An electrochemical synthesis method of imidazo[1,2-a]pyridine-3-aldehyde compounds

Abstract

The application discloses an electrochemical synthesis method of imidazole[1,2-a]pyridine-3-aldehyde compounds, which comprises the following steps: dissolving compound II, compound III and lithium perchlorate in a solvent in a molar ratio of 1:(1.2-4):1, taking a carbon cloth electrode as an anode and a platinum sheet electrode as a cathode, reacting under the conditions of 15-mA direct current and 50-75 DEG C for 1-6 hours, cooling to room temperature, removing the solvent, and purifying by column chromatography to obtain the imidazole[1,2-a]pyridine-3-aldehyde compounds; and the electrochemical method provided by the application uses trimethylamine as a formylating reagent to construct the imidazole[1,2-a]pyridine-3-aldehyde compounds, and compared with a traditional preparation method, the trimethylamine as the formylating reagent is not only cheap and easy to obtain, but also has higher atomic economy.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically, it relates to an electrochemical method for constructing imidazole[1,2-a]pyridine-3-aldehyde compounds using trimethylamine as a formylating agent. Background Technology

[0002] Imidazole[1,2-a]pyridine-3-aldehydes are a very important class of pharmaceutical intermediates, especially imidazo[1,2-a]pyridines functionalized at the C3 position of the imidazole ring, which possess a variety of pharmacological activities, such as antiviral, anticytotoxic, antibacterial, bactericidal, and anti-inflammatory activities. The most typical examples are the widely used antidepressant salinomycete and the anesthetic necropyridine, both of which are constructed from the structural framework contained in this class of compounds. Therefore, the synthesis of imidazole[1,2-a]pyridine-3-aldehydes has significant research value in the field of drug synthesis. Furthermore, organic electrosynthesis is considered a "green" and sustainable alternative to traditional methods because it can maximize atomic efficiency and minimize reagent waste by replacing stoichiometric redox reagents with electric current.

[0003] In 2015, Zheng's research group reported a method for formylation of the third position of imidazo[1,2-a]pyridine compounds using copper acetate as a catalyst, oxygen as an oxidant, and acetic acid as a solvent at 120 °C for 24 hours (Chem. Commun., 2015, 51, 1823-1825).

[0004]

[0005] In 2018, Hajra et al. reported a visible light-induced C-3 formylation of imidazo[1,2-a]pyridine using N,N,N',N'-tetramethylethylenediamine as the formylation reagent. This reaction required no external oxidant or metal catalyst, exhibited mild reaction conditions, and showed good functional group universality. The drawback was the long reaction time, requiring 36 hours to complete the transformation (Org. Biomol. Chem., 2018, 16, 3473–3478).

[0006]

[0007] In 2021, Zhong's research group reported an electrochemical indole C-3 formylation reaction using trimethylamine as the formylation agent. The reaction utilizes a recyclable polyethylene glycol / water solvent system and reacts at 80 °C for 24 hours to obtain the formylated product in 85% yield (Green Chem., 2021, 23, 4107–4113).

[0008]

[0009] In summary, current literature on the C-3 formylation of azazopyridines, especially imidazopyridines, either employs transition metal catalysts or traditional oxidants, and the reactions require high temperatures and long durations, increasing both cost and environmental burden. Therefore, developing a green chemistry method that is oxidant-free and metal-free for activating the C-3 position of imidazopyridine is of paramount importance. Summary of the Invention

[0010] The purpose of this invention is to provide an electrochemical synthesis method for imidazole[1,2-a]pyridine-3-aldehyde compounds.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] The first aspect of the present invention provides an electrochemical synthesis method for imidazole[1,2-a]pyridine-3-aldehyde compounds, comprising the following steps:

[0013]

[0014] Compound II, Compound III, and lithium perchlorate in a molar ratio of 1:(1.2-4):1 (preferably 1:2:1) were dissolved in a solvent. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 1-6 hours (preferably 3-5 hours) under the conditions of a direct current of 15 mA and a temperature of 50-75°C (preferably 50-70°C). After cooling to room temperature, the solvent was removed, and the imidazole[1,2-a]pyridine-3-aldehyde compound was obtained by column chromatography.

[0015] In compound II,

[0016] R1 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0017] R2 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0018] R3 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0019] R4 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0020] R5 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0021] R6 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0022] R7 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0023] R8 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0024] R9 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine).

