1,2,4-triazolidine compounds and methods of synthesis thereof

Abstract

The application belongs to the technical field of organic synthetic chemistry, and provides a 1,2,4-triazolane compound and a synthesis method thereof.The synthesis condition of the 1,2,4-triazolane compound is convenient, the reaction is carried out at room temperature, the steps are simple, and no complex equipment is needed, the electrolytic current is suitable for ordinary laboratories, the high cost problem caused by noble metals can be avoided, the reaction is realized by electron transfer between electrodes, no additional chemical oxidizing and reducing agent is needed, the solvent is environmentally friendly, meets the green chemistry demand, and has economic practicability and environmental protection value.Meanwhile, the synthesis method has excellent performance, can selectively construct a 1,2,4-triazolane ring system C-N bond, the product structure is single, the yield is as high as 90%, the synthesis cycle is short, the efficiency is high, the substrate application range is wide, and the 1,2,4-triazolane compound with various structures and rich substituents can be efficiently synthesized, thereby providing technical support for the construction of a drug research compound library.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, and particularly relates to a 1,2,4-triazolidine compound and its synthetic method. Background Technology

[0002] The triazolidine skeleton, as an important structure in medicinal chemistry, is widely found in drug molecules with various biological activities, including antibacterial, antitumor, anti-inflammatory, and anti-neurodegenerative disease effects. For example, Wang et al. (Adv. Synth. Catal. 2006, 348, 2391–2396.) discovered that 1,2,4-triazolidine is effective against human nasopharyngeal carcinoma (SUNE1) (IC). 50 =10.4mM) and human cervical cancer (HeLa) (IC) 50 Cell lines treated with 10.7 mM (=10.7 mM) all exhibited good cytotoxicity. The triazolidine derivative of the natural triterpene betulin also inhibited the replication of Semleeki forest virus (SFV) (IC50). 50 =6.1 μM (J. Nat. Prod., 2009, 72, 1917.). Compared with the interferon inhibition level of 1.0 ng / mL, the compound BUCMLD-B10A11 showed an inhibition rate of 45.1% ± 5.2% against HCV (Antimicrob. Agents Chemother., 2007, 51, 3756.). Furthermore, Cho et al. (J. Med. Chem. 2017, 60, 170−179.) reported the use of the small molecule modulator infloman to treat sepsis and reduce the production of pro-inflammatory cytokines. Given the broad application prospects of 1,2,4-triazolidine compounds, researchers are continuously exploring and developing their synthetic methods to meet the needs of drug development for these compounds.

[0003] The 1,3-dipolar cycloaddition reaction of dialkyl azodicarboxylates with highly reactive azomethine ylides is a typical method for synthesizing 1,2,4-triazolanes, but it usually relies on high temperatures and inert gas protection (Tetrahedron Letters, 1971, 6, 473–476.), making it complex and unsafe. Photocatalytic synthesis methods have also been applied to the preparation of 1,2,4-triazolane compounds. Shi bata et al. (J. Jpn. Soc. Colour Mater. 2002, 75, 106–110.) reported the irradiation of a TiO2 powder suspension in a methanol solution of azobenzene by a 300W high-pressure mercury lamp; however, the product system was complex, and the highest yield of 1,2,4-triazolane was only 45%, which is insufficient for efficient synthesis. Subsequently, Yang et al. (Green Chem., 2021, 23, 5806–5811.) reported... N The photocatalytic decarboxylation cycloaddition reaction of arylglycine and azobenzene yields 1,2,4-triazolane. Furthermore, this research group (Adv. Synth. Catal. 2023, 365, 4303–4309.) further reported a visible-light photocatalytic reaction of unstable imine ylides from alkyl tertiary amines. However, both of these photocatalytic methods also have limitations: limited adaptability to azobenzene substrates with heterocyclic and sterically hindered groups, and the difficulty in obtaining the key reaction precursor, aryl tertiary amine, results in a narrow range of applicable substrates, restricting their application in the synthesis of diverse compounds.

[0004] In recent years, organic electrosynthesis, with its characteristic of achieving redox reactions through electrons, has become a powerful and sustainable organic synthesis strategy, providing a new direction for the synthesis of 1,2,4-triazolane compounds. Li et al. (Org. Chem. Front., 2022, 9, 3769–3774.) developed an electrochemical [3+2] cycloaddition reaction of azobenzene with triazine derivatives. In addition, Wen et al. (ACS Sustainable Chem. Eng. 2023, 11, 16785−16792.) reported an electrochemical silver-catalyzed [2+2+1] decarboxylation cyclization reaction to generate 1,2,4-triazolane. However, these two electrochemical methods have limitations in terms of cost and application. The former relies on expensive triazine derivatives as reactants, and the latter requires the use of precious metal silver as a catalyst. Both increase the synthesis cost, which is not conducive to the further promotion and industrial application of the methods.

