Method for organic catalytic synthesis of beta-amido azole compound
Through the coordinated catalysis of copper metal catalysts and pyridine organic small molecules, the amine-azolylization reaction between olefin molecules is achieved, solving the problem of cumbersome synthesis process and limited product types, and achieving high efficiency and gentleness β-amine azole compounds under conditions have wide application potential.
Patent Information
- Application Number
- CN202411343195.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-25
- Publication Date
- 2025-01-10
AI Technical Summary
In the prior art, the synthesis process of amine-azolium compounds is complicated, and the types of synthesis products are limited, making it difficult to achieve the amine-azolylation reaction between olefin molecules.
The pyridine-based organic small molecules were synergistically synthesized by a copper metal catalyst, and the three-component reaction of olefins, fluorobisbenzenesulfonimide and azolylation reagent was achieved in one-step synthesis of β-amine azolytic compounds, expanding the synthetic product the substrate range.
It has achieved high yield and high chemical selectivity to obtain β-amine azole compounds, which have mild reaction conditions, simple operation, and wide universal substrates. It is suitable for organic pesticides and biomedical fields.
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Figure CN119285570A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of synthesis of beta-aminoazole compounds, and in particular to a method for synthesizing beta-aminoazole compounds by organic catalysis. Background Art
[0002] Aminazole compounds are widely found in natural products, pesticide preparations and active pharmaceutical molecules. They are also used as advantageous ligands in transition metal catalytic reaction systems or as organic synthesis building blocks to construct complex heterocyclic compounds. Therefore, the development of efficient strategies for the synthesis of aminoazole compounds and their derivatives is of great significance and potential application value in organic synthesis and biomedicine.
[0003] The simultaneous introduction of two functional groups, amine and azole, into organic molecules through the 1,2-difunctionalization reaction of olefins is one of the most convenient and efficient strategies for synthesizing amino-containing azole compounds. At present, only one case of intramolecular amine-azole reaction of olefins has been reported. In 2021, Wang Qiu and his colleagues used the remote migration strategy of aromatic heterocycles to induce the migration of aromatic heterocycles to inactive olefin carbons through the addition of amine radicals, thereby realizing the intramolecular amine-azole reaction of inactive olefins and synthesizing β-aminoazole compounds.
[0004] This reaction has the advantages of mild reaction conditions, good functional group compatibility, good chemical selectivity and regioselectivity. A series of β-aminoazole compounds can be efficiently obtained by this reaction. However, due to the intramolecular migration of aromatic heterocycles and the need for the substrate to contain a specific hydroxyl group, the olefin substrate requires specific synthesis, which limits the types of aminoazole compounds synthesized. Summary of the invention
[0005] The object of the present invention is to provide a method for organically catalyzing the synthesis of β-aminoazole compounds, so as to solve the technical problems in the prior art that the synthesis process of aminoazole compounds is complicated and the types of synthetic products are limited.
[0006] In order to solve the above technical problems, the present invention specifically provides the following technical solutions:
[0007] The present invention provides a method for organically catalyzing the synthesis of β-aminoazole compounds, comprising the following steps:
[0008] Under an argon atmosphere, copper metal catalyst and pyridine organic small molecules were added to the solvent and stirred at room temperature for 0.5 hours. The color of the system gradually changed from colorless to red.
[0009] Then, the reaction substrate fluorobisbenzenesulfonimide, olefin compound and azole substrate were added to the system in sequence, and stirred at room temperature for 6 hours;
[0010] After the reaction is completed, the solvent is drained to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a β-aminoazole compound.
[0011] As a preferred embodiment of the present invention, the copper metal catalyst is cuprous thiophene-2-carboxylate.
[0012] As a preferred embodiment of the present invention, the pyridine organic small molecule is L10.
[0013] As a preferred embodiment of the present invention, the azole substrate is any one or more of 2-(trimethylsilyl)thiazole, 2-(trimethylsilyl)benzothiazole, and 2-(trimethylsilyl)benzoxazole.
[0014] As a preferred embodiment of the present invention, the molar ratio of the copper metal catalyst to the olefin compound is 1:20.
[0015] As a preferred embodiment of the present invention, the molar ratio of the organic small molecule ligand L10 to the olefin compound is 1:16.67.
