A method for preparing aryl cyan compounds under mechanochemical conditions

Abstract

The application discloses a preparation method of aryl cyan compounds under mechanical chemical conditions in the technical field, and comprises the following steps: step 1) taking arylamine compounds as starting materials, cuprous cyanide as a cyanogen source, iron nitrate nonahydrate as an in-situ diazotization reagent, sodium bisulfite as a reducing agent, tetramethylpiperidine oxide as a single electron catalyst, and acetonitrile as a liquid auxiliary grinding agent, which are sequentially added into a ball mill; step 2) under an atmospheric environment, the ball mill is heated and ground, and after the reaction is completed and cooled to room temperature; and step 3) ethyl acetate is used to quench and transfer the mixture, the mixture is eluted through a short silica gel column with dichloromethane, concentrated, and then purified through flash column chromatography with ethyl acetate / petroleum ether as a developing agent to obtain aryl cyan compounds. The application does not need to use a large amount of organic solvents, shortens the reaction time, has mild reaction conditions, good substrate universality and a relatively high reaction yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing benzonitrile compounds. Background Technology

[0002] Benzonitrile structural units are widely found in key industrial fields such as pharmaceuticals, pesticides, dyes, and polymer materials. They are not only the core framework of many bioactive molecules but also important precursors for the synthesis of benzoic acid, benzamide, and other fine chemicals. Various methods for preparing nitrile compounds have been reported, such as the ammoniation and dehydration reaction of benzoic acid, the Rosenmond-von Braun reaction, the toluene amination reaction, and the Sandmeyer reaction. Among these, the Sandmeyer reaction, which uses inexpensive and readily available aromatic amines as raw materials and involves the conversion via an indispensable aromatic diazonium salt intermediate, is favored due to its low starting material cost and high reaction efficiency, and has become the most common method for preparing benzonitrile compounds. However, this method requires the pre-preparation of an explosive diazonium salt as a key intermediate, thus posing a significant safety hazard (J. Am. Chem. Soc. 1963, 85, 1792). The reaction formula is shown below:

[0003]

[0004] Since the beginning of the 21st century, this field has seen many modern expansions and innovations. Li et al. [1] reported a palladium-catalyzed cyanation reaction of aryl diazonium tetrafluoroborate, which uses acetonitrile as a non-metallic cyano source and successfully replaces the cuprous cyanide used in the traditional Sandmeyer reaction (Org. Chem. Front., 2015, 2, 231). Nevertheless, this system still relies on expensive transition metal catalysts and stoichiometric amounts of silver oxide, which is economically unsustainable and limits its application in large-scale production. The reaction equation is as follows:

[0005]

[0006] The Dughera team developed a more efficient Sandmeyer cyanation reaction that does not require copper catalysis. This method uses aryl and heteroaryl phthalimide diazonium salts as starting materials and tetrabutylammonium cyanide (Bu4NCN), which has lower safety risks, as the cyano source. It achieves efficient synthesis of aryl nitrile compounds in acetonitrile solvent at room temperature (Org. Biomol. Chem., 2016, 14, 1437). Although this method avoids the use of heavy metal catalysts, it still has the following limitations: First, although the phthalimide diazonium salts used as starting materials are more stable than ordinary diazonium salts, they still need to be synthesized and separated beforehand, posing potential safety risks and operational inconveniences; second, phthalimide, as a leaving group, has a large molecular weight, resulting in lower atom economy. The reaction equation is shown below:

[0007]

[0008] The methods described above have several drawbacks, including the use of complex catalytic systems, expensive transition metal catalysts, and the need for pre-prepared diazonium salt feedstocks, which pose an explosion risk. Although various strategies have been developed for the preparation of aryl cyanides, existing methods still have significant limitations. Given the crucial role of aryl cyanides in pharmaceuticals, pesticide synthesis, and materials science, it is essential to develop more efficient, safe, and environmentally friendly synthetic methods.

[0009] Another major drawback of existing methods is the need for large amounts of organic solvents and long reaction times, and under certain conditions, strict light protection or inert gas protection is required. In recent years, solvent-free mechanochemical methods have gradually emerged and attracted widespread attention in the organic chemistry community. Mechanochemistry is a method that uses mechanical force to promote chemical reactions. Unlike traditional solution chemistry reactions, mechanochemistry directly triggers intermolecular collisions and reactions through mechanical energy such as grinding, friction, or impact, without relying on large amounts of solvents or high temperatures. The rise of this field is due to its significant advantages in terms of environmental protection, economy, and sustainability.

