A method for synthesizing nitrogen-containing heterocyclic aromatic compounds

Abstract

The application discloses a method for synthesizing nitrogen-containing heterocyclic aromatic compounds, which uses an air-stable divalent nickel complex as a catalyst, uses a cheap and easily available benzophenone derivative as a photocatalyst, and uses an organic amine as an added base, so as to realize a C-N bond coupling reaction of a halogenated aromatic hydrocarbon and an N-nucleophile through light-nickel synergistic catalysis. The method is suitable for a series of electron-rich, electron-deficient and large steric (hetero) aryl bromides or chlorides, and various N-nucleophiles, and efficiently realizes N-arylation of heterocyclic aromatic compounds such as carbazole, indole, pyrazole and pyrrole. The application has the advantages of mild reaction conditions, simple operation, good compatibility of substrate functional groups, and can be applied to the late-stage modification of complex active molecules, realizes kilogram-scale amplification and continuous flow production, and provides a new research idea for developing light-nickel synergistic catalytic N-nucleophile arylization.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthesis of nitrogen-containing heterocyclic aromatic compounds, and particularly relates to a method for synthesizing nitrogen-containing heterocyclic aromatic compounds by photocatalysis. BACKGROUND

[0002] Nitrogen-containing heterocyclic aromatic compounds are widely used in the fields of medicine, pesticide and material science. Generally, the arylation of N-heterocyclic aromatic compounds is realized by the construction of C(sp 2 Nucleophilic substitution of electron-deficient halogenated aromatic compounds (J. Org. Chem. 2019, 84, 181-190; Angew. Chem. Int. Ed. 2012, 51, 8012-8016), transition metal palladium-catalyzed Buchwald-Hartwig amination (Chem. Soc. Rev. 2013, 42, 9283-9303; Chem. Rev. 2016, 116, 12564-12649) and copper-catalyzed Ullmann-Ma coupling reaction (Angew. Chem. Int. Ed. 2017, 56, 16136-16179). Due to the π-π conjugated structure of N-heterocyclic aromatic compounds, their special electronic or fluorescent properties have attracted the attention of chemists. Therefore, it is of great significance to develop efficient synthesis of N-heterocyclic aromatic compounds. Nucleophilic substitution of halogenated aromatic compounds is usually limited to electron-deficient halogenated aromatic compounds, and the substrates are limited, and the reaction temperature is high; transition metal palladium-catalyzed Buchwald-Hartwig amination needs to rely on complex and highly toxic phosphine ligands, low-solubility inorganic strong base, which is not economic and green, limiting its large-scale application. In addition, the problem of competitive N- and C-arylation selectivity has also been observed; copper-catalyzed Ullmann-Ma coupling reaction usually needs aryl iodide or bromide as the electrophilic aromatic reagent, and the required temperature is high, and inorganic strong base needs to be used, resulting in poor solubility and functional group compatibility.

[0003] Visible light catalyzed reaction of halogenated aromatic hydrocarbons and N-aryl nucleophiles has only copper and visible light synergistic catalytic C-N coupling reaction, which generally uses noble metal photosensitizer and low solubility inorganic strong base, which limits its large-scale production in industry and wide application in flow chemistry; nickel is abundant in the earth, low in price, and has multiple oxidation states, which is more prone to oxidative addition and exhibits high catalytic activity, so it has attracted widespread attention from scientists. The C-N coupling reaction catalyzed by light and nickel is promoted by single electron transfer or energy transfer pathway, which promotes the reduction elimination process of nickel catalyst. However, this catalytic mode depends on the use of noble metal photosensitizer (iridium, ruthenium, etc.), which is expensive and cannot be mass-produced. Therefore, it is of important research value and practical application prospect to develop a more mild, economical and efficient synthesis of nitrogen-containing heterocyclic aromatic compounds and post-functional group conversion. SUMMARY

[0004] The application provides a method for realizing the amination reaction of (hetero) aryl bromide or (hetero) aryl chloride by using visible light to induce stable divalent nickel complex (Angew. Chem. Int. Ed. 2020, 59, 12714-12719) and adding N-nucleophile, which not only solves the problem of high reaction temperature of copper catalyzed aryl halide, but also avoids the use of complex ligand, noble metal photosensitizer and inorganic base in transition metal catalysis.

[0005] In order to achieve the above purpose, the technical scheme adopted by the application is that the compound of formula I, N-nucleophile Nu-H of formula II, nickel catalyst, photosensitizer and organic base are added into an organic solvent, and irradiated in an argon atmosphere, and after the reaction is completed, the arylated product of the N-nucleophile of formula III is obtained after separation and purification.