[0016] As a preferred embodiment of the present invention, the molar ratio of the olefin compound, the fluorobisbenzenesulfonimide and the azole substrate is 1:1.4:1.5.
[0017] As a preferred embodiment of the present invention, the solvent is 1,2-dichloroethane.
[0018] As a preferred embodiment of the present invention, in the separation and purification process, the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate;
[0019] In the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is 5:1.
[0020] Compared with the prior art, the present invention has the following beneficial effects:
[0021] The present invention uses a copper metal catalyst in conjunction with a pyridine organic small molecule as a catalyst to catalyze a three-component reaction between molecules of an olefin, a fluorobisbenzenesulfonyl imide and an azole reagent, thereby realizing a one-step synthesis of a β-aminoazole compound. Moreover, since a wider range of reaction raw materials is used, the substrate range of the synthesized product is further expanded, and the target product β-aminoazole compound can be obtained with a high yield and high chemical selectivity.
[0022] The present invention has very good substrate universality and has good compatibility with olefins containing various functional groups and different azole heterocyclic substrates. At the same time, the method has the characteristics of relatively mild reaction conditions, safe and simple experimental operation, low toxicity of reaction substrates and environmental friendliness.
[0023] The reaction method disclosed by the invention has simple and readily available raw materials and reagents, wide applicability of the substrate, simple post-treatment process, and the obtained compound has potential application value in organic pesticides, biomedicine and organic synthesis. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] In order to more clearly illustrate the implementation methods of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for the implementation methods or the description of the prior art. Obviously, the drawings in the following description are only exemplary, and for ordinary technicians in this field, other implementation drawings can be derived from the provided drawings without creative work.
[0025] Figure 1 The present invention provides a schematic flow chart of a method for organically catalyzing the synthesis of β-aminoazole compounds;
[0026] Figure 2 Provides a summary statistical diagram of the synthesis efficiency of different ligands in catalytic reactions for the present invention;
[0027] Figure 3 Provides a summary statistical diagram of the synthesis efficiency of different ethylene substrates in catalytic reactions for the present invention;
[0028] Figure 4 Provides a summary statistical diagram of the reaction between azole reagents and different olefins for the present invention;
[0029] Figure 5 Provide the structural formula of the target product of the catalytic reaction for the present invention;
[0030] Figure 6 Provide the structural formula of the target product of the catalytic reaction for the present invention;
[0031] Figure 7 Provide the structural formula of the target product of the catalytic reaction for the present invention;
[0032] Figure 8 A catalytic cycle mechanism diagram of the catalytic reaction process is provided for the present invention. DETAILED DESCRIPTION
[0033] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0034] like Figure 1As shown, the present invention provides a method for organically catalyzing the synthesis of β-aminoazole compounds, comprising the following steps:
[0035] Step 1: In a glove box, under an argon atmosphere, add a copper metal catalyst, a pyridine organic small molecule and a solvent into a reaction bottle, stir and react at room temperature for 0.5 hours, and the color of the system gradually changes from colorless to red.
[0036] Step 2: Then, the reaction substrate fluorobisbenzenesulfonimide, olefin compound and azole substrate are added to the system in sequence, and the reaction is continued under stirring at room temperature for 6 hours.
[0037] Step 3: After the reaction is completed, the solvent is drained to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a β-aminoazole compound.
[0038] The reaction formula of the present invention is as follows:
[0039]
[0040] Wherein, R is a phenyl group having various substituents.
[0041] The currently developed systems for constructing β-aminoazole compounds mainly focus on intramolecular reactions, and the types of target compounds lack diversity, especially for the construction of C(sp 3 )-N bond and C(sp 3 Although the synthetic strategy and mechanism of the intermolecular amine difunctionalization reaction of olefin molecules have been relatively mature, the intermolecular amine-azole reaction of olefin molecules is difficult to carry out.
[0042] The invention uses a synthesized copper metal complex containing a 1,3-disubstituted-2-indolyl tridentate ligand as a catalyst, finds a suitable amination reagent and an azole source reagent and changes the reaction conditions to initiate a single electron transfer in the reaction, generates an amine free radical, and is captured by an olefin to add to an alkyl free radical, which further reacts with an azole nucleophile, thereby achieving an amination-azole reaction between olefin molecules.
