Synthetic method for green synthesis and construction of C-N bond

Abstract

The invention discloses a green synthesis method for constructing a C-N bond, which is mainly a method for mutually coupling the C-N bond formed by dehydrating indazoles and thiophene derivatives, and in addition to indazoles compounds, N-containing heterocyclic ring substrates such as indole and carbazole are also included. Belongs to the technical field of organic chemical synthesis. The preparation method comprises the following steps: taking a reaction device, and sequentially adding 1-(2-thienyl) ethanol compounds, indazole or other aza compounds and an ion pair catalyst Ph3C < + > [B (C6F5) 4] <->. The method is green, efficient, high in atom economy, mild in reaction condition and wide in substrate application range, a new route for synthesizing the indazole derivative is provided, and the method has the advantages of being novel, efficient, high in atom economy, mild in reaction condition, wide in substrate application range and the like; compared with a traditional noble metal catalyst, the catalyst used in the invention has the advantages of environmental friendliness, economy and the like.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry, and specifically relates to a green metal-free catalytic method for constructing C-N bonds, mainly a method for the C-N bond coupling reaction of thiophene derivatives and indazoles. This method realizes efficient coupling through an ion pair catalytic system, and has the advantages of environmental friendliness, low cost, wide substrate adaptability, etc. Background Art

[0002] In medicinal chemistry, thiophene and indazole derivatives are widely used in the development of anti-cancer, anti-inflammatory and other drugs due to their unique biological activities. Traditional C-N bond coupling reactions (such as Buchwald-Hartwig coupling) rely on precious metal catalysts such as palladium and copper, and have problems such as high cost, harsh reaction conditions (high temperature, long time), and metal residues affecting drug safety. Although metal-free catalytic systems have gradually developed in recent years, there is still no report on the coupling reaction of thiophene and indazole.

[0003] Indazole derivatives are playing an increasingly important role in drug discovery due to their wide range of biological activities. Compounds containing indazole structures have been widely proven to have various activities such as anti-inflammatory, analgesic, central nervous system, anti-allergic, anti-fungal and anti-arthritis. As shown below, for example, Bendazac and Benzidamine with 1H-indazole structures are common commercially available drugs with anti-inflammatory and analgesic effects; Granisetron, as a 5-HT3 receptor antagonist, is mainly used to prevent nausea and vomiting caused by cancer treatment. In addition, important progress has also been made in the synthetic methodology of indazole compounds. The development of new synthetic methods makes the synthesis of indazole derivatives more efficient and environmentally friendly, which is of great significance for the industrial production of drugs.

[0004] Summary of the Invention

[0005] The object of the present invention is to provide a green metal-free catalytic method for constructing C-N bonds, mainly the preparation method of thiophene-indazole compounds. In this preparation method, the required reaction raw materials (indazole or its derivatives) are cheap, easy to obtain, the substrate range is wide, the reaction conditions are mild (temperature is 40-60 °C), only a small amount of catalyst is used, the cost is low, and the reaction efficiency is high. The catalyst required in the preparation method of the present invention is a non-metal type catalyst. Compared with the existing metal-catalyzed synthesis methods, the synthesis process is easier to purify and there is no problem of metal residues. The prepared thiophene-indazole compounds have biological activities such as anti-cancer and anti-inflammatory.

[0006] To solve the technical problems of the present invention, the technical solution proposed is: a synthetic method for green synthesis of constructing C-N bonds, and the synthetic method route is as follows:

[0007]

[0008] Among them, R1 is any one of methyl, phenyl, sulfomethyl, chlorine, and bromine;

[0009] R2 is any one of methyl, cyclopropyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, phenyl, p-trifluoromethylphenyl, and p-methoxyphenyl;

[0010] R3 is any one of hydrogen, methyl, chlorine, bromine, iodine, trifluoromethyl, aldehyde group, and methoxy;

[0011] R4 is any one of hydrogen, carboxyl group, and ester group;

[0012] The specific preparation steps are as follows:

[0013] (1) Take a reaction device, and successively add thiophenol or thiophenol derivative of formula (I), indazole or substituted indazole compound of formula (II), and ionic pair catalyst Ph3C + [B(C6F5)4] - , and then add a solvent. The molar ratio between the thiophene compound, the substituted indazole compound, and the ionic pair catalyst is respectively 1:2:0.05

[0014] (2) Transfer the reaction flask to a heating device for heating, and quickly stir the reaction. After TLC detects the completion of the reaction, through separation and purification, the corresponding target product of formula (III) is obtained.

[0015] Preferably, the solvent is acetone, the heating temperature in step (2) is 40°C, and the reaction time is 12 hours.

