Multi-component'one-pot 'method for synthesizing carbazole derivative by taking water as reaction solvent

Abstract

The invention discloses a preparation method for simply and efficiently synthesizing a carbazole derivative by taking water as a reaction solvent and multiple components through a one-pot method, which is characterized in that a substituted N-pyrimidinyl aniline derivative (1), a 1, 3-diketone derivative (2), iodobenzene diacetic acid and sodium hydroxide are taken as initial raw materials, and rhodium is used for catalyzing carbon-hydrogen bond activation and cyclization reaction by taking water as a reaction solvent. The molar ratio of the N-pyrimidinyl aniline derivative (1) to the 1, 3-diketone derivative (2) to the iodobenzene diacetic acid to the sodium hydroxide is 1: (1-2): (1-2): (1-2); the reaction solvent is water. The catalyst used in the synthetic route can be recycled and reused, so that waste of a noble metal catalyst is avoided; meanwhile, the method has the characteristics of simple route operation, efficient reaction, high functional group universality and the like.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing a carbazole derivative. Background Art

[0002] Carbazole and its derivatives are important skeleton units of some natural products and synthetic compounds. The most representative of them are tetrahydrocarbazole derivatives. Due to their special structural properties, these compounds have unique chemical properties and are widely used in the biomedical field. For example, alstilobanine A, alstilobanine B, and alstilobanine C show excellent anti-malarial and anti-cancer drug activity, and tubifolidine shows excellent anti-aging and antioxidant capabilities.

[0003] Existing literature reports some synthesis methods of carbazole derivatives, such as:

[0004] 1. Angew. Chem. Int. Ed. 2017, 56(28): 8163–8167 reported the coupling reaction of indole and enyne catalyzed by trivalent rhodium or trivalent cobalt to synthesize carbazole derivatives;

[0005] 2. Org. Lett. 2019, 21(17): 7179–7183 reported the visible light photocatalytic reaction of tetralin and phenylhydrazine hydrochloride to synthesize carbazole compounds mediated by acridinium salts;

[0006] 3. Org. Chem. Front. 2018, 5(23): 3430–3434 reported the reaction of indole dienes and α,β-unsaturated aldehydes in the presence of chiral amine catalysts to synthesize polysubstituted tetrahydrocarbazoles;

[0007] 4. Angew. Chem. Int. Ed. 2015, 54(31): 9092–9096 reported the cycloaddition reaction of DDQ-oxidized 2-methyl-3-methyleneindolone and different electron-deficient dienophiles, which can synthesize polysubstituted tetrahydrocarbazoles.

[0008] There are still some limitations in the carbazole derivatives prepared by these methods, such as harsh reaction conditions, difficult to obtain reaction raw materials, expensive catalysts, difficult to recycle catalysts, and organic solvents polluting the environment. These shortcomings not only hinder the application of these methods in large-scale industrial production, but also pose challenges in the development of new drugs. Therefore, it is particularly important to develop simple and efficient methods for synthesizing carbazole derivatives. Summary of the invention

[0009] In order to overcome the defects of the prior art, the present invention provides a method for synthesizing carbazole derivatives by a multi-component "one-pot" method using water as a reaction solvent.

[0010] In order to achieve the above object, the present invention provides the following technical solutions:

[0011] The general synthesis method of carbazole derivatives is as follows:

[0012]

[0013] The synthesis method of carbazole derivatives is carried out according to the following steps:

[0014] Add N-pyrimidinylaniline derivative, 1,3-diketone derivative, iodobenzenediacetic acid, sodium hydroxide, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, silver hexafluoroantimonate and water to a reaction bottle with a rotor in sequence, heat to 80°C, time until the reaction is complete, cool to room temperature after the reaction is complete, extract, and purify by column chromatography to obtain the target compound. The molar ratio of N-pyrimidinylaniline derivative (1): 1,3-diketone derivative (2): iodobenzenediacetic acid: sodium hydroxide is 1:1-2:1-2:1-2; the reaction solvent is water; and the catalyst system is [Cp*RhCl2]2, AgSbF6.

