,129.48,129.40,128.76,128.75,128.63,128.25,123.97,120.95,77.35,77.03,76.72.

Example 28. Synthesis of compound I-24 represented by formula

N-phenylbenzamidine (0.2 mmol), 4-methyl phenyl isothiocyanate (0.24 mmol), tetrabutylamine iodide (0.20 mmol) and acetonitrile (1.5 mL), methanol (1.5 mL) were sequentially Put it into a three-necked reaction flask, use Pt(+)Pt(-) as the electrode, the current is 5mA, and place it in the air to react for 6 hours at room temperature. The reaction solution was separated by silica gel column chromatography, and the yield was 83%.

White solid, mp 193-195°C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.27 (m, 8H), 7.22 (d, J=7.8 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 6.91 (d, J= 8.0Hz, 2H), 2.31(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ164.02,157.04,148.18,136.67,133.38,130.21,130.13,130.03,129.37,128.73,128.69,128.73,128 77.33, 77.01, 76.69, 20.95.

Claims (7)

1. a method for preparing compound shown in formula I, is characterized in that, comprises the following steps: take amidine or o-amino nitrogen heterocyclic compound as raw material, raw material and isothiocyanate are dissolved in solvent, at room temperature Under the air system, add electrolyte, react under electrocatalytic conditions for 4 to 6 hours, and directly generate 1,2,4-thiadiazole skeleton and its fused ring; The molar ratio of thiocyanate is 1:1-1:1.5; the molar ratio of the electrolyte to amidine or o-amino nitrogen heterocyclic compound is 0.05:1-0.25:1.

Wherein, the amidine is the compound shown in formula II, the o-amino nitrogen heterocyclic compound is the compound shown in formula III, and the isothiocyanate is the compound shown in formula IV; R is aryl, alkyl, alkenyl; R ¹ -R ² are hydrogen, aryl; R ³ -R ⁶ are hydrogen, alkyl, alkoxy, halogen, benzo[5,6]; wherein aryl includes substituted phenyl and naphthyl; Wherein the substituent of the substituted phenyl group is selected from: halogen, alkyl, alkoxy, nitro, trifluoromethyl. 2. The method of claim 1, wherein the solvent is at least one of acetonitrile, water, and methanol. 3. The method of claim 2, wherein the solvent is a mixed solvent of acetonitrile and methanol; and the volume ratio of acetonitrile and methanol in the mixed solvent is 1-2:1-2. 4. method as claimed in claim 1 is characterized in that, described electrolyte is tetrabutylammonium iodide, tetrabutylammonium bromide, ammonium iodide, sodium iodide, potassium iodide, tetrabutyl tetrafluoroboric acid at least one of ammonium. 5. The method of claim 1, wherein the control current is 2mA-10mA in the reaction process. 6. The method of claim 1, wherein in the reaction process, a C electrode or a Pt electrode is used as a positive electrode, and a Pt electrode, a Sn electrode or a Zn electrode is used as a negative electrode. 7. The method of claim 6, wherein the C electrode is a C felt electrode, a C rod electrode or an RVC electrode.