Aryl nitrile compound synthesis method based on light-induced EDA
By using photo-induced EDA, aryl nitrile compounds are generated in an air atmosphere using EDA complexes. This solves the problems of C(sp2)-O bond breaking in aromatic hydrocarbons and cyanide source toxicity, and realizes efficient and green synthesis without metal catalysis. It is applicable to a variety of substrates and has broad industrial application prospects.
Patent Information
- Application Number
- CN202510964960.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-11
- Publication Date
- 2025-11-25
AI Technical Summary
Existing technologies for the cleavage of C(sp2)-O bonds in aromatic hydrocarbons and the synthesis of aryl nitrile compounds suffer from problems such as dependence on precious metals, harsh reaction conditions, high toxicity of cyanide sources, and poor substrate universality, making it difficult to achieve green, mild, and efficient synthesis.
The photoinduced EDA method is adopted, which utilizes the formation of an EDA complex between an electron-rich methoxy aromatic hydrocarbon and 1,4-dicyanobenzene. The intermediate aryl cationic radical is generated by visible light excitation, and then combined with the nucleophilic substitution of cyanide ions to achieve the cleavage of C(sp2)-O bond and the construction of CN bond to generate aryl nitrile compounds. The reaction is carried out in an air atmosphere, avoiding the use of precious metal catalysts and highly toxic cyanide sources.
The synthesis of aryl nitrile compounds without metal catalysis and with low toxicity cyanide source has been achieved. The reaction conditions are mild, the substrates are widely applicable, and the yield is high, showing significant potential for industrial application and meeting the requirements of green chemistry.
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of aryl nitrile compounds based on photo-induced EDA. BACKGROUND
[0002] C(sp 2 )-O bond of aromatic hydrocarbon is a key structural unit in natural products, drug molecules and functional materials (J. Am. Chem. Soc. 2016, 138, 8470.; ACS Catal. 2016, 6, 769.; Org. Lett. 2017, 19, 3199), but its high bond dissociation energy (such as the C-O bond of methoxy about 100 kcal / mol) and stable chemical properties make its bond activation extremely challenging (ACS Catal. 2024, 14, 24, 18774-18785).
[0003] Traditional methods rely on transition metal-catalyzed (such as Pd, Ni) cross-coupling, which requires harsh conditions of high temperature (>100℃) and inert gas atmosphere, and has defects of high cost of noble metal, complex operation and large environmental burden (Materials Review, 2016, 30(11): 7; Chinese J. Org. Chem., 2017, 37(2): 335-348).
[0004] Although the photo / electrochemical single electron transfer (SET) strategy developed in recent years can promote the activation of C-O bond by generating aryl cation radicals, the efficiency of photo catalysts is low, the electrode cost of electro catalysts is expensive, and the expandable range of substrates is limited (poor reactivity of polysubstituted aromatic hydrocarbons and heterocyclic systems, and extremely low yield) (ACS Catal., 2020, 10, 4906-4913; J. Am. Chem. Soc., 2016, DOI: 10.1021 / jacs.6b10998).
[0005] In addition, the functionalization reaction of inert methoxy C-O bond often needs pre-activation, such as conversion into triflate or sulfonate, which is complicated and has low atom economy. Therefore, the existing methods still have significant bottlenecks in greenness, universality and industrial application level, and it is urgent to develop a new strategy without pre-activation, mild conditions and environmental friendliness.
[0006] Cyanation reaction is the core means for synthesizing aryl nitrile compounds, but the existing technology faces the dual bottlenecks of high toxicity of cyanide source (such as KCN and NaCN) and harsh reaction conditions (ACS Catal. 2024, 14, 4, 2350-2357; Science, 351, 832-836 (2016)). The traditional photo / electrocatalytic system needs to add cyanide source additionally, and depends on the harsh conditions of inert gas atmosphere, which is difficult to further promote the practicalization process.
