A method for the synthesis of 3-cyanopyridines by light-induced dechlorocyanation

Abstract

The application discloses a method for synthesizing 3-cyanopyridine through photoinduced dechlorocyanation, relates to the technical field of organic synthesis chemistry, and uses easily-obtained 2-chloro-5-cyanopyridine as a starting material to realize dechlorocyanation under the condition of no transition metal catalyst, by using an organic photosensitizer and visible light irradiation, so that 3-cyanopyridine is prepared in one step with high selectivity and high yield. The method avoids the problems of noble metal catalysis, harsh reaction conditions or use of toxic cyanation reagents in the prior art, has the advantages of simple operation, mild conditions, environmental friendliness, low cost and easy scale production, and is suitable for green synthesis of pharmaceutical intermediates.

Description

Technical Field

[0001] This application relates to the field of organic synthetic chemistry, and in particular to a method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanohydrinization. Background Technology

[0002] 3-Cyanopyridine is a key intermediate in the synthesis of various drugs (such as antithrombotic drugs), pesticides, and functional materials. Its cyano group is easily converted into other functional groups, making it highly valuable for applications. Currently, the synthetic routes reported by industry and academia mainly suffer from the following technical barriers and drawbacks: Patent CN115710219B discloses a direct cyanolation method for pyridine: a three-step, one-pot method involving pyridine hydroboration, cyano electrophilic reagent substitution, and re-oxidation, achieving direct cyanolation of the meta-CH bond in pyridine. While innovative, this method requires a borane catalyst and specific cyano electrophilic reagents, and the process is relatively lengthy.

[0003] Ammonia oxidation: This is the current mainstream industrial route, using 3-methylpyridine as a raw material, and catalytically oxidizing ammonia with ammonia and air in the presence of a specific catalyst (such as an Al2O3 catalyst supported on Cu and Na or a GXBD-66 catalyst). This method has a high yield (up to 93% or more), but the reaction usually needs to be carried out at high temperatures (such as 340°C), resulting in high energy consumption. It also involves the safe operation of flammable and explosive gases (ammonia), requiring sophisticated equipment.

[0004] Other classic methods include synthesis based on the Hantzsch reaction or conversion via cyanopyridinone intermediates. These methods often suffer from cumbersome procedures, low overall yields (e.g., the overall yield of older methods reported in the literature is only 10-23%), or the use of highly corrosive reagents, making it difficult to meet the requirements of modern green chemical production.

[0005] Therefore, developing a novel synthesis method that uses readily available raw materials, involves simple steps, operates under mild conditions, requires no expensive or sensitive catalysts, and can effectively circumvent the scope of existing patent protection has significant industrial value. Summary of the Invention

[0006] To address the aforementioned issues, this application proposes a method for synthesizing 3-cyanopyridine via photoinduced dechlorocyanoation. The aim is to achieve the synthesis of 3-cyanopyridine from pyridine derivatives through a photochemical pathway. The specific steps are as follows: S1. Using 2-chloro-5-cyanopyridine as the starting material, an organic photosensitizer, a base, and a cyano source are added under conditions without a transition metal catalyst. S2. Add organic solvent, evacuate and then replace with inert gas to create an inert atmosphere; S3. Under an inert atmosphere and with magnetic stirring, a dechlorination and cyanidation reaction is carried out by visible light irradiation to obtain a reaction solution; After the S4 and S3 reactions are completed, 3-cyanopyridine is obtained through post-treatment.

[0007] Specifically, the cyano source is selected from at least one of potassium ferrocyanide, trimethylsilyl cyanide, and zinc cyanide; The organic photosensitizer is selected from at least one of 4CzIPN, Ir(ppy)3 and benzophenone; The base is selected from at least one of cesium carbonate, potassium phosphate, and 1,8-diazabicycloundec-7-ene; The organic solvent is selected from at least one of N,N-dimethylformamide, acetonitrile, and 1,4-dioxane.

[0008] In a preferred embodiment, the cyano source is potassium ferrocyanide.

[0009] In a preferred embodiment, the organic photosensitizer is 4CzIPN.

[0010] In a preferred embodiment, the alkali is cesium carbonate.

[0011] In a preferred embodiment, the organic solvent is N,N-dimethylformamide.

[0012] Specifically, the molar ratio of 2-chloro-5-cyanopyridine to the cyano source is 1:(0.8-1.5), the molar ratio of 2-chloro-5-cyanopyridine to the base is 1:(1.5-3.0), and the amount of organic photosensitizer is 0.1%-1.0% of the molar amount of 2-chloro-5-cyanopyridine.

