A method for electrochemically synthesizing asymmetric bis-heteroaromatic compounds

Abstract

The invention discloses a method for electrochemically synthesizing an asymmetric biheteroaromatic compound, wherein an imidazole [2,1-b] thiazole compound shown in formula I, a phenylacetylene compound shown in formula II, and an electrolyte are dissolved in a solvent to obtain a reaction solution; then an electrode is inserted into the reaction solution, and a constant current is connected in an open system to stir the reaction, thereby obtaining an asymmetric biheteroaromatic compound shown in formula III. Compared with the prior art, the method adopted in the present invention does not require the use of metal catalysts, oxidants, additives and other reagents, and the use of electrocatalytic technology is more environmentally friendly and economical, the reaction conditions are mild, and the post-processing is simple. The asymmetric biheteroaromatic compound prepared by the present invention lays a foundation for the research of drugs, metal catalyst ligands and standard agents.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and electrocatalysis, and specifically relates to a method for electrochemically synthesizing an asymmetric biheteroaromatic compound. Background Art

[0002] Biphenyl is an important structural scaffold with wide applications in many drugs, natural products, materials and metal catalyst ligands, which has attracted the attention and research of many organic chemists.

[0003] Traditionally, transition metal-catalyzed di-CH activation strategies are a direct and efficient approach to construct bi-aryl compounds because they avoid multi-step and pre-functionalization processes. However, waste is inevitably generated in the presence of stoichiometric amounts of oxidants and metal catalysts, which does not conform to the concept and requirements of green chemistry. The application of photocatalysis has also emerged as a promising strategy for di-CH activation to bi-aryl compounds. However, the use of complex and expensive photocatalysts increases the cost and is not conducive to industrial production. In this context, organic electrosynthesis is considered to be a powerful and environmentally friendly synthetic method that utilizes "electrons" as a cheap and non-polluting oxidant to achieve redox transformations without the use of external oxidants or reductants.

[0004] In recent years, some progress has been made in the electrochemical oxidative CH / CH cross-coupling under exogenous non-oxidizing conditions. [1-3] Homocoupling between (hetero)aromatics is easy to occur; in contrast, it is a huge challenge to achieve cross-coupling rather than homocoupling between two different heteroaromatic compounds under electrochemical conditions, and cross-coupling reactions between different heteroaromatic groups are usually limited to two simple heteroaromatic compounds, which sacrifices the richness of their products. In summary, the synthesis of asymmetric bis-heteroaromatic compounds by electrochemical oxidation without the need for external oxidants, metal catalysts and additives has the advantages of high efficiency, environmental friendliness and higher economic benefits. Therefore, it is urgent to develop a method for preparing asymmetric bis-heteroaromatic compounds by electrochemical oxidation without exogenous oxidants and metal catalysts.

[0005] References:

[0006] 1.Gao,Y.-Y.,Wang,Y.,Zhou,J.,Mei,H.-B.&Han,J.-L.An electrochemical oxidative homo-coupling reaction of imidazopyridine heterocycles tobiheteroaryls.Green Chem.20,583-587(2018).

[0007] 2. Beil, SB, Mueller, T., Sillart, SB, Franzmann, P., Bomm, A., Holtkamp, ​​M., Karst, U., Schade, W. & Waldvogel, SRActive molybdenum-based anode fordehydrogenative coupling reactions. Angew. Chem. Int. Ed. 57, 2450-2454 (2018).

[0008] 3.Zeng, Z.-Y., Goebel, JF, Liu, Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a method for electrochemically synthesizing asymmetric biheteroaromatic compounds in view of the deficiencies in the prior art. The method does not require the use of external metal catalysts and oxidants, but uses electrocatalytic oxidation, which is more environmentally friendly and in line with the development direction of green chemical synthesis.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] A method for electrochemically synthesizing an asymmetric biheteroaromatic compound, comprising dissolving an imidazole [2,1-b] thiazole compound shown in formula I, a phenylacetylene compound shown in formula II, and an electrolyte in a solvent to obtain a reaction solution; then inserting an electrode into the reaction solution, connecting a constant current in an open system to stir the reaction, and obtaining an asymmetric biheteroaromatic compound shown in formula III;

[0012]

[0013] Among them, R 1 is selected from hydrogen, alkyl, halogen, cyano or phenyl, preferably, R 1 is selected from hydrogen, methyl, fluorine, chlorine, cyano or phenyl, more preferably, R 1 Including but not limited to hydrogen, methyl substituted at the para position of the benzene ring, fluorine substituted at the para position of the benzene ring, chlorine substituted at the para position of the benzene ring, cyano substituted at the para position of the benzene ring or phenyl substituted at the para position of the benzene ring.

[0014] Among them, R 2 is selected from hydrogen or alkyl, preferably, R 2 is selected from hydrogen or methyl; R 3 is selected from hydrogen, methoxy, phenyl or halogen, preferably, R 3 is selected from hydrogen, methoxy, phenyl or fluorine.