[0015] The present invention further discloses that the catalyst of the synthesis method can be applied. The specific operation is to add ether to the reaction system after the reaction is completed, extract, and concentrate the organic phase to obtain a tetrahydrocarbazole derivative; add N-pyrimidinylaniline derivative (1), 1,3-diketone derivative (2), iodophenyldiacetic acid and sodium hydroxide to the aqueous phase for heating reaction, and repeat the above operation after the reaction is completed to obtain the tetrahydrocarbazole derivative. The experimental results show that the catalyst can be recycled and applied multiple times, and the product yield remains basically unchanged after multiple recycling and application, thereby avoiding the waste of the catalyst.

[0016] The present invention further discloses a carbazole derivative synthesized by the method. The method for synthesizing the carbazole derivative has the characteristics of simple operation, high reaction efficiency, high universality of functional groups, etc.

[0017] The synthesis method of the carbazole derivatives of the present invention is as follows:

[0018] Add N-pyrimidinylaniline derivative, 1,3-diketone derivative, iodobenzenediacetic acid, sodium hydroxide, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, silver hexafluoroantimonate and water to a reaction bottle with a rotor in sequence, heat to 80°C, time until the reaction is complete, cool to room temperature after the reaction is complete, extract, and purify by column chromatography to obtain the target compound. The molar ratio of N-pyrimidinylaniline derivative (1): 1,3-diketone derivative (2): iodobenzenediacetic acid: sodium hydroxide is 1:1-2:1-2:1-2; the reaction solvent is water; and the catalyst system is [Cp*RhCl2]2, AgSbF6.

[0019] The synthetic route of carbazole derivatives is as follows:

[0020]

[0021] 1) Add N-pyrimidinylaniline derivative, 1,3-diketone derivative, iodobenzenediacetic acid, sodium hydroxide, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, silver hexafluoroantimonate and water to a reaction bottle with a rotor in sequence, heat to 80°C, and count until the reaction is complete. After the reaction is completed, cool to room temperature, extract, and purify by column chromatography to obtain the target compound. The molar ratio of N-pyrimidinylaniline derivative (1): 1,3-diketone derivative (2): iodobenzenediacetic acid: sodium hydroxide is 1:1-2:1-2:1-2; the reaction solvent is water; and the catalyst system is [Cp*RhCl2]2, AgSbF6.

[0022] 2) The catalyst of the synthesis method of the present invention can be applied. The specific operation is to add ether to the reaction system after the reaction is completed, extract, and concentrate the organic phase to obtain a tetrahydrocarbazole derivative; add N-pyrimidinylaniline derivative (1), 1,3-diketone derivative (2), iodophenyldiacetic acid and sodium hydroxide to the aqueous phase for heating and reaction, and repeat the above operation after the reaction is completed to obtain a tetrahydrocarbazole derivative.

[0023] In the synthesis method of the present invention, preferably, the molar ratio of step 1) N-pyrimidinylaniline derivative (1): 1,3-diketone derivative (2): iodophenyldiacetic acid: sodium hydroxide is 1:1.5:1.5:1.5;

[0024] In the synthesis method of the present invention, preferably the reaction solvent in step 1) is water;

[0025] In the synthesis method of the present invention, the preferred catalyst system in step 1) is [Cp*RhCl2]2, AgSbF6;

[0026] In the synthesis method of the present invention, preferably, the solvent for extracting the aqueous phase in step 2) is diethyl ether.

[0027] The method for synthesizing carbazole derivatives disclosed in the present invention has the following positive effects:

[0028] The present invention provides a method for synthesizing carbazole derivatives by a multi-component "one-pot method" using water as a reaction medium. The carbazole derivatives synthesized by the method have the following advantages: the catalyst used can be recycled and reused, avoiding the waste of precious metal catalysts; the reaction solvent is water, effectively avoiding the pollution of the environment by organic solvents, and being green and environmentally friendly; the route is simple to operate, has a high reaction efficiency, and has the characteristics of high universality of functional groups. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Example 16-Methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one 1 HNMR spectrum;

[0030] Figure 2 Example 16-Methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one 13 C NMR spectrum. DETAILED DESCRIPTION

[0031] For the purpose of simplicity and clarity, the description of the known technology is appropriately omitted below to avoid unnecessary details affecting the description of the present technical solution. The following is a further description of the present invention's one-pot method for synthesizing carbazole derivatives using water as a reaction solvent, in combination with preferred embodiments, and in particular, the aniline derivatives, 1,3-diketone derivatives, iodophenyl diacetic acid, etc. used are all commercially available.