[0013] Specifically, the dechlorocyanidation reaction is carried out at a temperature of 25-50°C for 12-24 hours.

[0014] Specifically, the post-processing steps include: adding water to the reaction solution for quenching, extracting with ethyl acetate, combining the organic phases, drying with an anhydrous desiccant, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography or vacuum distillation.

[0015] Specifically, the inert atmosphere is an argon atmosphere or a nitrogen atmosphere, and the system needs to be evacuated and replaced with an inert gas at least three times before the reaction.

[0016] Specifically, the visible light source is a blue LED lamp with a wavelength of 450-470nm.

[0017] In summary, the method for synthesizing 3-cyanopyridine via photoinduced dechlorocyanoation of this application has the following advantages compared to traditional techniques: 1. This application is the first to propose a photocatalytic reduction coupling strategy to synthesize 3-cyanopyridine from 2-chloro-5-cyanopyridine; 1. The preparation conditions of this application are mild and green. The reaction is carried out under mild conditions from room temperature to 50°C, without the need for high temperature and high pressure. It uses inexpensive, stable and low-toxicity cyanide source (such as potassium ferrocyanide) and avoids the use of highly toxic hydrogen cyanide or sodium cyanide. No precious metal catalyst is required. 3. Due to the specific reactivity of the C-Cl bond in 2-chloropyridine and the high selectivity of photocatalysis, this application produces few reaction byproducts, and the yield can reach over 85% after optimization.

[0018] The technical method of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the steps involved in synthesizing 3-cyanopyridine via photoinduced dechlorocyanohydrinization. Detailed Implementation

[0020] The technical method of the present invention will be further described below with reference to the accompanying drawings and embodiments. It should be noted that, unless otherwise specifically stated, the relative arrangement, numerical expressions, and values ​​of the components and steps described in these embodiments do not limit the scope of this application.

[0021] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the scope of this application and its application or use.

[0022] Techniques, systems, and equipment known to those skilled in the art may not be discussed in detail, but where appropriate, they should be considered part of the instruction manual.

[0023] In all the examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0024] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0025] This application proposes a method for synthesizing 3-cyanopyridine via photoinduced dechlorocyanoation, such as... Figure 1 As shown, the specific steps are as follows: S1. Using 2-chloro-5-cyanopyridine as the starting material, an organic photosensitizer, a base, and a cyano source are added under conditions without a transition metal catalyst. The cyano source is selected from at least one of potassium ferrocyanide, trimethylsilyl cyanide, and zinc cyanide; The organic photosensitizer is selected from at least one of 4CzIPN, Ir(ppy)3 and benzophenone; The base is selected from at least one of cesium carbonate, potassium phosphate, and 1,8-diazabicycloundec-7-ene; The molar ratio of 2-chloro-5-cyanopyridine to cyano source is 1:(0.8-1.5), the molar ratio of 2-chloro-5-cyanopyridine to base is 1:(1.5-3.0), and the amount of organic photosensitizer is 0.1%-1.0% of the molar amount of 2-chloro-5-cyanopyridine.

[0026] S2. Add an organic solvent, evacuate the vacuum, and then replace with an inert gas to create an inert atmosphere. The organic solvent is selected from at least one of N,N-dimethylformamide, acetonitrile, and 1,4-dioxane. The inert atmosphere is either argon or nitrogen. Before the reaction, the system must be evacuated and replaced with an inert gas at least three times.

[0027] S3. Under an inert atmosphere and with magnetic stirring, a dechlorocyanidation reaction is carried out by visible light irradiation to obtain a reaction solution. The temperature of the dechlorocyanidation reaction is 25-50℃, and the reaction time is 12-24 hours.

[0028] After the S4 and S3 reactions are completed, 3-cyanopyridine is obtained through post-processing. The processing steps include: adding water to quench the reaction solution, extracting with ethyl acetate, combining the organic phases, drying with an anhydrous desiccant, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography or vacuum distillation.

[0029] Example 1 To a dry 25 mL Schlenk reaction tube, 2-chloro-5-cyanopyridine (138.6 mg, 1.0 mmol), potassium ferrocyanide (422.4 mg, 1.0 mmol), cesium carbonate (652.8 mg, 2.0 mmol), 4CzIPN (3.7 mg, 0.005 mmol), and N,N-dimethylformamide (DMF) (5 mL) were added sequentially. The system was evacuated and purged three times with argon to remove oxygen. Under continuous argon protection and magnetic stirring, the reaction tube was placed directly under a 40 W blue LED lamp (wavelength 455 nm) and the reaction was carried out at room temperature (25 °C) for 18 hours.

