Electrochemical partial hydrogenation of imidazopyridines

Abstract

The application discloses an electrochemical incomplete hydrogenation method of imidazopyridine compounds, which comprises the following steps: dissolving compound II, compound III and an electrolyte in a solvent in a molar ratio of 1:(1-5):1, taking a nickel electrode as a cathode, reacting under the conditions of passing 10-20 milliamperes of direct current and at a temperature of 50-90 DEG C for 12-20 hours, cooling to room temperature, removing the solvent, and purifying through column chromatography to obtain the imidazopyridine compound, i.e. compound I; compared with a traditional preparation method, the t-butyl hydrazine formate is cheap and easy to obtain as a hydrogenation reagent raw material, meanwhile, the electrocatalytic reaction condition is more moderate and efficient, the participation of transition metals and oxidants is avoided, the appeal for 'green chemistry' is further responded, the cost of commercialization of the imidazopyridine derivative is reduced, the foundation for industrial production of the imidazopyridine derivative is laid, and a new idea is provided for the incomplete hydrogenation reduction of nitrogen-containing heterocyclic compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically, it relates to an electrochemical incomplete hydrogenation method for imidazopyridine compounds using tert-butyl hydrazine carbamate as a hydrogenating agent. Background Technology

[0002] Hydrogenation is one of the most classic reactions in organic synthesis, and it also holds significant promise for applications in the synthesis of fine chemicals and pharmaceuticals. In particular, the attractive transfer hydrogenation strategy, which uses non-hydrogen donors instead of high-pressure hydrogen for direct hydrogenation, has become a hot topic in recent years. Over the past century, numerous transition metal and organocatalysts have been successfully developed using alcohols, formic acid, hydrazine, alkanes, cyclohexene, and water as "sacrificial" hydrogen donors. In electrochemistry, the hydrogenation of activated alkenes, alkynes, and ketones has been successfully achieved via electrochemical cathode transfer hydrogenation using ammonia, water, ammonium chloride, or dimethyl sulfoxide as hydrogen donors. However, studies on the selective hydrogenation of aromatic compounds using electrochemically induced transfer hydrogenation strategies are rarely reported. The first prominent study was the Birch reduction reaction of aromatics under refrigerated conditions using liquid ammonia as a hydrogen source (Tetrahedron Lett. 1987, 28, 1173-1174).

[0003]

[0004] Hydrogenation of N-heterocyclic aromatics is one of the most efficient methods for obtaining partially saturated N-heterocycles, which are building blocks of bioactive molecules and key intermediates in organic synthesis. Therefore, many valuable traditional methods have been identified based on transfer hydrogenation strategies. For example, in 2016, Song and colleagues developed palladium-catalyzed transfer hydrogenation reactions of imidazole compounds using water as a hydrogen donor (Org. Lett. 2016, 18, 4250-4253).

[0005]

[0006] In 2020, Wang's research group reported a selective electrochemical hydrogenation reaction of imidazole[1,2-a]pyridine using piperidine as a hydrogen source, achieving a 92% yield at room temperature with a current of 15 mA for 4 hours (Org. Lett. 2020, 22, 8824-8828).

[0007]

[0008] In summary, traditional hydrogen transfer strategies often require complex or expensive transition metal catalysts or are limited to harsh high-temperature and high-pressure reaction conditions. Therefore, developing metal-free, convenient, efficient, and environmentally friendly solutions using readily available hydrogen sources as hydrogen donors is a key scientific issue in the field of hydrogen transfer research. Tert-butyl hydrazine carbamate, as an abundant, inexpensive, and readily available organic reagent, often plays an important role in most organic reactions, but it has not yet been used as a hydrogen donor in hydrogen transfer reactions under electrochemical conditions. Summary of the Invention

[0009] The purpose of this invention is to provide a method for the electrochemical incomplete hydrogenation of imidazopyridine compounds.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] The first aspect of the present invention provides a method for the electrochemical incomplete hydrogenation of imidazopyridine compounds, comprising the following steps:

[0012]

[0013] Compound II, Compound III, and an electrolyte in a molar ratio of 1:(1-5):1 (preferably 1:2:1) are dissolved in a solvent. A nickel electrode is used as the cathode. The reaction is carried out for 12-20 h under the conditions of a direct current of 10-20 mA (preferably 15 mA) and a temperature of 50-90 °C (preferably 70 °C). After cooling to room temperature, the solvent is removed, and the mixture is purified by column chromatography to obtain an imidazopyridine compound, namely Compound I.

