A method of synthesizing a carbazole derivative

Abstract

The application discloses a method for synthesizing a carbazole derivative, which does not need transition metal catalysis, directly realizes intramolecular C-C bond coupling reaction by reaction of a photoinduced diarylamine with a Grignard reagent or n-butyl lithium, and obtains the carbazole derivative. The reaction system is simple, the operation is simple, the reaction condition is mild, and the yield is good; the traditional noble metal catalyst is avoided; and the method provides a new method for green and efficient synthesis of the carbazole derivative without transition metal catalysis for medicines, pesticides and organic materials.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthesis of carbazole derivatives, and particularly relates to a method for synthesizing carbazole derivatives by photoinduction from diarylamine as raw material. BACKGROUND

[0002] Carbazole is a common structural skeleton in natural products, medicines, pesticides and organic new materials. Therefore, in the past few decades, various strategies for synthesizing carbazole skeleton have been developed. At present, the synthesis of carbazole derivatives mainly relies on transition metal-catalyzed intramolecular and intermolecular coupling reactions. (1) Synthesis of carbazole by transition metal catalysis, such as: transition metal-catalyzed Buchwald-Hartwig amination reaction of 2-amino-2'-halogenated biphenyl or 2-aminobiphenyl (Bioorg. Med. Chem. Lett., 2007, 17, 1043-1046; J. Am. Chem. Soc., 2008, 130, 48, 16184-16186; J. Am. Chem. Soc., 2011, 133, 5996-6005); transition metal-catalyzed insertion reaction of azido intermediate of 2-azido biphenyl (Tetrahedron, 2007, 63, 10320-10329; J. Org. Chem., 2009, 74, 3225-3228). (2) Synthesis of carbazole compounds by transition metal catalysis, such as: the group of Ckermann reported the tandem reaction of palladium-catalyzed C-H bond activation and Buchwald-Hartwig amination (Angew. Chem., Int. Ed., 2007, 46, 1627-1629); the group of Jean reported the tandem reaction of palladium-catalyzed Suzuki cross-coupling and S N Ar reaction (Org. Lett., 2007, 9, 4893-4896); Fagnou et al. reported the coupling of intramolecular C-C bond of diarylamine to construct carbazole skeleton by palladium catalysis (J. Am. Chem. Soc., 2006, 128, 581-590; J. Org. Chem. 2008, 73, 5022-5028).

[0003] While these methods have achieved some progress, they require the preparation of complex starting materials (such as 2-amino or azidobiphenyl), and the preparation of complex functionalized biphenyls typically requires transition metal-catalyzed coupling reactions. Furthermore, these reactions or the preparation of their starting materials require transition metal catalysis, and the residues of transition metals can have toxic effects on drug activity and material properties. Transition metal-free organic synthesis reactions have long been a focus of attention in the pharmaceutical and chemical industries. Therefore, developing transition metal-free catalysis to synthesize high-value-added carbazole derivatives from commercially available or readily available starting materials via direct intramolecular C-C bond coupling is of significant research importance. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing carbazole derivatives under light irradiation via the reaction of diarylamines with a strong base without the need for a transition metal catalyst. This method avoids the problem of residual transition metals in the product by eliminating the use of transition metal catalysts.

[0005] To achieve the above objectives, the technical solution adopted in this invention is as follows: a diarylamine of formula I or I′ and a strong base are added sequentially to an organic solvent, and intramolecular C-C bonds are coupled under argon protection by light irradiation. After the reaction is complete, the reaction is quenched, separated, and purified to obtain a carbazole derivative of formula II or II′.

[0006]

[0007] In the formula, R 1 R 2 Each can be independently represented by any one of H, C1-C4 alkyl, C1-C4 alkoxy, phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, or hydroxyl.

[0008] In the above synthesis method, the strong base is any one of methyl magnesium chloride, isopropyl magnesium chloride, n-butyl magnesium chloride, tert-butyl magnesium chloride, phenyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium bromide, n-butyl magnesium chloride, tert-butyl magnesium chloride, phenyl magnesium bromide, n-butyllithium, sodium hydride, potassium tert-butoxide, and sodium tert-butoxide. Preferably, the amount of strong base used is 1.0 to 2.0 times the molar amount of the diarylamine.

