A method for synthesizing 1,4-disubstituted 1,2,3-triazoles

Abstract

The application discloses a synthesis method of 1,4-disubstituted 1,2,3-triazole and belongs to the technical field of organic synthesis. In an air atmosphere, an alkyne compound and an azide compound are subjected to a mechanical activation induced cycloaddition reaction in the presence of a copper catalyst, a 4-mercapto-1,2,3-triazole ligand and a promoter, and 1,4-disubstituted 1,2,3-triazole is obtained. The method has the following advantages: (1) toxic and volatile organic solvents can be avoided; (2) inert gas atmosphere can be avoided; (3) the reaction time is short; (4) the catalyst loading is low; (5) the yield is high; and (6) the functional group tolerance range is wide.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 1,4-disubstituted 1,2,3-triazoles, and particularly to a method for rapidly and efficiently synthesizing 1,4-disubstituted 1,2,3-triazoles by mechanical activation induction using azide compounds and alkyne compounds as raw materials under the action of a copper catalyst and 4-mercapto-1,2,3-triazole ligands, belonging to the field of organic synthesis technology. Background Technology

[0002] 1,4-Disubstituted 1,2,3-triazoles possess unique biological activity and photoelectric properties, and have wide application value in natural product chemistry, pharmaceuticals, and organic optoelectronic materials. The copper-catalyzed cycloaddition reaction of azides with alkynes (CuAAC) is the main route for preparing 1,4-disubstituted 1,2,3-triazoles. Traditional CuAAC reactions have the following drawbacks: (1) they require highly volatile and toxic organic solvents; (2) they require high catalyst loading; and (3) they have long reaction times. To meet the needs of green chemistry and sustainable development, mechanically induced CuAAC reactions have also been developed. For example, ball-milled multi-component CuAAC reactions involving alkynes, sodium azide, and benzyl bromide have yielded the target product 1,4-disubstituted 1,2,3-triazoles in high yields, but the reaction time is long and the substrate scope needs further expansion (Green Chem., 2013, 15, 617.). The resonant acoustic mixing method can also be applied to the CuAAC reaction under solvent-free conditions, but the applicability of this reaction still needs to be further improved (Chem. Sci., 2023, 14, 7475.). In addition, the above-mentioned mechanically induced reactions all require specially manufactured equipment, which is costly. Summary of the Invention

[0003] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing 1,4-disubstituted 1,2,3-triazoles. This method utilizes 4-mercapto-1,2,3-triazole ligands in the CuAAC reaction, enabling rapid, efficient, and green synthesis of 1,4-disubstituted 1,2,3-triazoles under solvent-free conditions. This method offers advantages such as mild reaction conditions, low catalyst loading, short reaction time, high product yield, broad substrate range, and environmental friendliness.

[0004] To achieve the above-mentioned technical objectives, the present invention provides a method for synthesizing 1,4-disubstituted 1,2,3-triazole. The method involves a mechanically activated induced cycloaddition reaction of an alkyne compound and an azide compound in the presence of a copper catalyst, a 4-mercapto-1,2,3-triazole ligand, and a promoter in an air atmosphere to obtain 1,4-disubstituted 1,2,3-triazole.

[0005] The alkyne compound has the following structural formula:

[0006] ;

[0007] The azide compound has the following structural formula:

[0008] ;

[0009] The 1,4-disubstituted 1,2,3-triazole has the following structural formula:

[0010] ;

[0011] in,

[0012] R 3 C1~C 10 aliphatic hydrocarbon group, or C6~C 12 The aromatic group, or the C7~C group composed of aliphatic hydrocarbon group and aromatic group. 12 The group, or, is a C1~C group composed of heteroatom-containing groups and / or halogen-containing groups and aliphatic hydrocarbon groups. 10 The group, or, is a C2~C group composed of heteroatom-containing groups and / or halogen-containing groups and aromatic groups. 12 The group, or, a C7~C group composed of heteroatom-containing groups and / or halogen-containing groups, aliphatic hydrocarbon groups, and aromatic hydrocarbon groups. 12 The group; or, is a trimethylsilyl group, an aromatic heterocyclic group or a benzo[a]heterocyclic group;

[0013] R 4 C1~C 10 aliphatic hydrocarbon group, or, C2~C 10 The aromatic group, or the C7~C group composed of aliphatic hydrocarbon group and aromatic group. 12 The group, or, is a C1~C group composed of heteroatom-containing groups and / or halogen-containing groups and aliphatic hydrocarbon groups. 10 The group, or, is a C2~C group composed of heteroatom-containing groups and / or halogen-containing groups and aromatic groups. 12 The group, or, a C7~C group composed of heteroatom-containing groups and / or halogen-containing groups, aliphatic hydrocarbon groups, and aromatic hydrocarbon groups. 12 The group is either an aromatic heterocyclic group or a benzo[a]heterocyclic group.

[0014] The key to this invention lies in the use of 4-mercapto-1,2,3-triazole ligands. These ligands mainly act on copper catalysts, influencing the catalytic activity of the catalyst through electronic and steric effects. They can significantly improve the catalytic efficiency of copper catalysts for the cycloaddition reaction between alkynes and azides, greatly shorten the cycloaddition reaction time (only 15 minutes, yield is almost the same after 20 minutes), reduce the amount of catalyst used, and make the cycloaddition reaction conditions mild, without the need for inert gas protection. At the same time, the reaction efficiency is high and there is no need to use harmful solvents as reaction media.

[0015] In the azide compound of the present invention, R 4 It can be benzyl or a benzyl derivative, for example, a benzyl derivative in which C1~C is substituted on the benzene ring. 10 alkyl groups, trifluoromethyl groups, halogen substituents, etc., R 4 It can be an aromatic group or an aromatic heterocyclic group, such as phenyl, naphthyl, quinolinyl, etc., R 4 It can be C1~C 10 Alkyl groups, such as n-hexyl, cyclohexyl, R 4 It can be tetrahydrofuranyl, dihydrobenzofuranyl, or sulfonyl, etc.

[0016] As a preferred embodiment, the azide compound has the following structural formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0017] R in the alkyne compound of the present invention 3 It can be C1~C10 The alkyl group can be a straight alkyl group or a branched alkyl group, R 3 It can be C1~C 10 Alkyl derivatives, for example, those containing halogen substituents or heteroatomic groups on the alkyl group, R 3 It can be C2~C 10 Ester group or trimethylsilyl group, R 3 It can be a phenyl group or a phenyl derivative. Phenyl derivatives, for example, contain electron-donating groups (-OMe, -Et, -Pr, -Me2N, etc.) or electron-withdrawing groups (-NO2, -Cl, -Br, -F, -CF3, -MeCO2, etc.) on the benzene ring. 3 It can be a heterocyclic group, such as pyridyl, pyrazinyl, or thiophene, etc.