[0005] In summary, although synthetic methods for 1,2,4-triazolanes have been continuously developed, existing techniques generally suffer from numerous problems, such as the need for high-temperature reactions, reliance on inert gas protection, high costs due to the use of precious metals and their ligands, and limited substrate applicability. Therefore, developing a green, efficient, and highly selective method for constructing CN bonds under mild reaction conditions to provide 1,2,4-triazolane compounds with a broad substrate range remains a significant challenge. To address this, this invention proposes a method for synthesizing 1,2,4-triazolane compounds. Summary of the Invention

[0006] The purpose of this invention is to provide a 1,2,4-triazolidine compound and its synthetic method, aiming to solve the problems mentioned in the background art. This invention achieves its objective through the following technical solution:

[0007] A 1,2,4-triazolidine compound, wherein the general structural formula of the 1,2,4-triazolidine compound is:

[0008] ;

[0009] Among them, Ar, Ar 1 Aryl 2 Refers to aryl, C 4-7 Heterocyclic groups and C 4-7 Heteroaryl, the aryl, C 4-7 Heterocyclic groups and C 4-7 The heteroaryl group may be substituted by 1, 2, or 3 Rs; the Rs are selected from C 1-6 Alkyl, C 1-6 Alkoxy, aryl, thiazolyl, pyridyl, oxazolyl, halogen, carbonyl, acyl, sulfonyl, ester, or cyano;

[0010] The 1,2,4-triazolidine compounds were synthesized via a metal-free electrocatalytic method, specifically by: ... N- Arylglycine reacts with azobenzene compounds under electrocatalytic conditions with an electrolyte, medium, and solvent, yielding 1,2,4-triazolidine compounds under predetermined electrode, current, temperature, and time conditions.

[0011] A method for synthesizing 1,2,4-triazolidine compounds according to the above-described method includes the following steps:

[0012] Step 1: Combine azobenzene compounds and N -Arylglycine is added to the reactor;

[0013] Step 2: Add the electrolyte, medium, and solvent to the reactor;

[0014] Step 3: Insert the electrodes into the reactor;

[0015] Step 4: Electrolyze the mixed solution under preset current and temperature conditions for a preset time to quench the reaction;

[0016] Step 5: Add organic solvent for extraction, dry and concentrate the organic phase, and then purify to obtain 1,2,4-triazolidine compounds.

[0017] Furthermore, the azobenzene compounds refer to azobenzene, 1,2-di-p-tolyldiazene, 1,2-bis(4-methoxyphenyl)diazene, 1,2-bis(4-fluorophenyl)diazene, 1,2-bis(4-(trifluoromethyl)phenyl)diazene, 1,2-di-m-tolyldiazene, 1-phenyl-2-(p-tolyl)diazene, 1-(4-(tert-butyl)phenyl)-2-phenyldiazene, 1-(4-benzylphenyl)-2-phenyldiazene, 1-([1,1'-biphenyl]-4-yl)-2-phenyldiazene, 1-(4-methoxyphenyl)-2-phenyldiazene, 1-phenyl-2-(4-(trifluoromethoxy)phenyl)diazene, 1-(4-(methylthio)phenyl)- 2-Phenylacetene, 1-(4-fluorophenyl)-2-phenyldiazene, 1-(4-chlorophenyl)-2-phenyldiazene, 1-(4-bromophenyl)-2-phenyldiazene, methyl 4-(benzodiazene)benzoate, ethyl 4-(benzodiazene)benzoate, 1-(4-(methylsulfonyl)phenyl)-2-phenyldiazene, 1-phenyl-2-(4-(trifluoromethyl)phenyl)diazene, 4-(phenyldiazene)benzonitrile, 1-phenyl-2-(m-tolyl)diazene, 1-phenyl-2-(o-tolyl)diazene, 1-(3,5-dimethylphenyl)-2-phenyldiazene, 1-(3-fluoro-4-methoxyphenyl)-2-phenyldiazene, 1-(2,3-dihydro-1 H -inden-5-yl)-2-phenyldiazene, 5-(phenyldiazene)benzo[ d ]Thiazole, 6-(phenyldiazeninyl)-3,4-dihydronaphthalene-1 (2 H One of the )-ketones.

[0018] Furthermore, the aforementioned N -Arylglycine refers to N -Phenylglycine, N -(p-Tolyl)glycine, N -(4-methoxyphenyl)glycine, N -(4-fluorophenyl)glycine, N -(4-chlorophenyl)glycine, N -(4-bromophenyl)glycine, N -(4-Benzylphenyl)glycine, N-([1,1'-biphenyl]-4-yl)glycine, N One of (3-fluoro-4-methoxyphenyl)glycine.

[0019] Furthermore, the electrolyte is a tetraalkyl-substituted quaternary ammonium salt compound.

[0020] Furthermore, the medium is 2,4,6-trimethylpyridine (2,4,6-collidine). N One of hydroxyphthalimide (NHPI), ferrocene, and pyridine.

[0021] Furthermore, the solvent is dichloromethane, acetonitrile (CH3CN), water, N , N -Dimethylformamide, N , N - One or more of the following solvents: dimethylacetamide, aromatic hydrocarbons, ethers, cyclic ethers, and alcohols.

[0022] Furthermore, the electrode is a combination of two of the following: graphite rod, stainless steel rod, molybdenum rod, copper rod, zinc rod, platinum sheet, titanium rod, carbon foam, and nickel foam.

[0023] Furthermore, the current intensity is 10mA, the temperature is room temperature, and the time is 5 hours.