[0006]

[0007] In the formula, Ar represents any one of aryl, substituted aryl, heterocyclic aryl, substituted heterocyclic aryl, specifically any one of phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, ester-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl, halogen-substituted phenyl, pyridyl, halogen-substituted pyridyl, C1-C4 alkyl-substituted pyridyl, quinolyl, isoquinolyl, C1-C4 alkyl-substituted quinolyl, pyrimidyl, C1-C4 alkyl-substituted pyrimidyl, C1-C4 alkyl-substituted indazolyl, C1-C4 alkyl-substituted benzothiazolyl, thienyl, C1-C4 alkyl-substituted thienyl, benzothienyl, phenylsulfoxide, etc.; X represents Br or Cl; the N-nucleophile Nu-H is any one of carbazole, C1-C4 alkyl-substituted carbazole, cyano-substituted carbazole, halogen-substituted carbazole, benzocarbazole, indazolyl, halogen-substituted indazolyl, C1-C4 alkyl-substituted indazolyl, indole, C1-C4 alkyl-substituted indole, C1-C4 alkoxy-substituted indole, halogen-substituted indole, 7-azaindole, pyrrole, phenyl-substituted pyrazole, C1-C4 alkyl-substituted pyrazole, 2H-pyrazolo[3,4-c]pyridine, etc., and H in the N-nucleophile Nu-H is H on the nitrogen atom.

[0008] In the above synthesis method, the nickel catalyst is a divalent nickel complex with the following structure, and preferably the amount of the nickel catalyst is 5% to 10% of the molar amount of the compound of formula I.

[0009]

[0010] In the above synthesis method, preferably the amount of the N-nucleophile is 1 to 2 times of the molar amount of the compound of formula I.

[0011] In the above synthesis method, the photosensitizer is any one of 4,4'-bis(N,N-dimethylamino)benzophenone, benzophenone, xanthone, tris(2-phenylpyridine)iridium(III), etc., and preferably the amount of the photosensitizer is 5% to 10% of the molar amount of the compound of formula I.

[0012] In the above synthesis method, the organic base is any one of diisopropylamine, triethylenediamine, triethylamine, etc., and preferably the amount of the organic base is 2 to 3 times of the molar amount of the compound of formula I.

[0013] In the above synthesis method, the organic solvent is any one of toluene, acetonitrile, tetrahydrofuran, etc.

[0014] In the above synthesis method, it is further preferred to react at 65 to 75°C for 12 to 24 hours under irradiation of purple light with a wavelength of 390 to 395 nm in an argon atmosphere.

[0015] The beneficial effects of the present application are as follows:

[0016] The reaction system of the present application is simple, the cheap divalent nickel complex system is used, the N-nucleophile is added, the amination reaction of aryl or heterocyclic aryl halide is realized under light condition, various nitrogen-containing heterocyclic aromatic hydrocarbon compounds are obtained, the reaction has higher economic benefit, the reaction condition is mild, the post-treatment is simple, the operation is convenient, and the use of complex ligand and inorganic base in transition metal catalysis is avoided. The present application is consistent with the current production concept of pursuing economy and environmental protection, and has important application prospect. DETAILED DESCRIPTION

[0017] The present application is further described in detail below in combination with examples, but the protection scope of the present application is not limited to these examples.

[0018] Example 1

[0019] In an argon atmosphere, 43.0 mg (0.2 mmol) of 4-bromobenzoic acid methyl ester, 50.2 mg (0.3 mmol) of carbazole, 9.9 mg (0.02 mmol) of divalent nickel complex, 5.4 mg (0.02 mmol) of 4,4'-bis(N,N-dimethylamino) benzophenone, 60.7 mg (0.6 mmol) of diisopropylamine, 2 mL of toluene and a magnetic stirrer were added into a reaction tube, and the reaction was carried out at 75°C under 390-395 nm purple light for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, saturated sodium chloride aqueous solution was added, and ethyl acetate was diluted and extracted to obtain an organic phase, and the crude product was obtained by reduced pressure distillation. The product was separated by column chromatography with a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 10:1 as an eluent, and a yellow solid with the following structure was obtained, and the yield was 98%.

[0020]

[0021] The nuclear magnetic resonance spectrum data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.6 Hz, 2H), 8.17 (d, J = 7.7 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.47-7.42 (m, 2H), 7.36-7.31 (m, 2H), 4.01 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 166.5, 142.1, 140.4, 131.5, 128.8, 126.5, 126.3, 123.9, 120.7, 120.5, 109.9, 52.4. HRMS (ESI) m / z C 20 H 15 N NaO2 [M + Na] + Theoretical value: 324.0995, measured value: 324.1002.

[0022] In this example, equal molar of benzophenone was used to replace 4,4'-bis(N,N- dimethylamino)benzophenone, and equal molar of acetonitrile was used to replace toluene, and the yield of the yellow solid was 82%.

[0023] In this example, equal molar of xanthone was used to replace 4,4'-bis(N,N- dimethylamino)benzophenone, and the yield of the yellow solid was 94%.