[0018] As a preferred embodiment, the alkyne has the following structural formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0019] As a preferred embodiment, the 1,4-bissubstituted 1,2,3-triazole has the following structural formula:

[0020] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0021] The cycloaddition reaction of the present invention has good tolerance to substrates, and most alkyne compounds and azide compounds can obtain good reaction results under the reaction conditions of the present invention.

[0022] As a preferred embodiment, the copper catalyst comprises CuSO4, CuI, CuBr, CuCl, Cu(OAc)2, CuI2, CuBr2, CuCl2, Cu2O, Cu2S, CuOAc, CuCO3, Cu(NO3)2, copper fluoride (CuF2), CuO, CuS, CuSO4, cuprous thiocyanate (CuSCN), and copper(I)(C)[1,3-bis(2,4,6-trimethylyl)imidazolium-2-ylidene]chloro[1,3-bis(2,4,6-trimethylyl)imidazolium-2-ylidene]copper(I)(C) 21 H 24 ClCuN2), Chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) (C 27 H 36 ClCuN2), copper trifluoromethanesulfonate (CuOTf), copper thiophene-2-carboxylate (C5H3SO2Cu), copper hexafluorophosphonate tetraacetonitrile (Cu(MeCN)4PF6), bis(1,4-diazabicyclo[2.2.2]octane)tetra(copper iodide(I)) (C 16 H 26 (CuI)4), 1,5-cyclooctadiene (hexafluoro-2,4-pentanedione)copper(I) (C 13 H 13 O2F6Cu), copper tetra(acetonitrile)tetrafluoroborate (Cu(MeCN)4BF4), (1,10-o-phenanthroline)(triphenylphosphine)copper bromide(I) (C 10 H7N2CuBr), (ethylcyclopentadienyl)(triphenylphosphine)copper(I) (C 25 H 24 CuP), trimethylphosphine (hexafluoroacetylacetone) copper(I) (C8H) 10 At least one of O2F6Pcu. The above-mentioned preferred copper catalysts have a certain promoting effect on the reaction. Among them, the mixed system of CuBr and Cu(OAc)2 shows the best catalytic effect, and the preferred molar percentage composition of the two is 40~60%:40~60%. Among the single copper catalysts, Cu(OAc)2 has the best catalytic effect.

[0023] As a preferred embodiment, the 4-mercapto-1,2,3-triazole ligand has the following structural formula:

[0024] ;

[0025] in,

[0026] R1 Selected from C1~C 10 alkane group or C1~C 10 alkyl-substituted phenyl groups;

[0027] R 2 Choose benzyl, C1~C 10 alkyl group or 2,2-dimethyl-1,3-dioxolane group;

[0028] or,

[0029] The 4-mercapto-1,2,3-triazole ligand has the following structural formula:

[0030] .

[0031] The 4-mercapto-1,2,3-triazole ligands are further preferably L1 to L5.

[0032] .

[0033] The 4-mercapto-1,2,3-triazole ligands (L1~L5) of this invention can all promote the smooth progress of the reaction. However, a large number of experiments show that L1 and L3 have the best promoting effect on the reaction, while L2 and L4 have the next best promoting effect, and L5 has the worst promoting effect on the reaction.

[0034] The 4-mercapto-1,2,3-triazole ligands of the present invention are synthesized by the following method: under the action of a copper catalyst (cat.1), an alkaline reagent (B1) and an additive (A1), a thiol (1) and a silicon-protected bromoalkyne are reacted in a solvent (S1) at a temperature of 0~120℃ for 10~180 min to generate an intermediate. The intermediate 2 is directly used for the next step of the reaction after simple purification by short silica gel column chromatography. Subsequently, the intermediate 2 and the azide (3) are reacted in a solvent (S2) at a temperature of 0~130℃ (T2) under the action of an alkaline reagent (B2) and a copper catalyst (cat.2) for 5~48 h. After extraction, drying, concentration and silica gel column chromatography, the 4-mercapto-1,2,3-triazole ligand (L) is obtained.

[0035] The synthesis reaction equation for the 4-mercapto-1,2,3-triazole ligand (L) of the present invention is as follows:

[0036]

[0037] The copper catalyst (cat. 1) is preferably any one of the following: CuI, CuBr, CuCl, Cu2O, cuprous sulfide: Cu2S, cuprous acetate: CuOAc, cuprous thiocyanate: CuSCN, copper(I) chloride: C21 H 24 ClCuN2, Chlorine [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper (I): C 27 H 36 ClCuN2, copper trifluoromethanesulfonate: CuOTf, copper thiophene-2-carboxylate: C5H3SO2Cu, copper hexafluorophosphonate tetraacetonitrile: Cu(MeCN)4PF6, bis(1,4-diazabicyclo[2.2.2]octane)tetra(copper iodide(I)): C 16 H 26 (CuI)4, 1,5-cyclooctadiene (hexafluoro-2,4-pentanedione)copper(I):C 13 H 13 O2F6Cu, copper tetra(acetonitrile)tetrafluoroborate: Cu(MeCN)4BF4, copper (1,10-o-phenanthroline)(triphenylphosphine)bromine(I): C 10 H7N2CuBr, (ethylcyclopentadienyl)(triphenylphosphine)copper(I):C 25 H 24 CuP, trimethylphosphine (hexafluoroacetylacetone) copper (I): C8H 10 O2F6PCu, copper iodide: CuI2, copper carbonate: CuCO3, copper nitrate: Cu(NO3)2, copper bromide: CuBr2, copper fluoride: CuF2, copper chloride: CuCl2, copper oxide: CuO, copper sulfide: CuS, copper acetate: Cu(OAc)2, copper sulfate: CuSO4.

[0038] The base reagent (B1) is preferably any one of the following: 4,4-di-tert-butylbipyridine (dtbpy), 2,2'-biimidazole, 1-phenylimidazole, 4-methylimidazole, 2-cyclohexylimidazole, 4,5-diphenylimidazole, 2,5-diphenylimidazole, 1-triphenylmethylimidazole, 2-ethyl-4-methylimidazole, 2,4,5-triphenylimidazole, 2-imidazolidineone, 1-benzylimidazole, 1-phenylimidazole-2-one, 1-cyclohexylimidazole-2-one, triethylamine, diisopropylamine, diisopropylethylamine, N,N'-dimethylethylenediamine. 1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl, 1,3-bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-dimethyldimethyl, 5-phenylthiazole, 2-ethylthiazole, 5-methylthiazole, imidazole, levamisole, benzimidazole, benzotriazole, 1-methyl-1,2,3-triazole, 1-(dibenzylaminomethyl)benzotriazole, 1,1′-carbonylbis(1,2,4-triazole).

[0039] The additive (A1) is preferably any one of the following: pyridine, 4-methylpyridine, 4-aminopyridine, 4-isopropylpyridine, 4,4ʹ-bipyridine sulfide 2,6-dimethylpyridine.