[0014] In compound II,

[0015] R1 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0016] R2 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0017] R3 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0018] R4 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0019] R5 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0020] R6 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0021] R7 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0022] R8 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0023] R9 is selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, and halogens (fluorine, chlorine, bromine, iodine);

[0024] Alternatively, R6 and R7 can form a six-membered ring with carbon (such as a phenyl group);

[0025] The electrolyte is selected from tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium bromide, and tetrabutylammonium tetrafluoroborate.

[0026] The anode is selected from platinum electrode, nickel electrode, and glassy carbon electrode.

[0027] The solvent is selected from dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, and hexafluoroisopropanol.

[0028] In compound II,

[0029] 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; or, R6 and R7 together with carbon form a phenyl group.

[0030] Compound II has one of the following structures:

[0031]

[0032] The imidazopyridine compound, namely compound I, is selected from one of the following structures:

[0033]

[0034]

[0035] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0036] This invention provides an electrochemical incomplete hydrogenation method for imidazo[1,2-a]pyridine compounds. By adjusting the reaction solvent, a stepwise hydrogenation reduction reaction of imidazo[1,2-a]pyridine can be achieved. Compared to traditional preparation methods, tert-butyl hydrazine carbamate is an inexpensive and readily available hydrogenation reagent. Furthermore, 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 imidazo[1,2-a]pyridine derivatives, laying the foundation for the industrial production of imidazo[1,2-a]pyridine derivatives, and providing a new approach for the hydrogenation reduction of nitrogen-containing heterocyclic compounds. Attached Figure Description

[0037] Figure 1 This is a schematic diagram of the proton NMR spectrum of compound I-1 prepared in Example 1.

[0038] Figure 2 This is a schematic diagram of the proton NMR spectrum of compound I-2 prepared in Example 2. Detailed Implementation

[0039] 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.

[0040] The specifications, purity, and manufacturers of the reagents used in this invention are shown in Table 1.

[0041] Table 1

[0042]

[0043]

[0044] The preparation method of compound II includes the following steps:

[0045]

[0046] Sodium bicarbonate (7.837 mmol, 1.56 equivalents) was added to an ethanol solution (30 mL) 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.

[0047] The 2-bromoacetophenone compounds are selected from 2-bromoacetophenone, 2-methyl-α-bromoacetophenone, 2-bromo-4'-methylacetophenone, 2-bromo-4'-fluoroacetophenone, 2-bromo-4'-methoxyacetophenone, and 2-bromo-2-acetylnaphthalene.

[0048] The 2-aminopyridine compounds are selected from 2-aminopyridine, 2-amino-4-methylpyridine, and 2-amino-3-methylpyridine.

[0049] Example 1

[0050]

[0051] The preparation method of compound I-1 includes the following steps: 2-phenylimidazolium[1,2-a]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 12 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-1 as a yellow solid with a yield of 75%. Figure 1 This is a schematic diagram of the proton NMR spectrum of compound I-1 prepared in Example 1. 1H NMR (600MHz, DMSO-d6) δ7.79–7.61(m,2H),7.45(s,1H),7.31(t,J=7.7Hz,2H),7.21–7.11(m,1H),3.95(t,J=5.9Hz ,2H),2.75(t,J=6.3Hz,2H),1.91(pd,J=5.4,2.5Hz,2H),1.85(pd,J=6.2,5.0,2.3Hz,2H).HRMS(ESI-TOF)m / z[M+H] + Calcd forC 13 H 15 N2199.1235, found 199.1238.

