A process for the synthesis of C-4 alkyl pyridines from alcohols as alkylating agents

Abstract

The application discloses a method for synthesizing C-4 alkyl pyridine by using alcohol as an alkylating agent, which uses cheap and abundant alcohol compounds as an alkyl source and commercially available 4-chloropyridine hydrochloride as a reaction raw material, uses organic amine as a base, uses an economical and green organic photosensitizer, and realizes one-step deoxygenation and arylization under the catalysis of a photo-oxidation-reduction catalytic nickel metal to realize the synthesis of C-4 alkyl pyridine. The method provides abundant primary / secondary / tertiary alkyl sources through alcohol compounds, and synthesizes C-4 alkyl pyridine with high chemical selectivity, overcomes the problem of being limited by alkyl sources, and does not produce by-products accompanied by reactions at other sites of pyridine, has mild conditions, is easy to scale up, and has good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthesis of C-4 alkyl pyridines, and particularly relates to a method for synthesizing C-4 alkyl pyridines by photo-oxidation and reduction of nickel catalysis, starting from alcohol as an alkylating agent and commercially available 4-chloropyridine hydrochloride. BACKGROUND

[0002] C-4 alkyl pyridines, as indispensable key intermediates in organic synthesis, are widely used in medicine, pesticides, perfumes and fine chemicals and other fields. Although traditional methods for preparing C-4 alkyl pyridines such as cross-coupling, Minisci reaction and C-H bond functionalization have been widely studied, these technologies usually face challenges such as complicated reaction steps, high cost, multiple reaction sites and insufficient selectivity. In order to overcome these limitations, researchers have been striving to explore new synthesis strategies, especially through unfunctionalized starting materials to achieve selective alkylation at the C-4 position, thereby avoiding competition at the C-2 position. The key to this strategy is to block the C-2 site by introducing a transient or covalently linked group on the pyridine nitrogen atom to ensure preferential reaction at the C-4 position. Although some progress has been made, such as the use of Ni / Lewis acid synergistic catalysis to achieve alkylation at the C-4 position by Nakao's group, this method is limited to olefins as alkyl sources and requires harsh reaction conditions, which must be carried out in a glove box, increasing the complexity and cost of operation (J. Am. Chem. Soc. 2010, 132, 13666-13668). Fier's group at Merck and Hong's group have also developed different synthesis strategies, but these methods are limited to specific carbon nucleophiles or involve complex protection group synthesis in multiple steps, making the overall reaction complex and time-consuming (J. Am. Chem. Soc. 2017, 139, 9499-9502, Nat. Commun. 2019, 10, 4117). Recently, Baran's team successfully achieved precise Minisi-type decarboxylation alkylation at the C-4 position of pyridine under acid-free conditions using maleate derivatives as pyridine blocking groups. Although this method shows some innovation, it still requires the pre-preparation of pyridine with blocking groups, increasing the complexity of synthesis steps (J. Am. Chem. Soc. 2021, 143, 11927-11933). Therefore, it is particularly important to develop a method for synthesizing C-4 alkyl pyridines using inexpensive and readily available basic chemicals without the need for pre-prepared pyridine as a starting material. This method not only has the advantages of green and sustainable, but also helps to effectively expand the library of C-4 alkyl pyridines, providing new raw material sources and process routes for research in the fields of medicine, pesticides and others. Through this strategy, we hope to reduce the cost of synthesis while improving the selectivity and efficiency of the reaction, promoting the development of organic synthesis chemistry. SUMMARY

[0003] The present application aims to provide a method for synthesizing C-4 alkyl pyridine with alcohol compound and C-4 alkyl pyridine hydrochloride as starting materials, without special equipment requirements, mild conditions, simple operation and economic process.

[0004] To achieve the above-mentioned purpose, the technical solution adopted by the present application is: adding alcohol compound of formula I, N-heterocyclic carbene reagent and pyridine as shown in formula II into organic solvent A, stirring at room temperature for 10-20 minutes under argon atmosphere, filtering the obtained reaction mixture, adding 4-chloropyridine hydrochloride, nickel catalyst, bipyridine, photosensitizer and base as shown in formula III into organic solvent B, irradiating under violet light in argon atmosphere, separating and purifying to obtain C-4 alkyl pyridine as shown in formula IV.