[0043] In order to achieve the above reaction, the synthesized binuclear copper metal complex or tetranuclear copper metal cluster is generally used as a catalyst, styrene 4-1a is a substrate, NFSI is an oxidant and an amine source, and 2-(trimethylsilyl)thiazole 4-3a is an azole source, and the reaction is carried out at room temperature. Unfortunately, the target reaction cannot be achieved by constantly changing the reaction solvent, metal complex catalyst, reaction temperature and other conditions, and the olefin in the system is quantitatively retained.
[0044] Furthermore, based on the fact that different copper salt catalysts cooperate with various neutral ligands to catalyze the difunctionalization reaction of olefins, the present invention further uses a catalyst system of copper salts in cooperation with neutral ligands, and systematically screens different copper salts, ligands, reaction solvents, reaction time and other conditions. Finally, copper metal catalysts are used in cooperation with pyridine organic small molecules as catalysts to catalyze the intermolecular three-component reaction of olefins, fluorobisbenzenesulfonyl imide and azole reagents, and the target product β-aminoazole compound can be obtained with high yield and high chemical selectivity.
[0045] At the same time, this method has the characteristics of relatively mild reaction conditions, safe and simple experimental operation, low toxicity of reaction substrates and environmental friendliness.
[0046] The reaction raw materials and reagents are simple and easy to obtain, the substrate has wide applicability, the post-treatment process is simple, and the obtained compound has potential application value in organic pesticides, biopharmaceuticals and organic synthesis.
[0047] In the present invention, in view of the crucial role of ligands in catalytic reactions, bipyridine and phenanthroline, as important neutral ligands, are widely used in transition metal catalytic reaction systems. Cu(CH3CN)4PF6 is selected as a catalyst, styrene, NFSI, and 2-(trimethylsilyl)thiazole are still used as reaction substrates, and dichloromethane is used as a reaction solvent. Different bipyridine, biquinoline, bridged bipyridine and phenanthroline ligands are screened at room temperature (see Figure 2 ). The results showed that the neutral ligands L1-L9 could not achieve the target reaction.
[0048] However, when ligand L10 (6,6'-dicyano-2,2'-bipyridine) was used, the target product could be obtained with a NMR yield of 36%, which may be related to the strong coordination effect of the cyano group; when the 6-position of bipyridine was replaced with acetic acid or ester group L11-L13, the catalytic reaction could also be achieved, especially when L12 substituted with methyl acetate was used as the ligand, the target product could be obtained with a NMR yield of 35%.
[0049] In the embodiment of the present invention, the ligand L10 is preferably selected as the best ligand for screening the subsequent reaction conditions. 6,6'-dicyano-2,2'-bipyridine has the following structural formula:
[0050]
[0051] In the present invention, the reaction solvent has an important influence on the reaction, as shown in Table 1:
[0052] Table 1
[0053]
[0054]
[0055] Table 1 shows that no matter it is a small polar solvent such as toluene (Tol), methyl tert-butyl ether (MTBE) or a large polar solvent such as dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), the reaction cannot be achieved; the target product can only be obtained at a lower yield in tetrahydrofuran (THF), chlorobenzene (PhCl), and acetone (Acetone); the target product can be obtained with a nuclear magnetic yield of 60% using acetonitrile (CH3CN); when 1,2-dichloroethane (DCE) is used as the reaction solvent, the yield of the reaction is greatly improved, and the target product can be obtained with a nuclear magnetic yield of 63%. Therefore, in a preferred embodiment of the present invention, DCE is used as the optimal solvent for the reaction.
[0056] In the above reaction, different copper salt catalysts have different catalytic effects, as shown in Table 2:
[0057] Table 2
[0058]
[0059] Table 2 shows that the reaction can be achieved by using cuprous halides such as cuprous chloride and cuprous bromide, but cuprous iodide cannot catalyze the reaction; when other monovalent copper salts such as cuprous acetate and cuprous cyanide are used, the catalytic effect is significantly improved, and the target product is obtained with 89% and 93% NMR yields respectively; when copper thiophene 2-carboxylate (CuTc) is used as a catalyst, 4-4a can be obtained with a NMR yield of 94%; it is worth noting that divalent copper salts such as copper trifluoromethanesulfonate can also catalyze the reaction with a NMR yield of 88%. In the control experiment, no copper salt was added and the reaction could not proceed normally.
