Method for organic catalytic synthesis of beta-alkyl nitrile compounds
The reaction of styrene with lauroyl peroxide and trimethylsilyl cyano in a specific solvent under copper salt and ligand catalyzed catalyzed, solving the difficulties in cyano-alkylation reaction between olefins and achieving efficient synthesis of β-alkyl compounds, with high yield and good universality.
Patent Information
- Application Number
- CN202510445147.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-10
- Publication Date
- 2025-07-11
AI Technical Summary
The difficulties in intermolecular cyano-alkylation reaction of olefins have not been fully solved, and it is difficult for the prior art to efficiently synthesize β-alkyl eye compounds.
The reaction time was carried out in a 1,2-dichloroethane solvent under the catalysis of copper salts (such as thiophene cuprous carboxylate) and ligands (such as 4,4',6,6'-tetramethyl-2,2'-bipyridine) at room temperature, using styrene, lauroyl peroxide and trimethylsilicone cyano as reactants for six hours.
The efficient synthesis of β-alkyl eye compounds was achieved, with an isolation yield of 86%, demonstrating good substrate universality and acyl peroxide universality.
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Figure CN120289261A_ABST
Abstract
Description
Technical Field
[0001] The present invention mainly relates to the technical field of the synthesis of β-alkyl nitrile compounds, and specifically provides a method for the organic catalytic synthesis of β-alkyl nitrile compounds. Background Art
[0002] Olefins are a class of cheap and readily available chemical raw materials, and the high-value conversion of olefin compounds has always been a frontier research field in organic chemistry. Among them, the 1,2-difunctionalization reaction of olefins is one of the important methods for simultaneously constructing polyfunctional compounds and realizing the efficient synthesis of complex molecules.
[0003] Organic cyanides are an important class of chemical intermediates. Due to their unique reactivity, they can be efficiently converted into various functional group compounds. These compounds can be chemically modified to generate important organic molecules such as aldehydes, ketones, organic amines, carboxylic acids, and azole compounds. From the perspective of molecular structure, cyanide compounds have a characteristic cyano functional group, and this structural feature endows them with unique physical and chemical properties. It is worth noting that cyanide compounds have a wide range of applications in multiple fields, and their structural units can be seen in important compounds such as functional materials, drug molecules, natural products, agrochemicals, dye molecules, and bioactive macromolecules, fully reflecting their important position in modern chemical synthesis and applications.
[0004] In recent years, the difunctionalization reaction of olefins has received extensive attention as an efficient olefin modification method. In the fields of arylation and fluoroalkylation, significant progress has been made in this type of reaction, but there are still difficulties in the intermolecular cyano-alkylation reaction of olefins, which need to be further developed and improved. Summary of the Invention
[0005] Based on this, the purpose of the present invention is to provide a method for the organic catalytic synthesis of β-alkyl nitrile compounds to solve the technical problems proposed in the above background art.
[0006] To achieve the above purpose, the present invention provides the following technical solution: The present invention provides a method for the organic catalytic synthesis of β-alkyl nitrile compounds, including the following steps: At room temperature, styrene, lauroyl peroxide, and trimethylsilyl cyanide are dissolved in a reaction solvent, and under the co-catalysis of a copper salt and a ligand, β-alkyl nitrile compounds are obtained.
[0007] According to an embodiment of the present invention, styrene is used as the reaction substrate, lauroyl peroxide is used as the oxidant and alkyl source, and trimethylsilyl cyanide is used as the cyano source.
[0008] According to an embodiment of the present invention, the ligand is 4,4',6,6'-tetramethyl-2,2'-bipyridine.
[0009] According to an embodiment of the present invention, the reaction solvent is 1,2-dichloroethane with a molar concentration of 0.2.
[0010] According to an embodiment of the present invention, the copper salt is cuprous thiophene-2-carboxylate.
[0011] According to an embodiment of the present invention, the equivalent of cuprous thiophene-2-carboxylate is 5 mol%.