[0032] General method for the synthesis of carbazole derivatives:

[0033] Add N-pyrimidinylaniline derivative (0.2mmol), 1,3-diketone derivative (0.3mmol), iodophenyldiacetic acid (97mg, 0.3mmol), sodium hydroxide (12mg, 0.3mmol), dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (6.2mg, 0.01mmol, 5mol%), silver hexafluoroantimonate (13.8mg, 0.04mmol, 20mol%) and water (2.0mL) to a reaction bottle with a rotor, heat to 80°C, time until the reaction is complete, cool to room temperature after the reaction is completed, extract, and purify by column chromatography to obtain the target compound. A series of carbazole derivatives were synthesized using this method, and the characterization data are as follows:

[0034] Example 1

[0035] 6-Methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 48 mg (87%). Pale yellow solid, melting point: 196-198°C. 1 H NMR (CDCl3, 400MHz) δ8.78 (d, 2H, J = 4.8Hz), 8.18–8.14 (m, 2H), 7.21 (d, 1H, J = 4.8Hz), 7.11 (d ,1H,J=8.4Hz),3.36(t,2H,J=6.0Hz),2.61(t,2H,J=6.4Hz),2.47(s,3H),2.23–2.16(m,2H). 13 C NMR (CDCl3, 100 MHz) δ 195.8, 158.4, 157.7, 152.5, 134.7, 133.7, 126.2, 125.6, 121.5, 118.2, 116.1, 113.9, 38.3, 26.4, 23.9, 21.5. High resolution mass spectrometry calculated value: C 17 H 16 N3O[M+H] + 278.1293, measured value: 278.1288.

[0036] Example 2

[0037] 9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 41 mg (78%). Pale yellow solid, melting point: 220-222°C. 1 H NMR(CDCl3,400MHz)δ8.85(dd,2H,J=4.8,0.8Hz),8.36-8.29(m,2H),7.36–7 .27(m,3H),3.39(t,2H,J=6.0Hz),2.65(t,2H,J=6.4Hz),2.27–2.21(m,2H). 13 C NMR (CDCl3, 100 MHz) δ 195.7, 158.6, 157.7, 152.5, 136.5, 126.0, 124.4, 124.1, 121.7, 118.5, 116.4, 114.2, 38.3, 26.3, 23.9. High resolution mass spectrometry calculated value: C 16 H 14 N3O[M+H] + 264.1137, measured value: 264.1132.

[0038] Example 3

[0039] 6-Methoxy-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 53 mg (90%). Pale yellow solid, melting point: 193-195°C. 1 H NMR (CDCl3, 400MHz) δ8.81 (d, 2H, J = 4.8Hz), 8.23 ​​(d, 1H, J = 9.2Hz), 7.84 (d, 1H, J = 2.8Hz), 7.24 (t, 1H, J = 4.8H z), 6.92 (dd, 1H, J = 9.2, 2.8Hz), 3.91 (s, 3H), 3.39 (t, 2H, J = 6.4Hz), 2.63 (t, 2H, J = 6.0Hz), 2.26–2.19 (m, 2H). 13 C NMR (CDCl3, 100 MHz) δ 195.9, 158.5, 157.7, 157.1, 152.7, 131.0, 127.0, 118.3, 116.3, 115.4, 113.8, 103.4, 56.0, 38.3, 26.6, 23.9. High resolution mass spectrometry calculated value: C 17 H 16 N3O2[M+H] + 294.1243, measured value: 294.1236.

[0040] Example 4

[0041] 6-tert-Butyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v / , 2:1). Yield: 57 mg (89%). Pale yellow solid, melting point: 147-149°C. 1 H NMR (CDCl3, 400MHz) δ8.78 (d, 2H, J = 4.8Hz), 8.38 (s, 1H), 8.23 ​​(d, 1H, J = 8.8Hz), 7.39 (dd, 1H, J = 8.8, 1.6 Hz), 7.20 (t, 1H, J = 4.8Hz), 3.36 (t, 2H, J = 6.0Hz), 2.62 (t, 2H, J = 6.0Hz), 2.23–2.17 (m, 2H), 1.42 (s, 9H). 13 C NMR (CDCl3, 100 MHz) δ 195.7, 158.4, 157.6, 152.5, 147.0, 134.5, 125.9, 122.2, 118.2, 117.7, 116.4, 113.8, 38.3, 34.9, 31.9, 26.3, 23.9. High resolution mass spectrometry calculated value: C 20 H 22 N3O[M+H]+ 320.1763, measured value: 320.1759.