[0024] Compared with the prior art, the beneficial effects of the present invention are:

[0025] This invention provides a metal-free electrocatalytic synthesis method for 1,2,4-triazolidine compounds, which can achieve multiple technical advantages:

[0026] From the perspective of synthesis conditions and ease of operation, this method eliminates the reliance on high temperatures and inert gas protection required by traditional synthesis, controlling the reaction temperature at room temperature. It eliminates the need for complex environmental control equipment, and the reaction process requires only three core steps: "feeding-electrolysis-post-treatment." The electrolysis process requires only a constant current of 10mA, which can be completed in a regular laboratory, significantly reducing operational difficulty and experimental risks. Simultaneously, it avoids the high costs associated with precious metals and their ligands, reducing environmental pollution from metal ions. The reaction achieves redox through electron transfer between electrodes, eliminating the need for additional chemical oxidants or reducing agents. Environmentally friendly reagents such as water can be used as solvents, meeting the needs of green chemistry development and combining economic practicality with environmental value.

[0027] In terms of synthetic performance and product quality, this invention can selectively construct CN bonds in the 1,2,4-triazolidine ring system, as shown in the nuclear magnetic resonance data in the examples ( 1 H NMR, 13C10 NMR confirmed that the target product has a single structure with no excess CN-bonded byproducts, exhibiting excellent selectivity and outstanding reaction efficiency. The yield of most products exceeded 70%, and the yield of some products (such as 1,2,4-triphenyl-1,2,4-triazolidine and 4-phenyl-1,2-di-p-tolyl-1,2,4-triazolidine) reached about 90%, far exceeding the highest yield of 45% of traditional photocatalytic methods. The 5-hour reaction time also shortened the synthesis cycle and improved production efficiency.

[0028] In terms of substrate applicability, this invention exhibits strong compatibility and can be adapted to a wide variety of reaction substrates. In particular, azobenzene compounds are compatible with derivatives with different electronically affected substituents, and can also be effectively adapted to substrates containing heterocyclic skeletons and sterically hindered groups, without being limited to a single structural type; N - Arylglycine substrates can also be substituted with different aryl groups as needed. This broad substrate adaptability completely breaks through the bottleneck of the limited effectiveness of existing synthetic methods on heterocyclic and sterically hindered substrates, and solves the problem of the narrow substrate range of existing methods. It can efficiently synthesize 1,2,4-triazolidine compounds with diverse structures and rich substituents, providing strong support for the construction of compound libraries in subsequent drug development. Attached Figure Description

[0029] Figure 1 For compound 3 1 1H NMR spectrum (400MHz, CDCl3).

[0030] Figure 2 For compound 3 13 C10 NMR spectrum (101 MHz, CDCl3).

[0031] Figure 3 For compound 4 1 1H NMR spectrum (400MHz, CDCl3).

[0032] Figure 4 For compound 4 13 C10 NMR spectrum (101 MHz, CDCl3).

[0033] Figure 5 For compound 5 1 1H NMR spectrum (400MHz, CDCl3).

[0034] Figure 6 For compound 5 13 C10 NMR spectrum (101 MHz, CDCl3).

[0035] Figure 7 For compound 6 11H NMR spectrum (400MHz, CDCl3).

[0036] Figure 8 For compound 6 13 C10 NMR spectrum (101 MHz, CDCl3).

[0037] Figure 9 For compound 7 1 1H NMR spectrum (400MHz, CDCl3).

[0038] Figure 10 For compound 7 13 C10 NMR spectrum (101 MHz, CDCl3).

[0039] Figure 11 For compound 8 1 1H NMR spectrum (400MHz, CDCl3).

[0040] Figure 12 For compound 8 13 C10 NMR spectrum (101 MHz, CDCl3).

[0041] Figure 13 For compound 9 1 1H NMR spectrum (400MHz, CDCl3).

[0042] Figure 14 For compound 9 13 C10 NMR spectrum (101 MHz, CDCl3).

[0043] Figure 15 For compound 10 1 1H NMR spectrum (400MHz, CDCl3).

[0044] Figure 16 For compound 10 13 C10 NMR spectrum (101 MHz, CDCl3).

[0045] Figure 17 For compound 11 1 1H NMR spectrum (400MHz, CDCl3).

[0046] Figure 18 For compound 11 13 C10 NMR spectrum (101 MHz, CDCl3).

[0047] Figure 19 For compound 12 1 1H NMR spectrum (400MHz, CDCl3).

[0048] Figure 20 For compound 12 13 C10 NMR spectrum (101 MHz, CDCl3).

[0049] Figure 21 For compound 13 1 1H NMR spectrum (400MHz, CDCl3).

[0050] Figure 22 For compound 13 13 C10 NMR spectrum (101 MHz, CDCl3).

[0051] Figure 23 For compound 14 1 1H NMR spectrum (400MHz, CDCl3).

[0052] Figure 24 For compound 14 13 C10 NMR spectrum (101 MHz, CDCl3).

[0053] Figure 25 For compound 15 1 1H NMR spectrum (400MHz, CDCl3).

[0054] Figure 26 For compound 15 13 C10 NMR spectrum (101 MHz, CDCl3).

[0055] Figure 27 For compound 16 1 1H NMR spectrum (400MHz, CDCl3).