[0007] In recent years, although the electron donor-acceptor (EDA) complex strategy can generate free radicals through photoexcitation, the reaction system needs to be strictly deoxygenated, and the cyanide source and electron acceptor need to be provided separately, resulting in large amount of reagents and economic inefficiency of the process. For example, although the EDA system developed by Zeng et al. (Nat. Commun., 2024, 15, 1455) achieves the cleavage of the C-O bond of methoxyl arene, it still needs exogenous cyanide and has limited substrate universality. SUMMARY
[0008] In order to overcome the deficiencies of the prior art, the present application provides a method for synthesizing aryl nitrile compounds based on photo-induced EDA, which realizes a green, air-compatible bifunctional EDA system with the ability to self-supply electron acceptors and cyanide sources, breaking through the core bottlenecks of noble metal dependence, harsh reaction conditions and high toxicity of cyanide sources in the existing C(sp 2 )-O bond cleavage, and realizing efficient molecular construction of C-N bond. Through visible light excitation of the bifunctional EDA complex formed by the electron-rich methoxyl arene and the electron-deficient 1,4-dicyanobenzene (1,4-DCB), intramolecular single electron transfer (SET) of the arene is triggered to generate a highly active aryl cation radical intermediate; the intermediate undergoes nucleophilic substitution with cyanide ions (CN - ) released in situ from DCB, simultaneously realizing cleavage of C(sp 2 )-O bond and directional introduction of cyanide, and constructing aryl nitrile product in one step. The present application does not need to rely on catalysts, oxidants and organic ligands, and the reaction conditions are mild, providing a new scheme for green and efficient C-N molecular construction.
[0009] In order to achieve the above purpose, the following technical scheme is adopted in the present application:
[0010] A method for synthesizing aryl nitrile compounds based on photo-induced EDA, comprising:
[0011] Under an air atmosphere, an electron-rich methoxyl arene, 1,4-dicyanobenzene and an inorganic base are dissolved in a solvent to form a homogeneous reaction system;
[0012] irradiating the homogeneous reaction system with a light source containing ultraviolet light with a wavelength of 200 nm-780 nm to excite the electron-rich methoxy arene and the 1,4-dicyanobenzene to form an EDA complex;
[0013] generating an aryl cation radical intermediate by photo-induced single electron transfer, and triggering the 1,4-dicyanobenzene to release cyanide ions; and
[0014] the aryl cation radical and the cyanide ions undergo a nucleophilic substitution reaction to break a C(sp 2 )-O bond and construct a C-N bond, to generate an aryl nitrile compound.
[0015] Further, the reaction temperature of the synthesis process is 20-30℃, the reaction time is 12-36 hours, and no metal catalyst, oxidant or chemical additive is added.
[0016] Further, the electron-rich methoxy arene includes a polysubstituted methoxy arene, a methoxy fused heteroarene, a bioactive molecule derivative or a natural product derivative.
[0017] The polysubstituted methoxy arene has a structure of introducing an electron-donating group, an electron-withdrawing group or a heterocyclic compound to a para position of an aromatic ring of a methoxy benzene; the electron-donating group is -Me, -Ph, -OMe or -NH2; the electron-withdrawing group is -F, -Cl, -Br, -I, 4-F-Ph, -NMeBoc, -COOMe, -NO2 or -CN; and the heterocyclic compound is pyridine, pyrazine, thiophene, pyrrole, benzothiophene or indole.
[0018] The natural product derivative includes eugenol derivatives, and the bioactive molecule derivative includes methoxybenzamide analogues.
[0019] Further, the electron-rich methoxy arene includes a polysubstituted methoxy arene; the polysubstituted methoxy arene includes 1,2,3-trimethoxybenzene, 1,2,3,5-tetramethoxybenzene or 5-chloro-1,2,3-tetramethoxybenzene.
[0020] Further, the electron-rich methoxy arene includes a methoxy fused heteroarene; the methoxy fused heteroarene includes fluorene, naphthalene, dibenzofuran, carbazole or diphenylamine derivatives.
[0021] Further, the electron-rich methoxy arene includes a bioactive molecule derivative or a natural product derivative; the bioactive molecule or natural product derivative includes tert-butylmethyl(3,4,5-trimethoxyphenyl)carbamate, 2-methoxy-9,9'-spirobifluorene, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalenecarboxylic acid methyl ester.
[0022] Further, the solvent is selected from at least one of N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or acetone.
[0023] Further, the inorganic base is selected from at least one of potassium acetate, sodium acetate, sodium bicarbonate, potassium fluoride, potassium carbonate, sodium carbonate, cesium carbonate;
[0024] Further, the molar amount of the inorganic base is 2.0-3.0 times of the molar amount of the electron-rich methoxy arene.