[0025] In compound II,

[0026] R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0027] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0028] R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0029] R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0030] R5 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0031] R6 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0032] R7 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0033] R8 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine;

[0034] R9 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine.

[0035] Compound II is selected from one of the following structures:

[0036]

[0037] The imidazole[1,2-a]pyridine-3-aldehyde compound is selected from one of the following structures:

[0038]

[0039] The solvent is acetonitrile and hexafluoroisopropanol in a volume ratio of 1:1.

[0040] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0041] This invention provides an electrochemical method for constructing imidazolium[1,2-a]pyridine-3-aldehyde compounds using trimethylamine as a formylation reagent. Compared to traditional preparation methods, trimethylamine, as a formylation reagent, is not only inexpensive and readily available, but also offers higher atom economy. Simultaneously, the electrocatalytic reaction conditions are milder and more efficient, avoiding the involvement of transition metals and oxidants, further responding to the call for "green chemistry," reducing the cost of commercializing imidazopyridine derivatives, and laying the foundation for the industrial production of imidazopyridine derivatives.

[0042] A similar invention patent is entitled "A novel method for constructing imidazole[1,2-a]pyridine-3-aldehyde using DMF as a formylation reagent" (patent application publication number CN110372696A). This invention uses N,N-dimethylformamide (DMF) as a formylation reagent, requires external oxygen as an oxidant, copper nitrate trihydrate as a catalyst, and requires a high temperature of 130°C for 1-48 hours to obtain the target product with a yield of only 35%.

[0043] Compared with the aforementioned patent, the present invention has the following advantages: it uses trimethylamine, which is inexpensive and readily available, as the formylation reagent, and uses electrocatalysis as the driving force, without the need for additional oxidants and metal catalysts to participate in the reaction, which has obvious advantages in "atom economy" and green environmental protection. Furthermore, the present invention can achieve a yield of 93% in just 5 hours at a lower temperature. Obviously, the new method provided by the present invention is superior to the comparative example. Attached Figure Description

[0044] Figure 1 This is a schematic diagram of the proton NMR spectrum of compound I-1.

[0045] Figure 2 This is a schematic diagram of the carbon spectrum of compound I-1. Detailed Implementation

[0046] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0047] The specifications, purity, and manufacturers of the reagents used in this invention are shown in Table 1.

[0048] Table 1

[0049]

[0050]

[0051] The preparation method of compound II includes the following steps:

[0052]

[0053] Sodium bicarbonate (7.837 mmol, 1.56 equivalents) was added to 20 mL of an ethanol solution containing 2-bromoacetophenone (5.024 mmol, 1.0 equivalent) and 2-aminopyridine (6.280 mmol, 1.25 equivalent). The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the resulting mixture was diluted with water (15 mL) and extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with 25 mL of brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain compound II of analytical grade.

[0054] The 2-bromoacetophenone compounds are selected from 2-bromoacetophenone, 2-bromo-4'-methylacetophenone, 2-bromo-4'-methoxyacetophenone, and 2-bromo-4'-fluoroacetophenone.

[0055] The 2-aminopyridine compounds are selected from 2-aminopyridine, 3-methyl-2-aminopyridine, 4-methyl-2-aminopyridine, 5-fluoro-2-aminopyridine, and 5-chloro-2-aminopyridine.

[0056] Example 1

[0057]

[0058] 2-Phenylidene-[1,2-A]pyridine (compound II-1, 0.5 mmol, 1 equivalent) and trimethylamine (compound III-1, 1.0 mmol, 2.0 equivalent) were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as the electrolyte, followed by 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) as the solvent. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 70 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / methanol = 100 / 5) to obtain the target product compound I-1 as a yellow solid, with a yield of 93%. Figure 1 and Figure 2 As shown, Figure 1 This is a schematic diagram of the proton NMR spectrum of compound I-1. Figure 2 This is a schematic diagram of the carbon spectrum of compound I-1.1 H NMR (400MHz, Chloroform-d) δ10.06(s,1H),9.65(d,1H),7.85–7.78(m,3H),7.60–7.56(m,1H),7.55–7.49(m,3H),7.12(t,J=6.9Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ179.75,158.40,147.80,132.38,130.60,129.98,129.93,129.02,128.92,120.81,117.52,115.46.HRMS(ESI-TOF)m / z[M+H] + Calcd forC 14 H 11 N2O2 23.0871, found 223.0895.