[0056] Figure 28 For compound 16 13 C10 NMR spectrum (101 MHz, CDCl3).

[0057] Figure 29 For compound 17 1 1H NMR spectrum (400MHz, CDCl3).

[0058] Figure 30 For compound 17 13 C10 NMR spectrum (101 MHz, CDCl3).

[0059] Figure 31 For compound 18 1 1H NMR spectrum (400MHz, CDCl3).

[0060] Figure 32 For compound 18 13 C10 NMR spectrum (101 MHz, CDCl3). Detailed Implementation

[0061] In order to provide a clearer understanding of the technical features, objectives and beneficial effects of the present invention, the technical solution of the present invention will now be described in detail below, but it should not be construed as limiting the scope of implementation of the present invention.

[0062] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0063] The structural formulas of compounds 3 to 18 in the examples are as follows:

[0064] ;

[0065] ;

[0066] .

[0067] Example 1: Preparation of 1,2,4-triphenyl-1,2,4-triazolidine (3);

[0068] Azobenzene (36.5 mg, 0.2 mmol, 1.0 eq.), N 2,4,6-Phenylexic acid (121 mg, 0.8 mmol, 4.0 eq.), 2,4,6-collidine (12.1 mg, 0.04 mmol, 0.5 eq.), n- Bu4NClO4 (103 mg, 0.3 mmol, 1.5 eq.) (electrolyte), H2O (0.5 mL), and CH3CN (3.0 mL) were added to a 10 mL round-bottom flask equipped with a magnetic stirrer. A fixed graphite rod anode (d = 5 mm) and platinum cathode were then inserted into the flask. The resulting solution was electrolyzed at a constant current of 10 mA (single-output DC power supply: KRP-305DM) for 5 hours at room temperature. After the reaction was complete, the reaction solution was diluted with ethyl acetate (5 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine (3 × 20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The desired product 3 was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 1 and Figure 2As shown. Yield: 90%, white solid, melting point: 134.5-135.1°C; 1 H NMR (400MHz, CDCl3): δ 7.32 –7.15 (m, 10H), 6.97 – 6.93 (t, J = 7.2Hz, 2H), 6.77 (t, J = 7.4Hz, 1H), 6.59(d, J = 8.0Hz, 2H), 4.87 (s, 2H), 4.69 (s, 2H). 13 C NMR (101MHz, CDCl3): δ150.2, 145.1, 129.4, 129.3, 121.6, 118.4, 115.0, 113.3, 67.1.

[0069] Example 2: Preparation of 4-phenyl-1,2-di-p-tolyl-1,2,4-triazolidine (4);

[0070] The preparation method of compound 4 is basically the same as that of compound 3 in Example 1, the main difference being that 1,2-di-p-tolyldiane (42.0 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1, and the desired product 4 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 150 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 CNMR spectra (101MHz, CDCl3) are as follows: Figure 3 and Figure 4 As shown. Yield: 91%, white solid, melting point: 130.1-131.2°C; 1 H NMR (400MHz, CDCl3): δ 7.29 – 7.23 (dd, J = 15.5, 7.9Hz, 2H), 7.12 (s,8H), 6.81 – 6.77 (t, J = 7.3Hz, 1H), 6.61 – 6.59 (d, J = 8.4Hz, 2H), 4.85 (s,2H), 4.68 (s, 2H), 2.31 (s, 6H). 13 C NMR (101MHz, CDCl3): δ 148.0, 145.2,130.9, 129.7, 129.3, 118.2, 115.1, 113.2, 67.1, 20.5.

[0071] Example 3: Preparation of 1,2-bis(4-methoxyphenyl)-4-phenyl-1,2,4-triazolidine (5);

[0072] The preparation method of compound 5 is basically the same as that of compound 3 in Example 1, with the main difference being that 1,2-bis(4-methoxyphenyl)diazepine (48.4 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1. The desired product 5 was obtained by purification using silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 5 and Figure 6 As shown. Yield: 71%, colorless oil; 1 H NMR (400MHz, CDCl3): δ 7.29 – 7.23 (dd, J = 14.9, 6.7Hz, 2H), 7.18 – 7.16 (d, J = 9.0Hz,4H), 6.88 – 6.86 (d, J = 9.0Hz, 4H), 6.81 – 6.78 (t, J = 7.3Hz, 1H), 6.61 –6.59 (d, J = 8.0Hz, 2H), 4.78 (s, 2H), 4.70 (s, 2H), 3.80 (s, 6H). 13 C NMR(101MHz, CDCl3): δ 154.8, 145.1, 144.1, 129.3, 129.1, 124.3, 120.9, 118.1,117.6, 116.7, 114.4, 114.1, 113.1, 68.6, 67.5, 55.6, 55.5.