[0024] In this example, equal molar of tris(2-phenylpyridine)iridium(III) was used to replace 4,4'-bis(N,N-dimethylamino)benzophenone, and the yield of the yellow solid was 83%.

[0025] Example 2

[0026] In this example, equal molar of 4-bromoanisole was used to replace methyl 4- bromobenzoate in Example 1, and other steps were the same as Example 1, and the white solid with the following structure was obtained with a yield of 97%.

[0027]

[0028] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.19 (d, J = 7.7 Hz, 2H), 7.51-7.47 (m, 2H), 7.47-7.41 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.35-7.29 (m, 2H), 7.16-7.11 (m, 2H), 3.94 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 159.0, 141.5, 130.4, 128.7, 126.0, 123.2, 120.4, 119.8, 115.2, 109.8, 55.7. HRMS (APCI) m / z C 19 H 16 NO[M+H] + : Theoretical value 274.1226, found value 274.1230.

[0029] Example 3

[0030] In this example, equal molar of p-bromotrifluoromethylbenzene was used to replace methyl 4-bromobenzoate in Example 1, and other steps were the same as Example 1, and the yellow solid product with the following structure was obtained with a yield of 98%.

[0031]

[0032] The nuclear magnetic resonance data of the obtained product were as follows: 1H NMR (400 MHz, CDCI3) δ 8.18 (d, J = 7.7 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.49 - 7.42 (m, 4H), 7.32 - 7.38 (m, 2H). 13 C NMR (100 MHz, CDCI3) δ 141.2, 140.4, 129.3 (q, J = 32.6 Hz), 127.2 (q, J = 3.7 Hz), 127.2, 126.4, 124.1 (d, J = 270.4 Hz), 123.9, 120.7, 120.6, 109.7. 19 F NMR (376 MHz, CDCI3) δ -62.30. HRMS (ESI) m / z C 19 H 13 F3N [M + H] + : Theoretical 312.0995, Found 312.1003.

[0033] Example 4

[0034] In this example, equimolar of m-bromofluorobenzene was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain yellow solid product with the following structure, and the yield was 71%.

[0035]

[0036] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDCI3) δ 8.18 (d, J = 7.7 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.49 - 7.42 (m, 4H), 7.32 - 7.38 (m, 2H). 13 C NMR (100 MHz, CDCI3) δ 163.6 (d, J = 246.6 Hz), 140.6, 139.4 (d, J = 9.9 Hz), 131.2 (d, J = 9.2 Hz), 126.2, 123.7, 122.8 (d, J = 3.2 Hz), 120.5, 120.4, 114.6 (d, J = 7.1 Hz), 114.4 (d, J = 8.8 Hz), 109.8. 19 F NMR (376 MHz, CDCI3) δ -110.45. HRMS (ESI) m / z C 18 H 13 FN [M + H] + : Theoretical 262.1027, Found 262.1036.

[0037] Example 5

[0038] In this example, equimolar 3,5-dimethoxybromobenzene was used to replace bromobenzene in Example 1, and other steps were the same as Example 1, to obtain a yellowish solid product with the following structure, and the yield was 89%.

[0039]

[0040] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.17 (d, J = 7.7 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 6.77 (s, 2H), 6.61 (s, 1H), 3.87 (s, 6H). 13 C NMR (100 MHz, CDC13) δ 161.8, 140.9, 139.5, 126.1, 123.5, 120.4, 120.0, 110.2, 105.4, 99.9, 55.7. HRMS (ESI) m / z C 20 H 18 NO2[M+H] + : Theoretical value 304.1332, found 304.1336.

[0041] Example 6

[0042] In this example, equimolar 2-bromobenzo[9,10]phenanthrene was used to replace bromobenzene in Example 1, and other steps were the same as Example 1, to obtain a yellow solid product with the following structure, and the yield was 97%.

[0043]

[0044] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.17 (d, J = 7.7 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 6.77 (s, 2H), 6.61 (s, 1H), 3.87 (s, 6H). 13C NMR (100 MHz, CDC13) δ 141.2, 136.8, 131.4, 130.3, 130.0, 129.5, 129.3, 129.0, 128.0, 127.7, 127.7, 127.6, 126.3, 126.1, 125.3, 123.7, 123.6, 123.6, 121.8, 120.6, 120.3, 110.0. HRMS (ESI) m / z C 30 H 19 NNa[M+Na] + : Theoretical value 416.1410, found 416.1413.

[0045] Example 7

[0046] In this example, equimolar 4-bromo-l,2-methylenedioxybenzene was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain yellow oily product with the following structure, and the yield was 95%.

