A method for ball-milling driven copper-catalyzed goldberg amination reaction of piezoelectric materials

Abstract

This invention provides a method for copper-catalyzed Goldberg amination reactions involving piezoelectric materials driven by ball milling, belonging to the field of organic synthesis technology. The mechanical force of ball milling induces the formation of a piezoelectric potential on the surface of the piezoelectric material, which participates in the regulation of the oxidation state of the copper salt catalyst and the catalytic cycle, thereby activating aryl halides and nitrogen-containing nucleophiles. The entire reactant mixture reacts in a ball mill to obtain target products such as N-arylamines or N-arylamides. This invention combines piezoelectric materials with a copper catalytic system, enabling efficient C-N bond construction in copper-catalyzed Goldberg amination reactions under mechanical ball milling conditions without external heating and with little or no solvent. Experiments show that the reaction hardly occurs without the participation of piezoelectric materials, confirming the irreplaceable nature of piezoelectric materials. The method of this invention is mild, environmentally friendly, simple to operate, and has broad substrate applicability, making it suitable for the green construction of the skeletons of N-arylamines or N-arylamides in pharmaceutical, pesticide, and functional material molecules.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and more specifically, to a method for a copper-catalyzed Goldberg amination reaction involving piezoelectric materials driven by ball milling. Background Technology

[0002] Carbon-nitrogen cross-coupling is an important method for constructing aromatic amine structures in pharmaceuticals, pesticides, and functional materials. Among them, the Goldberg amination reaction, as a classic CN bond construction method, has wide applications in the field of organic synthesis.

[0003] Currently, the Goldberg amination reaction mainly employs a copper catalytic system, carried out at high temperatures in organic solvents such as 1,4-dioxane and toluene. However, traditional methods suffer from the following technical drawbacks: harsh reaction conditions requiring prolonged high-temperature heating, resulting in high energy consumption and poor stability of the metal catalyst; large amounts of organic solvents are used, which does not meet the requirements of green chemistry development; and limited substrate applicability, exhibiting low reactivity towards inert aromatic chlorines and weakly nucleophilic, sterically hindered amines / amides, making it difficult to achieve efficient conversion under mild conditions.

[0004] To address these issues, mechanochemical synthesis techniques have gained attention in recent years. This technique can significantly reduce or even eliminate the use of organic solvents under ball milling conditions and improve the mixing efficiency of the reaction system. It has been successfully applied to various types of organic reactions, but related research has largely focused on palladium-catalyzed systems, with limited application in copper catalysis.

[0005] On the other hand, piezoelectric materials such as barium titanate can generate instantaneous local potentials under mechanical force, driving single-electron transfer processes, and have been attempted for a few mechanochemical redox reactions involving free radical CC / CN bonding. However, to date, there have been no publicly reported studies on the effective combination of piezoelectric materials and copper catalysis to achieve CN-bond coupling reactions of low-activity amide substrates with haloaromatics under ball milling conditions.

[0006] Therefore, how to establish a mild, green, and efficient new method for Goldberg amination reaction by utilizing the synergistic effect of piezoelectric materials and copper catalysis, while avoiding large amounts of organic solvents and prolonged high-temperature heating, to facilitate the construction of aromatic amine structures, remains a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0007] To address the aforementioned problems, this invention proposes a novel approach combining piezoelectric materials with copper catalysis, addressing the limitations of traditional Goldberg amination reactions, which rely on high temperatures, large amounts of organic solvents, and insufficient activity towards inert substrates. Under mechanical ball milling conditions, the continuous impact of the grinding balls on the piezoelectric material generates a transient local electric field. This electric field effectively polarizes or even activates the carbon-halogen bonds of inert aryl halides, while simultaneously participating in the valence state regulation and catalytic cycle of the copper catalyst. This allows for the efficient driving of CN-C coupling reactions between amide or amine substrates and halogenated aromatic hydrocarbons under mild conditions requiring no external heating, minimal or no organic solvents, and an air atmosphere.

[0008] This invention provides a method for a copper-catalyzed Goldberg amination reaction involving piezoelectric materials driven by ball milling, characterized by comprising the following steps: S1: Aromatic halides, nitrogen-containing nucleophiles, copper catalysts, piezoelectric materials, ligands, and bases are mixed and placed in a ball mill jar for ball milling to obtain a mixture containing products such as N-arylamines or N-arylamides; S2: The mixture obtained in S1 is post-processed to obtain products such as N-arylamines or N-arylamides.

[0009]

[0010] Preferably, the aryl halide has the structural formula Ar-X, where Ar is C6~C6. 16 Aryl or heteroaryl containing N, O, or S; X is Cl, Br, or I.