[0073] Example 4: Preparation of 1,2-bis(4-fluorophenyl)-4-phenyl-1,2,4-triazolidine (6);

[0074] The preparation method of compound 6 is basically the same as that of compound 3 in Example 1, with the main difference being that 1,2-bis(4-fluorophenyl)diazepine (43.6 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1. The desired product 6 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1). 1H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 7 and Figure 8 As shown. Yield: 86%, white solid, melting point: 118.2-119.1°C; 1 H NMR (400MHz, CDCl3): δ 7.21 (s, 3H), 7.09 (s, 4H), 6.96 (s, 4H), 6.77 (t, J = 7.4Hz, 1H), 6.59 – 6.54 (m, 2H), 4.70 (d, J = 23.0Hz, 4H). 13 CNMR (101MHz, CDCl3): δ158.3 (d, J = 242.4Hz), 146.5 (d, J = 2.0Hz), 145.0,129.5, 118.7, 116.6 (d, J = 8.2Hz), 115.8 (d, J = 22.4Hz), 113.4, 67.8.

[0075] Example 5: Preparation of 4-phenyl-1,2-bis(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine (7);

[0076] The preparation method of compound 7 is basically the same as that of compound 3 in Example 1, the main difference being that 1,2-bis(4-(trifluoromethyl)phenyl)diazepine (63.6 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1, and the desired product 7 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 9 and Figure 10 As shown. Yield: 56%, white solid, melting point: 83.5-85.1°C; 1 H NMR (400MHz, CDCl3): δ 7.58 – 7.56 (d, J = 8.5Hz, 4H), 7.31 –7.20 (m, 2H), 7.22 – 7.20 (d, J= 8.4Hz, 4H), 6.89 – 6.86 (t, J = 7.3Hz, 1H),6.67 – 6.65 (d, J = 7.9Hz, 2H), 4.94 (s, 2H), 4.78 (s, 2H). 13 C NMR (101MHz, CDCl3): δ 152.2, 144.6, 129.5, 126.7 (q, J = 3.8Hz), 125.7 (m), 123.3 (d, J =30.0Hz), 119.4, 114.5, 114.4, 113.7, 67.1.

[0077] Example 6: Preparation of 1-(4-(methylthio)phenyl)-2,4-diphenyl-1,2,4-triazolidine (8);

[0078] The preparation method of compound 8 is basically the same as that of compound 3 in Example 1, the main difference being that 1-(4-(methylthio)phenyl)-2-phenyldiazene (45.6 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1, and the desired product 8 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 11 and Figure 12 As shown. Yield: 83%, white solid, melting point: 102.2-103.1°C; 1 H NMR (400MHz, CDCl3): δ 7.34 – 7.24 (dq, J = 15.3, 8.0Hz, 6H),7.20 – 7.18 (d, J = 8.2Hz, 2H), 7.16 – 7.14 (d, J = 8.6Hz, 2H), 7.01 – 6.97(t, J = 7.2Hz, 1H), 6.83 – 6.80 (t, J = 7.2Hz, 1H), 6.63 – 6.61 (d, J =8.0Hz, 2H), 4.86 (s, 2H), 4.71 (s, 2H), 2.47 (s, 3H). 13C NMR (101MHz, CDCl3): δ 150.0, 148.5, 145.0, 129.9, 129.7, 129.4, 129.2, 121.6, 118.5, 115.7, 115.0, 113.3, 67.2, 67.1, 17.8.

[0079] Example 7: Preparation of ethyl 4-(2,4-diphenyl-1,2,4-triazolidine-1-yl)benzoate (9);

[0080] The preparation method of compound 9 is basically the same as that of compound 3 in Example 1, the main difference being that ethyl 4-(benzodiazenin)benzoate (50.8 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1, and the desired product 9 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 13 and Figure 14 As shown. Yield: 60%, colorless oil; 1 H NMR(400MHz, CDCl3): δ 8.03 (d, J = 8.8Hz, 2H), 7.32 (dtd, J = 23.4, 7.2, 1.8Hz,4H), 7.22 – 7.13 (m, 3H), 7.05 (t, J = 7.3Hz, 1H), 6.86 (t, J = 7.3Hz, 1H), 6.66 (d, J = 8.0Hz, 1H), 4.89 (s, 2H), 4.39 (q, J = 7.1Hz, 2H), 1.42 (t, J =7.1Hz, 3H). 13 C NMR (101MHz, CDCl3): δ 153.11, 149.8, 144.9, 131.2, 129.4,122.8, 122.4, 118.9, 115.5, 113.4, 67.9, 66.1, 60.6, 14.5.

[0081] Example 8: Preparation of 1-(4-(methanesulfonyl)phenyl)-2,4-diphenyl-1,2,4-triazolidine (10);

[0082] The preparation method of compound 10 is basically the same as that of compound 3 in Example 1, the main difference being that 1-(4-(methylsulfonyl)phenyl)-2-phenyldiazene (52.0 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1, and the desired product 10 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 15 and Figure 16 As shown. Yield: 68%, white solid, melting point: 181.2-183.1°C; 1 H NMR (400MHz, CDCl3): δ 7.86 – 7.84 (d, J = 8.8Hz,2H), 7.36 – 7.32 (t, J = 7.9Hz, 2H), 7.30 – 7.26 (t, J = 7.8Hz, 3H), 7.23 –7.21 (d, J = 8.8Hz, 2H), 7.16 – 7.14 (d, J = 8.2Hz, 2H), 7.07 – 7.04 (t, J =7.3Hz, 1H), 6.88 – 6.84 (t, J = 7.3Hz, 1H), 6.67 – 6.65 (d, J = 8.1Hz, 2H),5.01 (s, 1H), 4.93 – 4.88 (d, J = 18.9Hz, 2H), 4.61 (s, 1H), 3.04 (s, 3H). 13 CNMR (101MHz, CDCl3): δ 153.4, 149.4, 144.7, 131.6, 129.5, 129.4, 129.1,122.8, 119.2, 115.6, 113.7, 113.6, 68.3, 65.9, 44.9.