[0060] In a preferred embodiment of the present invention, CuTc is selected as the best copper salt catalyst for the reaction.
[0061] On the basis of the above improvement of catalytic yield, the present invention further optimizes the catalyst equivalent. When the CuTc loading is reduced to 5mol%, the reaction is almost unaffected, and the product can still be obtained with a nuclear magnetic yield of 93%. Further reducing the catalyst equivalent to 2mol%, the yield is reduced to 85%. Therefore, the catalyst equivalent is finally determined to be CuTc (5mol%) and L10 (6mol%).
[0062] In order to improve the atom economy and efficiency of the reaction, the present invention optimizes the reaction substrate equivalent and reaction time. See the following reaction formula:
[0063]
[0064] The statistical results are shown in Table 3:
[0065] Table 3
[0066]
[0067] As shown in Table 3, the reaction yield was not affected by reducing the amount of 4-2a and 4-3a in the above reaction formula to 1.4 equivalents and 1.5 equivalents respectively; the yield was reduced to 90% by further reducing the amount of 4-2a to 1.2 equivalents. The reaction was completed by shortening the reaction time to 6h; the yield was reduced to 89% by further shortening the reaction time to 3h. The reaction was not affected by reducing the amount of reaction solvent to 0.5mL.
[0068] Finally, in a preferred embodiment of the present invention, 4-2a is 1.4 equivalents, 4-3a is 1.5 equivalents, the amount of DCE solvent is 0.5 mL, and the reaction time is 6 h.
[0069] So far, in the present invention, the optimal reaction conditions are: 5 mol% CuTc as catalyst, 6 mol% L10 as ligand, DCE (0.2M) as reaction solvent, 1.4 equivalents of fluorobisbenzenesulfonimide 4-2a as oxidant and amine source, 1.5 equivalents of 2-(trimethylsilyl)thiazole 4-3a as azole source, reaction at room temperature for 6h, and finally obtaining the target product with an isolated yield of 92%.
[0070] The reaction formula is as follows:
[0071]
[0072] In the present invention, ethylene substrates have good substrate universality, see Figure 3 . Figure 3 It was shown that when the para-position of styrene was substituted by an electron-donating group, the reaction could proceed smoothly, and the target products (4-4b to 4-4e) were obtained with excellent yields. When the para-position was substituted by a halogen, the corresponding products (4-4f to 4-4h) could still be obtained with a yield of 81% to 84%. When a strong electron-withdrawing group, such as a trifluoromethyl group or an ester group, was introduced into the para-position, the reaction yield was reduced, and 4-4i and 4-4j were obtained with yields of 73% and 77%, respectively.
[0073] When there are substituents at the meta- and ortho-positions of styrene, the impact on the reaction yield is greater than that of the substitution at the para-position of styrene (4-4k to 4-4m); the reaction can still proceed smoothly when there are multiple substituents on the aromatic ring of styrene or the substrate steric hindrance is increased (4-4n and 4-4o), which shows that the electronic and steric effects of the substituents have a certain influence on the reaction. In further substrate expansion, it was found that the reaction also has certain limitations. When using inactive olefin substrates such as aliphatic, the reaction cannot occur. In addition, the reaction effect of heterocyclic olefins is poor. For example, using 2-vinylthiophene as a substrate, the corresponding product can only be obtained with a nuclear magnetic yield of 15%.
[0074] The present invention further describes the reaction of azole reagents with different olefins, and the reaction formula is as follows:
[0075]
[0076] For specific results, see Figure 4 , Figure 4 The results showed that the more electron-rich 2-(trimethylsilyl)benzoxazole has higher reactivity than 2-(trimethylsilyl)thiazole. It can obtain the target products with good to excellent yields when reacting with different olefins. Different substituents at different positions of the benzene ring can also achieve the reaction. It is worth noting that when 2-naphthylene is used as the substrate, the target product 4-5p can still be obtained with a yield of 68%. Using 2-(trimethylsilyl)benzothiazole as the azole source, the corresponding products (4-5q to 4-5s) can also be obtained with excellent yields.