[0040] The solvent (S1) is preferably any one of the following: acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, DMF, DMSO, dichloromethane, chloroform, methanol, ethanol, n-propanol, toluene, or diethyl ether.

[0041] The alkaline reagent (B2) is preferably any one of the following: tetrabutylammonium fluoride (TBAF), MeMgBr, tBuOK, K2CO3, Na2CO3, KOH, or NaOH.

[0042] The solvent (S2) is preferably any one of the following: tetrahydrofuran, methanol, ethanol, isopropanol, tert-butanol, acetone, acetonitrile, ethyl acetate, DMF, DMSO, 1,4-dioxane, toluene, diethyl ether, dichloromethane, or chloroform.

[0043] The preferred extractant used in the extraction is any one of the following: ethyl acetate, dichloromethane, chloroform, toluene, or petroleum ether.

[0044] The developing solvent used in the silica gel column chromatography is preferably any one of the following: petroleum ether, ethyl acetate, dichloromethane, chloroform, toluene, methanol, or a mixture of petroleum ether and ethyl acetate.

[0045] The copper catalyst (cat.2) is preferably one of the following: CuSO4, CuI, CuBr, CuCl, Cu(OAc)2, CuI2, CuBr2, CuCl2, Cu2O, Cu2S, CuOAc, CuCO3, Cu(NO3)2, copper fluoride: CuF2, CuO, CuS, CuSO4, cuprous thiocyanate: CuSCN, copper(I) chloride: C 21 H 24 ClCuN2, Chlorine [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper (I): C 27 H 36 ClCuN2, copper trifluoromethanesulfonate: CuOTf, copper thiophene-2-carboxylate: C5H3SO2Cu, copper hexafluorophosphonate tetraacetonitrile: Cu(MeCN)4PF6, bis(1,4-diazabicyclo[2.2.2]octane)tetra(copper iodide(I)): C 16 H 26 (CuI)4, 1,5-cyclooctadiene (hexafluoro-2,4-pentanedione)copper(I):C 13 H 13O2F6Cu, copper tetra(acetonitrile)tetrafluoroborate: Cu(MeCN)4BF4, copper (1,10-o-phenanthroline)(triphenylphosphine)bromine(I): C 10 H7N2CuBr, (ethylcyclopentadienyl)(triphenylphosphine)copper(I):C 25 H 24 CuP, trimethylphosphine (hexafluoroacetylacetone) copper (I): C8H 10 O2F6PCu, and mixtures of two or three of the above copper compounds.

[0046] As a preferred embodiment, the accelerator includes at least one selected from sodium ascorbate, 18-crown ether-6, sodium isoascorbate, sodium citrate, magnesium ascorbate 2-phosphate, ascorbic acid glyceride, and magnesium L-ascorbate. The accelerator primarily functions as a reducer, and compared to not adding an accelerator, it can increase the yield of the target product.

[0047] As a preferred embodiment, the molar ratio of the alkyne compound to the azide compound is 0.8~1:1~2.

[0048] As a preferred embodiment, the molar ratio of the alkyne compound to the 4-mercapto-1,2,3-triazole ligand is 1:0.005~0.5;

[0049] As a preferred embodiment, the molar ratio of the alkyne compound to the copper catalyst is 1:0.005~0.5;

[0050] As a preferred embodiment, the molar ratio of the alkyne compound to the promoter is 1:0.001~0.5.

[0051] As a preferred embodiment, the cycloaddition reaction is performed under the following conditions: temperature of 10-50°C and time of 5-150 min.

[0052] The mechanical activation involved in this invention includes, for example, grinding.

[0053] The 1,4-disubstituted 1,2,3-triazoles involved in this invention possess biological activity, specifically for example: 1,4-disubstituted 1,2,3-triazoles (III-77~III-83) respectively possess the following biological activities: III-77 has inhibitory activity against heat shock protein 90 (Hsp90); III-78 exhibits toxicity against Euphorbia heterophylla; III-79 has bactericidal activity against Asperisporium caricae; III-80 can inhibit Plasmodium falciparum strain 3D7, showing antimalarial potential; III-81 exerts a regulatory effect by blocking the Nrf2−Keap1 protein interaction; III-82 has an antidepressant effect; III-83 can significantly inhibit the mycelial growth of Colletotrichum gloeosporioides.

[0054] The synthetic reaction equation for the 1,4-disubstituted 1,2,3-triazole of the present invention (taking optimal reaction conditions as an example):

[0055]

[0056] In the synthesis of 1,4-disubstituted 1,2,3-triazole of the present invention, after the cycloaddition reaction is completed, the reaction mixture is washed with a solvent and then separated by silica gel column chromatography to obtain the target product. The solvent (S3) used for washing is water, n-hexane, n-heptane, n-pentane, isopentane, n-octane, isooctane, petroleum ether, diethyl ether, etc. The eluent used for silica gel column chromatography is at least one selected from petroleum ether, ethyl acetate, dichloromethane, chloroform, toluene, and methanol. Compared with the prior art, the technical advantages of the present invention are as follows:

[0057] 1) This invention can completely eliminate organic solvents (traditional methods require 5~50 mL / mmol of solvents such as THF / DMF), and uses mechanical grinding to drive the reaction, which fundamentally solves the problem of organic solvent pollution and conforms to the principles of green chemistry;

[0058] 2) The present invention is based on a better catalytic system, which can catalyze the reaction quickly under air atmosphere and no heating. The reaction mainly carries out cycloaddition reaction without self-coupling side reaction, while traditional cyclization reaction requires inert gas protection (traditional Ar / N2 atmosphere) and heating (traditional 60~100℃).

[0059] 3) The cyclization reaction of the present invention can reduce the total loading of copper catalyst from the traditional 5~10 mol% to 1 mol%, while shortening the reaction time to 5~150 minutes, and the yield of the target product is high. Detailed Implementation