[0005]

[0006] In the formula, R represents any one of primary, secondary and tertiary alkyl.

[0007] The above-mentioned nickel catalyst is selected from any one of nickel chloride dimethoxyethane and nickel bromide dimethoxyethane.

[0008] The above-mentioned bipyridine is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine and 4,4'-dimethoxy-2,2'-bipyridine.

[0009] The above-mentioned photosensitizer is selected from any one of dibenzoylnaphthalene and benzophenone.

[0010] The above-mentioned base is selected from any one of diisopropylamine, N,N-diisopropyl ethylamine and triethylamine.

[0011] The above-mentioned organic solvent A is selected from any one of cyclopentyl methyl ether, methyl tert-butyl ether and diethyl ether.

[0012] The above-mentioned organic solvent B is selected from any one of N,N-dimethylformamide and N,N-dimethylacetamide.

[0013] Further, in the above-mentioned method, preferably, the amount of alcohol compound is 1.1-2.2 times the molar amount of 4-chloropyridine hydrochloride.

[0014] Further, in the above-mentioned method, preferably, the amount of N-heterocyclic carbene reagent is 1.2-2.0 times the molar amount of 4-chloropyridine hydrochloride.

[0015] Further, in the above method, preferably the amount of the pyridine is 1.2-2.0 times the molar amount of the 4-chloropyridine hydrochloride.

[0016] Further, in the above method, preferably the amount of the nickel catalyst is 4%-15% of the molar amount of the 4-chloropyridine hydrochloride.

[0017] Further, in the above method, preferably the amount of the bipyridine is 4%-15% of the molar amount of the 4-chloropyridine hydrochloride.

[0018] Further, in the above method, preferably the amount of the photosensitizer is 4%-15% of the molar amount of the 4-chloropyridine hydrochloride.

[0019] Further, in the above method, preferably the amount of the base is 3.0-5.0 times the molar amount of the 4-chloropyridine hydrochloride.

[0020] Further, in the above method, preferably the reaction is carried out under argon atmosphere, under irradiation of purple light with a wavelength of 390-395 nm for 5-8 hours.

[0021] The beneficial effects of the present application are as follows:

[0022] The present application uses natural and abundant alcohol compounds as alkylating agents to provide abundant primary / secondary / tertiary alkyl sources, and commercial, inexpensive and stable 4-chloropyridine hydrochloride to achieve alcohol deoxygenation arylation reaction under light conditions "one pot two steps", to obtain various types of C-4 alkylpyridines. The reaction is simple in operation, mild in conditions, economical and efficient, and not only does not need to prepare pyridine with an introduced blocking group, but also develops a method for synthesizing C-4 alkylpyridine by using alcohol compounds instead of other organic molecules as reaction raw materials. The method of the present application can synthesize C-4 alkylpyridine with high chemical selectivity, overcomes the problem of limited alkyl source, and does not produce by-products of reaction at other sites of pyridine, is mild in conditions, easy to scale up, and has good application prospect. DETAILED DESCRIPTION

[0023] The present application will be further described in detail below in combination with examples, but the protection scope of the present application is not limited to these examples.

[0024] Example 1

[0025] In an argon atmosphere, 41.7 mg (0.4 mmol) of isopinocamphenol, 142.3 mg (0.36 mmol) of N-heterocyclic carbene reagent, 28.5 mg (0.36 mmol) of pyridine and 4 mL of cyclopentyl methyl ether were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer, and stirred for 15 minutes at room temperature. Thereafter, the resulting suspension was filtered under an argon atmosphere, and the filtrate was charged into a 10 mL reaction tube equipped with a magnetic stirrer, and 4.4 mg (0.02 mmol) of nickel chloride dimethoxyethane, 5.4 mg (0.02 mmol) of 4,4'-di-tert-butyl-2,2'-bipyridine, 5.2 mg (0.02 mmol) of dibenzoyl naphthalene, 30.0 mg (0.2 mmol) of 4-chloropyridine hydrochloride, 70.8 mg (0.7 mmol) of diisopropylamine, 1 mL of N,N-dimethylformamide were sequentially added, and reacted for 6 hours under ultraviolet light irradiation at 390 to 395 nm. After completion of the reaction, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate, and concentrated. The resulting product was separated by column chromatography using eluent of petroleum ether and acetone in a volume ratio of 3:1, to obtain a white solid having the following structural formula, with a yield of 75%.