[0010] The main advantages of mechanochemistry in organic synthesis include: (1) extremely high or zero solvent substitution rate: Traditional organic reactions usually require a large amount of organic solvent as a medium, while mechanochemical reactions are usually carried out under conditions of no solvent or only a small amount of liquid-assisted grinding (LAG), which greatly reduces environmental pollution and conforms to the principles of green chemistry; (2) mild reaction conditions and high safety: Mechanochemistry can drive the reaction through mechanical energy at room temperature and pressure, effectively avoiding the risk of diazonium salt explosion caused by improper heating or solvent treatment in the traditional Sandmeyer reaction; (3) significantly improved reaction efficiency: Since mechanical force acts directly on solid reactants, it increases the effective collision frequency between molecules, and many reactions can be completed in a short time without the need for a lengthy heating and stirring process; (4) simple process and easy to scale up: Mechanochemical equipment such as ball mills have relatively simple structures and standard operating procedures, making it easy to realize the transformation from laboratory research to large-scale production.

[0011] In general, mechanochemistry provides an environmentally friendly, efficient, and safe alternative route for organic synthesis and is gradually becoming an important part of the field of green chemistry. To date, the preparation of aryl cyanides typically relies on the pre-preparation of hazardous diazonium salts and the use of large amounts of organic solvents, inevitably leading to safety hazards and resource waste. Based on this, we designed and developed a novel mechanochemical synthesis method aimed at achieving the green preparation of aryl cyanides without transition metal involvement under solid-state conditions through in-situ generation of transient diazonium intermediates, as shown in the reaction equation below.

[0012] . Summary of the Invention

[0013] To address the shortcomings of existing technologies, this invention provides a method for preparing aryl cyanide compounds under mechanochemical conditions. The continuous mechanical energy generated by the vibration of the ball mill replaces the traditional thermal energy, the ball mill jar replaces the glass container, eliminating the need for large amounts of organic solvents, shortening the reaction time, providing mild reaction conditions, good substrate versatility, and high reaction yield, while avoiding the use of explosive aryl diazonium salts in the traditional Sandmeyer reaction.

[0014] The objective of this invention is achieved as follows:

[0015] The principle of this invention is as follows:

[0016] A method for preparing aryl cyanide compounds under mechanochemical conditions, comprising the following steps:

[0017] Step 1) Using aromatic amine compounds as starting materials, metal cyanide and ferric nitrate nonahydrate as in-situ diazotizing agents, sodium bisulfite as reducing agent, tetramethylpiperidine oxide as a single-electron catalyst, and polar solvent as a liquid auxiliary grinding agent, these materials are added sequentially into a ball mill.

[0018] Step 2) Under atmospheric conditions, the mixture is heated and ground in a ball mill. After the reaction is complete, it is cooled to room temperature.

[0019] Step 3) Quench and transfer the mixture with an organic solvent, elute and concentrate it with a short silica gel column in dichloromethane, and then purify it by rapid column chromatography with ethyl acetate / petroleum ether as the developing solvent to obtain aryl cyanide compounds.

[0020] Furthermore, the aromatic amine includes any one of the following:

[0021] .

[0022] Furthermore, the molar ratio of the aromatic amine compound to ferric nitrate nonahydrate is 1:2.5 to 1:4.5.

[0023] Furthermore, the molar ratio of the aromatic amine compound to sodium bisulfite is 1:1.5 to 1:4.5.

[0024] Furthermore, the molar ratio of the aromatic amine compound to tetramethylpiperidine oxide is 1:0.01 to 1:0.05.

[0025] Furthermore, the molar ratio of the aromatic amine compound to cuprous cyanide is 1:2.5 to 1:4.5.

[0026] Furthermore, the reaction gas atmosphere is air, and the reaction time is 0.5 hours to 1.0 hours.

[0027] 8. The preparation method according to claim 1 or 2, characterized in that the grinding balls in the ball mill are stainless steel grinding balls; the grinding jar is a stainless steel grinding jar; the volume of the grinding jar is 5.0 ml; the power of the ball mill is 30 Hz; and the diameter of the grinding balls is 10.0 mm.

[0028] Furthermore, the aryl cyanide compound comprises any one of the following:

[0029] .