[0009] In the above synthesis method, the preferred organic solvent is tetrahydrofuran, or a mixture of tetrahydrofuran and any one of 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether, toluene, or 1,4-dioxane.

[0010] In the above synthesis method, it is preferred to react at 60-80°C for 5-12 hours under an argon atmosphere and irradiated with near-violet light with a wavelength of 365-420 nm.

[0011] The beneficial effects of this invention are as follows:

[0012] The reaction system of the present application is simple, and the intramolecular C-C bond of a diarylamine is coupled to form a carbazole derivative under the action of a strong base without a transition metal catalyst through irradiation. The method is used to realize one-step synthesis of the carbazole alkaloid Glycozoline from simple raw materials, and further derivatization of Glycozoline to prepare Glycozolinol; meanwhile, a carbazole compound with a naphthalene ring and a large conjugated structure is also prepared. Since the method avoids the use of a transition metal, the reaction provides a simple and efficient new idea for synthesis of N-H carbazole in the fields of medicine, pesticide, and organic material. In addition, the method has the characteristics of high efficiency and economy, and has important application potential. DETAILED DESCRIPTION

[0013] 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.

[0014] Example 1

[0015] Under an argon atmosphere, 84.6 mg (0.5 mmol) of diphenylamine was added to a dry Schlenk tube equipped with a magnet, and then vacuumed and filled with argon for 3 times, then 1.5 mL of tetrahydrofuran was added, then 0.5 mL of 2.0 mol / L (1.0 mmol) phenylmagnesium chloride tetrahydrofuran solution was slowly added to the reaction tube under ice water bath conditions, then two 9W wavelength 390-395 nm LED lamps were used for irradiation, and the reaction was refluxed at 70°C for 5h. After the reaction was cooled to room temperature, the reaction was quenched with saturated NH4Cl aqueous solution, extracted with ethyl acetate (3 times x 15.0 mL), the obtained organic phase was washed with saturated NaCl solution, and the organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product; the crude product was separated and purified by column chromatography (eluent was a mixture of petroleum ether, dichloromethane and ethyl acetate in a volume ratio of 20:2:1), to obtain a white solid carbazole with the following structure, and the yield was 75%.

[0016]

[0017] The nuclear magnetic resonance spectrum data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.25 (br s, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.15 (t, J = 7.6 Hz, 2H); 13CNMR (100 MHz, DMSO-d6) δ 139.9, 125.7, 122.5, 120.3, 118.7, 111.1. The NMR data of this compound is consistent with the reported literature (Green Chem., 2018, 20, 1362-1366).

[0018] In this example, equal molar of isopropyl magnesium chloride was used to replace phenyl magnesium chloride, and the white solid product was obtained with a yield of 70%.

[0019] In this example, equal molar of sodium tert-butoxide was used to replace phenyl magnesium chloride, and the white solid product was obtained with a yield of 30%.

[0020] In this example, equal molar of n-butyllithium was used to replace phenyl magnesium chloride, and the white solid product was obtained with a yield of 80%.

[0021] Example 2

[0022] In this example, equal molar of 4-methyl-N-phenyl aniline was used to replace diphenylamine in Example 1, and other steps were the same as Example 1, and the white solid product with the following structure was obtained with a yield of 80%.

[0023]

[0024] The NMR data of the obtained product is as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.09 (br s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.23 - 7.17 (m, 1H), 7.15 - 7.08 (m, 1H), 2.46 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 140.1, 138.1, 127.3, 127.0, 125.5, 122.7, 122.4, 120.2, 120.0, 118.4, 111.0, 110.8, 21.2. The NMR data of this compound is consistent with the reported literature (Green Chem., 2018, 20, 1362-1366).

[0025] Example 3

[0026] In this example, equal molar of 4-methoxydiphenylamine was used to replace diphenylamine in Example 1, and other steps were the same as Example 1, and the white solid product with the following structure was obtained with a yield of 76%.