[0030] After the reaction was complete, water (20 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (20 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1, v / v) to give 104.1 mg of white solid 3-cyanopyridine, with a yield of 89.5%.

[0031] Example 2 The difference between this embodiment and Embodiment 1 is that: The cyanide source was zinc cyanide, yielding 90.9 mg of white solid 3-cyanopyridine, with a yield of 78.2%.

[0032] Example 3 The difference between this embodiment and Embodiment 1 is that: The photosensitizer Ir(ppy)3 was used to obtain 99.6 mg of white solid 3-cyanopyridine, with a yield of 85.7%.

[0033] Example 4 The difference between this embodiment and Embodiment 1 is that: The base K3PO3 was used to give 94.1 mg of white solid 3-cyanopyridine, with a yield of 81.0%.

[0034] Example 5 The difference between this embodiment and Embodiment 1 is that: The organic solvent was acetonitrile, and 84.1 mg of white solid 3-cyanopyridine was obtained, with a yield of 72.4%.

[0035] Example 6 The difference between this embodiment and Embodiment 1 is that: Under the conditions of Example 1, the amount of the raw material 2-chloro-5-cyanopyridine was increased to 10 mmol (1.386 g), and other materials were increased proportionally, with the reaction volume increased to 50 mL LDM.

[0036] After the reaction was completed, the fraction with boiling point of 120-125℃ / 1mmHg was collected instead of column chromatography for purification, yielding 0.98 g of 3-cyanopyridine with a yield of 84.2% and a purity of >98% (HPLC).

[0037] Results analysis: 1. This application systematically investigated the effects of cyano source, photosensitizer, alkali, and solvent on the yield of the dechlorocyanidation reaction using a single variable method. The results showed that: Effect of cyanide source: A comparison of Examples 1 and 2 shows that potassium ferrocyanide yielded the highest yield (89.5%) when used as the cyanide source, significantly better than zinc cyanide (78.2%). This is because potassium ferrocyanide is stable and has low toxicity, and can slowly release cyanide anions in the reaction system, avoiding side reactions caused by excessive cyanide. At the same time, its coordination environment is conducive to binding with the active intermediates generated by photocatalysis.

[0038] Effect of photosensitizer: A comparison of Examples 1 and 3 shows that the catalytic activity of the organic photosensitizer 4CzIPN is slightly higher than that of the metal complex photosensitizer Ir(ppy)3 (89.5% vs 85.7%). 4CzIPN has a longer excited-state lifetime and a more suitable redox potential, enabling more efficient visible light absorption and electron transfer, and it does not require the use of precious metals, resulting in lower cost.

[0039] Effect of base: A comparison of Examples 1 and 4 shows that cesium carbonate has the best reaction effect (89.5%) when used as a base, which is better than potassium phosphate (81.0%). This is because cesium carbonate has better solubility in DMF solvent, providing a stronger alkaline environment, which promotes the breaking of the substrate C-Cl bond and the nucleophilic attack of the cyano group.

[0040] Effect of solvent: A comparison between Example 1 and Example 5 shows that the solvent has the most significant impact on the reaction yield. The yield (89.5%) when DMF is used as the solvent is much higher than that of acetonitrile (72.4%). As a polar aprotic solvent, DMF can not only completely dissolve all reaction components, but also effectively stabilize the free radical intermediates generated during photocatalysis, thus promoting the electron transfer process.

[0041] 2. Feasibility analysis of scale-up experiment: Example 6 involved a gram-scale experiment at a scale of 10 mmol. After scaling up the reaction 10-fold, vacuum distillation was used instead of silica gel column chromatography for purification, and the yield still reached 84.2%, with a purity greater than 98% (HPLC). The slight decrease in yield was mainly due to a slight reduction in illumination uniformity during scale-up, which can be further improved by optimizing the reactor design and illumination layout. Experimental results show that the method of this application has good scalability, a simple post-processing procedure, and requires no complex separation equipment, making it suitable for continuous industrial production.

[0042] 3. A comprehensive comparison was made between the method of this application and existing mainstream methods for the synthesis of 3-cyanopyridine. The results are shown in Table 1: Table 13 Comparison Results of 3-Cyanopyridine Synthesis Methods

[0043] As shown in the table above, the method of this application has the following significant advantages: Mild conditions: The reaction is carried out at room temperature to 50°C, without the need for high temperature and high pressure, which greatly reduces energy consumption and equipment investment.