[0016] Preferably, the indazole compound is any one of indazole, 4-methyl-1H-indazole, 4-bromo-1H-indazole, 5-methylindazole, 5-chloro-1H-indazole, 5-iodo-1H-indazole, 5-trifluoromethyl-1H-indazole, 5-methoxy-1H-indazole, 7-bromo-1H-indazole, 6-bromo-1H-indazole, 4-bromo-6-chloro-1H-indazole, 4-bromo-5-methyl-1H-indazole, 5-bromo-6-methyl-1H-indazole, 3-bromocarbazole, 2,7-dibromocarbazole, methyl 1,2,3-triazole-4-carboxylate, methyl 2H-1,2,3-triazole-4-carboxylate, 5-phenyltetrazole, 2,3-dimethylindole, 2,3-diphenyl-1H-indole, 1,2,3,4-tetrahydrocarbazole, 6-chloropurine, ethyl 4-pyrazolecarboxylate, diethyl 3,5-pyrazoledicarboxylate, 1H-indazole-5-carbaldehyde, methyl 1H-indazole-3-carboxylate, benzotriazole, 1H-1,2,3-triazolo[4,5-b]pyridine.

[0017] Preferably, the specific preparation steps are as follows:

[0018] (1) Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add thiophenol or thiophenol derivative of formula (I) (0.2 mmol, 1.0 equiv.), indazole or substituted indazole compound of formula (II) (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%), and then add 1 mL of acetone;

[0019] (2) Transfer the reaction bottle to a metal bath at 40 °C and heat it, and rapidly stir the reaction for 12 h; after detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain the corresponding target product of formula (III).

[0020] Preferably, any one of the obtained compounds of formula (III) is as follows:

[0021]

[0022]

[0023] Compared with the prior art, the beneficial effects of the present invention are:

[0024] (1) The reaction raw materials (thiophene or its derivatives and indazole or its derivatives) required in the preparation method of the present invention are cheap and easily available. The thiophene-indole compounds are obtained by a one-step method, avoiding the problem that the existing synthesis methods of indole derivatives are still too cumbersome. In contrast, the method uses mild conditions with a temperature of 40 °C, is simple to operate and only requires the addition of 5 mol% catalyst. Compared with other reactions adding stoichiometric additives, it has low cost, high reaction efficiency and high atom economy, and can effectively reduce the generation of chemical waste. The reaction chemical formula is as follows:

[0025]

[0026] (2) As can be seen from (1), the reaction conditions are relatively mild. Starting from the raw materials and products to obtain the target product, only water is generated as the only by-product, with excellent atom economy.

[0027] (3) The raw materials used in the preparation process are cheap and easily available, and the target product can be obtained in high yield, indicating that this method has economic benefits.

[0028] (4) For the preparation method of the thiophene-indazole compounds provided by the present invention, the catalyst used belongs to a non-metal catalyst, has good functional group tolerance, a wide range of applicable reaction substrates, and high yields. As a pharmaceutical intermediate, there is no biological toxicity caused by metal residues.

[0029] (5) In step (2), the heating temperature is 40 °C, and the optimal reaction temperature is 40 °C. Lowering the reaction temperature is not conducive to the smooth progress of the reaction, and raising the reaction temperature does not improve the reaction effect either. The reaction time is 12 hours. The reaction time comparison results show that the reaction is extended to 12 hours to reach complete reaction. The molar ratios of the thiophene compounds, indazole compounds and the ion pair catalyst are respectively 1:2:0.05 - 0.10. In order to fully exert the catalytic efficiency of the ion pair catalyst Ph3C + [B(C6F5)4] - , the amount of the catalyst can be reduced to 5 mol% (5 × 10 4 ppm). Using an organic solvent as the reaction solvent can obtain the target product, but the reaction effects are all inferior to that of acetone. In a 0.2 mmol reaction scale, appropriately adjusting the amount of acetone has little effect on the reaction effect. In order to make the reaction substrates fully and evenly dispersed in the reaction system, acetone is selected as the solvent.

[0030] (6) When other ion pairs are selected to replace the ion pair catalyst Ph3C + [B(C6F5)4] - , the reaction effects all show a significant decline, indicating that the ion pair catalyst Ph3C + [B(C6F5)4]- The reaction effect is the best under this catalytic system. Therefore, the preparation route of the thiophene-indazole compounds provided by the present invention has the advantages of novelty, high efficiency, high atom economy, mild reaction conditions and wide substrate applicability, and has important potential application prospects in the fields of organic synthesis and drug synthesis. Description of the Drawings

[0031] Figure 1 1H NMR spectrum of 7-bromo-1-[1-(thiophen-2-yl)ethyl]-1H-indazole in Example 8 of the present invention;

[0032] Figure 2 13C NMR spectrum of 7-bromo-1-[1-(thiophen-2-yl)ethyl]-1H-indazole in Example 8 of the present invention;

[0033] Figure 3 1H NMR spectrum of methyl 1-[1-(thiophen-2-yl)ethyl]-1H-indole-3-carboxylate in Example 13 of the present invention;

[0034] Figure 4 13C NMR spectrum of methyl 1-[1-(thiophen-2-yl)ethyl]-1H-indole-3-carboxylate in Example 13 of the present invention;

[0035] Figure 5 Tumor growth curves of mice in each experimental group;

[0036] Figure 6 Comparison of tumor volumes in each group at the end of the experiment; Detailed Embodiments

[0037] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0038]

[0039]

[0040] Example 1:

[0041]

[0042] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it while rapidly stirring the reaction for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 42 mg of the target product with a yield of 92%.