[0030] This invention uses a stainless steel ball mill jar instead of a traditional glass reaction vessel. The mechanical stress and shear force generated by the left-right vibration of the stainless steel grinding balls within the jar serve as the energy source for the organic chemical reaction, avoiding the environmental pollution problems caused by the use of large amounts of organic solvents. Tetramethylpiperidine oxide is used as a single-electron catalyst to generate nitrogen dioxide, which participates in the subsequent diazotization process. The trace amounts of diazonium salt generated in situ serve as key intermediates, ultimately achieving the cyanation reaction. The entire experimental operation can be carried out under air conditions, eliminating the need for expensive transition metal catalysts and complex anhydrous and oxygen-free operations. Simultaneously, it accelerates the reaction rate and improves reaction efficiency.

[0031] The reaction formulas for the preparation of aryl cyanide compounds are as follows:

[0032]

[0033] In the formula, TEMPO represents tetramethylpiperidine oxide, KOtBu represents potassium tert-butoxide, jar represents a stainless steel ball mill jar, ball milling represents ball milling, and heating gun represents a hot air gun.

[0034] This invention utilizes aryl cyanide compounds as multifunctional intermediates in organic synthesis. Many methods for introducing cyanide groups into aromatic rings have been established, with transition metal-catalyzed cyanation reactions of aryl (pseudo)halides being a prominent example. These reactions are primarily the core components of various compounds, including pharmaceuticals, agricultural products, natural products, materials, and dyes. However, these reactions require the prior preparation of activating reagents for cyano conversion, severely limiting substrate types and significantly increasing operational difficulty. Therefore, there is an urgent need to develop methods that are highly atom-economical, easy to operate, require no inert gas protection, and have a wide substrate range adaptability.

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] This invention effectively utilizes the mechanical force generated by a ball mill to successfully prepare aryl cyanides in a short time, greatly shortening the reaction time, which traditional synthesis methods typically require much longer. It also avoids the use of expensive transition metal catalysts or high-pressure gas reaction conditions. Green synthesis is a constant theme in industrial production, and our developed mechanochemical synthesis method also avoids the use of large amounts of organic solvents.

[0037] The method for synthesizing aryl cyanide compounds under mechanochemical conditions provided by this invention does not require a large amount of organic solvent, shortens the reaction time, has mild reaction conditions, good substrate universality, and high reaction yield. It is a new method for synthesizing aryl cyanide compounds. Attached Figure Description

[0038] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0039] Figure 1 This is a schematic diagram of the reaction process according to an embodiment of the present invention.

[0040] Figure 2 This is a schematic diagram of the reaction apparatus according to an embodiment of the present invention. Detailed Implementation

[0041] 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. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0042] like Figure 1 As shown, this invention provides a method for preparing aryl cyanide compounds under mechanochemical conditions. The continuous mechanical energy generated by the vibration of a ball mill replaces traditional thermal energy, and the ball mill jar replaces the glass container. This eliminates the need for large amounts of organic solvents, shortens the reaction time, provides mild reaction conditions, has good substrate versatility, and achieves a high reaction yield. The method includes the following steps: using ethyl 4-aminobenzoate as the starting material, and sequentially adding a catalyst, such as... Figure 2 As shown, the mixture was ground with grinding balls, heated in an atmospheric environment with a 100°C hot air gun (approximately 80°C inside the container), and after cooling to room temperature, quenched with ethyl acetate and transferred. The mixture was then eluted and concentrated using a dichloromethane short silica gel column, followed by rapid column chromatography with ethyl acetate / petroleum ether as the eluent to obtain aryl cyanide compounds. The molar ratio of the aromatic amine compound to ferric nitrate nonahydrate was 1:2.5 to 1:4.5; the molar ratio of the aromatic amine compound to sodium bisulfite was 1:1.5 to 1:4.5; the ball mill was an MM 400 ball mill; the reaction vessel volume was 5 mL; the grinding balls were stainless steel; the grinding vessel was a stainless steel grinding vessel; the reaction atmosphere was air; the reaction time was 0.5 to 1.0 hours; the ball mill power was 30 Hz; and the grinding ball particle size was 10.0 mm.