[0025] Further, the light source includes a violet LED with a wavelength of 390±5nm, a blue LED with a wavelength of 420nm, an ultraviolet LED with a wavelength of 200-400nm, a xenon lamp or a sunlight simulator.
[0026] Compared with the prior art, the present application has the following advantages:
[0027] Breakthrough of noble metal dependence and cyanide toxicity bottleneck: traditional cyanation reaction needs to rely on palladium / nickel catalyst or toxic cyanide (such as KCN), which has the risk of metal residue and safety hazard. The present application realizes metal-free catalysis through bifunctional EDA complex (1,4-DCB), and DCB releases low-toxicity cyanide in situ, completely avoids the use of noble metal and toxic reagent, and reduces the cost;
[0028] Green production: abandon the toxic cyanide (KCN / NaCN) and pre-activation step (such as sulfonate) in traditional process, which is economical;
[0029] Air compatible mild reaction system: the reaction can be carried out efficiently at room temperature (25±2℃), normal pressure and air atmosphere, without the need for inert gas protection or high energy consumption equipment;
[0030] Substrate universality and precise modification ability: covering polysubstituted arene (such as 1,2,3,4-tetramethoxybenzene), heterocyclic system (pyridine, benzothiophene) and complex drug molecules (adapalene, trimethoprim), the cyanide is introduced directionally with a regioselectivity of >20:1 (see Example 1 for details), and the yield is high;
[0031] Significant potential for industrial application: the raw material 1,4-DCB is derived from biomass cellulose, which is low in cost and sustainable;
[0032] The present application combines EDA complex chemistry with C(sp 2 The present application provides a new scheme for the green synthesis of aryl nitrile compounds by combining EDA complex chemistry with C(sp BRIEF DESCRIPTION OF DRAWINGS
[0033] The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiments of the application and together with the description serve to explain the application. In the drawings:
[0034] Figure 1 Flow chart of the method of the present application;
[0035] Figure 2 NMR of the reaction product of 1,2,3-trimethoxybenzene with terephthalonitrile;
[0036] Figure 3 NMR of the reaction product of 1,2,3-trimethoxybenzene with terephthalonitrile;
[0037] Figure 4 NMR of the reaction product of 1,2,3,5-tetramethoxybenzene with terephthalonitrile;
[0038] Figure 5 NMR of the reaction product of 1,2,3,5-tetramethoxybenzene with terephthalonitrile;
[0039] Figure 6 NMR of the reaction product of 5-chloro-1,2,3-tetramethoxybenzene with terephthalonitrile;
[0040] Figure 7 NMR of the reaction product of 5-chloro-1,2,3-tetramethoxybenzene with terephthalonitrile;
[0041] Figure 8 NMR of the reaction product of tert-butyl methyl (3,4,5-trimethoxyphenyl)carbamate with terephthalonitrile;
[0042] Figure 9 NMR of the reaction product of tert-butyl methyl (3,4,5-trimethoxyphenyl)carbamate with terephthalonitrile;
[0043] Figure 10 NMR of the reaction product of 2-methoxy-9,9'-spirobifluorene with terephthalonitrile;
[0044] Figure 11 NMR of the reaction product of 2-methoxy-9,9'-spirobifluorene with terephthalonitrile;
[0045] Figure 12 NMR of the reaction product of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalenecarboxylic acid methyl ester with terephthalonitrile;
[0046] Figure 13The NMR carbon spectrum of the reaction product of methyl 6-[3-(1-adamantyl)-4- methoxyphenyl]-2-naphthoate and terephthalonitrile;
[0047] Figure 14 The NMR hydrogen spectrum of the reaction product of 1,4-dimethoxybenzene and terephthalonitrile;
[0048] Figure 15 The NMR carbon spectrum of the reaction product of 1,4-dimethoxybenzene and terephthalonitrile. DETAILED DESCRIPTION
[0049] In order to better understand the technical scheme of the present application, the technical scheme of the embodiments of the present application will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present application.
[0050] In the description of the present application, it should be understood that the relationship between the method steps can be in order or not in order, as long as the overall technical effect is not affected, and therefore it should not be understood as a limitation of the present application. The following description of the present application is only for understanding as a description of individual embodiments of the technical scheme of the present application, and other embodiments are not embodied in the following description, but it does not mean that the present application excludes these other embodiments, and the technical scheme of the present application is also not limited to the specific embodiments described below, and the protection scope of the present application is not limited to only the specific embodiments described below. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor should belong to the scope of protection of the present application.