[0026]

[0027] The nuclear magnetic resonance data of the resulting product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.45 (d, J = 5.2, 2H), 7.12 (d, J = 5.3, 2H), 2.76-2.65 (m, 2H), 2.19-1.97 (m, 1H), 1.80-1.73 (m, 2H), 1.29 (s, 6H); 13 CNMR (100 MHz, CDC13) δ 152.1, 149.6, 124.0, 70.6, 44.5, 30.2, 29.5; HRMS (APCI) m / z C 10 H 16 NO + [M+H] + : Theoretical value 166.1226, measured value 166.1237.

[0028] Example 2

[0029] In this example, equimolar 1,4-cyclohexanedimethanol was used to replace isopinocamphenol in Example 1, and other steps were the same as those in Example 1, to obtain a colorless oily product having the following structural formula, with a yield of 63%.

[0030]

[0031] The nuclear magnetic resonance data of the resulting product were as follows: 1H NMR (400 MHz, CDC13) δ 8.45 (d, J = 5.2, 2H), 7.11-7.01 (m, 2H), 3.49 (dd, J = 53.2, 6.6, 2H), 2.52 (dd, J = 31.7, 7.3, 2H), 2.04 (br, IH), 1.86-1.61 (m, 4H), 1.57-1.50 (m, IH), 1.47-1.41 (m, IH), 1.37-1.26 (m, IH), 1.05-0.84 (m, 3H); 13 CNMR (100 MHz, CDC13) δ 8.45 (d, J = 5.2, 2H), 7.11-7.01 (m, 2H), 3.49 (dd, J = 53.2, 6.6, 2H), 2.52 (dd, J = 31.7, 7.3, 2H), 2.04 (br, IH), 1.86-1.61 (m, 4H), 1.57-1.50 (m, IH), 1.47-1.41 (m, IH), 1.37-1.26 (m, IH), 1.05-0.84 (m, 3H); HRMS (APCI) m / z C 13 H 20 NO + [M+H] + : Theoretical value 206.1539, found value 206.1539.

[0032] Example 3

[0033] In this example, equimolar adamantane methanol was used to replace isopentyl alcohol in Example 1, and other steps were the same as in Example 1, to obtain a white solid with the following structure, and the yield was 66%.

[0034]

[0035] The nuclear magnetic resonance data of the obtained product are as follows: 1 H NMR (400 MHz, CDC13) δ 8.45 (d, J = 5.2, 2H), 7.11-7.01 (m, 2H), 3.49 (dd, J = 53.2, 6.6, 2H), 2.52 (dd, J = 31.7, 7.3, 2H), 2.04 (br, IH), 1.86-1.61 (m, 4H), 1.57-1.50 (m, IH), 1.47-1.41 (m, IH), 1.37-1.26 (m, IH), 1.05-0.84 (m, 3H); 13 CNMR (100 MHz, CDC13) δ 8.45 (d, J = 5.2, 2H), 7.11-7.01 (m, 2H), 3.49 (dd, J = 53.2, 6.6, 2H), 2.52 (dd, J = 31.7, 7.3, 2H), 2.04 (br, IH), 1.86-1.61 (m, 4H), 1.57-1.50 (m, IH), 1.47-1.41 (m, IH), 1.37-1.26 (m, IH), 1.05-0.84 (m, 3H); HRMS (APCI) m / z C 16 H 22 N + [M+H] +Calcd 214.1590, Found 214.1599.

[0036] Example 4

[0037] In this example, equimolar 2-adamantanemethanol was used to replace isopentyl alcohol in Example 1, and other steps were the same as in Example 1, to obtain white solid with the following structure, and the yield was 90%.

[0038]

[0039] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.51 (d, J = 5.3, 2H), 7.24 (d, J = 5.3, 2H), 2.95 (s, 1H), 2.45 (d, J = 4.0, 2H), 2.00 (d, J = 12.3, 3H), 1.91 (d, J = 12.4, 2H), 1.82-1.68 (m, 5H), 1.57 (d, J = 12.7, 2H); 13 C NMR (100 MHz, CDC13) δ 153.7, 149.8, 122.5, 46.5, 38.9, 37.7, 32.0, 30.6, 27.9, 27.7; HRMS (APCI) m / z C 15 H 20 N + [M+H] + Calcd 214.1590, Found 214.1599.