[0059] Example 2

[0060] The preparation method of compound I-2 includes the following steps:

[0061]

[0062] 8-Methyl-2-phenylimidazo[1,2-A]pyridine, i.e., compound II-2 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 60 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-2, with a yield of 85%. 1 H NMR (400MHz, Chloroform-d) δ10.03 (s, 1H), 9.51 (d, J = 6.7Hz, 1H), 7.91–7.67 (m, 2H), 7.59–7. 46(m,3H),7.37(dt,J=7.0,1.3Hz,1H),7.03(t,J=6.9Hz,1H),2.72(s,3H).HRMS(EI-TOF)calcd for C 15 H 12 N2O[M] +m / z=236.0950; found 236.0947.

[0063] Example 3

[0064] The preparation method of compound I-3 includes the following steps:

[0065]

[0066] 7-Methyl-2-phenylimidazo[1,2-A]pyridine, i.e., compound II-3 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 60 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-3, with a yield of 89%. 1 H NMR(400MHz,Chloroform-d)δ9.78(s,1H),9.28(d,J=6.9Hz,1H),7.60(dd,J=7.5,2.2Hz,2H),7.33 (d,J=2.0Hz,1H),7.31–7.22(m,3H),6.72(dd,J=7.0,1.7Hz,1H),2.28(s,3H).HRMS(ESI-TOF)calcd for([C 15 H 13 N2O] + [M+H] + m / z=237.1028; found 237.1027.

[0067] Example 4

[0068] The preparation method of compound I-4 includes the following steps:

[0069]

[0070] 6-Fluoro-2-phenylimidazo[1,2-A]pyridine, i.e., compound II-4 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, followed by 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 50 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-4, with a yield of 83%. 1 H NMR(400MHz,Chloroform-d)δ10.07(d,J=1.3Hz,1H),9.66(dt,J=4.2,2.0Hz,1H),8.05–7.70(m,3H),7.57–7.51(m,3H),7.51–7.46(m,1H).HRMS(EI-TOF)calcd for C 14 H9FN2O[M] + m / z=240.0699; found 240.0696.

[0071] Example 5

[0072] The preparation method of compound I-5 includes the following steps:

[0073]

[0074] 6-Chloro-2-phenylimidazo[1,2-A]pyridine, i.e., compound II-5 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, followed by 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 50 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-5, with a yield of 80%. 1H NMR(400MHz,Chloroform-d)δ10.07(s,1H),9.76(dd,J=2.1,0.8Hz,1H),7.85–7.80(m,2H) ,7.77(dd,J=9.4,0.9Hz,1H),7.58(d,J=2.1Hz,1H),7.57–7.52(m,3H).HRMS(EI-TOF)calcd for C 14 H9ClN2O[M] + m / z=256.0403; found 256.0406.

[0075] Example 6

[0076] The preparation method of compound I-6 includes the following steps:

[0077]

[0078] 2-(4-methylphenyl)imidazo[1,2-A]pyridine, i.e., compound II-6 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 3 hours under a direct current of 15 mA and a temperature of 70 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-6, with a yield of 90%. 1 H NMR(400MHz,Chloroform-d)δ10.05(s,1H),9.64(dt,J=6.8,1.2Hz,1H),7.79(dt,J=9.0,1.1Hz,1H),7.75–7.69(m,2H ),7.56(ddd,J=9.0,6.9,1.4Hz,1H),7.36–7.30(m,2H),7.10(td,J=6.9,1.3Hz,1H),2.44(s,3H).HRMS(ESI-TOF)calcd for([C 15 H 13 N2O] + [M+H] + m / z=237.1028; found 237.1029.

[0079] Example 7

[0080] The preparation method of compound I-7 includes the following steps:

[0081]

[0082] 2-(4-methoxyphenyl)imidazo[1,2-A]pyridine, i.e., compound II-7 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 3 hours under a direct current of 15 mA and a temperature of 70 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-7, with a yield of 88%. 1 H NMR(400MHz,Chloroform-d)δ10.04(s,1H),9.65(dt,J=6.8,1.2Hz,1H),7.80–7.76(m,3H), 7.61–7.53(m,1H),7.14–7.08(m,1H),7.07–7.03(m,2H),3.88(s,3H).HRMS(ESI-TOF)calcd for([C 15 H 13 FN2O] + [M+H] + m / z=253.0977; found 253.0978.