[0011] Preferably, the aryl or heteroaryl group is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, trifluoromethyl, cyano, carboxylic acid ester, acyl or sulfonyl groups.

[0012] Preferably, the nitrogen-containing nucleophile is an alkylamide, arylamide, primary amine, or secondary amine; the molar ratio of the nitrogen-containing nucleophile to the aryl halide is 1.0 to 3.0:1.

[0013] Preferably, the copper catalyst is selected from at least one of CuCl, CuBr, CuI, CuCl2, CuBr2, Cu(OAc)2, Cu(OTf)2 or CuSO4·5H2O; the amount of the copper catalyst is 0.5~20 mol of the molar amount of the aryl halide.

[0014] Preferably, the piezoelectric material is an inorganic ceramic material with piezoelectric properties; the amount of the piezoelectric material is 4 to 50 times the mass of the aryl halide.

[0015] Preferably, the base is an alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate, or alkali metal hydroxide; preferably, the base is selected from at least one of Cs2CO3, Na2CO3, K3PO4, K2CO3, KOH, or NaOH; the amount of the base used is 1 to 4 times the molar amount of the nitrogen-containing nucleophile.

[0016] Preferably, the mixture further includes a ligand; the ligand is a nitrogen-containing organic ligand; the amount of the ligand is 0 to 3 times the molar amount of the copper catalyst.

[0017] Preferably, the ball milling reaction is carried out in a planetary ball mill or a vibratory ball mill; the grinding balls used in the ball mill are made of stainless steel or zirconium oxide, and the diameter of the grinding balls is 3~15 mm; the ball milling frequency is 5~30 Hz; the ball milling reaction time is 0.25~12 hours; and the ball milling reaction temperature is ≤120℃.

[0018] Preferably, the post-processing step includes: adding an organic solvent to the ball milling jar after ball milling to disperse the solid, then separating the solid containing piezoelectric material and inorganic salt by filtration or centrifugation, collecting the solution containing the product, and drying, concentrating and purifying it to obtain products such as N-arylamine or N-arylamide.

[0019] In summary, the present invention has at least one of the following beneficial technical effects: 1. This invention combines mechanical ball milling with piezoelectric materials in the Goldberg amination reaction, eliminating the need for prolonged high-temperature heating and enabling efficient operation under solvent-free or minimal-solvent conditions. Compared to traditional methods, it significantly reduces the amount of organic solvent used and the post-processing burden, while avoiding the energy consumption and safety issues associated with prolonged high-temperature reactions, aligning with the development direction of green chemistry.

[0020] 2. Under the same reaction conditions, the removal of the piezoelectric material significantly reduced the reaction efficiency, even to the point of almost non-existence, proving that the piezoelectric material is not an inert solid filler. This invention induces a transient local electric field (piezoelectric effect) in the piezoelectric material through mechanical force. This electric field deeply participates in the valence state regulation and catalytic cycle of the copper catalyst, thereby constructing a piezoelectric-copper synergistic redox catalytic mode that differs from traditional solution-phase palladium / copper catalysis, providing a novel reaction pathway for CN bond construction.

[0021] 3. This invention uses readily available copper salts and commercially available piezoelectric ceramics as raw materials, resulting in a simple and low-cost system composition. The reaction can be carried out in an air atmosphere without the need for inert gas protection, making operation convenient. High yields can be obtained in a short time, with efficiency significantly superior to traditional methods. Furthermore, the piezoelectric materials can be recovered and recycled through simple filtration, further reducing costs. The ball milling process facilitates scale-up production from laboratory scale to multi-gram scale and even larger scales, making it suitable for the development of green synthesis processes for fine chemicals and pharmaceutical intermediates. Attached Figure Description

[0022] To more clearly illustrate the technical solutions of the embodiments of this application, the drawings used in the description of the embodiments of this application will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 The reaction diagram provided in Embodiment 1 of this application is shown; Figure 2 The figure showing the 1H NMR characterization results provided in Example 1 of this application is illustrated. Figure 3 The reaction diagram provided in Embodiment 2 of this application is shown; Figure 4 The figure showing the 1H NMR characterization results provided in Example 2 of this application is illustrated. Figure 5 The reaction diagram provided in Embodiment 3 of this application is shown; Figure 6 The figure showing the 1H NMR characterization results provided in Example 3 of this application is illustrated. Detailed Implementation

[0024] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. Based on the embodiments of the present invention, any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention. Furthermore, all other embodiments obtained by those skilled in the art without inventive effort are within the protection scope of the present invention.