[0083] Example 9: Preparation of 4-(2,4-diphenyl-1,2,4-triazol-1-yl)benzyl nitrile (11);

[0084] The preparation method of compound 11 is basically the same as that of compound 3 in Example 1, the main difference being that 4-(phenyldiazetenyl)benzonitrile (41.4 mg, 0.2 mmol) is used instead of the azobenzene used in Example 1, and the desired product 11 is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 17 and Figure 18 As shown. Yield: 71%, white solid, melting point: 144.2-145.1°C; 1 H NMR (400MHz, CDCl3): δ 7.58 – 7.56 (d, J = 8.8Hz, 2H), 7.35 – 7.26(m, 5H), 7.16 – 7.14 (d, J = 8.9Hz, 4H), 7.07 – 7.03 (t, J = 7.3Hz, 1H), 6.88– 6.84 (t, J = 7.4Hz, 1H), 6.66 – 6.64 (d, J = 7.9Hz, 2H), 4.99 (s, 1H), 4.90– 4.85 (d, J = 20.3Hz, 2H), 4.59 (s, 1H). 13 C NMR (101MHz, CDCl3): δ 152.5,149.5, 144.7, 133.6, 129.5, 129.4, 122.7, 119.6, 119.2, 115.6, 114.0, 113.6,103.2, 68.3, 65.8.

[0085] Example 10: Preparation of 1,4-diphenyl-2-(o-tolyl)-1,2,4-triazolidine (12);

[0086] The preparation method of compound 12 is basically the same as that of compound 3 in Example 1, the main difference being that 1-phenyl-2-(o-tolyl)diazepine (39.2 mg, 0.2 mmol) was used instead of the azobenzene used in Example 1, and the desired product 12 was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 19 and Figure 20 As shown. Yield: 86%, white solid, melting point: 104.2-105.5°C; 1 H NMR (400MHz, CDCl3): δ 7.31 (dt, J = 28.8, 8.4Hz, 9H), 7.16(t, J = 7.8Hz, 1H), 7.08 (d, J = 7.4Hz, 1H), 6.98 (t, J = 7.3Hz, 1H), 6.84(t, J = 7.4Hz, 1H), 6.63 (d, J = 8.0Hz, 2H), 4.93 (s, 2H), 4.64 (s, 2H), 2.54(s, 3H). 13 C NMR (101MHz, CDCl3): δ 150.1, 149.3, 144.9, 131.3, 130.4, 129.4,129.2, 129.1, 126.4, 124.2, 121.0, 118.4, 118.2, 115.0, 114.9, 113.1, 68.5,67.9, 19.1.

[0087] Example 11: 5-(2,4-diphenyl-1,2,4-triazolidine-1-yl)benzo[ d Preparation of thiazole (13);

[0088] The preparation method of compound 13 is basically the same as that of compound 3 in Example 1, the main difference being: the use of 5-(phenyldiazetenyl)benzo[ d Thiazole (47.8 mg, 0.2 mmol) was used to replace the azobenzene used in Example 1, and the desired product 13 was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 21 and Figure 22 As shown. Yield: 60%, yellow oil; 1 H NMR (400MHz, CDCl3): δ 8.98 (s, 1H), 7.98 (s, 1H), 7.86 – 7.84 (d, J= 8.8Hz,1H), 7.41 – 7.38 (d, J = 10.8Hz, 1H), 7.35 – 7.31 (t, J = 7.8Hz, 2H), 7.28 –7.24 (m, 4H), 7.02 – 6.98 (t, J = 7.2Hz, 1H), 6.83 – 6.79 (t, J = 7.4Hz, 1H),6.65 – 6.63 (d, J = 8.2Hz, 2H), 4.92 (s, 2H), 4.80 (s, 2H). 13 C NMR (101MHz, CDCl3): δ 155.0, 154.5, 149.9, 149.6, 145.0, 129.4, 129.2, 126.6, 122.1,121.7, 118.6, 115.1, 115.0, 113.4, 108.9, 67.7, 67.4.

[0089] Example 12: 6-(2,4-diphenyl-1,2,4-triazolidine-1-yl)-3,4-dihydronaphthalene-1 ( 2H Preparation of )-ketone (14);