[0043] 1-(1-(thiophen-2-yl)ethyl)-1H-indazole (1)

[0044]

[0045] TLC: Rf = 0.48 (PE / EA = 8 / 1); 42 mg, yield: 92%; colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.29–7.25 (m, 2H), 7.08–7.04 (m, 2H), 6.97 (dd, J = 5.1, 3.4 Hz, 1H), 6.06 (q, J = 7.0 Hz, 1H), 2.09 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 148.6, 143.8, 126.1, 125.9, 125.8, 121.8, 121.8, 121.0, 120.4, 117.7, 58.4, 22.9.

[0046] Example 2:

[0047]

[0048] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] -(0.01 mmol, 5 mol%). Then 1 mL of acetone was added. Then the reaction flask was transferred to a metal bath at 40 °C for heating, and the reaction was rapidly stirred for 12 h. After the reaction was completed by TLC detection, it was purified by silica gel column chromatography or preparative thin layer plate to obtain 45 mg of the target product with a yield of 73%.

[0049] 4-bromo-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (2)

[0050]

[0051] TLC: Rf = 0.49 (PE / EA = 8 / 1); 45 mg, yield: 73%; colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 5.1, 1.2 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.17–7.09 (m, 2H), 7.00 (dd, J = 5.1, 3.6 Hz, 1H), 6.06 (q, J = 7.0 Hz, 1H), 2.11 (d, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 148.4, 143.1, 126.9, 126.7, 126.0, 125.9, 124.3, 123.7, 121.9, 116.9, 113.0, 58.6, 22.7.

[0052] Example 3:

[0053]

[0054] A 3 mL white sample bottle equipped with a magnetic stirring rotor was successively added with 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.02 mmol, 10 mol%). Then 1 mL of acetone was added. Then the reaction flask was transferred to a metal bath at 40 °C for heating, and the reaction was rapidly stirred for 12 h. After the reaction was completed by TLC detection, it was purified by silica gel column chromatography or preparative thin layer plate to obtain 32 mg of the target product with a yield of 66%.

[0055] 5-methyl-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (3)

[0056]

[0057] TLC: Rf = 0.52 (PE / EA = 8 / 1); 32 mg, yield: 66%; colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.28–7.25 (m, 1H), 7.12 (dd, J = 8.9, 1.6 Hz, 1H), 7.07–7.03 (m, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 6.03 (q, J = 7.0 Hz, 1H), 2.40 (s, 3H), 2.08 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 147.3, 143.9, 131.0, 128.8, 126.8, 125.6, 125.5, 121.9, 119.9, 118.3, 117.2, 58.2, 22.6, 21.7.

[0058] Example 4:

[0059]

[0060] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and sequentially add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction flask to a metal bath at 40 °C and heat it while stirring rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 40 mg of the target product with a yield of 76%.

[0061] 5-chloro-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (4)

[0062]

[0063] TLC: Rf = 0.55 (PE / EA = 8 / 1); 40 mg, yield: 76%; orange liquid. 11H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 1.1 Hz, 1H), 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.20 (dd, J = 9.2, 2.0 Hz, 1H), 7.08 (d, J = 3.4 Hz, 1H), 6.98 (dd, J = 5.1, 3.5 Hz, 1H), 6.04 (q, J = 7.0 Hz, 1H), 2.09 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 146.8, 143.2, 127.3, 126.9, 125.9, 125.8, 122.0, 120.6, 119.1, 118.9, 58.4, 22.6.

[0064] Example 5:

[0065]

[0066] Take a 3 mL white sample vial equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction flask to a metal bath heated to 40 °C and stir the reaction rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 60 mg of the target product with a yield of 85%.

[0067] 5-iodo-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (5)

[0068]

[0069] TLC: Rf = 0.48 (PE / EA = 8 / 1); 60 mg, yield: 85%; orange oil. 11H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.82 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.47 (dd, J = 9.0, 1.6 Hz, 1H), 7.28 (dd, J = 5.1, 1.2 Hz, 1H), 7.07 (d, J = 3.4 Hz, 1H), 6.98 (dd, J = 5.1, 3.6 Hz, 1H), 6.03 (q, J = 7.1 Hz, 1H), 2.08 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 146.9, 143.2, 134.4, 129.2, 126.8, 125.9, 125.7, 123.9, 119.9, 119.5, 85.8, 58.4, 22.6.

[0070] Example 6:

[0071]

[0072] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it while stirring rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 44 mg of the target product with a yield of 75%.