[0077] It can be seen that in the present invention, the azole substrate can be selected within any range, in order to..., the azole substrate is any one or more of 2-(trimethylsilyl)thiazole, 2-(trimethylsilyl)benzothiazole, and 2-(trimethylsilyl)benzoxazole.
[0078] The eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 5:1.
[0079] In an embodiment of the present invention, the molar ratio of the copper metal catalyst to the olefin compound is 1:20.
[0080] In the embodiment of the present invention, the molar ratio of the organic small molecule ligand L10 to the olefin compound is 1:16.67.
[0081] In the embodiment of the present invention, the molar ratio of the reaction substrate olefin, fluorobisbenzenesulfonimide, and azole substrate is 1:1.4:1.5.
[0082] In summary, the general method for the copper-catalyzed amination-oxazolidinylation reaction of olefin molecules is as follows:
[0083]
[0084] In a glove box under argon atmosphere, CuTc (1.9 mg, 0.01 mmol, 0.05 equiv.) and L10 (2.5 mg, 0.012 mmol, 0.06 equiv.) were weighed and added to a 15 mL Schlenk glass reaction bottle, and then 0.5 mL DCE was added. The reaction was stirred at room temperature for 0.5 h, and the color of the system gradually changed from colorless to red. Subsequently, the reaction substrate NFSI (88.2 mg, 0.28 mmol, 1.4 equiv.), olefin (0.2 mmol, 1.0 equiv.) and azole reagent (0.3 mmol, 1.5 equiv.) were added to the system in sequence, and the reaction was continued at room temperature for 6 h.
[0085] The reaction was monitored by TLC. After the substrate disappeared, the reaction mixture was directly filtered through diatomaceous earth and eluted with ethyl acetate. The filtrate was concentrated and separated by column chromatography using n-hexane / ethyl acetate as eluent to obtain the purified product.
[0086] The structural formula of the purified product is Figures 5 to 7 shown.
[0087] The present invention is further described in detail below in conjunction with specific examples, but the implementation method and applicable substrates of the present invention are not limited thereto.
[0088] Example 1
[0089] 1. Reagent preparation:
[0090] Weigh cuprous thiophene-2-carboxylate (19 mg, 0.1 mmol, 0.05 equiv.); 6,6'-dicyano-2,2'-bipyridine (25 mg, 0.12 mmol, 0.06 equiv.); 1,2-dichloroethane 5 mL; fluorobisbenzenesulfonimide (882 mg, 2.8 mmol, 1.4 equiv.); 4-vinylbiphenyl (360 mg, 2.0 mmol, 1.0 equiv.); trimethylsilylbenzoxazole (574 mg, 3.0 mmol, 1.5 equiv.)
[0091] 2. Operation:
[0092] In a glove box under argon atmosphere, cuprous thiophene-2-carboxylate and 6,6'-dicyano-2,2'-bipyridine were added to a 15 ml Schlenk glass reaction bottle, and then 1,2-dichloroethane was added. The reaction was stirred at room temperature for 0.5 h, and the color of the system gradually changed from colorless to red.
[0093] Then, the reaction substrates fluorobisbenzenesulfonimide, 4-vinylbiphenyl and trimethylsilylbenzoxazole were added to the system in sequence, and the reaction was continued under stirring at room temperature for 6 hours;
[0094] The reaction was monitored by TLC. After the substrate disappeared, the reaction mixture was directly filtered through diatomaceous earth and eluted with ethyl acetate. The filtrate was concentrated and separated by column chromatography using n-hexane / ethyl acetate as eluent to obtain 1.07 g of a white purified product 4-5d with a yield of 90%.
[0095] The reaction formula of Example 1 is as follows:
[0096]
[0097] Example 2
[0098] 1. Reagent preparation:
[0099] Weigh cuprous thiophene-2-carboxylate (1.9 mg, 0.01 mmol, 0.05 equiv.); 6,6'-dicyano-2,2'-bipyridine (2.5 mg, 0.012 mmol, 0.06 equiv.); 0.5 ml of 1,2-dichloroethane; fluorobisbenzenesulfonimide (88.2 mg, 0.28 mmol, 1.4 equiv.); styrene (0.2 mmol, 1.0 equiv.); 2-(trimethylsilyl)thiazole (0.3 mmol, 1.5 equiv.)