[0083] Example 8

[0084] The preparation method of compound I-8 includes the following steps:

[0085]

[0086] 2-(4-fluorophenyl)imidazo[1,2-A]pyridine, i.e., compound II-8 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, followed by 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 50 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the pale yellow solid target product compound I-7, with a yield of 84%. 1 H NMR(400MHz,Chloroform-d)δ10.02(s,1H),9.64(dt,J=6.8,1.2Hz,1H),7.87(dd,J=8.8,5.4Hz,1H),7.84–7.7 7(m,2H),7.59(ddd,J=9.0,7.0,1.4Hz,1H),7.25–7.19(m,2H),7.17–7.09(m,1H).HRMS(ESI-TOF)calcdfor([C 14 H 10 FN2O] + [M+H] + m / z=241.0777; found 241.7779.

[0087] The reaction conditions for Examples 9-31 are shown in Table 2:

[0088] Table 2

[0089]

[0090]

[0091] Examples 9-13

[0092] Electrolyte selection

[0093] 2-Phenylidene imidazo[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. 0.5 mmol of the electrolyte lithium perchlorate (Example 9), tetrabutylammonium hexafluoride (Example 10), tetrabutylammonium perchlorate (Example 11), tetrabutylammonium hexafluorophosphate (Example 12), and tetrabutylammonium tetrafluoroborate (Example 13) were added respectively. Then, 5 mL of anhydrous acetonitrile (CH3CN) and... Using 5 mL of hexafluoroisopropanol (HFIP) as solvent, a carbon cloth electrode as the anode and a platinum sheet electrode as the cathode, the reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 70 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / methanol = 100 / 5) to obtain a yellow solid target product compound I-1, with corresponding yields of 93% (Example 9), 59% (Example 10), 67% (Example 11), 72% (Example 12), and 54% (Example 13). These results indicate that lithium perchlorate provides the optimal yield when used as the electrolyte.

[0094] Examples 14-16

[0095] Screening of working electrode materials

[0096] 2-Phenylidene[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A platinum electrode (Example 14), a nickel electrode (Example 15), and a glassy carbon electrode (Example 16) were used as anodes, and a platinum sheet electrode was used as cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 70 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the target product compound I-1 as a yellow solid with corresponding yields of 76% (Example 14), 22% (Example 15), and 58% (Example 16). The above results, compared with those of Example 9, show that the yield is optimal when carbon cloth electrode is used as the anode and platinum sheet electrode is used as the cathode material.

[0097] Examples 17-20

[0098] Solvent selection

[0099] 2-Phenylidene-[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte. Then, 10 mL of anhydrous acetonitrile (Example 17), 10 mL of dimethyl sulfoxide (Example 18), 10 mL of dichloroethane (Example 19), and 10 mL of... Using hexafluoroisopropanol (Example 20) as the solvent, a carbon cloth electrode as the anode and a platinum sheet electrode as the cathode, the reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 70°C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / methanol = 100 / 5) to obtain a yellow solid target product compound I-1, with corresponding yields of 70% (Example 17), 34% (Example 18), 11% (Example 19), and 45% (Example 20). These results, compared with those of Example 9, indicate that the optimal yield was achieved using 5 mL of anhydrous acetonitrile and 5 mL of hexafluoroisopropanol as the solvent.

[0100] Examples 21-23

[0101] Screening of operating current

[0102] 2-Phenylidene[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. The reaction was carried out under direct current of 10 mA (Example 21), 18 mA (Example 22), and 20 mA (Example 23) at a temperature of 70 °C for 5 hours. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / methanol = 100 / 5) to obtain the target product compound I-1 as a yellow solid with corresponding yields of 86% (Example 21), 68% (Example 22), and 45% (Example 23). The above results, compared with those of Example 9, show that the yield is optimal when the operating current is 15 mA.

[0103] Examples 24-27

[0104] Screening of reaction temperature

[0105] 2-Phenylimidazolo[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode as the cathode. A DC current of 15 mA was applied, and the reaction was carried out at temperatures of 25 °C, 50 °C, 90 °C, and 120 °C for 5 hours, respectively. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the target product compound I-1 as a yellow solid with corresponding yields of 8% (Example 24), 73% (Example 25), 88% (Example 26), and 65% (Example 27), respectively. The above results, compared with those of Example 9, show that the yield is optimal when the reaction temperature is 70 degrees Celsius.