[0073] 1-(1-(thiophen-2-yl)ethyl)-5-(trifluoromethyl)-1H-indazole (6)

[0074]

[0075] TLC: Rf = 0.60 (PE / EA = 8 / 1); 44 mg, yield: 75%; yellow oil. 11H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.97 (s, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.44 (dd, J = 9.1, 1.7 Hz, 1H), 7.31 (dd, J = 5.1, 1.3 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 7.00 (dd, J = 5.1, 3.6 Hz, 1H), 6.13–6.05 (m, 1H), 2.12 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 148.8, 142.9, 127.9, 127.9, 126.9, 126.0, 126.0, 124.0, 123.7, 123.3, 122.8, 122.0, 121.9, 121.9, 121.9, 120.2, 119.2, 119.2, 118.7, 58.7, 22.6. 19 19F NMR (376 MHz, CDCl3) δ -61.65.

[0076] Example 7:

[0077]

[0078] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C for heating, and rapidly stir the reaction for 12 h. After the reaction is completed by TLC detection, it is purified by silica gel column chromatography or preparative thin layer plate to obtain 44 mg of the target product, with a yield of 86%.

[0079] 5-methoxy-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (7)

[0080]

[0081] TLC: Rf = 0.46 (PE / EA = 8 / 1); 44 mg, yield: 86%; colorless oil. 11H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 1.8 Hz, 1H), 7.63 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 6.5 Hz, 1H), 7.05 (s, 1H), 7.01–6.93 (m, 2H), 6.83 (s, 1H), 6.01 (q, J = 7.1 Hz, 1H), 3.81 (s, 3H), 2.08 (d, J = 7.7 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 155.0, 145.2, 144.0, 126.8, 125.6, 125.5, 121.6, 120.7, 119.9, 119.0, 96.5, 58.2, 55.3, 22.6.

[0082] Example 8:

[0083]

[0084] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C for heating, and rapidly stir the reaction for 12 h. After the reaction is completed by TLC detection, it is purified by silica gel column chromatography or preparative thin layer plate to obtain 51 mg of the target product with a yield of 83%.

[0085] 7-bromo-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (8)

[0086]

[0087] TLC: Rf = 0.51 (PE / EA = 8 / 1); 51 mg, yield: 83%; colorless liquid. 1 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.32 (dd, J = 5.1, 1.2 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 7.01 (dd, J = 5.1, 3.5 Hz, 1H), 6.91 (dd, J = 8.3, 7.2 Hz, 1H), 6.20 (q, J = 7.0 Hz, 1H), 2.08 (d, J = 7.0 Hz, 3H).13 13C NMR (101 MHz, CDCl3) δ 146.8, 142.8, 128.7, 126.9, 126.2, 126.0, 122.6, 122.3, 121.9, 119.8, 111.0, 58.6, 23.0.

[0088] Example 9:

[0089]

[0090] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction flask to a metal bath at 40 °C and heat it, and rapidly stir the reaction for 12 h. After the reaction is completed by TLC detection, it is purified by silica gel column chromatography or preparative thin layer plate to obtain 40 mg of the target product with a yield of 65%.

[0091] 6-bromo-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (9)

[0092]

[0093] TLC: Rf = 0.57 (PE / EA = 8 / 1); 40 mg, yield: 65%; yellow liquid. 1 1H NMR (400 MHz, CDCl3) δ 7.94–7.86 (m, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 5.1, 1.1 Hz, 1H), 7.13 (dd, J = 8.8, 1.6 Hz, 1H), 7.08 (d, J = 3.1 Hz, 1H), 6.99 (dd, J = 5.2, 3.6 Hz, 1H), 6.03 (q, J = 7.0 Hz, 1H), 2.08 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 149.1, 143.2, 126.9, 125.9, 125.8, 125.4, 121.7, 121.4, 120.1, 120.0, 120.0, 58.4, 22.6.

[0094] Example 10:

[0095]

[0096] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction flask to a metal bath at 40 °C and heat it while rapidly stirring the reaction for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 36 mg of the target product with a yield of 53%.

[0097] 4-bromo-6-chloro-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (10)

[0098]

[0099] TLC: Rf = 0.45 (PE / EA = 8 / 1); 36 mg, yield: 53%; colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.66 (s, 1H), 7.31 (d, J = 5.0 Hz, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 7.01 (dd, J = 5.2, 3.6 Hz, 1H), 6.03 (qd, J = 7.0, 1.9 Hz, 1H), 2.09 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 148.0, 142.7, 131.8, 127.0, 126.1, 126.0, 125.3, 122.5, 122.3, 116.0, 113.7, 58.8, 22.6.

[0100] Example 11:

[0101]

[0102] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] -(0.01 mmol, 5 mol%). Then 1 mL of acetone was added. Then the reaction flask was transferred to a metal bath at 40 °C and heated with rapid stirring for 12 h. After the reaction was completed by TLC detection, it was purified by silica gel column chromatography or preparative thin layer plate to obtain 53 mg of the target product with a yield of 83%.