[0047]

[0048] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.15 (d, J = 7.7 Hz, 2H), 7.47-7.36 (m, 4H), 7.30 (t, J = 7.3 Hz, 2H), 7.02 (s, 3H), 6.11 (s, 2H). 13 C NMR (100 MHz, CDC13) δ 148.8, 147.1, 141.4, 131.5, 126.0, 123.3, 121.0, 120.4, 119.9, 109.9, 109.0, 108.6, 102.0. HRMS (ESI) m / z C 19 H 14 NO2[M+H] + : Theoretical value 288.1019, found 288.1028.

[0049] Example 8

[0050] In this example, equimolar 2-bromo-5-fluoropyridine was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain white solid product with the following structure, and the yield was 83%.

[0051]

[0052] The nuclear magnetic resonance data of the product obtained are as follows: 1H NMR (400 MHz, CDCI3) δ 8.59 (d, J = 2.3 Hz, 1 H), 8.15 (d, J = 7.7 Hz, 2 H), 7.76 (d, J = 8.3 Hz, 2 H), 7.67 - 7.58 (m, 2 H), 7.50 - 7.44 (m, 2 H), 7.35 (t, J = 7.4 Hz, 2 H). 13 C NMR (100 MHz, CDCI3) δ 157.6 (d, J = 253.5 Hz), 147.9 (d, J = 2.8 Hz), 139.7, 137.6 (d, J = 25.0 Hz), 126.4, 125.7 (d, J = 19.8 Hz), 124.3, 121.1, 120.4, 120.1 (d, J = 4.7 Hz), 110.9. 19 F NMR (376 MHz, CDCI3) δ -129.7. HRMS (ESI) m / z C 17 H 11 F N2Na [M + Na] + : Theoretical 285.0798, Found 285.0811.

[0053] Example 9

[0054] In this example, 7-bromoquinoline was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain yellow oily product with the structure as shown below, and the yield was 91%.

[0055]

[0056] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 8.59 (d, J = 2.3 Hz, 1 H), 8.15 (d, J = 7.7 Hz, 2 H), 7.76 (d, J = 8.3 Hz, 2 H), 7.67 - 7.58 (m, 2 H), 7.50 - 7.44 (m, 2 H), 7.35 (t, J = 7.4 Hz, 2 H). 13 C NMR (100 MHz, CDCI3) δ 151.5, 149.1, 140.7, 138.8, 136.1, 129.6, 127.3, 126.5, 126.3, 125.9, 123.9, 121.6, 120.5, 120.5, 109.9. HRMS (ESI) m / z C 21 H 15 N2[M + H] +: Calc. 260.1182, Found 260.1186.

[0057] Example 10

[0058] In this example, equimolar 2-methyl-5-bromopyrimidine was used to replace methyl 4-bromobenzoate in Example 1, and other steps were the same as Example 1, to obtain yellow solid product with the following structural formula, and the yield was 74%.

[0059]

[0060] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.91 (s, 2H), 8.15 (dd, J = 6.7, 1.7 Hz, 2H), 7.48-7.42 (m, 2H), 7.34 (t, J = 7.1 Hz, 4H), 2.91 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 167.1, 155.5, 140.6, 130.8, 126.6, 124.0, 121.1, 120.8, 109.1, 26.0. HRMS (ESI) m / z C 17 H 14 N3[M+H] + : Calc. 260.1182, Found 260.1186.

[0061] Example 11

[0062] In this example, equimolar 6-bromo-2-methyl-2H-indazole was used to replace methyl 4-bromobenzoate in Example 1, and other steps were the same as Example 1, to obtain brown oily product with the following structural formula, and the yield was 95%.

[0063]

[0064] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.91 (s, 2H), 8.15 (dd, J = 6.7, 1.7 Hz, 2H), 7.48-7.42 (m, 2H), 7.34 (t, J = 7.1 Hz, 4H), 2.91 (s, 3H). 13C NMR (100 MHz, CDC13) δ 149.3, 141.2, 135.5, 126.0, 124.2, 123.4, 121.7, 121.7, 121.3, 120.3, 119.9, 115.3, 110.1, 40.6. HRMS (ESI) m / z C 20 H 16 N3[M+H] + : Theoretical 298.1339, Found 298.1352.

[0065] Example 12

[0066] In this example, equimolar of bromo citronellol derivative was used to replace methyl 4-bromobenzoate in Example 1, and other procedures were the same as Example 1 to give the product as colorless oil with the structure shown below, and the yield was 85%.

[0067]

[0068] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.34 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 7.7 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.50-7.44 (m, 2H), 7.39-7.33 (m, 2H), 5.25-5.18 (m, 1H), 4.55-4.47 (m, 2H), 2.19-2.06 (m, 2H), 1.99-1.90 (m, 1H), 1.78 (s, 4H), 1.71 (s, 3H), 1.58-1.48 (m, 1H), 1.41-1.31 (m, 1H), 1.09 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 166.0, 142.0, 140.3, 131.4, 131.4, 129.1, 126.4, 126.2, 124.7, 123.9, 120.6, 120.5, 109.8, 63.8, 37.1, 35.6, 29.7, 25.8, 25.5, 19.6, 17.8. HRMS (ESI) m / z C 29 H 32 NO2[M+H] + : Theoretical 426.2428, Found 426.2430.