[0051] It should be noted that if the terms "first", "second", etc. appear in the specification and claims of the present application and the above-described drawings, the description is only for distinguishing similar objects, and does not have to be used to describe a specific order or sequence. It should be understood that the terms used in this way can be interchanged under appropriate circumstances, so that the embodiments of the present application described herein can be implemented in an order other than those illustrated or described herein. In addition, the terms "include" and "have" and any variations thereof are intended to cover non-exclusive inclusion, for example, a process, method, system, product or device that includes a series of steps or units does not have to be limited to only those steps or units clearly listed, but can include other steps or units that are not clearly listed or inherent to these processes, methods, products or devices.
[0052] In some embodiments, as shown in FIG. 1, the present application provides a method for synthesizing aryl nitrile compounds based on light-induced EDA, comprising: Figure 1
[0053] S1: dissolving the electron-rich methoxy aromatic hydrocarbon, 1,4-dicyano benzene and inorganic base in a solvent to form a homogeneous reaction system under air atmosphere;
[0054] Specifically, the electron-rich methoxy aromatic hydrocarbon includes polysubstituted methoxy aromatic hydrocarbon, methoxy fused heteroaromatic hydrocarbon, bioactive molecule derivative or natural product derivative.
[0055] The polysubstituted methoxy aromatic hydrocarbon has a structure of introducing electron-donating group, electron-withdrawing group or heterocyclic compound to the para position of the aromatic ring of methoxy benzene; the electron-donating group is -Me, -Ph, -OMe or -NH2; the electron-withdrawing group is -F, -Cl, -Br, -I, 4-F-Ph, -NMeBoc, -COOMe, -NO2 or -CN; the heterocyclic compound is pyridine, pyrazine, thiophene, pyrrole, benzothiophene or indole; specifically, the electron-rich methoxy aromatic hydrocarbon includes polysubstituted methoxy aromatic hydrocarbon; the polysubstituted methoxy aromatic hydrocarbon includes 1,2,3-trimethoxy benzene, 1,2,3,5-tetramethoxy benzene or 5-chloro-1,2,3-tetramethoxy benzene.
[0056] The methoxy fused heteroaromatic hydrocarbon includes fluorene, naphthalene, dibenzofuran, carbazole or diphenylamine derivative.
[0057] The natural product derivative includes eugenol derivative, and the bioactive molecule derivative includes trimethoprim analog. Specifically, the bioactive molecule or natural product derivative includes tert-butyl methyl (3,4,5-trimethoxyphenyl) carbamate, 2-methoxy-9,9'-spirobifluorene, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene carboxylic acid methyl ester.
[0058] The solvent is at least one selected from N-methyl pyrrolidone, acetonitrile, dimethyl sulfoxide, N,N-dimethyl formamide or acetone.
[0059] The inorganic base is at least one selected from potassium acetate, sodium acetate, sodium bicarbonate, potassium fluoride, potassium carbonate, sodium carbonate and cesium carbonate.
[0060] The molar amount of the inorganic base is 2.0-3.0 times of the molar amount of the electron-rich methoxy aromatic hydrocarbon.
[0061] S2: irradiating the homogeneous reaction system with a light source containing ultraviolet light with a wavelength of 200-780 nm to excite the electron-rich methoxy aromatic hydrocarbon and 1,4-dicyano benzene to form EDA complex;
[0062] Specifically, the light source includes violet LED with a wavelength of 390±5 nm, blue LED with a wavelength of 420 nm, ultraviolet LED with a wavelength of 200-400 nm, xenon lamp or solar simulator.
[0063] S3: generating aryl cation radical intermediates through photo-induced single electron transfer and triggering cyanide release from 1,4-dicyanobenzene; and
[0064] S4: nucleophilic substitution reaction between the aryl cation radical and cyanide to break C(sp 2 )-O bond and construct C-N bond, generating aryl nitrile compounds;
[0065] Specifically, the above synthesis process has a reaction temperature of 20-30°C and a reaction time of 12-36 hours, without adding metal catalysts, oxidants or chemical additives.
[0066] The following is the experimental operation procedure of the method of the present application, including reaction system construction, reaction condition setting, and reaction monitoring and product analysis.