[0103] 4-bromo-5-methyl-1-(1-(thiophen-2-yl)ethyl)-1H-indazole (11)

[0104]

[0105] TLC: Rf = 0.51 (PE / EA = 8 / 1); 53 mg, yield: 83%; yellow liquid. 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 4.9 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 6.98 (t, J = 4.2 Hz, 1H), 6.03 (q, J = 7.0 Hz, 1H), 2.45 (s, 3H), 2.10 (d, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 147.3, 143.4, 130.1, 129.6, 127.9, 126.8, 125.8, 125.7, 124.3, 121.5, 116.5, 113.2, 58.5, 22.6, 21.7.

[0106] Example 12:

[0107]

[0108] A 3 mL white sample bottle equipped with a magnetic stirring rotor was successively added with 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then 1 mL of acetone was added. Then the reaction flask was transferred to a metal bath at 40 °C and heated with rapid stirring for 12 h. After the reaction was completed by TLC detection, it was purified by silica gel column chromatography or preparative thin layer plate to obtain 49 mg of the target product with a yield of 76%.

[0109] 5-bromo-6-methyl-1-(1-(thiophen-2-yl)ethyl)-1H-indazole(12)

[0110]

[0111] TLC: Rf = 0.47 (PE / EA = 8 / 1); 49 mg, yield: 76%; yellow liquid. 1 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 10.6 Hz, 2H), 7.59 (s, 1H), 7.28 (d, J = 5.0 Hz, 1H), 7.06 (d, J = 3.6 Hz, 1H), 6.98 (t, J = 4.3 Hz, 1H), 6.01 (q, J = 7.0 Hz, 1H), 2.48 (s, 3H), 2.08 (d, J = 7.6 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 147.9, 143.5, 135.2, 126.8, 125.8, 125.6, 123.0, 121.5, 120.0, 119.4, 117.9, 58.3, 24.0, 22.6.

[0112] Example 13:

[0113]

[0114] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), carbazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it while stirring rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 24 mg of the target product, with a yield of 34%.

[0115] 3-bromo-9-(1-(thiophen-2-yl)ethyl)-9H-carbazole(13)

[0116]

[0117] TLC: Rf = 0.44 (PE); 24 mg, yield: 34%; yellow liquid. 11H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2.0 Hz, 1H), 8.05 (dt, J = 7.8, 1.0 Hz, 1H), 7.46–7.38 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.27–7.22 (m, 2H), 7.14 (d, J = 8.8 Hz, 1H), 7.01–6.93 (m, 2H), 6.16 (q, J = 7.0 Hz, 1H), 2.01 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 144.8, 139.8, 138.0, 128.1, 126.9, 126.3, 125.3, 124.8, 123.0, 122.4, 120.5, 119.6, 112.1, 111.6, 110.1, 77.3, 77.0, 76.7, 49.8, 18.8.

[0118] Example 14:

[0119]

[0120] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and sequentially add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), carbazole derivative (0.4 mmol, 2.0 equiv.), and the ion-pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it while rapidly stirring the reaction for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin-layer plate to obtain 29 mg of the target product with a yield of 33%.

[0121] 2,7-dibromo-9-(1-(thiophen-2-yl)ethyl)-9H-carbazole (14)

[0122]

[0123] TLC: Rf = 0.47 (PE); 29 mg, yield: 33%; yellow liquid. 11H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 1.7 Hz, 2H), 7.35 (dd, J = 8.3, 1.6 Hz, 2H), 7.28 (d, J = 5.2 Hz, 1H), 7.02–6.96 (m, 2H), 6.08 (q, J = 6.9 Hz, 1H), 2.02 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 144.0, 140.5, 127.2, 125.8, 125.2, 123.1, 122.1, 121.6, 119.7, 113.5, 50.2, 19.0.

[0124] Example 15:

[0125]

[0126] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C for heating, and stir the reaction rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 23 mg of the target product with a yield of 41%.

[0127] 9-(1-(thiophen-2-yl)ethyl)-2,3,4,9-tetrahydro-1H-carbazole (15)

[0128]

[0129] TLC: Rf = 0.50 (PE); 23 mg, yield: 41%; yellow liquid. 11H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 6.3, 2.4 Hz, 1H), 7.22 (d, J = 5.1 Hz, 1H), 7.15–7.10 (m, 1H), 7.08–7.00 (m, 2H), 6.95 (dd, J = 5.0, 3.5 Hz, 1H), 6.86 (d, J = 5.8 Hz, 1H), 5.82 (q, J = 7.0 Hz, 1H), 2.74 (q, J = 7.3 Hz, 3H), 2.65–2.55 (m, 1H), 1.95 (d, J = 7.1 Hz, 3H), 1.89 (d, J = 34.2 Hz, 4H). 13 13C NMR (101 MHz, CDCl3) δ 146.7, 135.3, 135.2, 128.3, 126.9, 125.0, 124.4, 120.6, 118.9, 117.9, 110.7, 110.5, 49.7, 23.6, 23.2, 23.1, 21.2, 20.3.

[0130] Example 16:

[0131]

[0132] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ionic pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it, and stir the reaction rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 35 mg of the target product with a yield of 74%.