[0069] Example 13

[0070] In this example, equimolar 1,3-dibromopyridine was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain the pale yellow solid product with the following structural formula, and the yield was 85%.

[0071]

[0072] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.19 (dd, J = 7.6, 2.9 Hz, 4H), 8.08 (dd, J = 8.2, 3.8 Hz, 5H), 7.64 (d, J = 7.9 Hz, 2H), 7.51-7.44 (m, 4H), 7.42-7.34 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 151.7, 140.5, 139.6, 126.5, 124.7, 121.4, 120.3, 115.0, 112.1. HRMS (ESI) m / z C 29 H 19 N3Na[M + Na] + : Theoretical value 432.1471, found value 432.1465.

[0073] Example 14

[0074] In this example, equimolar 4-chlorophenyl methyl sulfone was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain the pale yellow solid product with the following structural formula, and the yield was 97%.

[0075]

[0076] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.19 (dd, J = 7.6, 2.9 Hz, 4H), 8.08 (dd, J = 8.2, 3.8 Hz, 5H), 7.64 (d, J = 7.9 Hz, 2H), 7.51-7.44 (m, 4H), 7.42-7.34 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 143.0, 140.1, 138.7, 129.4, 127.2, 126.5, 124.1, 121.1, 120.6, 109.6, 44.6. HRMS (ESI) m / z C 19 H 15 NNaO2S[M + Na] + : Theoretical value 344.0716, found value 344.0714.

[0077] Example 15

[0078] In this example, equal molar of 4-chloro-2-methylpyridine was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain yellow solid product with the following structural formula, with a yield of 96%.

[0079]

[0080] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.72 (d, J = 5.4 Hz, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.47 - 7.41 (m, 3H), 7.37 (dd, J = 5.4, 1.7 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 2.70 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 160.8, 151.0, 145.9, 139.6, 126.4, 124.2, 121.0, 120.6, 120.0, 117.9, 109.9, 24.8. HRMS (ESI) m / z C 18 H 15 N2[M+H] + : Theoretical value 259.1230, found 259.1228.

[0081] Example 16

[0082] In this example, equal molar of 4-chloro-2-methylpyrimidine was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other steps were the same as Example 1, to obtain yellow solid product with the following structural formula, with a yield of 65%.

[0083]

[0084] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.72 (d, J = 5.4 Hz, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.47 - 7.41 (m, 3H), 7.37 (dd, J = 5.4, 1.7 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 2.70 (s, 3H). 13C NMR (100 MHz, CDC13) δ 168.5, 159.1, 157.6, 139.4, 126.6, 125.9, 122.2, 119.6, 116.4, 115.7, 24.4. HRMS (ESI) m / z C 17 H 13 N3Na [M + Na] + : Found 282.1005.

[0085] Example 17

[0086] In this example, equal molar of 6-chloroisoquinoline was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other procedures were the same as Example 1 to give the product as a yellow solid with the structure shown below, in 96% yield.

[0087]

[0088] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 9.37 (s, 1H), 8.62 (d, J = 5.8 Hz, 1H), 8.18 (d, J = 7.7 Hz, 3H), 8.01 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 5.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H). 13 CNMR (100 MHz, CDC13) δ 152.3, 143.8, 140.5, 139.6, 136.8, 129.9, 127.3, 126.6, 126.3, 123.9, 123.3, 120.7, 120.6, 120.4, 109.7. HRMS (ESI) m / z C 21 H 14 N2Na [M + Na] + : Found 317.1045.

[0089] Example 18

[0090] In this example, equal molar of clofibrate was used to replace 4-bromobenzoic acid methyl ester in Example 1, and other procedures were the same as Example 1 to give the product as a yellow oil with the structure shown below, in 51% yield.

[0091]

[0092] The NMR data of the product obtained are as follows: 1H NMR (400 MHz, CDC13) δ 8.14 (d, J = 7.7 Hz, 2H), 7.41 (t, J = 8.5 Hz, 4H), 7.34 (d, J = 8.1 Hz, 2H), 7.31 - 7.25 (m, 2H), 7.07 (d, J = 8.7 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.71 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 174.2, 154.9, 141.3, 131.7, 128.2, 126.0, 123.3, 120.4, 120.3, 119.9, 109.8, 79.7, 61.7, 25.6, 14.3. HRMS (ESI) m / z C 24 H 23 NNaO3[M + Na] + : Theoretical value 396.1570, found 396.1566.

[0093] Example 19

[0094] In this example, equimolar of bromobenzene was used to replace 4-bromobenzoic acid methyl ester in Example 1, equimolar of 3,6-di-tert-butylcarbazole was used to replace carbazole in Example 1, and other steps were the same as Example 1, to obtain white solid product with the following structure, and the yield was 92%.