[0012] According to an embodiment of the present invention, the reaction temperature is 40 °C.
[0013] According to an embodiment of the present invention, the equivalent of 4,4',6,6'-tetramethyl-2,2'-bipyridine is 6 mol%.
[0014] According to an embodiment of the present invention, 1.5 equivalents of lauroyl peroxide is used as the oxidizing agent and alkyl source, and 1.5 equivalents of trimethylsilyl cyanide is used as the cyano source.
[0015] According to an embodiment of the present invention, the reaction is carried out at room temperature for 6 hours.
[0016] In summary, the present invention mainly has the following beneficial effects:
[0017] The optimal reaction conditions are as follows: using 5 mol% of cuprous thiophene-2-carboxylate as the catalyst, 6 mol% of 4,4',6,6'-tetramethyl-2,2'-bipyridine as the ligand, 1,2-dichloroethane with a molar concentration of 0.2 as the reaction solvent, 1.5 equivalents of lauroyl peroxide as the oxidizing agent and alkyl source, 1.5 equivalents of trimethylsilyl cyanide as the cyano source, reacting at room temperature for 6 hours, and finally obtaining the target product with a separation yield of 86%. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 It is the chemical reaction formula of the optimal reaction conditions of the present invention;
[0019] Figure 2 It is the reaction formula of the active olefin of the present invention;
[0020] Figure 3 It is the target product and yield of each active olefin reaction of the present invention;
[0021] Figure 4 It is the reaction formula of the acyl peroxide of the present invention;
[0022] Figure 5 It is the target product and yield of each acyl peroxide reaction of the present invention. DETAILED DESCRIPTION OF THE INVENTION
[0023] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. The embodiments described below by referring to the accompanying drawings are exemplary and are only used to explain the present invention, and should not be construed as a limitation to the present invention.
[0024] Next, according to the overall structure of the present invention, its embodiments will be described.
[0025] Embodiment
[0026] Please refer specifically to the attached Figure 1 As shown, in a preferred embodiment of the present invention,
[0027] The optimal reaction conditions are as follows: copper(I) thiophene-2-carboxylate at 5 mol% as the catalyst, 4,4',6,6'-tetramethyl-2,2'-bipyridine at 6 mol% as the ligand, 1,2-dichloroethane with a molar concentration of 0.2 as the reaction solvent, lauroyl peroxide at 1.5 equivalents as the oxidant and alkyl source, trimethylsilyl cyanide at 1.5 equivalents as the cyano source, reacting at room temperature for 6 hours, and finally obtaining the target product with a separation yield of 86%.
[0028] It should be noted that in this embodiment: Screening of ligands: Bipyridine and phenanthroline, as important neutral ligands, are widely used in transition metal catalytic reaction systems. Therefore, copper(I) thiophene-2-carboxylate was selected as the catalyst, and styrene, lauroyl peroxide, and trimethylsilyl cyanide were still used as the reaction substrates, and dichloroethane was used as the reaction solvent. Different bipyridine, biquinoline, bridged bipyridine, and phenanthroline ligands were screened at room temperature. The results showed that the ligands containing phenanthroline had a lower yield. Fortunately, when the ligand 4,4',6,6'-tetramethyl-2,2'-bipyridine was used, the target product could be obtained with a 80% NMR yield; changing the bipyridine could also achieve the catalytic reaction, but the NMR efficiency was lower. Therefore, the ligand 4,4',6,6'-tetramethyl-2,2'-bipyridine was selected as the best ligand;
[0029] Screening of reaction solvents: The reaction solvent has an important influence on the reaction. Next, the effects of different aprotic solvents on this reaction were investigated, such as dichloroethane, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, and dimethyl sulfoxide. Experiments found that the target product could not be obtained in tetrahydrofuran and dimethyl sulfoxide, and only a low yield of the target product could be obtained in acetone, dimethylacetamide, and acetonitrile; using 1,2-dichloroethane and dichloromethane could obtain the target product with 80% and 77% NMR yields respectively; therefore, 1,2-dichloroethane was the optimal solvent for the reaction;