[0060] To make the above-mentioned features, advantages, and objectives of the present invention more apparent, the present invention will be described in detail below with reference to specific embodiments. Many specific details are set forth in the description below to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0061] The following example illustrates the synthesis of ligands using thiophenol, silyl-protected bromoalkynes, and azides as reaction substrates: Cu(MeCN)₄PF₆ (0.0373 g, 0.1 mmol) was completely dissolved in degassed acetonitrile (9 mL) under nitrogen atmosphere. Bromoethynyltriisopropylsilane (0.2613 or 0.5226 g, 1.0 or 2.0 mmol), thiol 1 (1.1 or 2.2 mmol), dtbbpy (0.013 g, 0.2 mmol, 20 mol%), 2,6-dimethylpyridine (0.055 mL, 2.0 mmol), and degassed acetonitrile (20 mL) were added to a 100 mL Schlenk tube equipped with a magnetic stir bar. The Cu(MeCN)₄PF₆ acetonitrile solution was then added to the Schlenk tube. The mixture was stirred at room temperature for 20 minutes and then concentrated under vacuum to obtain a crude reaction mixture. The residue was extracted with EtOAc (30 mL) and saturated NH4Cl aqueous solution (20 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated after filtration. The crude residue was subjected to short-column chromatography on silica gel (hexane) to extract alkynyl sulfide 2, which was used directly for the next step without further purification. Crude product 2 was dissolved in THF (10 mL), and TBAF (1.0 M THF solution, 1.0 mL, 1.0 mmol) was added at 0 °C. The mixture was stirred at room temperature for 10 hours. Then CuI (0.0190 g, 0.1 mmol), azide 3 (1.1 mmol), and nPrOH (20 mL) were added. The mixture was stirred at 100 °C for 15 hours. After quenching the mixture with 20 mL of saturated NH4Cl aqueous solution, the product was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated after filtration. The crude residue was subjected to column chromatography on silica gel (petroleum ether / EtOAc, 4:1) to obtain pure L1~L5.

[0062] Example 1

[0063] The structural formula of the target product is as follows: The target product is a white solid with a yield of 81%.

[0064] 1 H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.36 (br, 3H), 7.25-7.21 (m,4H), 7.05 (d, J = 8.0 Hz, 2H), 5.51 (s, 2H), 2.28 (s, 3H).

[0065] Example 2

[0066] The structural formula of the target product is as follows: Adding N,N'-dimethylethylenediamine (DMEDA) (0.0070 g, 0.08 mmol) to the reaction system resulted in a white solid with a yield of 65%. Melting point (MP): 66°C–68°C. 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.1 Hz, 2H), 4.55 (d, J = 11.8 Hz, 1H), 4.48-4.40 (m, 2H), 4.13-4.09 (m, 1H), 3.72 (dd, J = 8.2, 5.3 Hz, 1H), 2.29 (s, 3H), 1.32 (d, J = 4.0Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 138.88, 136.75, 131.41, 129.65, 129.42,128.37, 109.97, 73.58, 65.99, 52.21, 26.38, 24.93, 20.78. HRMS-ESI (m / z) [M+H + Calcd for C 15 H 20 O2N3S 306.1276; Found, 306.1277.

[0067] Example 3

[0068] The structural formula of the target product is as follows: The target product is a white solid with a yield of 76%. Melting point (MP): 111 °C - 113 °C. 1H NMR (400 MHz, CDCl3) δ 7.50 (s,2H), 7.38 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.3 Hz, 6H), 7.17 (s, 1H), 7.07(d, J = 8.0 Hz, 4H), 5.49 (s, 4H), 2.29 (s, 6H). 13C NMR (101 MHz, CDCl3) δ140.33, 137.24, 135.41, 131.21, 130.11, 129.99, 129.90, 128.42, 127.50,126.65, 53.94, 21.00. HRMS-ESI (m / z) [M+H+] Calcd for C 26 H 25 N6S2 485.1582;Found, 485.1585.

[0069] The following examples are examples using phenylacetylene and benzyl azide as reaction substrates, and the optimal reaction conditions obtained through condition optimization experiments: 2.0 mmol phenylacetylene, 2.0 mmol benzyl azide, 0.02 mmol 4-mercapto-1,2,3-triazole ligand (L1), 0.02 mmol CuBr, 0.02 mmol Cu(OAc)2·H2O, and 0.08 mmol NaAsc were added to an agate mortar. After grinding for 15 minutes at room temperature, the reaction mixture was washed twice with water, followed by three washes with cold petroleum ether to obtain the desired 1,4-disubstituted 1,2,3-triazole III-1. The product was a white solid with a yield of 96%. Example 4

[0070] The structural formula of the target product is as follows: III-1 is a white solid.

[0071] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.0 Hz, 1H), 7.66 (s, 1H), 7.42-7.36 (m, 5H), 7.33-7.29 (m, 3H), 5.58 (s, 2H).

[0072] The following experimental groups 1-19, using the above examples as a reference, compare and illustrate the reaction of phenylacetylene with benzyl azide under different conditions to produce 1-benzyl-4-phenyl-1H-1,2,3-triazole (xyz represents mol%).

[0073]

[0074] The experimental groups 1-5 in the table above investigated the catalytic effects of different 4-mercapto-1,2,3-triazole ligands (L1-L5) on the cycloaddition reaction of alkynes and azides. The experiments showed that all tested ligands could effectively promote the cycloaddition reaction of alkynes and azides, but when L1 was used, the yield of the target product could reach 72%, which was significantly better than other ligands.

[0075] The experimental groups 6-15 in the table above investigated the catalytic effects of different copper catalysts on the reaction. The experiments showed that all tested copper catalysts could effectively promote the cycloaddition reaction of alkynes and azide compounds. However, when using a mixed system (CuBr / Cu(OAc)2), the yield of the target product could reach 96%, which was significantly better than other copper catalysts.

[0076] The table above shows that experimental groups 15-20 investigated the effects of different catalyst loadings and reaction times on the reaction. The experiments showed that the CuBr / Cu(OAc)2 mixed catalyst system could facilitate the reaction. However, when the total catalyst loading was 1 mol% and the reaction time was 15 minutes (experimental group 15), the yield of the target product could reach 96%, which was significantly better than other combinations of conditions (0.5 mol% loading yielded 52%, and 1.5 mol% loading did not improve the yield). At the same time, the experimental data confirmed that there was an optimal range for the reaction time (the yield decreased to 82% at 10 minutes, and did not further improve the yield at 20 minutes), which fully demonstrated the sensitivity of the catalytic system to the reaction conditions.

[0077] The above optimization experiments were conducted at a substrate scale of 2.0 mmol. First, different copper catalysts (0.02 mmol CuSO4, 0.02 mmol CuI, 0.02 mmol CuBr, etc.) were screened. It was found that 0.02 mmol Cu(OAc)2 alone showed the best effect (73% yield), but the mixture of 0.02 mmol CuBr and 0.02 mmol Cu(OAc)2 exhibited a significant synergistic effect (yield increased to 96%). Subsequently, different ligands L1–L5 were examined at 0.02 mmol, confirming that 0.02 mmol 4-mercapto-1,2,3-triazole (L1) had the best catalytic performance (yield 72–96%, but 22% without ligand). Further optimization showed that the reaction 0.02 mmol CuBr + 0.02 mmol Cu(OAc)2 + 0.02 mmol L1 + 0.08 mmol NaAsc was the optimal system, with a reaction time of 15 minutes (the yield was almost indistinguishable after 20 minutes). Reducing the catalyst to 0.005 mmol (total) resulted in a sharp drop in yield to 52%, while increasing it to 0.015 mmol did not improve efficiency. Ultimately, the core conditions were established as "0.02 mmol mixed copper catalyst + 0.02 mmol L1 + 0.08 mmol NaAsc + 15 minutes of grinding / 2.0 mmol substrate".