[0133] methyl 1-(1-(thiophen-2-yl)ethyl)-1H-1,2,3-triazole-5-carboxylate (16)

[0134]

[0135] TLC: Rf = 0.31 (PE / EA = 5 / 1); 35 mg, yield: 74%; white solid. 11H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.34 (dd, J = 5.2, 1.1 Hz, 1H), 7.10 (dd, J = 3.5, 1.0 Hz, 1H), 7.04–6.99 (m, 1H), 6.17 (q, J = 7.0 Hz, 1H), 3.91 (s, 3H), 2.04 (d, J = 6.9 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 161.1, 141.2, 139.8, 127.3, 126.6, 126.6, 125.8, 56.0, 52.2, 22.4.

[0136] Example 17:

[0137]

[0138] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ionic pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it, and stir the reaction rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 33 mg of the target product with a yield of 70%.

[0139] methyl 2-(1-(thiophen-2-yl)ethyl)-2H-1,2,3-triazole-4-carboxylate (17)

[0140]

[0141] TLC: Rf = 0.33 (PE / EA = 5 / 1); 33 mg, yield: 70%; white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.34 (dd, J = 5.1, 1.2 Hz, 1H), 7.10 (d, J = 3.6 Hz, 1H), 7.01 (dd, J = 5.1, 3.6 Hz, 1H), 6.17 (q, J = 7.0 Hz, 1H), 3.91 (s, 3H), 2.04 (d, J = 7.1 Hz, 3H). 1313C NMR (101 MHz, CDCl3) δ 161.3, 141.3, 140.0, 127.4, 126.7, 126.7, 125.9, 56.2, 52.3, 22.5.

[0142] Example 18:

[0143]

[0144] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ionic pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath heated to 40 °C and stir the reaction rapidly for 12 h. After detecting the completion of the reaction by TLC, purify it by silica gel column chromatography or preparative thin layer plate to obtain 46 mg of the target product, with a yield of 90%.

[0145] 5-phenyl-2-(1-(thiophen-2-yl)ethyl)-2H-tetrazole (18)

[0146]

[0147] TLC: Rf = 0.28 (PE / EA = 20 / 1); 46 mg, yield: 90%; colorless liquid. 1 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.5, 2.2 Hz, 2H), 7.48 (s, 1H), 7.46 (d, J = 1.6 Hz, 2H), 7.30 (dd, J = 5.1, 1.2 Hz, 1H), 7.17 (d, J = 3.7 Hz, 1H), 6.98 (dd, J = 5.1, 3.6 Hz, 1H), 6.40 (q, J = 7.1 Hz, 1H), 2.16 (d, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 165.0, 141.3, 130.2, 128.8, 127.9, 127.4, 126.8, 126.3, 126.2, 58.8, 21.8.

[0148] Example 19:

[0149]

[0150] Take a 3 mL white sample vial equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction vial to a metal bath at 40 °C and heat while rapidly stirring the reaction for 12 h. After the reaction is completed as detected by TLC, purify by silica gel column chromatography or preparative thin layer plate to obtain 22 mg of the target product with a yield of 44%.

[0151] 2,3-dimethyl-1-(1-(thiophen-2-yl)ethyl)-1H-indole (19)

[0152]

[0153] TLC: Rf = 0.46 (PE); 22 mg, yield: 44%; brown liquid. 1 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 7.12–7.00 (m, 3H), 6.96 (dd, J = 5.1, 3.5 Hz, 1H), 6.89–6.86 (m, 1H), 5.88 (q, J = 7.0 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 1.97 (d, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 146.6, 134.8, 131.9, 129.3, 126.8, 124.9, 124.2, 120.4, 118.6, 118.0, 110.6, 107.5, 49.8, 20.0, 10.9, 8.9.

[0154] Example 20:

[0155]

[0156] Take a 3 mL white sample vial equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] -(0.02 mmol, 10 mol%). Then 1 mL of acetone was added. Then the reaction flask was transferred to a metal bath heated to 40 °C and the reaction was stirred rapidly for 12 h. After completion of the reaction was detected by TLC, it was purified by silica gel column chromatography or preparative thin layer plate to obtain 38 mg of the target product with a yield of 72%.

[0157] 6-chloro-9-(1-(thiophen-2-yl)ethyl)-9H-purine(20)

[0158]

[0159] TLC: Rf = 0.29 (PE / EA = 5 / 1); 38 mg, yield: 72%; white solid. 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.10 (s, 1H), 7.35–7.28 (m, 1H), 7.16–7.10 (m, 1H), 7.04–6.98 (m, 1H), 6.23 (q, J = 7.1 Hz, 1H), 2.07 (d, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CHLOROFORM-D) δ 152.0, 151.3, 151.2, 143.4, 142.1, 131.8, 127.4, 126.4, 50.2, 22.0.

[0160] Example 21:

[0161]

[0162] A 3 mL white sample bottle equipped with a magnetic stirring rotor was successively charged with 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then 1 mL of acetone was added. Then the reaction flask was transferred to a metal bath heated to 40 °C and the reaction was stirred rapidly for 12 h. After completion of the reaction was detected by TLC, it was purified by silica gel column chromatography or preparative thin layer plate to obtain 38 mg of the target product with a yield of 72%.