[0095]

[0096] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.14 (d, J = 7.7 Hz, 2H), 7.41 (t, J = 8.5 Hz, 4H), 7.34 (d, J = 8.1 Hz, 2H), 7.31 - 7.25 (m, 2H), 7.07 (d, J = 8.7 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.71 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 174.2, 154.9, 141.3, 131.7, 128.2, 126.0, 123.3, 120.4, 120.3, 119.9, 109.8, 79.7, 61.7, 25.6, 14.3. HRMS (ESI) m / z C 26 H 30 N[M + H] + : Theoretical value 356.2373, found 356.2371.

[0097] Example 20

[0098] In this example, equal molar of 9H-carbazole-3-carbonitrile was used to replace carbazole in Example 1, and other procedures were the same as Example 1, to obtain the white solid product with the following structural formula, and the yield was 85%.

[0099]

[0100] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.42 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 8.9 Hz, 3H), 7.54-7.48 (m, 1H), 7.44 (dd, J = 8.3, 3.0 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 4.00 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 166.2, 142.1, 141.2, 140.7, 131.7, 129.9, 129.5, 127.8, 126.7, 125.4, 124.0, 122.6, 121.9, 120.9, 120.2, 110.6, 110.4, 103.5, 52.6. HRMS (ESI) m / z C 21 H 14 N2NaO2[M + Na] + : Theoretical value 349.0947, found 349.0951.

[0101] Example 21

[0102] In this example, equal molar of bromobenzene was used to replace methyl 4-bromobenzoate in Example 1, and equal molar of 3-chlorocarbazole was used to replace carbazole in Example 1, and other procedures were the same as Example 1, to obtain the yellow oil product with the following structural formula, and the yield was 55%.

[0103]

[0104] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.42 (s, 1H), 8.31 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 8.9 Hz, 3H), 7.54-7.48 (m, 1H), 7.44 (dd, J = 8.3, 3.0 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 4.00 (s, 3H). 13C NMR (100 MHz, CDC13) δ 141.6, 141.4, 137.3, 131.9, 130.2, 128.0, 127.2, 126.4, 122.9, 122.1, 121.3, 120.5, 120.5, 120.4, 110.1, 110.0. HRMS (ESI) m / z C 18 H 13 Cl N[M+H] + : Theoretical 278.0731, Found 278.0739.

[0105] Example 22

[0106] In this example, equimolar 7H-benzo[c]carbazole was used to replace carbazole in Example 1, and other steps were the same as Example 1, to obtain yellow solid product with the following structure, and the yield was 90%.

[0107]

[0108] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.88 (d, J = 8.3 Hz, 1H), 8.71-8.65 (m, 1H), 8.36-8.30 (m, 2H), 8.02 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.79-7.74 (m, 1H), 7.72-7.66 (m, 2H), 7.59 (d, J = 8.9 Hz, 1H), 7.58-7.46 (m, 4H), 4.03 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 166.4, 141.7, 139.7, 138.1, 131.5, 129.9, 129.8, 129.3, 129.3, 127.7, 127.3, 127.2, 124.8, 124.4, 123.5, 123.5, 122.3, 121.3, 116.2, 111.5, 110.3, 52.5. HRMS (ESI) m / z C 24 H 17 NNaO2[M+Na] + : Theoretical 374.1151, Found 374.1159.

[0109] Example 23

[0110] In this example, equimolar bromobenzene was used to replace methyl 4-bromobenzoate in Example 1, and equimolar 5-methoxyindole was used to replace carbazole in Example 1, and other steps were the same as Example 1, to obtain yellow oil product with the following structure, and the yield was 89%.

[0111]

[0112] The NMR spectral data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 7.54-7.48 (m, 5H), 7.40-7.34 (m, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 9.0, 2.5 Hz, 1H), 6.64 (d, J = 3.2 Hz, 1H), 3.90 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 154.7, 140.1, 131.2, 130.0, 129.7, 128.5, 126.4, 124.1, 112.6, 111.5, 103.4, 102.9, 56.0. HRMS (ESI) m / z C 15 H 13 N NaO [M + Na] + : Theoretical value 246.0889, found 246.0896.

[0113] Example 24

[0114] In this example, equimolar 2-bromobenzonitrile is used to replace methyl 4-bromobenzoate in Example 1, equimolar indole is used to replace carbazole in Example 1, and other steps are the same as those in Example 1, to obtain a yellow solid product with the following structural formula, and the yield is 81%.

[0115]

[0116] The NMR spectral data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 7.54-7.48 (m, 5H), 7.40-7.34 (m, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 9.0, 2.5 Hz, 1H), 6.64 (d, J = 3.2 Hz, 1H), 3.90 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 154.7, 140.1, 131.2, 130.0, 129.7, 128.5, 126.4, 124.1, 112.6, 111.5, 103.4, 102.9, 56.0. HRMS (ESI) m / z C 15 H 10 N2Na [M + Na] +: Calcd 241.0736, Found 241.0738.