[0067] 1. Reaction system construction
[0068] In a dry 25 mL quartz reaction tube, add electron-rich methoxy arene (0.2 mmol), 1,4-dicyanobenzene (DCB, 0.6 mmol), and inorganic base (0.4 mmol) in sequence, followed by injection of solvent (1.5 mL) as a solvent and electron donor. Dissolve the solids completely by magnetic stirring (800 rpm) to form a homogeneous dark brown solution. Perform the reaction directly under air atmosphere without inert gas protection.
[0069] 2. Reaction condition setting
[0070] Fix the reaction tube horizontally directly below a 390 nm purple LED array (wavelength 390±5 nm, light intensity 30 mW / cm 2 , light source distance 15 cm) to ensure uniform light coverage of the reaction liquid surface. Perform the reaction at room temperature (25±2°C) without additional temperature control equipment. Continue the light exposure for 24 hours, and the color of the reaction system gradually changes from dark brown to light yellow.
[0071] 3. Reaction monitoring and product analysis
[0072] Take samples every 6 hours to track the reaction progress by thin layer chromatography (TLC, developing agent: petroleum ether / ethyl acetate = 4:1) until the starting material point (Rf = 0.7) completely disappears and the product point (Rf = 0.3) significantly appears. After the reaction is completed, transfer the mixture to a rotary evaporator, concentrate and remove the NMP solvent under reduced pressure at 40°C. Add 10 mL of deionized water to the residue, extract with dichloromethane (3×10 mL), combine the organic phases and dry with anhydrous sodium sulfate. Purify the crude product by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1) to obtain the target product. Then confirm the structure by melting point determination (82-84°C) and nuclear magnetic resonance hydrogen spectrum.
[0073] Specific examples 1-7 are as follows:
[0074] Example 1: 1,2,3-Trimethoxybenzene with terephthalonitrile
[0075] In a 25 mL dry quartz reaction tube, 1,2,3-trimethoxybenzene (0.2 mmol, 33.8 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg) and potassium acetate (KOAc, 0.4 mmol, 39.26 mg) were accurately weighed, and N-methylpyrrolidone (NMP, 1.5 mL) was injected as the solvent and electron donor. Magnetic stirring (800 rpm) was applied until complete dissolution, forming a homogeneous dark brown solution. The reaction was carried out directly under an air atmosphere without inert gas protection. Next, the reaction tube was fixed horizontally directly below a 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm2, source distance 15 cm), ensuring uniform illumination of the reaction liquid surface. The reaction was carried out at room temperature (25 ± 2°C) with continuous illumination for 24 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure at 40°C to remove NMP, and the residue was added to 10 mL of deionized water. The organic phase was extracted with dichloromethane (3 x 10 mL), combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1), and the target component was collected to obtain white needle-like crystals of 2,6-dimethoxybenzonitrile. 2
[0076] As shown in Figure 2 and Figure 3 , the structure of the product was confirmed by nuclear magnetic resonance 1 HNMR (400 MHz, CDC13) δ = 7.43 (t, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 3.89 (s, 6H) ppm.13C NMR (101 MHz, CDC13) δ = 162.7, 134.8, 114.2, 103.5, 91.3, 56.3 ppm) The final separation yield was 97%.
[0077] Example 2: 1,2,3,5-Tetramethoxybenzene with terephthalonitrile
[0078] Accurately weigh 1,2,3,5-tetramethoxybenzene (0.2 mmol, 39.7 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg), and potassium acetate (KOAc, 0.4 mmol, 39.26 mg) into a 25 mL dry quartz reaction tube, and add N-methylpyrrolidone (NMP, 1.5 mL) as a solvent and electron donor. Stir magnetically (800 rpm) until completely dissolved, forming a homogeneous dark brown solution. The reaction was carried out directly in air without the need for inert gas protection. Next, the reaction tube was horizontally fixed directly below a 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm²). 2 The light source was positioned 15 cm away from the reaction liquid to ensure uniform illumination. The reaction was carried out at room temperature (25 ± 2 °C) for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure at 40 °C to remove NMP. The residue was added to 10 mL of deionized water and extracted with dichloromethane (3 × 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1). The target fraction was collected to obtain 2,4,6-trimethoxybenzonitrile.