[0090] The preparation method of compound 14 is basically the same as that of compound 3 in Example 1, the main difference being: the use of 6-(phenyldiazetenyl)-3,4-dihydronaphthalene-1 (2 H The desired product 14 was obtained by replacing the azobenzene used in Example 1 with ketone (50.0 mg, 0.2 mmol) by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1). 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 23 and Figure 24 As shown. Yield: 60%, yellow oil; 1 H NMR (400MHz, CDCl3): δ 8.03 – 8.01 (d, J = 8.7Hz, 1H), 7.35 – 7.31 (t, J = 7.9Hz, 2H), 7.29 – 7.25 (m, 3H), 7.17 – 7.15 (d, J= 7.9Hz, 2H), 7.06 –7.01 (q, J = 7.1Hz, 2H), 6.94 (s, 1H), 6.86 – 6.83 (t, J = 7.3Hz, 1H), 6.66 –6.64 (d, J = 7.9Hz, 2H), 4.99 (s, 1H), 4.88 (s, 2H), 4.59 (s, 1H), 2.94 –2.91 (t, J = 5.8Hz, 2H), 2.63 – 2.60 (t, J = 6.4Hz, 2H), 2.15 – 2.09 (p, J =6.2Hz, 2H). 13 C NMR (101MHz, CDCl3): δ 197.1, 153.1, 149.7, 146.6, 144.8,129.5, 129.4, 129.3, 126.1, 122.4, 118.9, 115.4, 113.4, 112.3, 112.2, 68.0,65.7, 38.9, 30.2, 23.3.

[0091] Example 13: Preparation of 4-(4-chlorophenyl)-1,2-diphenyl-1,2,4-triazolidine (15);

[0092] The preparation method of compound 15 is basically the same as that of compound 3 in Example 1, the main difference being: the method used... N -(4-chlorophenyl)glycine (148 mg, 0.8 mmol) replaced the substance used in Example 1. N -Phenylated glycine was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain the desired product 15. 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 25 and Figure 26 As shown. Yield: 82%, white solid, melting point: 132.2-133.8°C; 1 H NMR (400MHz, CDCl3): δ 7.35 – 7.31 (m, 5H), 7.24 – 7.19 (t, J = 9.2Hz, 5H), 7.04 – 7.00 (m, 2H), 6.57 – 6.52 (t,J = 9.4Hz, 2H), 4.88 (s, 2H), 4.71 (s, 2H). 13 C NMR (101MHz, CDCl3): δ 149.9, 143.6, 129.3, 129.2,121.7, 115.0, 114.3, 67.1.

[0093] Example 14: Preparation of 4-(4-bromophenyl)-1,2-diphenyl-1,2,4-triazolidine (16);

[0094] The preparation method of compound 16 is basically the same as that of compound 3 in Example 1, the main difference being: [The method used is missing here, likely due to an error in the original text]. N -(4-bromophenyl)glycine (183 mg, 0.8 mmol) replaced the substance used in Example 1. N -Phenylated glycine was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain the desired product 16. 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 27 and Figure 28 As shown. Yield: 72%, white solid, melting point: 138.2-139.7°C; 1 H NMR (400MHz, CDCl3): δ 7.35 – 7.29 (m, 6H), 7.22 – 7.20 (d, J= 8.0Hz, 4H), 7.02 – 6.99 (t, J = 7.2Hz, 2H), 6.49 – 6.47 (d, J = 8.4Hz, 2H), 4.86 (s, 2H), 4.68 (s, 2H). 13 C NMR (101MHz, CDCl3): δ 149.9, 143.9, 132.1,129.2, 121.7, 115.0, 114.7, 110.3, 67.0.

[0095] Example 15: Preparation of 4-(4-benzylphenyl)-1,2-diphenyl-1,2,4-triazolidine (17);

[0096] The preparation method of compound 17 is basically the same as that of compound 3 in Example 1, the main difference being: [The method used is missing here, likely due to an error in the original text]. N -(4-Benzylphenyl)glycine (193 mg, 0.8 mmol) replaced the substance used in Example 1. N-Phenylated glycine was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain the desired product 17. 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 29 and Figure 30 As shown. Yield: 70%, yellow oil; 1 H NMR (400MHz, CDCl3): δ 7.33 – 7.27 (q, J = 7.8, 7.4Hz, 6H), 7.20 – 7.16 (m, 7H), 7.09 – 7.07 (d, J = 8.3Hz, 2H), 7.00 – 6.97 (t, J = 7.2Hz, 2H), 6.58 – 6.56(d, J = 8.3Hz, 2H), 4.87 (s, 2H), 4.70 (s, 2H), 3.91 (s, 2H). 13 C NMR (101MHz, CDCl3): δ 150.2, 143.6, 141.8, 131.1, 129.9, 129.2, 128.8, 128.5, 126.0,121.6, 115.0, 113.6, 67.4, 41.0.

[0097] Example 16: Preparation of 4-([1,1'-biphenyl]-4-yl)-1,2-diphenyl-1,2,4-triazolidine (18);

[0098] The preparation method of compound 18 is basically the same as that of compound 3 in Example 1, the main difference being: [The method used is missing here, likely due to an error in the original text]. N -([1,1'-biphenyl]-4-yl)glycine (182 mg, 0.8 mmol) replaced the substance used in Example 1. N -Phenylated glycine was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain the desired product 18. 1 H NMR spectrum (400MHz, CDCl3) and 13 The C NMR spectra (101 MHz, CDCl3) are as follows: Figure 31 and Figure 32 As shown. Yield: 71%, white solid, melting point: 113.8-115.6°C; 1 H NMR (400MHz, CDCl3): δ 7.57 – 7.51 (dd, J= 15.2,8.0Hz, 4H), 7.45 – 7.41 (t, J = 7.6Hz, 2H), 7.35 – 7.31 (t, J = 7.8Hz, 5H),7.24 – 7.22 (d, J = 8.0Hz, 4H), 7.02 – 6.98 (t, J = 7.2Hz, 2H), 6.70 – 6.68(d, J = 8.5Hz, 2H), 4.95 (s, 2H), 4.76 (s, 2H). 13 C NMR (101MHz, CDCl3): δ150.0, 144.3, 140.8, 131.2, 129.2, 128.7, 128.0, 126.4, 121.6, 115.0, 114.1,113.5, 67.0.