[0043] Example 1

[0044] The preparation of compound 2 is shown in the following reaction formula:

[0045]

[0046] In a 1.5 mL stainless steel ball mill jar containing a 7 mm stainless steel ball, compound 1 (23.6 mg, 0.2 mmol), cuprous cyanide (71.6 mg, 0.8 mmol), ferric nitrate nonahydrate (323.2 mg, 0.8 mmol), sodium sulfite (50.4 mg, 0.4 mmol), TMEPO (3.1 mg, 0.02 mmol), and acetonitrile (168 μL, η = 0.35 μL / mg) were added sequentially. The mixture was reacted in a ball mill at 100 °C and 30 Hz for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, the ball mill jar was opened, and the resulting mixture was quenched with ethyl acetate and transferred to a 50 mL beaker. The crude mixture was eluted with dichloromethane through a short silica gel column. Finally, the crude mixture was concentrated and purified by rapid column chromatography (using ethyl acetate / petroleum ether as the eluent) to obtain the corresponding compound 2 (14.1 mg, 55%).

[0047] The product structure characterization data are as follows:

[0048] 1 H NMR (400 MHz, Chloroform-d) δ 7.79 (s, 4H); 13 C NMR (101 MHz, Chloroform-d) δ 132.8, 117.0, 116.7 ppm.

[0049] Example 2

[0050] The preparation of compound 4 is shown in the following reaction formula:

[0051]

[0052] In a 1.5 mL stainless steel ball mill jar containing a 7 mm stainless steel ball, compound 3 (27.6 mg, 0.2 mmol), cuprous cyanide (71.6 mg, 0.8 mmol), ferric nitrate nonahydrate (323.2 mg, 0.8 mmol), sodium sulfite (50.4 mg, 0.4 mmol), TMEPO (3.1 mg, 0.02 mmol), and acetonitrile (168 μL, η = 0.35 μL / mg) were added sequentially. The mixture was reacted in a ball mill at 100 °C and 30 Hz for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, the ball mill jar was opened, and the resulting mixture was quenched with ethyl acetate and transferred to a 50 mL beaker. The crude mixture was eluted with dichloromethane through a short silica gel column. Finally, the crude mixture was concentrated and purified by rapid column chromatography (using ethyl acetate / petroleum ether as the eluent) to give the corresponding compound 4 (10.9 mg, 37%).

[0053] The product structure characterization data are as follows:

[0054] 1 H NMR (600 MHz, Chloroform-d) δ 8.36 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H); 13 C NMR (151 MHz, Chloroform-d) δ 150.0, 133.4, 124.3,118.3,116.8 ppm.

[0055] Example 3

[0056] The preparation of compound 6 is shown in the following reaction formula:

[0057]

[0058] In a 1.5 mL stainless steel ball mill jar containing a 7 mm stainless steel ball, compound 5 (43.8 mg, 0.2 mmol), cuprous cyanide (71.6 mg, 0.8 mmol), ferric nitrate nonahydrate (323.2 mg, 0.8 mmol), sodium sulfite (50.4 mg, 0.4 mmol), TMEPO (3.1 mg, 0.02 mmol), and acetonitrile (168 μL, η = 0.35 μL / mg) were added sequentially. The mixture was reacted in a ball mill at 100 °C and 30 Hz for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, the ball mill jar was opened, and the resulting mixture was quenched with ethyl acetate and transferred to a 50 mL beaker. The crude mixture was eluted with dichloromethane through a short silica gel column. Finally, the crude mixture was concentrated and purified by rapid column chromatography (using ethyl acetate / petroleum ether as the eluent) to give the corresponding compound 6 (20.6 mg, 45%).

[0059] The product structure characterization data are as follows:

[0060] 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J = 8.4 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H); 13 C NMR (101 MHz, Chloroform-d) δ 138.4, 133.1, 118.2, 111.6,100.3 ppm.

[0061] Example 4

[0062] The preparation of compound 8 is shown in the following reaction formula:

[0063]

[0064] In a 1.5 mL stainless steel ball mill jar containing a 7 mm stainless steel ball, compound 7 (27.0 mg, 0.2 mmol), cuprous cyanide (71.6 mg, 0.8 mmol), ferric nitrate nonahydrate (323.2 mg, 0.8 mmol), sodium sulfite (50.4 mg, 0.4 mmol), TMEPO (3.1 mg, 0.02 mmol), and acetonitrile (168 μL, η = 0.35 μL / mg) were added sequentially. The mixture was then reacted in a ball mill at 100 °C and 30 Hz for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, the ball mill jar was opened, and the resulting mixture was quenched with ethyl acetate and transferred to a 50 mL beaker. The crude mixture was eluted with dichloromethane through a short silica gel column. Finally, the crude mixture was concentrated and purified by rapid column chromatography (using ethyl acetate / petroleum ether as the eluent) to obtain the corresponding compound 8 (13.8 mg, 48%).