[0100] 2. Operation:
[0101] In a glove box under argon atmosphere, cuprous thiophene-2-carboxylate and 6,6'-dicyano-2,2'-bipyridine were added to a 15 ml Schlenk glass reaction bottle, and then 1,2-dichloroethane was added. The reaction was stirred at room temperature for 0.5 h, and the color of the system gradually changed from colorless to red.
[0102] Then, the reaction substrates fluorobisbenzenesulfonimide, styrene and 2-(trimethylsilyl)thiazole were added to the system in sequence, and the reaction was continued under stirring at room temperature for 6 hours;
[0103] After the reaction was completed, the solvent was removed in vacuo to obtain a crude product, which was separated and purified by column chromatography (developing solvent: petroleum ether / ethyl acetate = 5:1) to obtain product 4-4a with a yield of 92%.
[0104] Then, 1,3,5-trimethoxybenzene (0.1 mmol) was added to the system as an internal standard, and 5 mL of ethyl acetate was added to completely dissolve the mixture in the system. The system sample was transferred for 1 H NMR and GC-MS detection.
[0105] 3. Characterization:
[0106] The structural formula of the main product is as follows:
[0107]
[0108] The structural characterization data of the obtained product are shown below:
[0109] 1 H NMR (500MHz, CDCl3, 298K): δ (ppm) 7.74–7.71 (m, 5H), 7.73 (dd, J = 9.4, 5.5Hz, 2H), 7.52–7.40 (m, 6H), 7.36–7.31 (m ,3H)7.20(d,J=3.2Hz,1H),5.05(dd,J=8.9,5.5Hz,1H),4.72(dd,J=15.4,9.1Hz,1H),4.46(dd,J=15.5,5.5Hz,1H). 13 C NMR (125MHz, CDCl3, 298K): δ (ppm) 170.9, 143.2, 139.6, 139.5, 134.3, 130.0, 129.5, 129.2, 128.5, 119.9, 53.1, 50.0. HRMS: m / z (ESI)calcd.for C 23 H 20 N2O4S3[M+H] + :485.0658,found:485.0656.
[0110] Verification Example 1
[0111] Part of the steps were the same as those in Example 2, except that the reaction substrate contained a free radical scavenger TEMPO (46.9 mg, 0.3 mmol, 1.5 equiv.).
[0112] The reaction formula of Verification Example 1 is as follows:
[0113]
[0114] Verification Example 2
[0115] Part of the steps were the same as those in Example 2, except that the reaction substrate contained a free radical inhibitor BHT (66.1 mg, 0.3 mmol, 1.5 equiv.).
[0116] The reaction formula is as follows:
[0117]
[0118] Verification Example 3
[0119] The same steps as in Example 2, except that the ethylene solvent in the reaction substrate was 4-1t (44.1 mg, 0.2 mmol, 1.0 equiv.);
[0120] At the same time, the reaction was continued to be stirred at room temperature for 6 hours, and the reaction was monitored by TLC. After the substrate disappeared, the reaction mixture was directly filtered through diatomaceous earth and rinsed with ethyl acetate. The filtrate was concentrated and n-hexane / ethyl acetate was used as the eluent.
[0121] Column chromatography was used to separate 65 mg of a white purified product 4-5t with a yield of 51%.
[0122] The reaction formula is as follows:
[0123]
[0124] Examples 1 and 2 show that the catalytic reaction can be carried out on a gram scale, is practical, and has a high yield.
[0125] Verification Example 1 was a free radical capture experiment, and it was found that the standard reaction was almost completely inhibited, and GC-MS detected the generation of TEMPO-N(SO2Ph)2 and β-TEMPO amino products in the system, with NMR yields of 28% and 11%, respectively.
[0126] Verification Example 2 is to add 1.5 equivalents of free radical inhibitor 2,6-di-tert-butyl-p-cresol BHT (Scheme 4-6b) to the standard reaction system, and the target reaction yield is greatly reduced to 32%. These results indicate that the reaction may have undergone a free radical process and that amine radical species were generated.