[0079] like Figure 4 and Figure 5 As shown, by nuclear magnetic resonance (NMR) 1 ¹H NMR (400 MHz, CDCl₃) δ = 6.06 (s, 2H), 3.88 (s, 6H), 3.85 (s, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ = 165.4, 163.8, 114.9, 90.4, 84.1, 56.1, 55.7 ppm) confirmed the product structure. The final separation yield reached 91%.
[0080] Example 3: 5-Chloro-1,2,3-Tetramethoxybenzene and terephthalonitrile
[0081] Accurately weigh 5-chloro-1,2,3-tetramethoxybenzene (0.2 mmol, 40.6 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg), and potassium acetate (KOAc, 0.4 mmol, 39.26 mg) into a 25 mL dry quartz reaction tube, and add N-methylpyrrolidone (NMP, 1.5 mL) as a solvent and electron donor. Stir magnetically (800 rpm) until completely dissolved, forming a homogeneous dark brown solution. The reaction was carried out directly in air without the need for inert gas protection. Next, the reaction tube was horizontally fixed directly below a 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm²). 2The reaction was carried out under air atmosphere without inert gas protection. Next, the reaction tube was fixed horizontally under the 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm2, light source distance 15 cm) to ensure uniform illumination covering the reaction liquid surface. The whole reaction was carried out at room temperature (25 ± 2°C) for 24 hours of continuous illumination. After the reaction was completed, the reaction liquid was concentrated at 40°C under reduced pressure to remove NMP, 10 mL of deionized water was added to the residue, extracted with dichloromethane (3 x 10 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1), and the target component was collected to obtain 4-chloro-2,6-dimethoxybenzonitrile.
[0082] As shown in Figure 6 and Figure 7 , the structure of the product was confirmed by nuclear magnetic resonance 1 HNMR (400 MHz, CDC13) δ = 6.56 (s, 2H), 3.90 (s, 6H) ppm.13C NMR (101 MHz, CDC13) δ = 162.9, 141.2, 113.4, 104.9, 90.4, 56.7 ppm). The final separation yield reached 80%.
[0083] Example 4: tert-butyl methyl (3,4,5-trimethoxyphenyl) carbamate and p- benzenedicarbonitrile
[0084] In a 25 mL dry quartz reaction tube, tert-butyl methyl (3,4,5-trimethoxyphenyl) carbamate (0.2 mmol, 59.53 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg) and potassium acetate (KOAc, 0.4 mmol, 39.26 mg) were accurately weighed, and N-methyl pyrrolidone (NMP, 1.5 mL) was injected as a solvent and electron donor. Magnetic stirring (800 rpm) until complete dissolution, forming a homogeneous solution. The reaction was carried out without inert gas protection, directly under air atmosphere. Next, the reaction tube was fixed horizontally under the 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm 2 , light source distance 15 cm) to ensure uniform illumination covering the reaction liquid surface. The whole reaction was carried out at room temperature (25 ± 2°C) for 24 hours of continuous illumination. After the reaction was completed, the reaction liquid was concentrated at 40°C under reduced pressure to remove NMP, 10 mL of deionized water was added to the residue, extracted with dichloromethane (3 x 10 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1), and the target component was collected to obtain tert-butyl (4-cyano-3,5-dimethoxyphenyl) (methyl) carbamate.
[0085] As shown in Figure 8 and Figure 9 , the structure of the product was confirmed by nuclear magnetic resonance 1¹H NMR (400 MHz, CDCl₃) δ = 6.50 (s, 2H), 3.87 (s, 6H), 3.27 (s, 3H), 1.48 (s, 9H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ = 162.5, 153.8, 149.9, 114.2, 100.5, 87.8, 81.6, 56.3, 37.1, 28.2 ppm) confirmed the product structure. The final separation yield reached 97%.
[0086] Example 5: 2-Methoxy-9,9'-spirodifluorene and terephthalonitrile
[0087] Accurately weigh 2-methoxy-9,9'-spirodifluorene (0.2 mmol, 69.29 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg), and potassium acetate (KOAc, 0.4 mmol, 39.26 mg) into a 25 mL dry quartz reaction tube, and add N-methylpyrrolidone (NMP, 1.5 mL) as a solvent and electron donor. Stir magnetically (800 rpm) until completely dissolved to form a homogeneous solution. The reaction is carried out directly in air without the need for inert gas protection. Next, fix the reaction tube horizontally directly below a 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm²). 2 The light source was positioned 15 cm away from the reaction liquid to ensure uniform illumination. The reaction was carried out at room temperature (25 ± 2 °C) for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure at 40 °C to remove NMP. The residue was added to 10 mL of deionized water and extracted with dichloromethane (3 × 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1). The target fraction was collected to obtain 9,9'-spirodifluorene-2-carboxynitrile.