[0052] Example 2

[0053]

[0054] The preparation method of compound I-2 includes the following steps: 7-methyl-2-phenylimidazolium[1,2-a]pyridine, i.e., compound II-2 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 12 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-2 as a yellow solid with a yield of 70%. Figure 2 This is a schematic diagram of the proton NMR spectrum of compound I-2 prepared in Example 2. 1 H NMR (600MHz, DMSO-d6) δ7.84–7.67(m,2H),7.45(s,1H),7.31(t,J=7.8Hz,2H),7.19–7.08(m,1H),4.20–3.78(m,2 H),3.02–2.78(m,1H),2.32(dd,J=16.4,10.5Hz,1H),2.12–1.83(m,2H),1.72–1.48(m,1H),1.07(d,J=6.5Hz,3H). 13C NMR(151MHz,Chloroform-d)δ143.32,141.43,134.40,131.24,128.68,126.78,124.93,114.20,113.16,45 .10,29.76,23.04;IR(film)2938,2864,1717,1604,1511,1380,1318,1188,1073,949,909,727,694,507cm -1 ;HRMS(ESI-TOF)calcd for([C 15 H 19 N2] + [M+H] + m / z=213.1392; found 213.1380.

[0055] Example 3

[0056]

[0057] The preparation method of compound I-3 includes the following steps: 8-methyl-2-phenylimidazolium[1,2-a]pyridine, i.e., compound II-3 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 14 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-3 as a yellow solid with a yield of 68%. 1 HNMR(600MHz,DMSO-d6)δ7.74(dd,J=8.1,1.5Hz,2H),7.34(t,J=7.7Hz,2H),7.25–7.15(m,1H),7.01(s,1H),4.11 –3.77(m,2H),3.16–2.93(m,1H),2.13–2.00(m,2H),1.96–1.84(m,1H),1.63–1.49(m,1H),1.45(d,J=6.9Hz,3H). 13C NMR(151MHz,Chloroform-d)δ149.86,140.61,134.69,128.50,126.40,124.87,113.87,45.13,30.26,29.82,21.65,1 9.97; IR(film)3116,3067,2975,2940,1719,1643,1504,1473,1365,1303,1245,1080,1065,919,864,786,724,694cm -1 ;HRMS(ESI-TOF)calcd for([C 14 H 17 N2] + [M+H] + m / z=213.1392; found 213.1380.

[0058] Example 4

[0059]

[0060] The preparation method of compound I-4 includes the following steps: 2-(o-tolyl)imidazolium[1,2-a]pyridine, i.e., compound II-4 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 16 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-4 as a yellow solid with a yield of 65%. 1 HNMR(400MHz,Chloroform-d)δ7.83(dd,J=7.7,1.4Hz,1H),7.33–7.03(m,3H),6.90(s,1H),3.99(t ,J=5.8Hz,2H),2.93(t,J=6.3Hz,2H),2.46(s,3H),2.06–1.86(m,4H); HRMS(ESI-TOF)calcdfor([C 14 H 17 N2] + [M+H] + m / z=213.1385; found 213.1386.

[0061] Example 5

[0062]

[0063] The preparation method of compound I-5 includes the following steps: 2-(p-tolyl)imidazolium[1,2-a]pyridine, i.e., compound II-5 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 16 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-5 as a yellow solid with a yield of 82%. 1 HNMR(400MHz,Chloroform-d)δ7.76–7.48(m,2H),7.15(d,J=7.9Hz,2H),7.02(d,J=1.1Hz,1H),3 .96(t,J=5.8Hz,2H),2.92(t,J=6.1Hz,2H),2.34(s,3H),2.11–1.88(m,4H); HRMS(ESI-TOF)calcd for([C 14 H 17 N2] + [M+H] + m / z=213.1392; found 213.1385.

[0064] Example 6

[0065]

[0066] The preparation method of compound I-6 includes the following steps: 2-(p-fluorophenyl)imidazolium[1,2-a]pyridine, i.e., compound II-6 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n[Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 16 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-6 as a yellow solid with a yield of 70%. 1 HNMR(400MHz,Chloroform-d)δ7.78–7.63(m,2H),7.12–6.96(m,3H),3.97(t,J=5.8Hz,2H),2.92(t,J=6.2Hz,2H),2.14–1.73(m,4H); HRMS(ESI-TOF)calcd for([C 13 H 14 FN2] + [M+H] + m / z=217.1136; found 217.1128.