[0117] Example 25

[0118] In this example, equal molar 7-fluoroindole was used to replace carbazole in Example 1, and other steps were the same as Example 1, to obtain the white solid product with the following structural formula, and the yield was 95%.

[0119]

[0120] The nuclear magnetic resonance data of the product obtained are as follows: 1 H NMR (400 MHz, CDC13) δ 8.16 (d, J = 8.6 Hz, 2H), 7.55-7.49 (m, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 3.3 Hz, 1H), 7.15-7.07 (m, 1H), 6.97 (dd, J = 12.6, 7.9 Hz, 1H), 6.75 (dd, J = 3.1, 2.4 Hz, 1H), 3.97 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 166.5, 149.9 (d, J = 245.5 Hz), 144.0 (d, J = 1.5 Hz), 133.7 (d, J = 4.4 Hz), 130.5, 130.0, 128.3, 124.9 (d, J = 3.7 Hz), 123.4 (d, J = 9.2 Hz), 121.2 (d, J = 6.7 Hz), 117.1 (d, J = 3.6 Hz), 108.9 (d, J = 18.6 Hz), 105.4 (d, J = 1.8 Hz), 52.3. 19 F NMR (376 MHz, CDC13) δ -124.93. HRMS (ESI) m / z C 16 H 12 FNNaO2[M + Na] + : Calcd 241.0736, Found 241.0738.

[0121] Example 26

[0122] In this example, equal molar indazole was used to replace methyl 4-bromobenzoate in Example 1, and other steps were the same as Example 1, to obtain the yellow solid product with the following structural formula, and the yield was 78%.

[0123]

[0124] The nuclear magnetic resonance data of the product obtained are as follows: 1H NMR (400MHz, CDCl3) δ8.23(d,J=5.1Hz,2H),8.20(s,1H),7.86(d,J=8.4Hz,2H),7.8 1(dd,J=8.0,4.0Hz,2H),7.47(t,J=7.7Hz,1H),7.26(t,J=7.5Hz,1H),3.95(s,3H). 13 C NMR (100MHz, CDCl3) δ166.5,144.1,138.8,136.7,131.2,127.8,127.8,126.0,122.2,121.7,121.5,110.7,52.3.HRMS(ESI)m / z C 15 H 12 N₂NaO₂[M+Na] + Theoretical value: 275.0791, measured value: 275.0799.

[0125] Example 27

[0126] In this embodiment, equimolar 3-chloro-indazole was used to replace carbazole in Example 1, and the other steps were the same as in Example 1, resulting in a white solid product with the following structural formula, with a yield of 80%.

[0127]

[0128] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.18(d,J=8.7Hz,2H),7.76(dd,J=19.4,9.5Hz,4H),7.50(t,J=7.8Hz,1H),7.33-7.27(m,1H),3.94(s,3H). 13 C NMR (100MHz, CDCl3) δ166.4,143.3,139.8,137.5,131.2,129.0,128.0,123.1,122.9,121.3,120.4,111.0,52.4.HRMS(ESI)m / z C 15 H 12 ClN2O2[M+H] + Theoretical value: 287.0582, measured value: 287.0591.

[0129] Example 28

[0130] In this embodiment, equimolar 2H-indazole was used to replace carbazole in Example 1, and the other steps were the same as in Example 1, resulting in a yellow solid product with the following structural formula, with a yield of 82%.

[0131]

[0132] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 8.22 (d, J = 4.7 Hz, 2H), 8.19 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.81 (dd, J = 8.2, 3.9 Hz, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 3.95 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 166.5, 144.1, 138.7, 136.6, 131.2, 127.8, 127.7, 126.0, 122.2, 121.7, 121.5, 110.7, 52.3. HRMS (ESI) m / z C 15 H 12 N2NaO2[M + Na] + : Theoretical value 275.0791, found 275.0798.

[0133] Example 29

[0134] In this example, equimolar pyrrole is used to replace carbazole in Example 1, and other steps are the same as those in Example 1, to obtain white solid product with the following structural formula, and the yield is 75%.

[0135]

[0136] The NMR data of the product obtained are as follows: 1 H NMR (400 MHz, CDCI3) δ 8.22 (d, J = 4.7 Hz, 2H), 8.19 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.81 (dd, J = 8.2, 3.9 Hz, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 3.95 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 166.5, 144.1, 138.7, 136.6, 131.2, 127.8, 127.7, 126.0, 122.2, 121.7, 121.5, 110.7, 52.3. HRMS (ESI) m / z C 12 H 11 NNaO2[M + Na] + : Theoretical value 275.0791, found 275.0798.