[0088] like Figure 10 and Figure 11 As shown, by nuclear magnetic resonance (NMR) 1 ¹H NMR (400 MHz, CDCl₃) δ = 6.50 (s, 2H), 3.87 (s, 6H), 3.27 (s, 3H), 1.48 (s, 9H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ = 162.5, 153.8, 149.9, 114.2, 100.5, 87.8, 81.6, 56.3, 37.1, 28.2 ppm) confirmed the product structure. The final separation yield reached 79%.
[0089] Example 6: Methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid ester and terephthalonitrile
[0090] In a 25 mL dry quartz reaction tube, accurately weighed 6-[3-(1-adamantyl)-4- methoxyphenyl]-2-naphthoic acid methyl ester (0.2 mmol, 82.51 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg) and potassium acetate (KOAc, 0.4 mmol, 39.26 mg), injected N-methylpyrrolidone (NMP, 1.5 mL) as solvent and electron donor. Magnetic stirring (800 rpm) until complete dissolution, forming a homogeneous solution. Without inert gas protection, directly in the air atmosphere to carry out the reaction. Next, the reaction tube was fixed horizontally directly below the 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm2, light source distance 15 cm), ensuring uniform illumination of the reaction liquid surface. The whole reaction was carried out at room temperature (25 ± 2 °C), and the illumination lasted for 24 hours. After the reaction was completed, the reaction liquid was concentrated at 40 °C under reduced pressure to remove NMP, the residue was added with 10 mL of deionized water, extracted with dichloromethane (3 x 10 mL), the organic phase was combined and dried with anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1), and the target component was collected to obtain 6-[3-(1-adamantyl)-4-cyanophenyl]-2-naphthoic acid methyl ester. 2 , light source distance 15 cm), ensuring uniform illumination of the reaction liquid surface. The whole reaction was carried out at room temperature (25 ± 2 °C), and the illumination lasted for 24 hours. After the reaction was completed, the reaction liquid was concentrated at 40 °C under reduced pressure to remove NMP, the residue was added with 10 mL of deionized water, extracted with dichloromethane (3 x 10 mL), the organic phase was combined and dried with anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1), and the target component was collected to obtain 6-[3-(1-adamantyl)-4-cyanophenyl]-2-naphthoic acid methyl ester.
[0091] As shown in Figure 12 and Figure 13 , the structure of the product was confirmed by nuclear magnetic resonance (1H NMR and 13C NMR). The final separation yield reached 90%. 1 HNMR (400 MHz, CDC13) δ = 8.64 (s, 1H), 8.18-8.00 (m, 3H), 7.96 (d, J = 8.6 Hz, 1H), 7.85-7.67 (m, 3H), 7.66-7.54 (m, 1H), 4.00 (s, 3H), 2.33-2.10 (m, 9H), 1.82 (m, 6H) ppm.13C NMR (101 MHz, CDC13) δ = 167.2, 154.4, 144.9, 139.7, 136.5, 135.7, 132.2, 130.9, 130.3, 128.7, 128.1, 126.4, 126.2, 126.1, 125.7, 125.1, 120.5, 109.4, 52.5, 41.3, 41.2, 37.7, 36.9, 36.5, 29.0 ppm) confirmed the structure of the product. The final separation yield reached 90%.
[0092] Example 7: 1,4-Dimethoxybenzene and terephthalonitrile
[0093] Accurately weigh 1,4-dimethoxybenzene (0.2 mmol, 27.63 mg), 1,4-dicyanobenzene (DCB, 0.6 mmol, 73.91 mg), and potassium acetate (KOAc, 0.4 mmol, 39.26 mg) into a 25 mL dry quartz reaction tube, and add N-methylpyrrolidone (NMP, 1.5 mL) as a solvent and electron donor. Stir magnetically (800 rpm) until completely dissolved to form a homogeneous solution. The reaction is carried out directly in air without the need for inert gas protection. Next, fix the reaction tube horizontally directly below a 390 nm purple LED array (wavelength 390 ± 5 nm, light intensity 30 mW / cm²). 2 The light source was positioned 15 cm away from the reaction liquid to ensure uniform illumination. The reaction was carried out at room temperature (25 ± 2 °C) for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure at 40 °C to remove NMP. The residue was added to 10 mL of deionized water and extracted with dichloromethane (3 × 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15:1). The target fraction was collected to obtain 4-methoxybenzonitrile.