[0027]

[0028] The NMR data of the product obtained is as follows: 1 H NMR (400 MHz, CDC13) δ 8.04 (d, J = 7.8 Hz, 1H), 7.90 (br s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.25 - 7.15 (m, 1H), 7.08 (dd, J = 8.8, 2.4 Hz, 1H), 3.94 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 154.1, 140.4, 134.5, 125.9, 123.9, 123.5, 120.4, 119.2, 115.2, 111.4, 110.9, 103.4, 56.2. The NMR data of this compound is consistent with the reported literature (J. Org. Chem. 2009, 74, 3225-3228).

[0029] Example 4

[0030] In this example, equimolar N-phenyl-4-biphenylamine is used to replace diphenylamine in Example 1, and other steps are the same as those in Example 1, to obtain a white solid with the following structural formula, and the yield is 56%.

[0031]

[0032] The NMR data of the product obtained is as follows: 1 H NMR (400 MHz, DMSO-d6) δ 11.33 (br s, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.71 (dd, J = 8.4, 1.8 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.54 - 7.45 (m, 3H), 7.43 - 7.38 (m, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 141.3, 140.2, 139.3, 131.0, 128.8, 126.7, 126.3, 125.7, 124.6, 123.1, 122.6, 120.4, 118.6, 118.3, 111.3, 111.1. The NMR data of this compound is consistent with the reported literature (J. Org. Chem., 2009, 74, 3225-3228).

[0033] Example 5

[0034] In this example, equimolar N-phenyl-2-naphthylamine was used to replace diphenylamine in Example 1, the reaction time was extended to 12 hours, and other steps were the same as Example 1, to obtain a white solid with the following structural formula, and the yield was 63%.

[0035]

[0036] The nuclear magnetic resonance data of the obtained product is as follows: 1 H NMR (400 MHz, CDC13) δ 8.80 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.36 (br s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.66 - 7.35 (m, 5H); 13 C NMR (100 MHz, CDC13) δ 138.6, 137.2, 130.1, 129.3, 127.6, 127.0, 124.5, 124.1, 123.4, 123.2, 122.2, 120.4, 115.6, 112.7, 111.3. The nuclear magnetic resonance data of this compound is consistent with the known literature report (Org. Biomol. Chem., 2016, 14, 122-130).

[0037] Example 6

[0038] In this example, equimolar 4,4'-dimethyldiphenylamine was used to replace diphenylamine in Example 1, and other steps were the same as Example 1, to obtain a white solid with the following structural formula, and the yield was 78%.

[0039]

[0040] The nuclear magnetic resonance data of the obtained product is as follows: 1 H NMR (400 MHz, CDC13) δ 7.84 (s, 3H), 7.30 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 2.52 (s, 6H); 13 C NMR (100 MHz, CDC13) δ 138.2, 128.6, 127.1, 123.6, 120.3, 110.4, 21.6. The nuclear magnetic resonance data of this compound is consistent with the known literature report (Angew. Chem. Int. Ed., 2014, 53, 3505-3509).

[0041] Example 7

[0042] In this example, equimolar N-(4-methoxyphenyl)-4-methylaniline was used to replace diphenylamine in Example 1, and other steps were the same as Example 1, to obtain white solid carbazole alkaloid Glycozoline with the following structural formula, and the yield was 70%.

[0043]

[0044] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (br s, 1H), 7.87 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.98 (dd, J = 8.8, 2.2 Hz, 1H), 3.83 (s, 3H), 2.45 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 152.8, 138.7, 134.8, 126.7, 126.5, 122.6, 122.5, 119.9, 114.5, 111.5, 110.7, 102.9, 55.6, 21.1. The nuclear magnetic data of the compound were consistent with the known literature report (J. Org. Chem., 2018, 83, 7347-7359).

[0045] Example 8

[0046] In this example, equimolar 4,4'-dimethoxydiphenylamine was used to replace diphenylamine in Example 1, and other steps were the same as Example 1, to obtain white solid product with the following structural formula, and the yield was 85%.