[0163] ethyl 1-(1-(thiophen-2-yl)ethyl)-1H-pyrazole-4-carboxylate(21)

[0164]

[0165] TLC: Rf = 0.52 (PE / EA = 5 / 1); 46 mg, yield: 92%; colorless liquid. 1 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.88 (s, 1H), 7.28 (dd, J = 5.1, 1.3 Hz, 1H), 7.02 (d, J = 3.5 Hz, 1H), 6.97 (dd, J = 5.1, 3.6 Hz, 1H), 5.76 (q, J = 7.1 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.96 (d, J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 163.1, 143.3, 141.0, 130.9, 127.0, 125.9, 125.7, 115.2, 60.3, 57.4, 22.3, 14.5.

[0166] Example 22:

[0167]

[0168] Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and successively add 1-(thiophen-2-yl)ethanol (0.2 mmol, 1.0 equiv.), indazole derivative (0.4 mmol, 2.0 equiv.), and the ionic pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%). Then add 1 mL of acetone. Then transfer the reaction bottle to a metal bath at 40 °C and heat it while stirring rapidly for 12 h. After the reaction is completed as detected by TLC, purify it by silica gel column chromatography or preparative thin-layer plate to obtain 53 mg of the target product with a yield of 93%.

[0169] methyl 1-(1-(thiophen-2-yl)ethyl)-1H-indazole-3-carboxylate (22)

[0170]

[0171] TLC: Rf = 0.58 (PE / EA = 8 / 1); 53 mg, yield: 93%; colorless oil. 11H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.0 Hz, 1H), 7.38–7.33 (m, 2H), 7.29 (ddd, J = 8.0, 5.5, 2.5 Hz, 1H), 7.21 (dd, J = 5.1, 1.2 Hz, 1H), 7.00–6.95 (m, 1H), 6.92 (dd, J = 5.1, 3.6 Hz, 1H), 6.23 (q, J = 7.2 Hz, 1H), 4.04 (s, 3H), 2.13 (d, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 163.2, 143.8, 139.7, 134.8, 126.9, 126.9, 125.6, 125.2, 124.5, 123.4, 122.4, 110.5, 56.2, 52.2, 21.2.

[0172] Example 22:

[0173] Anti-tumor activity detection:

[0174] SPF-grade female BALB / C mice, 5 - 6 weeks old and weighing 18 - 20 g, were purchased from the Henan Experimental Animal Center. These mice were divided into five groups, namely the first group to the fifth group.

[0175] Approximately one week after inoculation, the tumor grew to 100 mm 3 , using PBS as the solvent, solutions with appropriate concentrations were prepared from Drug One, Drug Two, Drug Three, and Drug Four, and the mice were administered by intratumoral injection. Among them, the first group to the fifth group used a 1 mL syringe for intratumoral injection, and the injection volume of the solution was 50 μL. The molar amounts of the drugs used were the same.

[0176] Table 1

[0177] Mouse Injection solution Dosing dose Molar amount The first group PBS solution —— —— The second group Compound 10 3 μg 12 nmol The third group Compound 20 5 μg 12 nmol The fourth group Compound 36 3 μg 12 nmol The fifth group Compound 46 4 μg 12 nmol

[0178] For the mice in the first group to the fifth group of this example, the drugs were administered once every 3 days for a total of 2 times. During the drug administration process, the body weight and tumor volume of the mice were measured every 2 days until 22 days after drug administration. Among them, the method for measuring the tumor volume was: using a vernier caliper to measure the major axis (l) and minor axis (w) of the tumor, and according to the volume formula: v = 0.5 × l × w 2 , the tumor volume was calculated. After 22 days, the treatment ended, and the mice were euthanized, the tumors were dissected, photographed, and the results were analyzed. The experimental results are as Figure 5 、 Figure 6 shown.

[0179] As Figures 5 to 6As shown, an intratumoral rapid injection dose of 5 μg of Compound 20, 3 μg of Compound 36, and 4 μg of Drug 46 can all effectively inhibit tumor growth, while there is no significant difference in the experimental results between the group with 3 μg of Compound 10 and the group injected with PBS. This result indicates that Compound 20, Compound 36, Compound 46, and their derivatives have anti-tumor activity.

[0180] Comparative Example 1: Comparison of Catalysts

[0181]

[0182] Table 2

[0183]

[0184] Select other ion pairs to replace the ion pair catalyst Ph3C + [B(C6F5)4] - , the reaction effect shows a significant decline, indicating that the ion pair catalyst Ph3C + [B(C6F5)4] - has the best reaction effect under this catalytic system.

[0185] Comparative Example 2: Comparison of Reaction Solvents

[0186]

[0187] Table 3

[0188]

[0189] When other solvents replace acetone as the reaction solvent, the yields of the target products all show varying degrees of decline and even cause the catalyst to lose its catalytic activity.