[0067] Example 7

[0068]

[0069] The preparation method of compound I-7 includes the following steps: 2-(p-methoxyphenyl)imidazolium[1,2-a]pyridine, i.e., compound II-7 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 18 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-7 as a yellow solid with a yield of 64%. 1 H NMR(400MHz,Chloroform-d)δ7.73–7.57(m,2H),6.96(s,1H),6.89(d,J=8.8Hz,2H),3.95(t ,J=5.8Hz,2H),3.81(s,3H),2.91(t,J=6.2Hz,2H),2.03–1.88(m,4H); HRMS(ESI-TOF)calcd for([C 14 H 17 N2O] +[M+H] + m / z=229.1341; found 229.1349.

[0070] Example 8

[0071]

[0072] The preparation method of compound I-8 includes the following steps: 7-methyl-2-(p-tolyl)imidazolium[1,2-a]pyridine, i.e., compound II-8 (0.5 mmol, 1 equivalent), and tert-butyl hydrazinocarbamate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 18 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-8 as a yellow solid with a yield of 68%. 1 H NMR(400MHz,Chloroform-d)δ7.82–7.47(m,2H),7.15(d,J=7.9Hz,2H),7.02(s,1H),4.47–3.72(m,2H),3.3 5–2.90(m,1H),2.61–2.37(m,1H),2.33(s,3H),2.15–1.92(m,2H),1.77–1.57(m,1H),1.14(d,J=6.6Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ145.27,140.87,136.05,131.65,129.21,124.62,113.27,43.99,32.76,30.93,2 8.01,21.21;IR(film)2954,2923,1708,1558,1511,1480,1449,1329,1303,1186,909,824,764,727,646,509cm -1 ;HRMS(ESI-TOF)calcd for([C 15 H 19 N2] + [M+H] + m / z=227.1548; found 227.1538.

[0073] Example 9

[0074]

[0075] The preparation method of compound I-9 includes the following steps: 2-(p-tert-butylphenyl)imidazolium[1,2-a]pyridine, i.e., compound II-9 (0.5 mmol, 1 equivalent), and tert-butyl hydrazine carboxylate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 16 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-9 as a yellow solid with a yield of 60%. 1 H NMR(600MHz,Chloroform-d)δ7.84–7.51(m,2H),7.45–7.32(m,2H),7.02(s,1H),3.97(t, J=5.9Hz,2H),2.93(t,J=6.4Hz,2H),2.02–1.97(m,2H),1.97–1.92(m,2H),1.32(s,9ZH). 13 C NMR(151MHz,Chloroform-d)δ149.50,145.21,140.66,131.68,125.52,124.58,113.59,44.96,34.62,31.50,24.69 ,23.19,21.28;IR(film)3409,3133,2960,2876,1911,1706,1617,1512,1481,1379,1194,949,826,762,670,532cm -1 ;HRMS(ESI-TOF)calcd for([C 17 H 23 N2] + [M+H] + m / z=255.1861; found 255.1851.

[0076] Example 10

[0077]

[0078] The preparation method of compound I-10 includes the following steps: 2-naphthyl-2-imidazolium[1,2-a]pyridine, i.e., compound II-10 (0.5 mmol, 1 equivalent), and tert-butyl hydrazinocarbamate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), are placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate is added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 16 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 / ethyl acetate = 2 / 1) to obtain the target product compound I-10 as a yellow solid with a yield of 64%. 1 H NMR(400MHz,Chloroform-d)δ8.28(s,1H),7.90–7.75(m,4H),7.50–7.36(m,2H) ),7.16(s,1H),3.97(t,J=5.7Hz,2H),2.96(t,J=6.1Hz,2H),2.12–1.73(m,4H). 13 C NMR(101MHz,Chloroform-d)δ145.58,140.37,133.91,132.51,131.67,128.09,128.05,127.63,126.06,125.24,123.65,122.60,114.49, 44.93,24.63,23.03,21.12; IR(film)3052,2947,2186,1712,1628,1518,1424,1374,1318,1196,1071,933,905,858,756,725,641,475cm -1 ;HRMS(ESI-TOF)calcdfor([C 17 H 17 N2] + [M+H] + m / z=249.1392; found 249.1380.