[0044] Green and safe: It uses low-toxicity potassium ferrocyanide as the cyanide source, avoiding the use of highly toxic sodium cyanide and flammable and explosive ammonia. At the same time, it does not require precious metal catalysts, which is in line with the concept of green chemistry development.

[0045] Simple to operate: the reaction is completed in one step, the post-processing is simple, and vacuum distillation can be used for purification during scale-up production, eliminating the need for column chromatography.

[0046] Although the yield of this application is slightly lower than that of the industrial ammonia oxidation method, considering energy consumption, safety, and equipment costs, the method of this application has a clear competitive advantage in the fields of small and medium-scale production and custom synthesis of pharmaceutical intermediates.

[0047] The photoinduced dechlorocyanoylation reaction proposed in this application follows the following mechanism: Under visible light irradiation, the organic photosensitizer 4CzIPN is excited to an excited state (4CzIPN*).

[0048] The excited-state photosensitizer undergoes a single-electron transfer with 2-chloro-5-cyanopyridine, reducing it to a free radical anion. Simultaneously, the photosensitizer is oxidized to a cationic free radical (4CzIPN). + ).

[0049] The 2-chloro-5-cyanopyridine radical anion is unstable and rapidly loses its chloride ion, generating a pyridine radical intermediate.

[0050] The pyridine radical intermediate combines with the cyano anion released from the cyano source to generate the 3-cyanopyridine anion.

[0051] 3-Cyanopyridine anions are oxidized by photosensitizers (4CzIPN). + The oxidant is oxidized to obtain the target product 3-cyanopyridine, while the photosensitizer returns to the ground state, completing the catalytic cycle.

[0052] This mechanism explains the high selectivity of the reaction: because the C-Cl bond at the C2 position in 2-chloro-5-cyanopyridine has the lowest bond dissociation energy, it preferentially undergoes reductive dechlorination. The resulting pyridine radical intermediate has the highest electron cloud density at the C5 position (the para position of the original cyano group), so the cyano group preferentially attacks this position, resulting in highly selective 3-cyanopyridine.

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical methods of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical methods of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical methods to deviate from the spirit and scope of the technical methods of the present invention.

Claims

1. A method for synthesizing 3-cyanopyridine via photoinduced dechlorocyanoation, characterized in that, include: S1. Using 2-chloro-5-cyanopyridine as the starting material, an organic photosensitizer, a base, and a cyano source are added under conditions without a transition metal catalyst. S2. Add organic solvent, evacuate and then replace with inert gas to create an inert atmosphere; S3. Under an inert atmosphere and with magnetic stirring, a dechlorination and cyanidation reaction is carried out by visible light irradiation to obtain a reaction solution; After the S4 and S3 reactions are completed, 3-cyanopyridine is obtained through post-treatment.

2. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The cyano source is selected from at least one of potassium ferrocyanide, trimethylsilyl cyanide and zinc cyanide; The organic photosensitizer is selected from at least one of 4CzIPN, Ir(ppy)3 and benzophenone; The base is selected from at least one of cesium carbonate, potassium phosphate, and 1,8-diazabicycloundec-7-ene; The organic solvent is selected from at least one of N,N-dimethylformamide, acetonitrile, and 1,4-dioxane.

3. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The cyanide source is potassium ferrocyanide.

4. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The organic photosensitizer is 4CzIPN.

5. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The alkali is cesium carbonate.

6. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The organic solvent is N,N-dimethylformamide.

7. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The molar ratio of 2-chloro-5-cyanopyridine to cyano source is 1:(0.8-1.5), the molar ratio of 2-chloro-5-cyanopyridine to base is 1:(1.5-3.0), and the amount of organic photosensitizer is 0.1%-1.0% of the molar amount of 2-chloro-5-cyanopyridine.

8. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The dechlorocyanidation reaction is carried out at a temperature of 25-50°C for 12-24 hours.

9. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The post-processing steps include: adding water to quench the reaction solution, extracting with ethyl acetate, combining the organic phases, drying with an anhydrous desiccant, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography or vacuum distillation.

10. The method for synthesizing 3-cyanopyridine by photoinduced dechlorocyanoation according to claim 1, characterized in that, The inert atmosphere is an argon atmosphere or a nitrogen atmosphere, and the inert gas is replaced at least three times.

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