[0040] Example 5

[0041] In this example, equimolar 3-hydroxybutyric acid methyl ester was used to replace isopentyl alcohol in Example 1, and other steps were the same as in Example 1, to obtain white solid with the following structure, and the yield was 73%.

[0042]

[0043] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.50 (d, J = 5.1, 2H), 7.16-7.10 (m, 2H), 3.61 (s, 3H), 3.32-3.20 (m, 1H), 2.66-2.51 (m, 2H), 1.28 (d, J = 7.0, 3H); 13 C NMR (100 MHz, CDC13) δ 172.2, 154.6, 150.1, 122.3, 51.8, 41.7, 35.9, 21.3; HRMS (APCI) m / z C 10 H14 NO2 + [M+H] + : Theoretical value 180.1019, found 180.1017.

[0044] Example 6

[0045] In this example, isopentyl glycol in Example 1 was replaced with equimolar N-BOC-3-hydroxypiperidine, and other steps were the same as Example 1 to obtain yellow oil with the following structure, and the yield was 83%.

[0046]

[0047] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.53 (d, J = 4.8, 2H), 7.21-7.09 (m, 2H), 4.12 (s, 2H), 2.81-2.74 (m, 2H), 2.68 (d, J = 11.0, 1H), 2.02 (d, J = 11.4, 1H), 1.76-1.72 (m, 1H), 1.68-1.56 (m, 2H), 1.47 (s, 9H); 13 C NMR (100 MHz, CDC13) δ 154.7, 152.1, 149.9, 122.5, 79.7, 49.3, 44.2, 41.7, 31.0, 28.4, 25.0; HRMS (APCI) m / z C 15 H 22 N2NaO2 + [M+Na] + : Theoretical value 285.1573, found 285.1571.

[0048] Example 7

[0049] In this example, isopentyl glycol in Example 1 was replaced with equimolar cyclododecanol, and other steps were the same as Example 1 to obtain white solid with the following structure, and the yield was 55%.

[0050]

[0051] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.53 (d, J = 4.8, 2H), 7.21-7.09 (m, 2H), 4.12 (s, 2H), 2.81-2.74 (m, 2H), 2.68 (d, J = 11.0, 1H), 2.02 (d, J = 11.4, 1H), 1.76-1.72 (m, 1H), 1.68-1.56 (m, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDC13) δ 156.7, 149.7, 123.4, 39.6, 30.9, 24.0, 23.9, 23.6, 23.4, 22.6; HRMS (APCI) m / z C 17 H 28 N + [M+H] + : Calcd. 246.2216, Found 246.2212.

[0052] Example 8

[0053] In this example, equal molar of 2-indanol was used to replace isopentyl alcohol in Example 1, and other procedures were the same as Example 1, to obtain white solid with the following structure, with a yield of 89%.

[0054]

[0055] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.45 (d, J = 5.1, 2H), 7.10 (d, J = 5.2, 2H), 2.73-2.65 (m, 1H), 2.44-2.30 (m, 2H), 1.83-1.73 (m, 1H), 1.67-1.50 (m, 3H), 1.49-1.40 (m, 1H), 1.40-1.31 (m, 1H), 1.28 (d, J = 8.9, 1H), 1.25-1.17 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 156.5, 149.7, 122.6, 46.8, 42.4, 38.6, 36.9, 36.3, 30.5, 28.9; HRMS (APCI) m / z C 12 H 26 N + [M+H] + : Calcd. 174.1277, Found 174.1273.

[0056] Example 9

[0057] In this example, equal molar of 2-indanol was used to replace isopentyl alcohol in Example 1, and other procedures were the same as Example 1, to obtain white solid with the following structure, with a yield of 89%.

[0058]

[0059] The NMR data of the product obtained are as follows: 1H NMR (400 MHz, CDC13) δ 8.52 (d, J = 4.9, 2H), 7.28 (dd, J = 5.4, 3.4, 2H), 7.25 - 7.17 (m, 4H), 3.74 - 3.61 (m, 1H), 3.40 (dd, J = 15.6, 8.3, 2H), 3.09 (dd, J = 15.6, 8.2, 2H); 13 C NMR (100 MHz, CDC13) δ 154.6, 149.8, 142.2, 126.8, 124.5, 122.5, 44.5, 40.2; HRMS (APCI) m / z C 14 H 14 N + [M+H] + : Calcd. 196.1121, Found 196.1125.