[0030] Screening of copper catalysts: Different copper salt catalysts were investigated. The reaction can be achieved using cuprous halides such as cuprous chloride and cuprous iodide, but the reaction yield is low. When using other cuprous salts such as cuprous acetate and cuprous cyanide, the catalytic effect is also not good. Subsequently, cuprous 2 - thiophenecarboxylate and cuprous sulfide were tried, and the target product was obtained with NMR yields of 80% and 71% respectively. It is worth noting that cupric salts such as copper trifluoromethanesulfonate can also catalyze the reaction with an NMR yield of 75%. In the control experiment, without adding any copper salt, the reaction could not proceed normally. Finally, cuprous 2 - thiophenecarboxylate was selected as the best copper salt catalyst for the reaction;
[0031] Screening of catalyst equivalents: When the loading amount of cuprous 2 - thiophenecarboxylate was reduced to 5 mol%, the reaction was hardly affected, and the target product could still be obtained with an NMR yield of 79%. Further reducing the catalyst equivalent to 2 mol% resulted in a yield reduction to 71%. Therefore, the catalyst equivalent of cuprous 2 - thiophenecarboxylate was finally determined to be 5 mol%;
[0032] Screening of reaction temperature: Increasing the temperature will affect the reaction. When the reaction was carried out at 25 °C, the target product was obtained with an NMR yield of 80% after 12 h of reaction. When the reaction temperature was 40 °C, the reaction yield increased to 86%. When the temperature was increased to 80 °C, the reaction yield decreased to 84%. Therefore, the optimal reaction temperature is 40 °C.
[0033] Screening of other reaction conditions: To improve the atom economy and efficiency of the reaction, the substrate equivalents and reaction time of the reaction were subsequently investigated. Reducing the lauroyl peroxide by 1.2 equivalents respectively did not affect the reaction yield; shortening the reaction time to 6 h, the reaction could be completed; further shortening the reaction time to 3 h resulted in a yield reduction to 72%. Reducing the reaction solvent amount to 0.5 mL did not affect the reaction. Finally, the lauroyl peroxide was determined to be 1.5 equivalents, trimethylsilyl cyanide was 1.5 equivalents, the solvent amount of 1,2 - dichloroethane was 0.5 mL, and the reaction time was 6 hours.
[0034] Please refer specifically to the attached Figure 2 、 3 As shown, in another preferred embodiment of the present invention,
[0035] General applicability of olefins:
[0036] The optimal reaction conditions are as follows: using cuprous 2 - thiophenecarboxylate at 5 mol% as the catalyst, 4,4',6,6'-tetramethyl-2,2'-bipyridine at 6 mol% as the ligand, 1,2 - dichloroethane with a molar concentration of 0.2 as the reaction solvent, 1.5 equivalents of lauroyl peroxide as the oxidant and alkyl source, 1.5 equivalents of trimethylsilyl cyanide as the cyano source, and reacting at room temperature for 6 hours;
[0037] Under the optimal reaction conditions, the reaction of vinyl substrates was first investigated. The experimental results showed that the reaction had good substrate generality. When the para-position of styrene was substituted by an electron-donating group, the reaction could occur smoothly with a relatively low yield. When there was a halogen substitution at the para-position, the yield increased, and the corresponding product could be obtained with a yield of 76% to 84%. When a strong electron-withdrawing group such as trifluoromethyl or cyano was introduced at the para-position, the reaction yield increased, and 3-4i and 3-4f were obtained with yields of 96% and 84% respectively. When there were substituents at the ortho- and meta-positions of styrene, the target product could also be obtained with a good yield. When there were multiple substituents on the aromatic ring of styrene or the substrate steric hindrance was increased, the reaction could still proceed smoothly, indicating that the electronic and steric effects of substituents had a certain impact on the reaction.