[0042] Example 5

[0043] 6-Fluoro-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 40 mg (71%). Pale yellow solid, melting point: 207-209°C. 1 HNMR(CDCl3,400MHz)δ8.85(d,2H,J=4.8Hz),8.31–8.28(m,1H),8.01(dd,1H,J=8.8,2.4Hz),7.29(t,1H ,J=4.8Hz),7.20(td,1H,J=9.2,2.8Hz),3.41(t,2H,J=6.4Hz),2.64(t,2H,J=6.4Hz),2.27–2.21(m,2H). 13 CNMR(CDCl3,100MHz)δ195.5,160.4(d,J=239.4Hz),158.6,157.6,153.6,132.8,127.1(d,J=10.9Hz),11 8.6, 116.3 (d, J = 3.7Hz), 115.5 (d, J = 9.0Hz), 112.1 (d, J = 25.1Hz), 107.4 (d, J = 24.6Hz), 38.2, 26.6, 23.9. 19 F NMR (CDCl3, 376MHz) δ-119.4. High resolution mass spectrometry calculated value: C 16 H 13 FN3O[M+H] + 282.1043, measured value: 282.1037.

[0044] Example 6

[0045] 6-Chloro-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 47 mg (79%). Pale yellow solid, melting point: 183-185°C. 1 HNMR (CDCl3, 400MHz) δ8.82 (d, 2H, J = 4.8Hz), 8.30 (d, 1H, J = 2.0Hz), 8.23 ​​(d, 1H, J = 9.2Hz), 7.28 (t, 1H, J=4.8Hz),7.22(dd,1H,J=9.2,2.4Hz),3.39(t,2H,J=6.0Hz),2.62(t,2H,J=6.0Hz),2.25–2.18(m,2H).13 CNMR (CDCl3, 100MHz)δ195.4,158.6,157.5,153.4,134.8,129.8,127.2,124.5,121.2,118.7,115.8,115.6,38.2,26.5,23.8. High resolution mass spectrometry calculated value: C 16 H 13 ClN3O[M+H] + 298.0747, measured value: 298.0743.

[0046] Example 7

[0047] 6-Bromo-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 51 mg (75%). Pale yellow solid, melting point: 193-195°C. 1 HNMR (CDCl3, 400MHz) δ8.81 (d, 2H, J = 4.8Hz), 8.43 (d, 1H, J = 1.6Hz), 8.16 (d, 1H, J = 9.2Hz), 7.33 (dd, 1H ,J=8.8,2.2Hz),7.28(t,1H,J=4.8Hz),3.37(t,2H,J=6.8Hz),2.61(t,2H,J=6.4Hz),2.24–2.17(m,2H). 13 CNMR (CDCl3, 100MHz)δ195.3,158.5,157.4,153.2,135.1,127.6,127.1,124.1,118.7,117.5,116.0,115.6,38.1,26.4,23.8. High resolution mass spectrometry calculated value: C 16 H 13 BrN3O[M+H] + 342.0242, measured value: 342.0236.

[0048] Example 8

[0049] 6-iodo-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 62 mg (80%). Pale yellow solid, melting point: 226-228°C. 1HNMR (CDCl3, 400MHz) δ8.83 (d, 2H, J = 6.4Hz), 8.67 (d, 1H, J = 1.2Hz), 8.07 (d, 1H, J = 8.8Hz), 7.55 (dd, 1H ,J=8.4,1.2Hz),7.29(t,1H,J=4.8Hz),3.38(t,2H,J=6.0Hz),2.62(t,2H,J=6.0Hz),2.24–2.18(m,2H). 13 CNMR (CDCl3, 100MHz)δ195.4,158.6,157.5,152.9,135.8,132.9,130.3,128.2,118.7,116.4,115.5,88.5,38.2,26.4,23.8. High resolution mass spectrometry calculated value: C 16 H 13 IN3O[M+H] + 390.0103, measured value: 390.0095.