[0025] Specific experimental steps or conditions are not specified in the embodiments; they can be performed according to the conventional experimental steps or conditions described in the prior art. Reagents and other instruments used, unless otherwise specified, are all commercially available conventional reagent products. Furthermore, the accompanying drawings are merely illustrative diagrams of the embodiments of the present invention and are not necessarily drawn to scale. The same reference numerals in the drawings denote the same or similar parts, and therefore, repeated descriptions of them will be omitted. Some block diagrams shown in the drawings are functional entities and do not necessarily correspond to physically or logically independent entities.

[0026] Techniques, methods, and devices known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques, methods, and devices should be considered part of this specification.

[0027] In the description of this invention, it should be understood that the use of terms such as "first" and "second" to define components is merely for the purpose of distinguishing the corresponding components. Unless otherwise stated, the above terms have no special meaning and therefore should not be construed as limiting the scope of protection of this invention.

[0028] Furthermore, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0029] To enable those skilled in the art to better understand this application, the following embodiments are provided to illustrate in detail a method for copper-catalyzed Goldberg amination reaction involving ball milling driven piezoelectric materials.

[0030] Example Example 1 Synthesis of N-phenylacetamide In a 5 mL ball mill jar, bromobenzene (94.2 mg, 0.6 mmol), acetamide (53 mg, 0.9 mmol), copper chloride (16.1 mg, 0.09 mmol), barium titanate (560 mg, 2.4 mmol), potassium carbonate (124 mg, 0.9 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (25.6 mg, 0.18 mmol) were added sequentially, along with four 8 mm diameter stainless steel grinding balls. The jar was sealed and placed in a ball mill, where the reaction was milled at 30 Hz for 15 minutes. The reaction equation is as follows. Figure 1 As shown.

[0031] After the reaction was complete, the ball mill jar was opened, and the reaction mixture was transferred to a beaker. The ball mill jar and grinding balls were washed repeatedly with dichloromethane, and the washings were combined. The resulting suspension was filtered to remove insoluble solids (including piezoelectric materials and inorganic salts), and the filtrate was collected. The filtrate was concentrated under reduced pressure and then purified by column chromatography (eluents: petroleum ether and ethyl acetate) to obtain the target product N-phenylacetamide (acetanilide).

[0032] like Figure 2 As shown, the product was characterized by proton nuclear magnetic resonance spectroscopy, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ2.18 (s, 3H), 7.08-7.12 (t, 1H), 7.30-7.34 (t, 2H), 7.45-7.50 (d, 2H), 7.18(br, 1H); Example 2 Synthesis of N-(4-trifluoromethylphenyl)acetamide In a 5 mL ball mill jar, 4-bromotrifluorotoluene (135 mg, 0.6 mmol), acetamide (53 mg, 0.9 mmol), copper chloride (16.1 mg, 0.09 mmol), barium titanate (560 mg, 2.4 mmol), potassium carbonate (124 mg, 0.9 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (25.6 mg, 0.18 mmol) were added sequentially. Four 8 mm diameter stainless steel grinding balls were added to the jar, which was then sealed and placed in a planetary ball mill. The reaction was milled at 30 Hz for 15 minutes. The reaction equation is as follows. Figure 3 As shown.

[0033] After the reaction was complete, the ball mill jar was opened, and the reaction mixture was transferred to a beaker. The ball mill jar and grinding balls were washed several times with dichloromethane (3 × 10 mL), and the washings were combined. The resulting suspension was filtered to remove insoluble solids (including piezoelectric materials and inorganic salts), and the filtrate was collected. The filtrate was concentrated under reduced pressure and then purified by column chromatography (eluents were petroleum ether and ethyl acetate) to obtain the target product N-(4-trifluoromethylphenyl)acetamide.

[0034] like Figure 4 As shown, the product was characterized by proton nuclear magnetic resonance spectroscopy, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ2.19 (s, 3H), 7.54-7.56 (d, 2H), 7.62-7.64 (d, 2H), 7.64 (br, 1H).

[0035] Trace amounts of residual solvent ethyl acetate were detected in the NMR spectrum (δ 4.12, 2.05, 1.26), which did not affect the confirmation of the product structure.

[0036] Example 3 Synthesis of N-(4-methoxyphenyl)acetamide In a 5 mL ball mill jar, p-bromoanisole (112 mg, 0.6 mmol), acetamide (53 mg, 0.9 mmol), copper chloride (16.1 mg, 0.09 mmol), barium titanate (560 mg, 2.4 mmol), potassium carbonate (124 mg, 0.9 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (25.6 mg, 0.18 mmol) were added sequentially. Four 8 mm diameter stainless steel grinding balls were added to the jar, which was then sealed and placed in a planetary ball mill. The reaction was milled at 30 Hz for 15 minutes. The reaction equation is as follows. Figure 5 As shown.