[0038] Please refer specifically to the attached Figure 4 、 5 As shown, in another preferred embodiment of the present invention,
[0039] Generality of acyl peroxides
[0040] First, the primary carbon radical nonyl radical 3-5a was screened to obtain a yield of 71%. The aliphatic radical substituted by olefin 3-5f gave a yield of 68%. The aliphatic radicals substituted by chlorine atom 3-5c and bromine atom 3-5d gave yields of 73% and 70% respectively. It can be concluded that the length of the aliphatic alkane chain has a slight impact on the reaction, mainly affecting the yield by influencing the radical activity.
[0041] The working principle of the present invention is as follows:
[0042] Using cuprous thiophene-2-carboxylate at 5 mol% as the catalyst, 4,4',6,6'-tetramethyl-2,2'-bipyridine at 6 mol% as the ligand, 1,2-dichloroethane with a molar concentration of 0.2 as the reaction solvent, 1.5 equivalents of lauroyl peroxide as the oxidant and alkyl source, and 1.5 equivalents of trimethylsilyl cyanide as the cyano source, reacting at room temperature for 6 hours;
[0043] LPO: Lauroyl peroxide;
[0044] TMSCN: Trimethylsilyl cyanide;
[0045] CuTc: Cuprous thiophene-2-carboxylate;
[0046] L11: 4,4',6,6'-tetramethyl-2,2'-bipyridine;
[0047] DCE: 1,2-Dichloroethane.
[0048] Although embodiments of the present invention have been shown and described, the specific embodiments are merely explanations of the present invention and not limitations thereof. The specific features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples. After reading this specification, those skilled in the art may make modifications, substitutions, and variations that do not make creative contributions to the embodiments as needed, but as long as they are within the scope of the claims of the present invention, they are protected by the patent law.
Claims
1. A method for the organic catalytic synthesis of β-alkyl nitrile compounds, characterized in that , including the following steps: At room temperature, dissolve styrene, lauroyl peroxide, and trimethylsilyl cyanide in a reaction solvent, and under the co-catalysis of a copper salt and a ligand, obtain β-alkyl nitrile compounds.
2. The method for organocatalytic synthesis of β-alkyl nitrile compounds according to claim 1, wherein Styrene is the reaction substrate, lauroyl peroxide is used as the oxidant and alkyl source, and trimethylsilyl cyanide is used as the cyano source.
3. The method for organocatalytic synthesis of β-alkyl nitrile compounds according to claim 1, wherein The ligand is 4,4',6,6'-tetramethyl-2,2'-bipyridine.
4. A method for the organic catalytic synthesis of β-alkyl nitrile compounds according to claim 1, characterized in that, The reaction solvent is 1,2-dichloroethane with a molar concentration of 0.
2.
5. A method for the organic catalytic synthesis of β-alkyl nitrile compounds according to claim 1, characterized in that, The copper salt is cuprous thiophene-2-carboxylate.
6. The method for organocatalytic synthesis of β-alkyl nitrile compounds according to claim 5, characterized in that, The equivalent of cuprous thiophene-2-carboxylate is 5 mol%.
7. A method for the organic catalytic synthesis of β-alkyl nitrile compounds according to claim 1, characterized in that, The reaction temperature is 40 °C.
8. A method for the organic catalytic synthesis of β-alkyl nitrile compounds according to claim 3, characterized in that, The equivalent of 4,4',6,6'-tetramethyl-2,2'-bipyridine is 6 mol%.
9. The method for organocatalytic synthesis of β-alkyl nitrile compounds according to claim 2, wherein, 1.5 equivalents of lauroyl peroxide are used as the oxidant and alkyl source, and 1.5 equivalents of trimethylsilyl cyanide are used as the cyano source.
10. A method for the organic catalytic synthesis of β-alkyl nitrile compounds according to claim 1, characterized in that, React at room temperature for 6 hours.