[0047]

[0048] The nuclear magnetic resonance data of the obtained product were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.75 (br s, 1H), 7.49 (d, J = 2.0 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 8.6, 2.4 Hz, 2H), 3.91 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 153.8, 135.4, 123.8, 115.4, 111.7, 103.1, 56.2. The nuclear magnetic data of the compound were consistent with the known literature report (J. Org. Chem., 2018, 83, 7347-7359).

[0049] Example 9

[0050] In this example, equimolar 2,2-dinaphthylamine was used to replace diphenylamine in Example 1, the reaction time was extended to 12 hours, and other steps were the same as Example 1. A white solid product with the following structure was obtained, and the yield was 60%.

[0051]

[0052] The nuclear magnetic resonance data of the obtained product are as follows: 1 H NMR (400 MHz, CDC13) δ 9.28 (d, J = 8.4 Hz, 2H), 8.38 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.75 (t, J = 7.6 Hz, 2H), 7.59 (t, J = 7.4 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H); 13 C NMR (100 MHz, CDC13) δ 136.2, 130.1, 129.3, 129.3, 126.9, 125.6, 125.3, 123.4, 117.7, 112.7. The nuclear magnetic resonance data of this compound are consistent with the known literature report (Chem. Commun., 2019, 55, 13749-13752).

[0053] The carbazole alkaloid Glycozoline synthesized in the above Example 7 can be further derivatized to prepare Glycozolinol, and the specific method is as follows:

[0054] 105.6 mg (0.5 mmol) of Glycozoline was dissolved in 5.0 mL of DCM, cooled to -78°C, and then 1.0 mL of 1 mol / L (1 mmol) boron tribromide solution in dichloromethane was added. The reaction mixture was heated to room temperature and stirred at room temperature for 4 hours. Then cooled with methanol, the mixture was transferred to a separation funnel with ethyl acetate, washed with saturated NaCl aqueous solution several times, extracted with ethyl acetate, and then the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography with petroleum ether: acetone eluent (volume ratio 3:1) to obtain white solid product Glycozolinol with the following structure, and the yield was 85%.

[0055]

[0056] The nuclear magnetic resonance data of the obtained product are as follows: 1H NMR (400 MHz, DMSO-d6) δ 10.72 (br s, 1H), 8.89 (br s, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 7.32 - 7.21 (m, 2H), 7.13 (d, J = 8.2 Hz, 1H), 6.92 - 6.82 (m, 1H), 2.43 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 150.2, 138.7, 134.1, 126.5, 126.2, 122.9, 122.4, 119.8, 114.8, 111.2, 110.5, 104.7, 21.0. This data is consistent with the known literature report (Chem. Commun., 2021, 57, 5274-5277).

Claims

1. A method for synthesizing carbazole derivatives, characterized in that: The diaryl amine and strong base shown in Formula I or I′ are added sequentially to an organic solvent, and intramolecular C-bond coupling is carried out by irradiation with near-violet light with a wavelength of 365–420 nm under argon protection. After the reaction is complete, the reaction is quenched, separated and purified to obtain the carbazole derivative shown in Formula II or II′. In the formula, R 1 R 2 Each can be independently represented by any one of H, C1-C4 alkyl, C1-C4 alkoxy, phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, or hydroxyl. The strong base is any one of methyl magnesium chloride, isopropyl magnesium chloride, n-butyl magnesium chloride, tert-butyl magnesium chloride, phenyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium bromide, n-butyl magnesium chloride, tert-butyl magnesium chloride, phenyl magnesium bromide, n-butyllithium, sodium hydride, potassium tert-butoxide, and sodium tert-butoxide.

2. The method for synthesizing carbazole derivatives according to claim 1, characterized in that: The amount of the strong base used is 1.0 to 2.0 times the molar amount of the diarylamine.

3. The method for synthesizing carbazole derivatives according to claim 1, characterized in that: The organic solvent is tetrahydrofuran, or a mixture of tetrahydrofuran with any one of 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether, toluene, or 1,4-dioxane.

4. The method for synthesizing carbazole derivatives according to claim 1, characterized in that: Under argon protection, the reaction is carried out at 60–80 °C for 5–12 hours under near-violet light with a wavelength of 365–420 nm.

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