[0127] Verification Example 3 is a "radical clock" experiment. The three-membered ring substrate 4-1t underwent a three-membered ring opening reaction under standard conditions, and the cis-addition-dominated product 4-5t was obtained with an isolated yield of 51% and a diastereoselectivity of 4:1. This experiment shows that the reaction may have undergone a process in which the generated amine radical species added to the olefin to generate an alkyl radical intermediate.
[0128] Based on the above experimental results, the catalytic cycle mechanism of the reaction is shown in Figure 8 .
[0129] 1) The monovalent copper compound interacts with the amination reagent 4-2a to generate the active species int.I;
[0130] 2) int.I further reacts with trimethylsilylazole compounds to obtain divalent copper intermediate int.II, namely LCu(II)Azol, while releasing amine radicals and trimethylsilyl fluoride;
[0131] 3) At the same time, the amine radical rapidly adds to the olefin to produce the alkyl radical intermediate int.III;
[0132] 4) The alkyl radical intermediate int.III oxidizes LCu(II)Azol to obtain the trivalent copper intermediate int.IV, which then undergoes reductive elimination to obtain the catalytic product and release the copper catalyst, ultimately completing the catalytic cycle.
[0133] It should be noted that the generated alkyl radical may be oxidized to a carbon cation and then captured by an azole anion to generate the target product.
[0134] In summary, the reaction of the present invention undergoes a copper-catalyzed single electron transfer process. NFSI, which serves as both an oxidant and an amine source, generates amine radical species under the action of copper metal, which is captured and added by olefins to generate alkyl radicals. Subsequently, the alkyl radicals react with divalent copper species of azoles to generate trivalent copper intermediates, and finally the trivalent copper metal center is reduced and eliminated to obtain the target product.
[0135] The invention provides a method for synthesizing a beta-aminoazole compound, and belongs to the technical field of organic synthesis, pesticide and pharmaceutical chemical synthesis.
[0136] This method uses cuprous thiophene-2-carboxylate and bipyridine molecules as catalysts, olefins, fluorobisbenzenesulfonyl imide and a variety of azole reagents as reaction raw materials, and realizes a three-component amination-azole difunctionalization reaction between olefin molecules, providing a direct and efficient new method for the preparation of a series of new aminoazole compounds.
[0137] The present invention uses cheap and readily available copper salts and pyridine small molecules as catalysts, has mild reaction conditions, has excellent chemical and regional selectivity, as well as good functional group compatibility and substrate universality, and the obtained compounds have potential application value in organic pesticides, biomedicine and organic synthesis.
[0138] The above embodiments are only exemplary embodiments of the present application and are not intended to limit the present application. The protection scope of the present application is defined by the claims. Those skilled in the art may make various modifications or equivalent substitutions to the present application within the essence and protection scope of the present application, and such modifications or equivalent substitutions shall also be deemed to fall within the protection scope of the present application.
Claims
1. A method for synthesizing β-aminoazole compounds by organic catalysis, characterized in that: The steps include: Under an argon atmosphere, copper metal catalyst and pyridine organic small molecules were added to the solvent and stirred at room temperature for 0.5 hours. The color of the system gradually changed from colorless to red. Then, the reaction substrate fluorobisbenzenesulfonimide, olefin compound and azole substrate were added to the system in sequence, and stirred at room temperature for 6 hours; After the reaction is completed, the solvent is drained to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a β-aminoazole compound.
2. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: The copper metal catalyst is cuprous thiophene-2-carboxylate.
3. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: The pyridine organic small molecule is L10.
4. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: The azole substrate is any one or more of 2-(trimethylsilyl)thiazole, 2-(trimethylsilyl)benzothiazole, and 2-(trimethylsilyl)benzoxazole.
5. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: The molar ratio of the copper metal catalyst to the olefin compound is 1:
20.
6. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 3, characterized in that: The molar ratio of the organic small molecule ligand L10 to the olefin compound is 1:16.
67.
7. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: The molar ratio of the olefin compound, the fluorobisbenzenesulfonimide and the azole substrate is 1:1.4:1.
5.
8. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: The solvent is 1,2-dichloroethane.
9. The method for organically catalyzing the synthesis of β-aminoazole compounds according to claim 1, characterized in that: In the separation and purification process, the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate; In the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is 5:1.