[0037] After the reaction was complete, the ball mill jar was opened, and the reaction mixture was transferred to a beaker. The ball mill jar and grinding balls were washed several times with dichloromethane (3 × 10 mL), and the washings were combined. The resulting suspension was filtered to remove insoluble solids (including piezoelectric materials and inorganic salts), and the filtrate was collected. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluents: petroleum ether and ethyl acetate) to obtain the target product N-(4-methoxyphenyl)acetamide.

[0038] like Figure 6 As shown, the product was characterized by proton nuclear magnetic resonance spectroscopy, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ2.15 (s, 3H), 3.79 (s, 3H), 6.84-6.87 (d, 2H), 7.37-7.39 (d, 2H), 7.05 (br,1H).

[0039] In summary, the examples successfully achieved CN coupling reactions with acetamide using unsubstituted bromobenzene (R=H), 4-bromotrifluorotoluene with a strong electron-withdrawing substituent (R=CF3), and p-bromoanisole with an electron-donating substituent (R=OMe) under the same reaction conditions, yielding the corresponding N-arylacetamide products in good yields. The structure of the target products was confirmed by 1H NMR spectroscopy data. These results demonstrate that the copper-catalyzed Goldberg amination reaction method involving piezoelectric materials provided in this invention exhibits good applicability and reaction efficiency for aryl bromide substrates with different electronic effects, reflecting the universality and high efficiency of this method.

[0040] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0041] Although preferred embodiments of the present application have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the embodiments of the present application.

[0042] Finally, it should be noted that in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or terminal device that includes said element.

[0043] The above provides a detailed description of a method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials driven by ball milling. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of this application. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the ideas of this application. Therefore, the content of this specification should not be construed as a limitation of this application.

Claims

1. A method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials, characterized in that, Includes the following steps: S1: Aromatic halides, nitrogen-containing nucleophiles, copper catalysts, piezoelectric materials, ligands, and bases are mixed and placed in a ball mill jar for ball milling to obtain a mixture containing products such as N-arylamines or N-arylamides; S2: The mixture obtained in S1 is post-processed to obtain products such as N-arylamines or N-arylamides.

2. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The aryl halide has the structural formula Ar-X, where Ar is C6~C6. 16 Aryl or heteroaryl containing N, O, or S; X is Cl, Br, or I.

3. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 2, characterized in that, The aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, trifluoromethyl, cyano, carboxylic acid ester, acyl or sulfonyl groups.

4. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The nitrogen-containing nucleophile is an alkylamide, arylamide, primary amine, or secondary amine; the molar ratio of the nitrogen-containing nucleophile to the aryl halide is 1.0~3.0:

1.

5. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The copper catalyst is selected from at least one of CuCl, CuBr, CuI, CuCl2, CuBr2, Cu(OAc)2, Cu(OTf)2 or CuSO4·5H2O; the amount of the copper catalyst is 0.5~20 mol of the molar amount of the aryl halide.

6. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The piezoelectric material is an inorganic ceramic material, a polymer material, an organic piezoelectric material, or a composite material with piezoelectric properties; the amount of the piezoelectric material is 4 to 50 times the mass of the aryl halide.

7. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The base is an alkali metal carbonate, alkaline earth metal carbonate, alkali metal phosphate, or alkali metal hydroxide; preferably, the base is selected from at least one of Cs2CO3, Na2CO3, K3PO4, K2CO3, KOH, or NaOH; the amount of the base used is 1 to 4 times the molar amount of the nitrogen-containing nucleophile.

8. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The mixture also includes ligands; the ligands are nitrogen-containing organic ligands; the amount of the ligands is 0 to 3 times the molar amount of the copper catalyst.

9. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The grinding balls have a diameter of 3~15 mm; the grinding frequency is 5~30 Hz; the grinding reaction time is 0.25~12 hours; and the grinding reaction temperature is ≤120℃.

10. The method for copper-catalyzed Goldberg amination reaction involving piezoelectric materials according to claim 1, characterized in that, The post-processing steps include: adding an organic solvent to the ball mill jar after ball milling to disperse the solid, then separating the solid containing piezoelectric materials and inorganic salts by filtration or centrifugation, collecting the solution containing the product, and drying, concentrating and purifying it to obtain products such as N-arylamines or N-arylamides.

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