[0015] Specifically, the electrolyte is any one of tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate, and lithium perchlorate, or a combination thereof, preferably tetra-n-butylammonium tetrafluoroborate.

[0016] Specifically, the molar ratio of the imidazole [2,1-b] thiazole compound represented by formula I, the phenylacetylene compound represented by formula II and the electrolyte is 1:1 to 1.2:1, preferably 1:1:1.

[0017] Specifically, the solvent is any one or a combination of acetonitrile, ethanol, and water, and preferably the volume ratio of acetonitrile, ethanol, and water is 8:1.2:1.

[0018] Specifically, the concentration of the imidazole [2,1-b] thiazole compound represented by formula I in the solvent is 0.02 to 0.03 mmol / mL, preferably 0.02 mmol / mL.

[0019] Specifically, the electrodes include a positive electrode and a negative electrode, the positive electrode is a carbon cloth electrode, and the negative electrode is a platinum electrode.

[0020] Specifically, the constant current is 8-10 mA, preferably 8 mA.

[0021] Specifically, the reaction temperature is 45-65°C, preferably 55°C, and the reaction time is 1.5-2h, preferably 1.5h.

[0022] Beneficial effects:

[0023] (1) Compared with the prior art, the method adopted by the present invention does not require the use of metal catalysts, oxidants, additives and other reagents. The use of electrocatalytic technology is more environmentally friendly and economical, the reaction conditions are mild, and the post-treatment is simple.

[0024] (2) The asymmetric biheteroaromatic compounds prepared by the present invention lay a foundation for the research of drugs, metal catalyst ligands and standard agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0026] Figure 1It is the hydrogen nuclear magnetic resonance spectrum of 3a in the present invention.

[0027] Figure 2 It is the carbon NMR spectrum of 3a in the present invention.

[0028] Figure 3 It is the hydrogen nuclear magnetic resonance spectrum of 3b in the present invention.

[0029] Figure 4 It is the carbon NMR spectrum of 3b in the present invention.

[0030] Figure 5 It is the hydrogen nuclear magnetic resonance spectrum of 3c in the present invention.

[0031] Figure 6 It is the carbon nuclear magnetic resonance spectrum of 3c in the present invention.

[0032] Figure 7 It is the nuclear magnetic resonance fluorine spectrum of 3c in the present invention.

[0033] Figure 8 It is the hydrogen nuclear magnetic resonance spectrum of 3d in the present invention.

[0034] Fig. 9 It is the 3d carbon nuclear magnetic resonance spectrum of the present invention.

[0035] Fig.10 It is the hydrogen nuclear magnetic resonance spectrum of 3e in the present invention.

[0036] Fig.11 It is the carbon nuclear magnetic resonance spectrum of 3e in the present invention.

[0037] Fig.12 It is the hydrogen nuclear magnetic resonance spectrum of 3f in the present invention.

[0038] Fig.13 It is the carbon nuclear magnetic resonance spectrum of 3f in the present invention.

[0039] Fig.14 It is the hydrogen nuclear magnetic resonance spectrum of 3g in the present invention.

[0040] Fig.15 It is the carbon NMR spectrum of 3g in the present invention.

[0041] Fig.16 It is the hydrogen nuclear magnetic resonance spectrum of 3h in the present invention.

[0042] Fig.17 It is the carbon nuclear magnetic resonance spectrum of 3h in the present invention.

[0043] Fig.18 It is the hydrogen nuclear magnetic resonance spectrum of 3i in the present invention.

[0044] Fig.19It is the carbon nuclear magnetic resonance spectrum of 3i in the present invention.

[0045] Fig. 20 It is the nuclear magnetic resonance fluorine spectrum of 3i in the present invention.

[0046] Fig.21 It is the hydrogen nuclear magnetic resonance spectrum of 3j in the present invention.

[0047] Fig. 22 It is the carbon NMR spectrum of 3j in the present invention. DETAILED DESCRIPTION

[0048] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0049] The reactions in the following examples were all carried out in an electrolytic cell without separation, and the electrodes were inserted into the reaction solution.

[0050] Example 1

[0051] 6-Phenylimidazole [2,1-b] thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55 °C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode, the constant current was controlled to 8 mA, the reaction time was 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL×3) and water (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3a with a yield of 84%.

[0052] Example 2

[0053] 6-(p-Tolyl)imidazole[2,1-b]thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was about 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL × 3) and water (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3b with a yield of 85%.

[0054] Example 3

[0055] 6-(4-Fluorophenyl)imidazole[2,1-b]thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was about 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, the reaction solution was extracted with ethyl acetate (50 mL×3) and water (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3c with a yield of 50%.

[0056] Example 4

[0057] 6-(4-chlorophenyl)imidazole[2,1-b]thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was about 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, the reaction solution was extracted with ethyl acetate (50 mL×3) and water (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3d with a yield of 61%.

[0058] Example 5

[0059] 4-(Imidazolo[2,1-b]thiazol-6-yl)benzonitrile (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was about 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL×3) and water (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3e with a yield of 20%.