[0050] Example 9

[0051] 9-(2-pyrimidinyl)-6-trifluoromethyl-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 56 mg (85%). Yellow solid, melting point: 171-174°C. 1 H NMR (CDCl3, 400MHz) δ8.82 (d, 2H, J = 4.8Hz), 8.57 (s, 1H), 8.34 (d, 1H, J = 8.4Hz), 7.48 (d, 1H, J = 1.6Hz), 7.30 (t, 1H, J = 4.8Hz), 3.35 (t, 2H, J = 6.4Hz), 2.61 (t, 2H, J = 6.0Hz), 2.24–2.17 (m, 2H). 13 C NMR(CDCl3,100MHz)δ195.3,158.5,157.1,153,9,137.8,125.8(q,J=31.7Hz),125.6,124.9(q,J= 270.3Hz), 123.6, 120.9 (q, J = 3.6Hz), 118.9, 118.8 (q, J = 9.2Hz), 115.9, 114.8, 38.0, 26.2, 23.6. 19 F NMR (CDCl3, 376MHz) δ-60.8. High resolution mass spectrometry calculated value: C 17 H 13 F3N3O[M+H] + 332.1011, measured value: 332.1006.

[0052] Example 10

[0053] 8-Methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 46 mg (83%). Pale yellow solid, melting point: 142-144°C. 1 HNMR (CDCl3, 400MHz) δ8.91 (d, 2H, J = 4.8Hz), 8.20 (d, 2H, J = 3.2Hz), 7.43 (t, 1H, J = 4.8Hz), 7.23 (t, 1H, J = 9.6Hz),7.04-7.03(m,1H),3.86(t,2H,J=6.4Hz),2.60(t,2H,J=6.0Hz),2.22–2.16(m,2H),1.95(s,3H). 13 C NMR (CDCl3, 100 MHz) δ 195.1, 158.9, 157.8, 152.5, 136.1, 126.9, 125.9, 123.7, 121.9, 120.4, 119.8, 114.9, 38.3, 23.5, 20.2. High resolution mass spectrometry calculated value: C 17 H 16 N3O[M+H] + 278.1293, measured value: 278.1288.

[0054] Embodiment 11

[0055] 8-Methoxy-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / dichloromethane / ethyl acetate (v / v / v, 2:1:1). Yield: 49 mg (84%). Pale yellow solid, melting point: 153-155°C. 1 HNMR (CDCl3, 400MHz) δ8.87 (d, 2H, J = 4.8Hz), 7.91 (dd, 1H, J = 8.4, 1.6Hz), 7.39 (t, 1H, J = 4.8Hz), 7.22 (t, 1H, J =8.0Hz), 6.75 (d, 1H, J = 7.6Hz), 3.64 (s, 3H), 2.88 (t, 2H, J = 7.2Hz), 2.60 (t, 2H, J = 6.0Hz), 2.22–2.16 (m, 2H). 13 C NMR (CDCl3, 100 MHz) δ 195.1, 158.4, 157.7, 152.2, 146.8, 127.4, 126.5, 124.3, 120.1, 115.0, 114.6, 106.3, 55.9, 38.3, 23.5, 23.2. High resolution mass spectrometry calculated value: C17 H 16 N3O2[M+H] + 294.1243, measured value: 294.1238.

[0056] Example 12

[0057] 8-Chloro-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / dichloromethane / ethyl acetate (v / v / v, 2:1:1). Yield: 45 mg (76%). Pale yellow solid, melting point: 122-124°C 1 H NMR (CDCl3, 400MHz) δ8.92 (d, 2H, J = 4.8Hz), 8.27-8.23 (m, 1H), 7.45 (t, 1H, J = 5.2Hz) ,7.23-7.22(m,2H,),2.85(t,2H,J=6.4Hz),2.60(t,2H,J=6.0Hz),2.24–2.18(m,2H). 13 C NMR (CDCl3, 100 MHz) δ 194.7, 158.9, 156.4, 153.3, 133.3, 127.9, 126.5, 124.4, 120.8, 120.6, 117.4, 114.6, 38.2, 23.3, 23.1. High resolution mass spectrometry calculated value: C 16 H 13 ClN3O[M+H] + 298.0747, measured value: 298.0740.

[0058] Embodiment 13

[0059] 7-Methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 45 mg (81%). Pale yellow solid, melting point: 192-194°C. 1 HNMR (CDCl3, 400MHz) δ8.83 (d, 2H, J = 4.4Hz), 8.20 (d, 2H, J = 7.6Hz), 8.08 (s, 1H), 7.26-7 .15(m,2H),3.35(t,2H,J=5.6Hz),2.62(t,2H,J=6.0Hz),2.48(s,3H),2.23–2.19(m,2H). 13C NMR (CDCl3, 100 MHz) δ 195.7, 158.6, 157.7, 152.0, 136.8, 134.3, 125.5, 123.7, 121.3, 118.4, 116.4, 114.1, 38.3, 26.2, 23.1, 22.3. High resolution mass spectrometry calculated value: C 17 H 16 N3O[M+H] + 278.1293, measured value: 278.1287.