[0078] Examples 5 to 39 below examine the reaction effects of different azide compounds on the conversion to 1,4-disubstituted 1,2,3-triazole under the most preferred reaction conditions.

[0079] Example 5

[0080] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-5 is a white solid with a yield of 83%. 1 H NMR (400 MHz, CDCl3) d 7.61 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.39-7.36 (m, 3H), 7.32-7.30 (m, 2H), 7.24 (dd, J = 8.3, 2.0 Hz, 1H), 6.87 (d, J =8.3 Hz, 1H), 5.56 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H).

[0081] Example 6

[0082] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-13 is a white solid with a yield of 61%. 1 H NMR (400 MHz, CDCl3) d 9.42 (s, 1H), 8.49 (t, J = 2.8 Hz, 2H), 8.08 (s,1H), 7.42-7.38 (m, 3H), 7.35-7.33 (m, 2H), 5.61 (s, 2H).

[0083] Example 7

[0084] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-17 is a white solid with a yield of 76%. 1 H NMR (400 MHz, CDCl3) d 7.38-7.33 (m, 3H), 7.30 (s, 1H), 7.26-7.24 (m,2H), 6.48 (s, 1H), 5.49 (s, 2H), 2.36-2.33 (m, 2H), 2.18-2.16 (m, 2H), 1.76-1.71 (m, 2H), 1.67-1.61 (m, 2H).

[0085] Example 8

[0086] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-24 is a white solid with a yield of 70%. Melting point (MP): 116°C-118°C. 1 H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.50 (d,J = 7.5 Hz, 1H), 7.46 (s, 1H), 7.36 (t, J = 3.4 Hz, 1H), 7.30-7.28 (m, 1H),7.25-7.21 (m, 2H), 7.08-7.05 (m, 1H), 5.53 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ143.51, 136.65, 132.62, 132.01, 130.98, 130.73, 127.61, 126.55, 125.19,124.31, 123.13, 118.98, 53.46. HRMS-ESI (m / z) [M + H +Calcd for C 13 H 11 BrN3S319.9857; Found, 319.9859.

[0087] Example 9

[0088] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-25 is a white solid with a yield of 75%. 1 H NMR (400 MHz, CDCl3) d 8.07 (s, 1H), 7.41 (dd, J = 8.5, J = 6.5 Hz,1H), 6.98 (m, 2H), 5.69 (t, J = 5.7 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.39(t, J = 7.1 Hz, 3H).

[0089] Example 10

[0090] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-27 is a white solid with a yield of 60%. Melting point (MP): 120 °C-122 °C. 1 H NMR (400 MHz, CDCl3) d 9.00 (dd, J = 4.3, 1.8 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.83 (d, J = 8.2 Hz,1H), 7.79-7.77 (m, 2H), 7.67 (d, J = 8.6 Hz, 1H), 7.53-7.47 (m, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 7.3 Hz, 1H), 6.28 (s, 2H). 13 C NMR (101 MHz, CDCl3) d150.24, 147.74, 145.86, 136.49, 133.38, 130.81, 129.88, 128.93,128.75, 128.43, 127.97, 126.52, 125.69, 121.69, 120.71, 49.85. HRMS-ESI (m / z)[M + H + Calcd for C 18 H 15 N4 287.1297; Found, 287.1299.

[0091] Example 11

[0092] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-34 was a white solid, with a yield of 86%. Melting point (MP): 106°C-108°C. 1 H NMR (400 MHz, CDCl3) d 7.77 (d, J = 7.8 Hz, 2H), 7.49 (s, 1H), 7.41 (t, J = 8.0 Hz, 2H), 7.32 (t, J = 7.7 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 4.60-4.52 (m, 4H), 3.19-3.12 (m, 4H). 13 C NMR (101 MHz, CDCl3) d 159.2, 147.4, 130.7, 128.9, 128.8, 128.2, 128.0, 127.6, 125.7, 125.3, 119.9, 109.4, 71.2, 52.2, 36.2, 29.6. HRMS-ESI (m / z) [M + H + ] Calcdfor C 18 H 18 N3O 292.1450; Found, 292.1453.

[0093] Example 12

[0094] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-36 was a white solid, with a yield of 85%. Melting point (MP): 86°C-88°C. 1 H NMR (400 MHz, CDCl3) d 7.80 (d, J = 7.8 Hz, 2H), 7.76 (s, 1H), 7.44-7.39(m, 4H), 7.35-7.30 (m, 3H), 7.26-7.23 (m, 1H), 4.58 (t, J = 6.8 Hz, 2H), 3.44(t, J = 6.8 Hz, 2H). 13 C NMR (101 MHz, CDCl3) d 147.7, 133.8, 130.5, 130.4, 129.3, 128.8, 128.2, 127.3, 125.7, 120.2, 49.5, 34.2. HRMS-ESI (m / z) [M + H + ]Calcd for C 16 H 16 N3S 282.1065; Found, 282.1067.

[0095] Example 13

[0096] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-39 was a white solid with a yield of 74%. Melting point (MP): 145°C-147°C. 1 H NMR (400 MHz, CDCl3) d 8.12 (s, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.8 Hz, 3H), 2.63 (t, J= 7.6 Hz, 2H), 2.44 (s, 3H), 1.68 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 143.1, 138.8, 134.8, 130.2, 129.0, 127.8, 125.7, 120.4,117.3, 37.8, 24.5, 21.1, 13.8. HRMS-ESI (m / z) [M + H + Calcd for C 18 H 20 N3278.1657; Found, 278.1659.

[0097] Example 14

[0098] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-40 was a white solid, with a yield of 74%. Melting point (MP): 169°C-171°C. 1 HNMR (400 MHz, CDCl3) d 8.12 (s, 1H), 7.81 (d, J = 7.9 Hz, 2H), 7.66 (d, J =8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.8 Hz, 3H), 2.63 (t, J =7.6 Hz, 2H), 2.44 (s, 3H), 1.68 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d 160.0, 148.1, 138.9, 134.7, 131.6, 130.2, 129.9, 120.4,118.2, 117.8, 114.4, 110.8, 55.4, 21.1. HRMS-ESI (m / z) [M + H + ] Calcd forC16 H 16 N3O 266.1293; Found, 266.1294.