[0060] Example 6

[0061] 6-([1,1'-biphenyl]-4-yl)imidazole[2,1-b]thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was about 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL × 3) and water (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3f with a yield of 75%.

[0062] Example 7

[0063] 6-Phenylimidazole [2,1-b] thiazole (0.2mmol, 1.0equiv), phenylacetylene (0.2mmol, 1.0equiv), tetrabutylammonium tetrafluoroborate (0.2mmol, 1.0equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8mL), ethanol (1.2mL) and water (1mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35mm x15mm) was used as the positive electrode, a platinum electrode (10mm x10mm x0.1mm) was used as the negative electrode, a constant current of 8mA was controlled, the reaction time was about 1.5h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, the reaction solution was extracted with ethyl acetate (50mL×3) and water (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as the developing solvent to obtain 3g of the target product with a yield of 38%.

[0064] Example 8

[0065] 2-Methyl-6-phenylimidazole [2,1-b] thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55°C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was about 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL × 3) and water (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3h with a yield of 52%.

[0066] Example 9

[0067] 6-Phenylimidazole [2,1-b] thiazole (0.2 mmol, 1.0 equiv), p-fluorophenylacetylene (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55 °C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, and a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode. The constant current was controlled to 8 mA, the reaction time was 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL×3) and water (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3i with a yield of 46%.

[0068] Example 10

[0069] 6-Phenylimidazole [2,1-b] thiazole (0.2 mmol, 1 equiv), 4-ethynyl-1, 1'-biphenyl (0.2 mmol, 1.0 equiv), and tetra-n-butylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55 °C, a carbon cloth electrode (35 mm x 15 mm) was used as the positive electrode, a platinum electrode (10 mm x 10 mm x 0.1 mm) was used as the negative electrode, the constant current was controlled to 8 mA, the reaction time was 1.5 h, and the reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction, the reaction solution was extracted with ethyl acetate (50 mL×3) and water (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as a developing solvent to obtain the target product 3j with a yield of 48%.

[0070] Comparative Example 1

[0071] This embodiment is carried out under no current conditions:

[0072] 6-Phenylimidazole [2,1-b] thiazole (0.2 mmol, 1.0 equiv), p-methoxyphenylacetylene (0.2 mmol, 1.0 equiv), tetrabutylammonium tetrafluoroborate (0.2 mmol, 1.0 equiv) were weighed and dissolved in a mixed solvent containing acetonitrile (8 mL), ethanol (1.2 mL) and water (1 mL) for reaction. The reaction temperature was controlled at 55 ° C. The reaction time was 1.5 h. No current was applied during the reaction. The reaction progress was detected by TLC (petroleum ether: ethyl acetate = 1: 1). After the reaction was completed, the reaction solution was extracted with ethyl acetate (50 mL × 3) and water (50 mL × 3), the organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate. After concentration, the crude product was separated by silica gel column chromatography using dichloromethane / ethyl acetate / petroleum ether as the developing solvent, and the yield of the target product 3a was 0%.

[0073] The present invention provides a method and method for electrochemically synthesizing asymmetric biheteroaromatic compounds. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for electrochemically synthesizing an asymmetric bis-heteroaromatic compound, It is characterized in that The imidazole [2,1-b] thiazole compound of formula I, the phenylacetylene compound of formula II, and an electrolyte are dissolved in a solvent to obtain a reaction solution; then an electrode is inserted into the reaction solution, and a constant current is connected in an open system to stir the reaction, thereby obtaining an asymmetric biheteroaromatic compound of formula III; Among them, R 1 is selected from hydrogen, alkyl, halogen, cyano or phenyl; R 2 is selected from hydrogen or alkyl; R 3 is selected from hydrogen, methoxy, phenyl or halogen; The molar ratio of the imidazole [2,1-b] thiazole compound shown in formula I to the phenylacetylene compound shown in formula II is 1:1 to 1.

2.

2. The method according to claim 1, It is characterized in that The electrolyte is any one of tetra-n-butylammonium tetrafluoroborate, tetra-n-butylammonium hexafluorophosphate and lithium perchlorate or a combination of several of them.

3. The method according to claim 1, It is characterized in that The molar ratio of the imidazole [2,1-b] thiazole compound represented by formula I to the electrolyte is 1:

1.

4. The method according to claim 1, It is characterized in that The solvent is any one of acetonitrile, ethanol and water or a combination of several of them.

5. The method according to claim 1, It is characterized in that The concentration of the imidazole [2,1-b] thiazole compound represented by formula I in the solvent is 0.02 to 0.03 mmol / mL.

6. The method according to claim 1, It is characterized in that The electrodes include a positive electrode and a negative electrode, the positive electrode is a carbon cloth electrode, and the negative electrode is a platinum electrode.

7. The method according to claim 1, It is characterized in that The constant current is 8-10 mA.

8. The method according to claim 1, It is characterized in that The reaction temperature is 45-65°C and the reaction time is 1.5-2h.

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