[0060] Example 10

[0061] In this example, isopentyl alcohol was replaced by equimolar 3-hydroxytetrahydrofuran in Example 1, and other steps were the same as Example 1, to obtain colorless oil with the structure as follows, and the yield was 85%.

[0062]

[0063] The nuclear magnetic resonance data of the product obtained were as follows: 1 H NMR (400 MHz, CDC13) δ 8.65 - 8.44 (m, 2H), 7.18 (d, J = 5.0, 2H), 4.18 - 4.02 (m, 2H), 3.91 (q, J = 7.8, 1H), 3.76 (dd, J = 8.7, 6.5, 1H), 3.43 - 3.33 (m, 1H), 2.46 - 2.34 (m, 1H), 2.01 - 1.94 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 152.4, 150.1, 122.8, 74.1, 68.5, 44.4, 34.2; HRMS (APCI) m / z C9H 12 NO + [M+H] + : Calcd. 150.0913, Found 150.0910.

[0064] Example 11

[0065] In this example, isopentyl alcohol was replaced by equimolar Boc-L-phenylglycinol in Example 1, and other steps were the same as Example 1, to obtain white solid with the structure as follows, and the yield was 60%.

[0066]

[0067] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 8.44 (d, J = 5.0, 2H), 7.34-7.24 (m, 3H), 7.19 (dd, J = 6.8, 2.0, 2H), 6.99 (d, J = 5.4, 2H), 5.05 (d, J = 8.0, 1H), 5.02-4.83 (m, 1H), 3.20-2.98 (m, 2H), 1.38 (s, 9H); 13 C NMR (100 MHz, CDCI3) δ 155.1, 149.7, 146.8, 141.2, 128.8, 127.8, 126.6, 124.8, 79.9, 55.5, 42.7, 28.4; HRMS (ESI-TOF) m / z C 18 H 22 N2NaO2 + [M+Na] + : Theoretical value 321.1573, found 321.1582.

[0068] Example 12

[0069] In this example, isopentyldiol in Example 1 is replaced with equimolar of androstenone, and other steps are the same as Example 1, to obtain white solid with the following structure, and the yield is 85%.

[0070]

[0071] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 8.44 (d, J = 5.0, 2H), 7.34-7.24 (m, 3H), 7.19 (dd, J = 6.8, 2.0, 2H), 6.99 (d, J = 5.4, 2H), 5.05 (d, J = 8.0, 1H), 5.02-4.83 (m, 1H), 3.20-2.98 (m, 2H), 1.38 (s, 9H); 13CNMR (100 MHz, CDC13) δ 221.5, 156.2, 149.8, 122.4, 54.7, 51.5, 47.9, 46.8, 44.0, 38.6, 36.0, 36.0, 35.6, 35.2, 31.6, 31.0, 29.0, 28.5, 21.9, 20.4, 13.9, 12.5; HRMS (ESI-TOF) m / z C 24 H 33 NNaO + [M+Na] + : Theoretical value 374.2454, found 374.2466.

[0072] Example 13

[0073] In this example, equimolar adamantanol was used to replace isopentyl alcohol in Example 1, and other steps were the same as Example 1, to obtain a white solid with the following structure, and the yield was 42%.

[0074]

[0075] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.54 (q, J = 5.1 Hz, 2H), 7.29 (q, J = 4.5, 3.8 Hz, 2H), 2.15 (q, J = 3.3 Hz, 3H), 1.96-1.89 (m, 6H), 1.81 (p, J = 12.2 Hz, 7H); 13 C NMR (100 MHz, CDC13) δ 160.1, 149.8, 120.5, 42.5, 36.7, 36.4, 28.8; HRMS (APCI) m / z C 15 H 20 N + [M+H] + : Theoretical value 214.1590, found 214.1592.

[0076] Example 14

[0077] In this example, equimolar 3-hydroxy-3-methylazetidine-1-carboxylic acid tert-butyl ester was used to replace isopentyl alcohol in Example 1, and other steps were the same as Example 1, to obtain a white solid with the following structure, and the yield was 50%.