[0099] Example 15

[0100] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-45 is a white solid with a yield of 82%. Melting point (MP): 115 °C-117 °C. 1 H NMR (400 MHz, CDCl3) d 7.80 (d, J = 7.1 Hz,2H), 7.66 (s, 1H), 7.43-7.37 (m, 5H), 7.34-7.27 (m, 2H), 5.67 (s, 2H), 4.46(s, 2H). 13 C NMR (101 MHz, CDCl3) d 148.22, 133.86, 133.27, 130.46, 130.35,129.98, 129.47, 129.41, 128.80, 128.23, 125.68, 119.56, 52.32, 51.30. HRMS-ESI(m / z) [M + H + Calcd for C 16 H 15 N6 291.1358; Found, 291.1361.

[0101] Example 16

[0102] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-49 is a white solid with a yield of 83%. Melting point (MP): 117 °C-122 °C. 1 H NMR (400 MHz, CDCl3) d 7.67 (d, J = 8.9Hz, 2H), 7.54 (s, 1H), 7.32 (q, J = 2.7 Hz, 4H), 6.75 (d, J = 8.8 Hz, 2H), 5.56 (s, 2H), 4.35 (s, 2H), 2.98 (s, 6H). 13 C NMR (101 MHz, CDCl3) d150.36,148.75, 135.90, 135.04, 128.77, 128.34, 126.59, 118.57, 118.00, 112.36,54.22, 53.61, 40.39. HRMS-ESI (m / z) [M + H + Calcd for C 18 H 20 N7 334.1780; Found,334.1781.

[0103] Example 17

[0104] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-50 is a white solid with a yield of 80%. Melting point (MP): 113 °C-116 °C; 1 H NMR (400 MHz, CDCl3) d 7.68 (s, 1H), 7.57-7.51 (m, 2H), 7.38-7.32 (m, 5H), 7.03-6.98 (m, 1H), 5.59 (s, 2H), 4.36 (s, 2H). 13 C NMR (101 MHz, CDCl3) d 148.22, 133.86, 133.27, 130.46, 130.35, 129.98, 129.47, 129.41, 128.80, 128.23, 125.68, 119.56, 52.32, 51.30. 19 F NMR (376 MHz, CDCl3) d -112.64. HRMS-ESI (m / z) [M + H + Calcd for C 16 H 14 FN6 309.1264;Found, 309.1266.

[0105] Example 18

[0106] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-53 is a white solid with a yield of 73%. Melting point (MP): 149 °C-152 °C. 1 H NMR (400 MHz, CDCl3) d8.07 (d, J = 8.4Hz, 2H), 7.88 (d, J = 6.8 Hz, 2H), 7.77 (s, 1H), 7.37-7.32 (m, 4H), 5.60 (s, 2H), 4.36 (s, 2H), 3.92 (s, 3H). 13 C NMR (101 MHz, CDCl3) d 166.71, 147.23,136.28, 134.69, 134.49, 130.15, 129.58, 128.91, 128.51, 125.43, 120.36,54.19, 53.88, 52.11. HRMS-ESI (m / z) [M + H + Calcd for C 18 H 17 N6O2 349.1413; Found,349.1414.

[0107] Example 19

[0108] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-54 is a white solid with a yield of 72%. Melting point (MP): 111 °C-113 °C. 1 H NMR (400 MHz, CDCl3) d 8.56 (t, J = 1.9Hz, 1H), 8.23 ​​(d, J = 7.8 Hz, 1H), 8.18-8.15 (m, 1H), 7.82 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.39-7.35 (m, 4H), 5.62 (s, 2H), 4.38 (s, 2H). 13 C NMR (101MHz, CDCl3) d 148.59, 146.12, 136.46, 134.29, 132.21, 131.44, 129.89, 128.98,128.61, 122.77, 120.43, 120.36, 54.20, 54.03. HRMS-ESI (m / z) [M + H + ] Calcd forC16 H 14 N7O2 336.1209; Found, 336.1211.

[0109] Example 20

[0110] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-55 is a white solid with a yield of 65%. Melting point (MP): 58°C-60°C. 1 H NMR (400 MHz, CDCl3) d 8.54 (d, J = 4.5 Hz, 1H), 8.18 (d, J = 6.9 Hz, 1H), 8.07 (s, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.37-7.32 (m, 4H), 7.23-7.20 (m, 1H), 5.60 (s, 2H), 4.35 (s, 2H). 13 C NMR (101MHz, CDCl3) d 150.07, 149.30, 148.76, 136.90, 136.19, 134.43, 128.84, 128.68,122.88, 121.91, 120.20, 54.18, 53.90. HRMS-ESI (m / z) [M + H + Calcd for C 15 H 14 N7292.1311; Found, 292.1313.

[0111] Example 21

[0112] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-56 is a white solid with a yield of 62%. Melting point (MP): 106 °C-108 °C. 1 H NMR (400 MHz, CDCl3) d 7.59 (s, 1H), 7.36-7.31 (m, 5H), 7.28 (dd, J = 5.1, 1.2 Hz, 1H), 7.05 (dd, J = 5.1, 3.6 Hz, 1H), 5.57 (s, 2H), 4.36 (s, 2H).13 C NMR (101 MHz, CDCl3) d 143.38, 136.23, 134.58,132.73, 128.89, 128.48, 127.57, 125.09, 124.21, 118.95, 54.23, 53.82. HRMS-ESI(m / z) [M + H + Calcd for C 14 H 13 N6S 297.0922; Found, 297.0923.

[0113] Example 22

[0114] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-57 was a white solid, with a yield of 58%. Melting point (MP): 64 °C-66 °C. 1 H NMR (400 MHz, CDCl3) d 7.83 (d, J = 7.1 Hz, 2H), 7.74 (s, 1H), 7.43 (t, J =7.7 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 4.40 (t, J = 7.2 Hz, 2H), 3.25 (t, J =6.9 Hz, 2H), 1.99–1.92 (m, 2H), 1.62-1.55 (m, 2H), 1.42-1.29 (m, 10H). 13 C NMR (101 MHz, CDCl3) d 147.73, 130.66, 128.81, 128.08, 125.66, 119.35, 51.36,50.35, 30.27, 28.86, 28.83, 28.73, 26.54, 26.35. HRMS-ESI (m / z) [M + H + ] Calcdfor C 16 H 23 N6 299.1984; Found, 299.1985.

[0115] Example 23

[0116] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-60 is a white solid with a yield of 85%. Melting point (MP): 118 °C-120 °C. 1 H NMR (400 MHz, CDCl3) d 7.90 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.39-7.30 (m,4H), 7.18 (d, J = 6.9 Hz, 1H), 5.54 (s, 2H), 3.09 (s, 1H). 13 C NMR (101 MHz, CDCl3) d 147.41, 136.41, 135.02, 131.76, 130.56, 130.45, 129.26, 129.02,128.88, 128.06, 126.06, 126.02, 122.65, 119.77, 83.14, 77.60, 53.50. HRMS-ESI(m / z) [M + H + Calcd for C 17 H 13 ClN3 294.0798; Found, 294.0799.