[0094] like Figure 14 and Figure 15 As shown, by nuclear magnetic resonance (NMR) 1 ¹H NMR (400 MHz, CDCl₃) δ = 7.58–7.56 (d, J = 8.0 Hz, 2H), 6.95–6.93 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H) ppm. ¹³C NMR (101 MHz, CDCl₃) δ = 162.9, 134.1, 119.4, 114.8, 104.0, 55.6 ppm) confirmed the product structure. The final separation yield reached 98%.
[0095] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims. The selected and described embodiments are intended to best elucidate the principles of this application and its practical application, thereby enabling other those skilled in the art to best utilize this application with various modifications suitable for the contemplated specific purpose, as well as the various described embodiments.
Claims
1. A method for synthesizing aryl nitrile compounds based on light-induced EDA, characterized in that, The application relates to a method for synthesizing aryl nitrile compounds based on photo-induced electron-donor-acceptor (EDA) reaction. The electron-rich methoxy aromatic hydrocarbon, 1,4-dicyanobenzene and inorganic base are dissolved in a solvent to form a homogeneous reaction system under an air atmosphere; The homogeneous reaction system is irradiated by a light source containing ultraviolet light with a wavelength of 200nm-780nm to excite the electron-rich methoxy aromatic hydrocarbon and 1,4-dicyanobenzene to form an EDA complex; An aryl cation radical intermediate is generated by photo-induced single electron transfer, and cyanide ions are released from 1,4-dicyanobenzene; and The aryl cation radical undergoes nucleophilic substitution reaction with cyanide ion to break C(sp 2 )-O bond and construct C-N bond, to generate aryl nitrile compound.
2. The method according to claim 1, wherein the reaction temperature is 20-30 DEG C, the reaction time is 12-36 hours, and no metal catalyst, oxidant or chemical additive is added.
3. The method according to claim 1, wherein the electron-rich methoxy aromatic hydrocarbon comprises polysubstituted methoxy aromatic hydrocarbon, methoxy fused heteroaromatic hydrocarbon, derivative of bioactive molecule or derivative of natural product.
4. The method according to claim 1, wherein the electron-rich methoxy aromatic hydrocarbon comprises polysubstituted methoxy aromatic hydrocarbon, and the polysubstituted methoxy aromatic hydrocarbon comprises 1,2,3-trimethoxybenzene, 1,2,3,5-tetramethoxybenzene or 5-chloro-1,2,3-tetramethoxybenzene.
5. The method according to claim 1, wherein the electron-rich methoxy aromatic hydrocarbon comprises methoxy fused heteroaromatic hydrocarbon, and the methoxy fused heteroaromatic hydrocarbon comprises fluorene, naphthalene, dibenzofuran, carbazole or diphenylamine derivative.
6. The method according to claim 1, wherein the electron-rich methoxy aromatic hydrocarbon comprises derivative of bioactive molecule or derivative of natural product, and the derivative of bioactive molecule or natural product comprises tert-butylmethyl (3,4,5-trimethoxyphenyl) carbamate, 2-methoxy-9,9'-spirobifluorene or 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalenecarboxylic acid methyl ester.
7. The method according to claim 1, wherein the solvent is at least one selected from N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide or acetone. 8. The method of claim 1, wherein the inorganic base is at least one selected from the group consisting of potassium acetate, sodium acetate, sodium bicarbonate, potassium fluoride, potassium carbonate, sodium carbonate, and cesium carbonate.
9. The method of claim 8, wherein the inorganic base is used in an amount of 2.0-3.0 times the amount of the electron-rich methoxyarene.
10. The method of claim 1, wherein the light source comprises a violet LED with a wavelength of 390±5 nm, a blue LED with a wavelength of 420 nm, an ultraviolet LED with a wavelength of 200-400 nm, a xenon lamp, or a solar simulator.