[0099] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent.

Claims

1. A method for synthesizing 1,2,4-triazolidine compounds, characterized in that, The general structural formula of the 1,2,4-triazolidine compounds is: ； Among them, Ar, Ar 1 Aryl 2 Refers to aryl, C 4-7 Heterocyclic groups and C 4-7 Heteroaryl, the aryl, C 4-7 Heterocyclic groups and C 4-7 The heteroaryl group may be substituted by 1, 2, or 3 Rs; the Rs are selected from C 1-6 Alkyl, C 1-6 Alkoxy, aryl, thiazolyl, pyridyl, oxazolyl, halogen, carbonyl, acyl, sulfonyl, ester, or cyano; The 1,2,4-triazolidine compounds were synthesized by a metal-free electrocatalytic method. Specifically, N-arylglycine and azobenzene compounds were reacted with electrolyte, medium and solvent under electrocatalytic conditions. Under preset electrode, current, temperature and time conditions, 1,2,4-triazolidine compounds were obtained. The electrolyte is a tetraalkyl-substituted quaternary ammonium salt compound; The medium is one of 2,4,6-trimethylpyridine, N-hydroxyphthalimide, ferrocene, and pyridine; The current intensity is 5-15mA, the temperature is room temperature, and the time is 4-6 hours.

2. The synthesis method according to claim 1, characterized in that, Includes the following steps: Step 1: Add azobenzene compounds and N-arylglycine to the reactor; Step 2: Add the electrolyte, medium, and solvent to the reactor; Step 3: Insert the electrodes into the reactor; Step 4: Electrolyze the mixed solution under preset current and temperature conditions for a preset time to quench the reaction; Step 5: Add organic solvent for extraction, dry and concentrate the organic phase, and then purify to obtain 1,2,4-triazolidine compounds.

3. The synthesis method according to claim 2, characterized in that, The azobenzene compounds mentioned refer to azobenzene, 1,2-di-p-tolyldiazene, 1,2-bis(4-methoxyphenyl)diazene, 1,2-bis(4-fluorophenyl)diazene, 1,2-bis(4-(trifluoromethyl)phenyl)diazene, 1,2-di-m-tolyldiazene, 1-phenyl-2-(p-tolyl)diazene, 1-(4-(tert-butyl)phenyl)-2-phenyldiazene, 1-(4-benzylphenyl)-2-phenyldiazene, 1-([1,1'-biphenyl]-4-yl)-2-phenyldiazene, 1-(4-methoxyphenyl)-2-phenyldiazene, 1-phenyl-2-(4-(trifluoromethoxy)phenyl)diazene, 1-(4-(methylthio)phenyl)-2-phenyldiazene, 1-(4-fluorophenyl)-2-phenyldiazene, 1-(4-chlorophenyl)- 2-Phenylon, 1-(4-bromophenyl)-2-phenyldiazene, methyl 4-(benzodiazene)benzoate, ethyl 4-(benzodiazene)benzoate, 1-(4-(methylsulfonyl)phenyl)-2-phenyldiazene, 1-phenyl-2-(4-(trifluoromethyl)phenyl)diazene, 4-(phenyldiazene)benzonitrile, 1-phenyl-2-(m-tolyl)diazene, 1-phenyl One of the following: 2-(o-tolyl)diazepine, 1-(3,5-dimethylphenyl)-2-phenyldiazepine, 1-(3-fluoro-4-methoxyphenyl)-2-phenyldiazepine, 1-(2,3-dihydro-1H-inden-5-yl)-2-phenyldiazepine, 5-(phenyldiazepine)benzo[d]thiazole, and 6-(phenyldiazepine)-3,4-dihydronaphthyl-1(2H)-one.

4. The synthesis method according to claim 2, characterized in that, The N-arylglycine refers to one of N-phenylglycine, N-(p-tolyl)glycine, N-(4-methoxyphenyl)glycine, N-(4-fluorophenyl)glycine, N-(4-chlorophenyl)glycine, N-(4-bromophenyl)glycine, N-(4-benzylphenyl)glycine, N-([1,1'-biphenyl]-4-yl)glycine, and N-(3-fluoro-4-methoxyphenyl)glycine.

5. The synthesis method according to claim 2, characterized in that, The solvent is one or a combination of two or more of the following: dichloromethane, acetonitrile, water, N,N-dimethylformamide, N,N-dimethylacetamide, aromatic hydrocarbons, ethers, cyclic ethers, and alcohols.

6. The synthesis method according to claim 2, characterized in that, The electrode is a combination of two of the following: graphite rod, stainless steel rod, molybdenum rod, copper rod, zinc rod, platinum sheet, titanium rod, carbon foam, and nickel foam.

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