[0117] Example 24

[0118] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-61 is a white solid with a yield of 74%. Melting point (MP): 98°C-100°C. 1 H NMR (400 MHz, CDCl3) d 9.02–9.00 (m, 1H), 8.20 (d, J = 9.4 Hz, 1H), 8.00 (s, 1H), 7.86-7.80 (m, 3H), 7.69 (d, J = 6.9 Hz,1H), 7.53-7.47 (m, 2H), 7.40 (d, J= 7.7 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.27 (s, 2H), 3.07 (s, 1H). 13 C NMR (101 MHz, CDCl3) d 150.23, 146.68, 145.79,136.41, 133.12, 131.42, 131.03, 129.94, 129.17, 128.96, 128.73, 128.36,126.42, 126.00, 122.45, 121.64, 120.86, 83.29, 77.39, 49.85. HRMS-ESI (m / z) [M + H + Calcd for C 20 H 15 N4 311.1297; Found, 311.1298.

[0119] Example 25

[0120] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-64 was a white solid, with a yield of 69%. Melting point (MP): 61 °C-63 °C. 1 H NMR (400 MHz, CDCl3) d 7.93 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.76 (s,1H), 7.45 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 4.40 (t, J = 7.2 Hz,2H), 3.11 (s, 1H), 1.98-1.91 (m, 2H), 1.37-1.30 (m, 6H), 0.89 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) d146.73, 131.57, 130.94, 129.23, 128.86,126.01, 122.61, 119.61, 83.25, 77.48, 50.45, 31.11, 30.24, 26.11, 22.37,13.90. HRMS-ESI (m / z) [M + H + Calcd for C 16 H 20 N3 254.1657; Found, 254.1658.

[0121] Example 26

[0122] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-65 is a white solid with a yield of 73%. Melting point (MP): 114 °C-116 °C. 1 H NMR (400 MHz, CDCl3) d 7.89 (s, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.68 (s, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.39-7.31(m, 5H), 5.59 (s, 2H), 4.36 (s, 2H), 3.09 (s, 1H). 13 C NMR (101 MHz, CDCl3) d 147.36, 136.24, 134.59, 131.73, 130.66, 129.27, 128.91, 128.51, 126.03,122.64, 119.71, 83.17, 77.56, 54.21, 53.85. HRMS-ESI (m / z) [M + H + ] Calcd forC 18 H 15 N6 315.1358; Found, 315.1359.

[0123] Example 27

[0124] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-66 was a white solid, with a yield of 66%. Melting point (MP): 40 °C-42 °C. 1 H NMR (400 MHz, CDCl3) d 7.93 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.76 (s,1H), 7.45 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 4.39 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 6.9 Hz, 2H), 3.11 (s, 1H), 1.98-1.91 (m, 2H), 1.62-1.55 (m, 2H), 1.37-1.33 (m, 8H). 13 C NMR (101 MHz, CDCl3) d 146.73, 131.57, 130.88,129.20, 128.86, 125.98, 122.60, 119.62, 83.21, 77.51, 51.31, 50.37, 30.20,28.82, 28.78, 28.69, 26.50, 26.29. HRMS-ESI (m / z) [M + H + Calcd for C 18 H 23 N6323.1984; Found, 323.1986.

[0125] Example 28

[0126] The structural formula of the target product is as follows: The procedure is the same as in Example 1. III-71 is a white solid with a yield of 65%. Melting point (MP): 184 °C-186 °C. 1 H NMR (400 MHz, CDCl3) d 7.79 (s,2H), 7.71 (s, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.43 (t, J= 6.2 Hz, 1H), 7.35-7.28 (m, 7H), 5.58 (s, 4H). 13C NMR (101 MHz, DMSO-d6) δ 145.34, 136.48,133.69, 132.71, 130.83, 129.42, 127.84, 127.67, 127.46, 124.76, 123.66,122.36, 52.87. HRMS-ESI (m / z) [M + H + Calcd for C 24 H 19 Cl2N6 461.1048; Found,461.1049.

[0127] Example 29

[0128] The structural formula of the target product is as follows: Steps: Add CuBr (0.0007 g, 0.005 mmol), Cu(OAc)₂ (0.0009 g, 0.005 mmol), ligand L1 (0.0014 g, 0.005 mmol), sodium ascorbate (0.0040 g, 0.02 mmol), DMEDA (0.0018 g, 0.02 mmol), and alkyne to the agate mortar. (0.5 mmol) and azide ( (0.5 mmol). The mixture was then rapidly ground for 30 minutes. The reaction mixture was then washed twice with water and three times with cold hexane to produce the desired pure form of N-sulfonyl-1,2,3-triazole. III-72 was a white solid in 97% yield. 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.16 (d, J = 7.2Hz, 2H), 7.83 (d, J = 6.9 Hz, 2H), 7.74 (t, J = 7.5 Hz, 1H), 7.62 (d, J =15.6 Hz, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H).

[0129] Example 30

[0130] The structural formula of the target product is as follows: The steps are the same as in Example 77. III-74 are white solids with a yield of 82%. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.09-8.04 (m, 3H), 7.66 (d, J =8.0 Hz, 1H), 7.42-7.39 (m, 3H), 7.22 (d, J = 7.7 Hz, 1H), 2.46 (s, 3H).

[0131] Example 31

[0132] The structural formula of the target product is as follows: The steps are the same as in Example 77. III-75 are white solids with a yield of 90%. 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.73(d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 2.66(q, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H).

[0133] Example 32

[0134] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-77 is a white solid with a yield of 93%. 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.8 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.50 (s, 2H), 3.81 (s, 3H), 1.31 (s, 9H).

[0135] Example 33

[0136] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-78 is a white solid with a yield of 86%. 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.31-7.28 (m, 1H), 7.24-7.20(m, 2H), 7.17-7.12 (m, 3H), 6.91 (d, J = 8.6 Hz, 2H), 5.54 (s, 2H), 5.15 (s,2H), 3.82 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.28 (s, 3H).

[0137] Example 34

[0138] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-79 was a white solid with a yield of 87%. 1 H NMR (400 MHz, CDCl3) d 7.93(s, 1H), 7.83 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.64–4.60 (m, 1H), 4.54-4.45 (m, 2H), 4.16 (dd, J =8.8, 6.2 Hz, 1H), 3.78 (dd, J = 8.8, 5.8 Hz, 1H), 1.39 (d, J = 17.8 Hz, 6H).

[0139] Example 35

[0140] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-80 was a white solid with a yield of 80%. 1 H NMR (400 MHz, CDCl3) d 7.83 (d, J = 7.0 Hz, 2H), 7.77 (s, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.34 (t, J= 7.4 Hz, 1H), 4.46 (t, J = 7.0 Hz, 2H), 3.59 (t, J = 6.3 Hz, 2H), 2.18-2.11(m, 2H), 1.88–1.81 (m, 2H).