[0065] The product structure characterization data are as follows:

[0066] 1 H NMR (400 MHz, Chloroform-d) δ 8.08 – 7.99 (m, 2H), 7.83 – 7.73 (m,2H), 2.64 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 196.5, 139.9, 132.5,128.7, 117.9, 116.4, 26.7 ppm.

[0067] Example 5

[0068] The preparation of compound 10 is shown in the following reaction formula:

[0069]

[0070] In a 1.5 mL stainless steel ball mill jar containing a 7 mm stainless steel ball, compound 9 (39.3 mg, 0.2 mmol), cuprous cyanide (71.6 mg, 0.8 mmol), ferric nitrate nonahydrate (323.2 mg, 0.8 mmol), sodium sulfite (50.4 mg, 0.4 mmol), TMEPO (3.1 mg, 0.02 mmol), and acetonitrile (168 μL, η = 0.35 μL / mg) were added sequentially. The mixture was then reacted in a ball mill at 100 °C and 30 Hz for 1 h using a hot air gun. After the reaction was complete, the mixture was cooled to room temperature, the ball mill jar was opened, and the resulting mixture was quenched with ethyl acetate and transferred to a 50 mL beaker. The crude mixture was eluted with dichloromethane through a short silica gel column. Finally, the crude mixture was concentrated and purified by rapid column chromatography (using ethyl acetate / petroleum ether as the eluent) to give the corresponding compound 10 (21.3 mg, 52%).

[0071] The product structure characterization data are as follows:

[0072] 1 H NMR (400 MHz, Chloroform-d) δ 7.48 – 7.44 (m, 2H); 13 C NMR (101MHz, Chloroform-d) δ 140.0, 139.0, 128.5, 113.0, 112.7 ppm.

[0073] The examples provided above demonstrate that the present invention provides a method for preparing aryl cyanide compounds that does not require the use of large amounts of solvent, shortens the reaction time, has good substrate versatility, and achieves a high reaction yield. It is a novel method for synthesizing aryl cyanide compounds.

[0074] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing an aryl cyanide compound under mechanochemical conditions, characterized by, Includes the following steps: Step 1) Using aromatic amine compounds as starting materials, metal cyanide and ferric nitrate nonahydrate as in-situ diazotizing agents, sodium bisulfite as reducing agent, tetramethylpiperidine oxide as a single-electron catalyst, and polar solvent as a liquid auxiliary grinding agent, these materials are added sequentially into a ball mill. Step 2) Under atmospheric conditions, the mixture is heated and ground in a ball mill. After the reaction is complete, it is cooled to room temperature. Step 3) Quench and transfer the mixture with an organic solvent, elute and concentrate it with a short silica gel column in dichloromethane, and then purify it by rapid column chromatography with ethyl acetate / petroleum ether as the developing solvent to obtain aryl cyanide compounds.

2. The preparation method according to claim 1, characterized in that, The aromatic amine includes any one of the following: 。 3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the aromatic amine compound to ferric nitrate nonahydrate is 1:2.5 to 1:4.

5.

4. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the aromatic amine compound to sodium bisulfite is 1:1.5 to 1:4.

5.

5. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the aromatic amine compound and tetramethylpiperidine oxide is 1:0.01 to 1:0.

05.

6. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the aromatic amine compound to cuprous cyanide is 1:2.5 to 1:4.

5.

7. The preparation method according to claim 1 or 2, characterized in that, The reaction gas atmosphere is air, and the reaction time is 0.5 hours to 1.0 hours.

8. The preparation method according to claim 1 or 2, characterized in that, The grinding balls in the ball mill are stainless steel grinding balls; the grinding jar is a stainless steel grinding jar; the volume of the grinding jar is 5.0 ml; the power of the ball mill is 30 Hz; and the diameter of the grinding balls is 10.0 mm.

9. The preparation method according to claim 1 or 2, characterized in that, The aryl cyanide compound is any one of the following: 。

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