[0106] Examples 28-29

[0107] Screening of reaction time

[0108] 2-Phenylidene imidazo[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and trimethylamine, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as the electrolyte, along with 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) as solvents. The reaction was carried out at 70 °C for 3 hours (Example 28) and 7 hours (Example 29) using a carbon cloth electrode as the anode and a platinum sheet electrode as the cathode, with a 15 mA DC current. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / methanol = 100 / 5) to obtain a yellow solid target product, compound I-1, with yields of 53% (Example 28) and 89% (Example 29), respectively. These results, compared with those of Example 9, indicate that a reaction time of 5 hours yielded the optimal product.

[0109] Examples 30-31

[0110] Screening of raw material molar ratio

[0111] 2-Phenylimidazolo[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and different equivalents of trimethylamine, i.e., compound III-1 (1.5 mmol, 1.5 equivalent, Example 30) and (2.0 mmol, 4 equivalent, Example 31), were placed in a 50 mL three-necked flask. Lithium perchlorate ([LiClO4], 0.5 mmol, 1 equivalent) was added as an electrolyte, and 5 mL of anhydrous acetonitrile (CH3CN) and 5 mL of hexafluoroisopropanol (HFIP) were added as solvents. A carbon cloth electrode was used as the anode and a platinum sheet electrode was used as the cathode. The reaction was carried out for 5 hours under a direct current of 15 mA and a temperature of 70 °C. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: dichloromethane / methanol = 100 / 5) to obtain the target product compound I-1 as a yellow solid with yields of 90% (Example 30) and 85% (Example 31), respectively. The results above, compared with those of Example 9, show that the yield is optimal when 2 equivalents of compound III participate in the reaction, i.e., the optimal molar ratio of compound II to compound III is 1:2.

[0112] Comparative Example 1

[0113] Example 1 from the patent application with publication number CN110372696A is used as Comparative Example 1.

[0114] In a 25 mL test tube, 0.2 mmol of imidazole[1,2-a]pyridine and 0.1 mmol of copper nitrate trihydrate were added, along with 2 mL of N,N-dimethylformamide (DMF) as the reaction solvent. An oxygen-filled balloon was attached, and the mixture was stirred at 130°C. After the reaction was detected by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted oxygen was slowly released. The reaction solution was filtered, and the solvent was removed by rotary evaporation under reduced pressure. The solution was then purified by column chromatography to obtain imidazole[1,2-a]pyridine-3-aldehyde, with a yield of 35%.

[0115] In this invention, green electrochemistry is used as the oxidation driving force in the preparation steps, avoiding the cost and environmental burden caused by the use of transition metal catalysts. Furthermore, the reaction can be carried out in an air atmosphere, avoiding the use of oxygen and significantly reducing the safety risks of the preparation. In addition, the preparation temperature of this invention is consistently below 70 degrees Celsius, avoiding the safety hazards associated with high-temperature reactions. Finally, the expected aldehyde-modified product is obtained with an excellent yield of up to 93%, which is a significant advantage compared to Comparative Example 1.

[0116] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An electrochemical synthesis method for imidazole[1,2-a]pyridine-3-aldehyde compounds, comprising the following steps: Compound II, Compound III, and lithium perchlorate in a molar ratio of 1:(1.2~4):1 were dissolved in a solvent. A carbon cloth electrode was used as the anode and a platinum sheet electrode was used as the cathode. The reaction was carried out for 1~6 hours under the conditions of a DC current of 15 mA and a temperature of 50~75℃. After cooling to room temperature, the solvent was removed and the target compound was purified by column chromatography. In the formula: R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R5 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R6 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R7 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R8 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine; R9 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, and chlorine.

2. The electrochemical synthesis method according to claim 1, characterized in that, The compound represented by formula II is selected from one of the following compounds: 。 3. The electrochemical synthesis method according to claim 1, characterized in that, Wherein the formula The compound shown is selected from one of the following compounds: 。 4. The electrochemical synthesis method according to any one of claims 1 to 3, characterized in that, The solvent used is a mixture of acetonitrile and hexafluoroisopropanol in a volume ratio of 1:1.

Images