[0079] The reaction conditions for Examples 11 to 29 are shown in Table 2:

[0080] Table 2

[0081]

[0082]

[0083] Examples 11-14

[0084] Electrolyte selection: 2-Phenylidene[1,2-a]pyridine (compound II-1, 0.5 mmol, 1 equivalent) and tert-butyl hydrazinocarbamate (compound III-1, 1.0 mmol, 2.0 equivalent) were placed in a 50 mL three-necked flask. 0.5 mmol of each of the following electrolytes were added: tetrabutylammonium hexafluorophosphate (Example 11), tetrabutylammonium perchlorate (Example 12), tetrabutylammonium bromide (Example 13), and tetrabutylammonium tetrafluoroborate (Example 14). Then, 10 mL of electrolyte was added. Using dimethyl sulfoxide (DMSO) as the solvent, a platinum electrode as the anode and a nickel electrode as the cathode, the reaction was carried out for 12 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 / ethyl acetate = 2 / 1) to obtain a yellow solid target product compound I-1, with corresponding yields of 75% (Example 11), 15% (Example 12), 54% (Example 13), and 72% (Example 14). These results indicate that tetrabutylammonium hexafluorophosphate provides the optimal yield when used as the electrolyte.

[0085] Examples 15-17

[0086] Screening of working electrode materials

[0087] 2-Phenylidene[1,2-a]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and tert-butyl hydrazinocarbamate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate was added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode (Example 15), a nickel electrode (Example 16), and a glassy carbon electrode (Example 17) were used as anodes, and a platinum sheet electrode as cathode. The reaction was carried out for 12 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 / ethyl acetate = 2 / 1) to obtain a yellow solid target product compound I-1, with corresponding yields of 68% (Example 15), 42% (Example 16), and 50% (Example 17), respectively. The results compared with Example 11 show that the yield is optimal when a platinum sheet electrode is used as the anode and a nickel electrode as the cathode material.

[0088] Examples 18-21

[0089] Solvent selection

[0090] 2-Phenylidene[1,2-a]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and tert-butyl hydrazinocarbamate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate was added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and then 10 mL of anhydrous acetonitrile (Example 18), 10 mL of tetrahydrofuran (Example 19), 10 mL of dichloroethane (Example 20), and 10 mL of hexafluoroisopropanol (Example 21) were added as solvents. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 12 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 / ethyl acetate = 2 / 1) to obtain a yellow solid target product compound I-1, with corresponding yields of 48% (Example 18), 18% (Example 19), 15% (Example 20), and 24% (Example 21). The results compared with Example 11 show that dimethyl sulfoxide was used as the solvent for the optimal yield.

[0091] Examples 22-24

[0092] Screening of operating current

[0093] 2-Phenylidene[1,2-a]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and tert-butyl hydrazinocarbamate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate was added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out under direct current of 10 mA (Example 22), 20 mA (Example 23), and 25 mA (Example 24) at 70°C for 12 hours. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / ethyl acetate = 2 / 1) to obtain a yellow solid target product compound I-1, with corresponding yields of 69% (Example 22), 65% (Example 23), and 49% (Example 24). The results compared with Example 11 show that the optimal yield was achieved with a working current of 15 mA.

[0094] Examples 25-27

[0095] Screening of reaction temperature

[0096] 2-Phenylidene[1,2-a]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and tert-butyl hydrazinocarbamate, i.e., compound III-1 (1.0 mmol, 2.0 equivalent), were placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate was added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. A 15 mA DC current was applied, and the reaction was carried out at temperatures of 25°C, 90°C, and 120°C for 12 hours, respectively. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / ethyl acetate = 2 / 1) to obtain a yellow solid target product compound I-1, with corresponding yields of 12% (Example 25), 70% (Example 26), and 56% (Example 27), respectively. The results compared with Example 11 show that the optimal yield was achieved at a reaction temperature of 70°C.