[0137] Example 30

[0138] In this example, equimolar 3-phenylpyrazole was used to replace carbazole in Example 1, and other steps were the same as those in Example 1, to obtain yellow solid product with the following structural formula, and the yield was 45%.

[0139]

[0140] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 8.14 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 166.5, 153.8, 143.4, 132.8, 131.3, 128.8, 128.5, 128.2, 127.7, 126.1, 118.1, 106.1, 52.3. HRMS (ESI) m / z C 17 H 14 N2NaO2[M+Na] + : Theoretical value 301.0947, measured value 301.0952.

[0141] Example 31

[0142] In this example, equimolar 2H-pyrazolo[3,4-c]pyridine was used to replace carbazole in Example 1, and other steps were the same as those in Example 1, to obtain yellow solid product with the following structural formula, and the yield was 40%.

[0143]

[0144] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDC13) δ 9.34 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.29 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 8.7 Hz, 2H), 7.71 (dd, J = 5.5, 1.0 Hz, 1H), 3.96 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 166.3, 143.2, 140.6, 135.8, 134.9, 131.5, 129.9, 128.7, 121.6, 115.2, 52.5. HRMS (ESI) m / z C 14 H11 N3NaO2[M + Na] + : Calcd. 276.0743, Found 276.0746.

[0145] Example 32

[0146] In this example, 2-bromo-5-trifluoromethylpyridine was used instead of 4-bromobenzoic acid methyl ester in Example 1, 7-azaindole was used instead of carbazole in Example 1, and other steps were the same as in Example 1 to obtain the product as a white solid in a yield of 48%.

[0147]

[0148] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDC13) δ 9.24 (d, J = 8.8 Hz, 1H), 8.72 (s, 1H), 8.44-8.39 (m, 2H), 8.05 (dd, J = 8.8, 2.3 Hz, 1H), 7.95 (dd, J = 7.8, 1.2 Hz, 1H), 7.20 (dd, J = 7.8, 4.8 Hz, 1H), 6.67 (d, J = 3.9 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 153.2, 148.0, 145.6 (q, J = 4.2 Hz), 143.5, 135.7 (q, J = 3.2 Hz), 129.4, 126.3, 123.9, 123.9 (d, J = 270 Hz), 122.2 (d, J = 161.0 Hz), 118.0, 114.8, 104.0. 19 F NMR (376 MHz, CDC13) δ -61.89. HRMS (ESI) m / z C 13 H8F3N3Na [M + Na] + : Calcd. 286.0563, Found 286.0571.

Claims

1. A method of synthesizing a nitrogen-containing heterocyclic arene compound, characterized by: The compound of formula I is reacted with N-nucleophile Nu-H, a nickel catalyst, a photosensitizer, an organic base in an organic solvent under argon atmosphere under the irradiation of purple light with wavelength of 390-395 nm at 65-75 ℃ for 12-24 hours, and after the reaction is completed, the arylated product of N-nucleophile of formula III is obtained through separation and purification; In the formula, Ar represents any one of phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, cyano-substituted phenyl, trifluoromethyl-substituted phenyl, halogenated phenyl, pyridyl, halogenated pyridyl, C1-C4 alkyl-substituted pyridyl, quinolyl, isoquinolyl, C1-C4 alkyl-substituted quinolyl; X represents Br or Cl; the N-nucleophile Nu-H is any one of carbazole, C1-C4 alkyl-substituted carbazole, cyano-substituted carbazole, halogenated carbazole, benzocarbazole, indazolyl, halogenated indazolyl, C1-C4 alkyl-substituted indazolyl, indolyl, C1-C4 alkyl-substituted indolyl, C1-C4 alkoxy-substituted indolyl, halogenated indolyl, 7-azaindolyl, pyrrole, and H in Nu-H is H on the nitrogen atom; The nickel catalyst is a divalent nickel complex with the following structure: The photosensitizer is any one of 4,4'-bis(N,N-dimethylamino)benzophenone, benzophenone, xanthone, tris(2-phenylpyridine)iridium(III); The organic base is any one of diisopropylamine, triethylenediamine, and triethylamine; The amount of the nickel catalyst is 5%-10% of the molar amount of the compound of formula I; The amount of the photosensitizer is 5%-10% of the molar amount of the compound of formula I.

2. The method of synthesizing nitrogen-containing heterocyclic arene-based compounds according to claim 1, characterized by: The amount of the N-nucleophile is 1-2 times of the molar amount of the compound of formula I.

3. The method of synthesizing nitrogen-containing heterocyclic arene-based compounds according to claim 1, characterized by: The amount of the organic base is 2-3 times of the molar amount of the compound of formula I.

4. The method of synthesizing nitrogen-containing heterocyclic arene-based compounds according to claim 1, characterized by: The organic solvent is any one of toluene, acetonitrile, and tetrahydrofuran.

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