[0141] Example 36

[0142] The structural formula of the target product is as follows: The procedure was the same as in Example 1, except that DEMEA (0.0070 g, 0.08 mmol) was added to the reaction system. III-81 was a white solid with a yield of 72%. 1 H NMR (400 MHz, CDCl3) d 8.69(t, J = 2.0 Hz, 1H), 8.34-8.32 (m, 2H), 8.23-8.20 (m, 1H), 7.67-7.63 (m, 2H),7.59 (dd, J = 7.9, 2.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.6Hz, 1H), 2.48 (s, 3H).

[0143] Example 37

[0144] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-82 is a white solid with a yield of 68%. 1 H NMR (400 MHz, CDCl3) d 8.06 (s, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.72(dd, J = 7.5, 1.7 Hz, 1H), 7.66 (td, J = 7.6, 1.8 Hz, 1H), 7.60 (td, J = 7.6,1.4 Hz, 1H), 7.54-7.52 (m, 1H), 7.30 (d, J = 8.2 Hz, 2H), 2.70 (q, J = 7.6Hz, 2H), 2.20 (s, 3H), 1.28 (t, J= 7.6 Hz, 3H).

[0145] Example 38

[0146] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-83 is a white solid with a yield of 60%. 1 H NMR (400 MHz, CDCl3) d 8.15 (s, 1H), 7.89 (d, J = 9.1 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1H), 6.75-6.72 (m, 2H), 6.00-5.90 (m, 1H), 5.36 (s, 2H), 5.11-5.06 (m, 2H), 3.88 (s, 3H), 3.34 (d, J = 6.7Hz, 2H).

[0147] Example 39

[0148] The structural formula of the target product is as follows: The steps are the same as in Example 1. III-84 is a white solid with a yield of 84%. 1 H NMR (400 MHz, CDCl3) d 8.18 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.49-7.32 (m, 6H), 7.18 (t, J = 7.7 Hz, 1H), 5.60 (s, 2H).

Claims

1. A method for synthesizing 1,4-disubstituted 1,2,3-triazole, characterized in that: In an air atmosphere, alkyne compounds and azide compounds undergo mechanically activated induced cycloaddition reactions in the presence of a copper catalyst, a 4-mercapto-1,2,3-triazole ligand, and a promoter to yield 1,4-disubstituted 1,2,3-triazole. The alkyne compound has the following structural formula: ； The azide compound has the following structural formula: ； The 1,4-disubstituted 1,2,3-triazole has the following structural formula: ； in, R 3 C1~C 10 aliphatic hydrocarbon group, or C6~C 12 The aromatic group, or the C7~C group composed of aliphatic hydrocarbon group and aromatic group. 12 The group, or, is a C1~C group composed of heteroatom-containing groups and / or halogen-containing groups and aliphatic hydrocarbon groups. 10 The group, or, is a C2~C group composed of heteroatom-containing groups and / or halogen-containing groups and aromatic groups. 12 The group, or, a C7~C group composed of heteroatom-containing groups and / or halogen-containing groups, aliphatic hydrocarbon groups, and aromatic hydrocarbon groups. 12 The group; or, is a trimethylsilyl group, an aromatic heterocyclic group or a benzo[a]heterocyclic group; R 4 C1~C 10 aliphatic hydrocarbon group, or C6~C 12 The aromatic group, or the C7~C group composed of aliphatic hydrocarbon group and aromatic group. 12 The group, or, is a C1~C group composed of heteroatom-containing groups and / or halogen-containing groups and aliphatic hydrocarbon groups. 10 The group, or, is a C2~C group composed of heteroatom-containing groups and / or halogen-containing groups and aromatic groups. 12 The group, or, a C7~C group composed of heteroatom-containing groups and / or halogen-containing groups, aliphatic hydrocarbon groups, and aromatic hydrocarbon groups. 12 The group is either an aromatic heterocyclic group or a benzo[a]heterocyclic group.

2. The method for synthesizing 1,4-disubstituted 1,2,3-triazole according to claim 1, characterized in that: The azide compound has the following structural formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

3. The method for synthesizing 1,4-disubstituted 1,2,3-triazole according to claim 1, characterized in that: The alkyne has the following structural formula: , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

4. The method for synthesizing 1,4-disubstituted 1,2,3-triazole according to claim 1, characterized in that: The 1,4-disubstituted 1,2,3-triazole has the following structural formula: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , or .

5. The method for synthesizing 1,4-disubstituted 1,2,3-triazole according to claim 1, characterized in that: The copper catalyst includes CuSO4, CuI, CuBr, CuCl, Cu(OAc)2, CuI2, CuBr2, CuCl2, Cu2O, Cu2S, CuOAc, CuCO3, Cu(NO3)2, CuF2, CuO, CuS, CuSO4, CuSCN, and C. 21 H 24 ClCuN2, C 27 H 36 ClCuN2, CuOTf, C5H3SO2Cu, Cu(MeCN)4PF6, C 16 H 26 (CuI)4、C 13 H 13 O₂F₆Cu, Cu(MeCN)₄BF₄, C 10 H7N2CuBr, C 25 H 24 CuP, C8H 10 At least one of O2F6Pcu.

6. The method for synthesizing 1,4-disubstituted 1,2,3-triazole according to claim 1, characterized in that: The 4-mercapto-1,2,3-triazole ligand has the following structural formula: ； in, R 1 Selected from C1~C 10 alkane group or C1~C 10 alkyl-substituted phenyl groups; R 2 Choose benzyl, C1~C 10 alkyl group or 2,2-dimethyl-1,3-dioxolane group; or, The 4-mercapto-1,2,3-triazole ligand has the following structural formula: 。 7. The method for synthesizing 1,4-disubstituted 1,2,3-triazole according to claim 1, characterized in that: The promoter includes at least one of sodium ascorbate, 18-crown ether-6, sodium isoascorbate, sodium citrate, magnesium ascorbate 2-phosphate, ascorbate glycerol, and magnesium L-ascorbate.

8. A method for synthesizing a 1,4-disubstituted 1,2,3-triazole according to any one of claims 1 to 4, characterized in that: The molar ratio of the alkyne compound to the azide compound is 0.8~1:1~2.

9. A method for synthesizing a 1,4-disubstituted 1,2,3-triazole according to any one of claims 1 to 4, characterized in that: The molar ratio of the alkyne compound to the 4-mercapto-1,2,3-triazole ligand is 1:0.005~0.5; The molar ratio of the alkyne compound to the copper catalyst is 1:0.005~0.5; The molar ratio of the alkyne compound to the accelerator is 1:0.001~0.

5.

10. A method for synthesizing a 1,4-disubstituted 1,2,3-triazole according to any one of claims 1 to 4, characterized in that: The conditions for the cycloaddition reaction are: temperature 10~50℃, time 5~150 min.

Images