[0097] Examples 28-29

[0098] Screening of raw material molar ratio

[0099] 2-Phenylidene-[1,2-A]pyridine, i.e., compound II-1 (0.5 mmol, 1 equivalent), and different equivalents of tert-butyl hydrazine carboxylate, i.e., compound III-1 (0.5 mmol, 1 equivalent, Example 28) and (1.5 mmol, 3 equivalent, Example 29), were placed in a 50 mL three-necked flask, and the electrolyte tetrabutylammonium hexafluorophosphate was added simultaneously. n [Bu4NPF6], 0.5 mmol, 1 equivalent), and 10 ml of dimethyl sulfoxide (DMSO) were added as solvent. A platinum electrode was used as the anode and a nickel electrode as the cathode. A 15 mA DC current was applied, and the reaction was carried out at 70 °C for 12 hours. After cooling to room temperature, the solvent was evaporated, and the product was purified by dry column chromatography (eluent: dichloromethane / ethyl acetate = 2 / 1) to obtain a yellow solid target product, compound I-1, with yields of 65% (Example 28) and 70% (Example 29). The results compared with Example 11 show that the optimal yield was achieved when 2 equivalents of compound III-1 were used in the reaction.

[0100] Comparative Example 1

[0101] Compound 2p from the literature Org. Lett. 2016, 18, 4250-4253 (DOI: 10.1021 / acs.orglett.6b01999) was used as Comparative Example 1. B2pin2 (152.4 mg, 0.6 mmol) and Pd(OAc)2 (4.5 mg, 0.02 mmol) were added to a Schenk tube fitted with a stir bar, and the tube was backfilled with nitrogen at least three times. Then, 2.0 mL of solvent and 25.8 mg of quinoline (0.2 mmol) were added via syringe. The mixture was stirred at room temperature for approximately 10 h. The mixture was then extracted with ethyl acetate, repeated three times. The combined organic layer was distilled under reduced pressure, and the product was purified by column chromatography using petroleum ether and ethyl acetate as eluents.

[0102] 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 substrates of the imidazopyridine compounds in Comparative Example 1 are limited to only five phenyl-substituted compounds, while the substrates of this invention have a broader scope. In summary, this invention has significant advantages compared to Comparative Example 1.

[0103] 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. A method for the incomplete electrochemical hydrogenation of imidazopyridine compounds, characterized in that, Includes the following steps: ； Compound II, Compound III, and electrolyte were dissolved in a solvent with a molar ratio of 1:(1~5):

1. A nickel electrode was used as the cathode. The reaction was carried out for 12~20 h under the conditions of a DC current of 10~20 mA and a temperature of 50~90℃. After cooling to room temperature, the solvent was removed, and the mixture was purified by column chromatography to obtain imidazopyridine compounds, namely Compound I. In compound II, R1 is selected from hydrogen and C1~C10 alkyl groups; R2 is selected from hydrogen and C1~C10 alkyl groups; R3 is selected from hydrogen and C1~C10 alkyl groups; R4 is selected from hydrogen and C1~C10 alkyl groups; R5 is selected from hydrogen, C1~C10 alkyl, C1~C10 alkoxy, and halogen; R6 is selected from hydrogen, C1~C10 alkyl, C1~C10 alkoxy, and halogen; R7 is selected from hydrogen, C1~C10 alkyl, C1~C10 alkoxy, and halogen; R8 is selected from hydrogen, C1~C10 alkyl, C1~C10 alkoxy, and halogen; R9 is selected from hydrogen, C1~C10 alkyl, C1~C10 alkoxy, and halogen; Alternatively, R6 and R7 can form a six-membered ring with carbon. The electrolyte is selected from tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium bromide, and tetrabutylammonium tetrafluoroborate. The anode is selected from platinum electrode, nickel electrode, and glassy carbon electrode.

2. The electrochemical incomplete hydrogenation method for imidazopyridine compounds according to claim 1, characterized in that, The solvent is selected from dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dichloroethane, and hexafluoroisopropanol.

3. The electrochemical incomplete hydrogenation method for imidazopyridine compounds according to claim 1, characterized in that, In compound II, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and tert-butyl; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and tert-butyl; R3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and tert-butyl; R4 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and tert-butyl. 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; Alternatively, R6 and R7 can combine with carbon to form a phenyl group.

4. The method for the electrochemical incomplete hydrogenation of imidazopyridine compounds according to claim 3, characterized in that, Compound II has one of the following structures: 。 5. The method for the electrochemical incomplete hydrogenation of imidazopyridine compounds according to claim 1, characterized in that, The imidazopyridine compound, namely compound I, is selected from one of the following structures: 。

Images