[0078]

[0079] The nuclear magnetic resonance data of the product obtained are as follows: 1H NMR (400 MHz, CDCI3) δ 8.55 (d, J = 4.5 Hz, 2H), 7.13 (d, J = 4.7 Hz, 2H), 4.12 (d, J = 8.4 Hz, 2H), 3.91 (d, J = 8.2 Hz, 2H), 1.60 (s, 3H), 1.42 (s, 9H); 13 C NMR (100 MHz, CDCI3) δ 156.5, 155.5, 150.1, 120.6, 79.9, 61.2, 37.5, 28.4, 28.0; HRMS (ESI-TOF) m / z C 14 H 20 N2NaO2 + [M+Na] + : Calcd. 271.1417, Found 271.1416.

[0080] Example 15

[0081] In this example, 3-methyloxetane-3-ol was used to replace isopentyl alcohol in Example 1, and other steps were the same as Example 1, to obtain colorless oil with the following structure, and the yield was 50%.

[0082]

[0083] The nuclear magnetic resonance data of the product obtained were as follows: 1 H NMR (400 MHz, CDCI3) δ 8.55 (d, J = 4.5 Hz, 2H), 7.13 (d, J = 4.7 Hz, 2H), 4.12 (d, J = 8.4 Hz, 2H), 3.91 (d, J = 8.2 Hz, 2H), 1.60 (s, 3H), 1.42 (s, 9H); 13 C NMR (100 MHz, CDCI3) δ 156.5, 155.5, 150.1, 120.6, 79.9, 61.2, 37.5, 28.4, 28.0; HRMS (ESI-TOF) m / z C 12 NO + [M+H] + : Calcd. 271.1417, Found 271.1416.

Claims

1. A method for synthesizing C-4 alkylpyridine using alcohol as an alkylating agent, characterized in that: An alcohol compound of formula I, an N-heterocarbene reagent as shown in formula II, and pyridine are added to an organic solvent A, and the mixture is stirred at room temperature for 10 to 20 minutes under argon. The resulting reactant is filtered, and the filtrate, 4-chloropyridine hydrochloride as shown in formula III, a nickel catalyst, bipyridine, a photosensitizer, and a base are added to an organic solvent B. The mixture is irradiated with ultraviolet light under an argon atmosphere, and the reaction is completed, followed by separation and purification to obtain a C-4 alkylpyridine as shown in formula IV. In the formula, R represents any one of primary, secondary, and tertiary alkyl groups; The nickel catalyst is selected from any one of nickel chloride dimethoxyethane and nickel bromide dimethoxyethane; The bipyridine is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 4,4'-dimethoxy-2,2'-bipyridine; The photosensitizer is selected from any one of dibenzoylnaphthalene and benzophenone; The base is selected from any one of diisopropylamine, N,N-diisopropylethylamine and triethylamine; The organic solvent A is selected from any one of cyclopentyl methyl ether, methyl tert-butyl ether, and diethyl ether; The organic solvent B is selected from any one of N,N-dimethylformamide and N,N-dimethylacetamide.

2. The method for synthesizing C-4 alkylpyridine by using alcohol as an alkylating agent according to claim 1, characterized in that: The amount of the alcohol compound used is 1.1 to 2.2 times the molar amount of 4-chloropyridine hydrochloride.

3. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: The amount of the N-heterocarbene reagent used is 1.2 to 2.0 times the molar amount of 4-chloropyridine hydrochloride.

4. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: The amount of pyridine used is 1.2 to 2.0 times the molar amount of 4-chloropyridine hydrochloride.

5. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: The amount of the nickel catalyst used is 4% to 15% of the molar amount of 4-chloropyridine hydrochloride.

6. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: The amount of bipyridine used is 4% to 15% of the molar amount of 4-chloropyridine hydrochloride.

7. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: The amount of the photosensitizer used is 4% to 15% of the molar amount of 4-chloropyridine hydrochloride.

8. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: The amount of the base used is 3.0 to 5.0 times the molar amount of 4-chloropyridine hydrochloride.

9. The method for synthesizing C-4 alkylpyridine by using alcohol as alkylating agent according to claim 1, characterized in that: In an argon atmosphere, the reaction is carried out under irradiation with violet light having a wavelength of 390 to 395 nm for 5 to 8 hours.

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