[0190] Comparative Example 3: Comparison of the Amount of Reaction Solvent Acetone

[0191]

[0192] Table 4

[0193]

[0194] In a 0.2 mmol reaction scale, appropriately adjusting the amount of acetone has little effect on the reaction effect (<9%), and 1.0 mL of acetone is selected to make the reaction substrate fully and evenly dispersed in the reaction system.

[0195] Comparative Example 4: Comparison of Reaction Time

[0196]

[0197] Table 5

[0198]

[0199] The comparison results of the reaction time show that when the reaction is extended to 12 hours, a complete reaction is achieved. Continuing to extend the reaction time, the yield does not increase significantly.

[0200] Comparative Example Five: Comparison of the amount of catalyst

[0201]

[0202] Table 6

[0203]

[0204] In order to fully exert the catalytic efficiency of the ion pair catalyst Ph3C + [B(C6F5)4] - the amount of the catalyst can be reduced to 5 mol%.

[0205] Comparative Example Six: Comparison of the reaction temperature

[0206]

[0207] Table 7

[0208]

[0209] The optimal reaction temperature is 40 °C. Increasing the reaction temperature does not improve the reaction effect.

[0210] Comparative Example Seven: Comparison of the amount of reactant 2a

[0211]

[0212] Table 8

[0213]

[0214] The comparison results show that when the amount of 2a is 0.4 mmol, a complete reaction is achieved.

Claims

1. A synthetic method for green synthesis of C-N bonds, characterized in that: The synthetic route is as follows: Among them, R1 is any one of methyl, phenyl, sulfomethyl, chlorine, and bromine; R2 is any one of methyl, cyclopropyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, phenyl, p-trifluoromethylphenyl, and p-methoxyphenyl; R3 is any one of hydrogen, methyl, chlorine, bromine, iodine, trifluoromethyl, aldehyde group, and methoxy; R4 is any one of hydrogen, carboxyl group, and ester group; The specific preparation steps are as follows: (1) Take a reaction device and sequentially add thiophenol or thiophenol derivative of formula (I), indazole or substituted indazole compound of formula (II), and ionic pair catalyst Ph3C + [B(C6F5)4] - , then add a solvent, and the molar ratios between the compound of formula (I), the compound of formula (II), and the ionic pair catalyst are respectively 1:2:0.05 - 0.10; (2) Transfer the reaction flask to a heating device for heating, and rapidly stir the reaction. After the reaction is completed as detected by TLC, through separation and purification, the corresponding target product of formula (Ⅲ) is obtained.

2. The synthetic method for constructing C-N bonds by green synthesis according to claim 1, wherein: The solvent is acetone. In step (2), the heating temperature is 40 °C and the reaction time is 12 hours.

3. The synthetic method for constructing a C-N bond by green synthesis according to claim 1, wherein: The indazole or substituted indazole compound of formula (II) is any one of indazole, 4-methyl-1H-indazole, 4-bromo-1H-indazole, 5-methylindazole, 5-chloro-1H-indazole, 5-iodo-1H-indazole, 5-trifluoromethyl-1H-indazole, 5-methoxy-1H-indazole, 7-bromo-1H-indazole, 6-bromo-1H-indazole, 4-bromo-6-chloro-1H-indazole, 4-bromo-5-methyl-1H-indazole, 5-bromo-6-methyl-1H-indazole, 3-bromocarbazole, 2,7-dibromocarbazole, methyl 1,2,3-triazole-4-carboxylate, methyl 2H-1,2,3-triazole-4-carboxylate, 5-phenyltetrazole, 2,3-dimethylindole, 2,3-diphenyl-1H-indole, 1,2,3,4-tetrahydrocarbazole, 6-chloropurine, ethyl 4-pyrazolecarboxylate, diethyl 3,5-pyrazoledicarboxylate, 1H-indazole-5-carbaldehyde, methyl 1H-indazole-3-carboxylate, benzotriazole, 1H-1,2,3-triazolo[4,5-b]pyridine.

4. The synthetic method for constructing a C-N bond by green synthesis according to claim 1, wherein: The specific preparation steps are as follows: (1) Take a 3 mL white sample bottle equipped with a magnetic stirring rotor, and sequentially add thiophenol or thiophenol derivative of formula (I) (0.2 mmol, 1.0 equiv.), indazole or substituted indazole compound of formula (II) (0.4 mmol, 2.0 equiv.), ion pair catalyst Ph3C + [B(C6F5)4] - (0.01 mmol, 5 mol%), and then add 1 mL of acetone; (2) Transfer the reaction flask to a metal bath at 40 °C for heating, and rapidly stir the reaction for 12 h; after the reaction is completed as detected by TLC, through silica gel column chromatography or preparative thin-layer plate purification, the corresponding target product of formula (Ⅲ) is obtained.

5. The synthetic method for constructing a C-N bond by green synthesis according to claim 1, wherein: Any one of the obtained compounds of formula (Ⅲ) is as follows:

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