[0060] Embodiment 14

[0061] 7-Methoxy-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / dichloromethane / ethyl acetate (v / v / v, 2:1:1). Yield: 52 mg (89%). Pale yellow solid, melting point: 170-172°C. 1 H NMR (CDCl3, 400MHz) δ8.81 (d, 2H, J = 4.8Hz), 8.19 (d, 1H, J = 8.8Hz), 7.91 (s, 1H), 7.25-7.23 (m, 1H), 6.9 5(dd,1H,J=8.4,2.0Hz),3.86(s,3H),3.35(t,2H,J=6.4Hz),2.61(t,2H,J=6.4Hz),2.23–2.17(m,2H). 13 C NMR (CDCl3, 100 MHz) δ 195.7, 158.5, 157.7, 151.8, 137.4, 122.0, 119.9, 118.3, 116.4, 112.0, 99.5, 55.9, 38.2, 26.4, 24.0. High resolution mass spectrometry calculated value: C 17 H 16 N3O2[M+H] + 294.1240, measured value: 294.1237.

[0062] Embodiment 15

[0063] 7-Chloro-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 44 mg (73%). Pale yellow solid, melting point: 196-198°C. 1HNMR (CDCl3, 400MHz) δ8.31 (d, 2H, J = 4.8Hz), 8.37 (s, 1H), 8.22 (d, 1H, J = 8.4Hz), 7 .29-7.27(m,2H,),3.37(t,2H,J=6.0Hz),2.62(t,2H,J=6.0Hz),2.25–2.20(m,2H). 13 C NMR (CDCl3, 100 MHz) δ 195.3, 158.6, 157.4, 153.0, 136.8, 130.2, 124.6, 124.5, 122.3, 118.6, 116.1, 114.8, 38.2, 26.4, 23.8. High resolution mass spectrometry calculated value: C 16 H 13 ClN3O[M+H] + 298.0747, measured value: 298.0741.

[0064] Example 16

[0065] 7,8-Dimethyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 44 mg (76%). Pale yellow solid, melting point: 145-147°C. 1 H NMR (CDCl3, 400MHz) δ8.90 (d, 2H, J = 4.4Hz), 8.06 (d, 1H, J = 7.2Hz), 7.42-7.39 (m, 1H), 7.15 (d, 1H, J =8.0Hz),2.85(t,2H,J=6.0Hz),2.68(t,2H,J=6.0Hz),2.35(s,3H),2.21–2.17(m,2H),1.78(s,3H). 13 CNMR (CDCl3, 100MHz)δ195.1,159.0,158.4,152.6,137.1,133.2,126.4,124.5,120.2,120.2,119.1,115.1,38.2,23.6,23.5,20.4,16.2. High resolution mass spectrometry calculated value: C 18 H 18 N3O[M+H] + 292.1450, measured value: 292.1446.

[0066] Embodiment 17

[0067] 7-Chloro-8-methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / dichloromethane / ethyl acetate (v / v / v, 2:1:1). Yield: 45 mg (72%). Pale yellow solid, melting point: 183-185°C. 1 HNMR (CDCl3, 400MHz) δ8.92 (d, 2H, J = 5.2Hz), 8.10 (d, 1H, J = 8.4Hz), 7.45 (t, 1H, J = 4.8Hz), 7.33 (d,1H,J=8.4Hz),2.85(t,2H,J=6.4Hz),2.59(t,2H,J=6.8Hz),2.22–2.16(m,2H),1.92(s,3H). 13 C NMR (CDCl3, 100 MHz) δ 194.9, 159.2, 157.8, 153.3, 137.0, 131.2, 126.2, 124.8, 120.6, 120.3, 120.2, 114.8, 38.2, 23.5, 23.4, 16.9. High resolution mass spectrometry calculated value: C 17 H 15 ClN3O[M+H] + 312.0904, measured value: 312.0900.

[0068] Embodiment 18

[0069] 8-Methyl-7-nitro-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / dichloromethane / ethyl acetate (v / v / v, 1:1:1). Yield: 43 mg (67%). Yellow solid, melting point: 207-209°C. 1 HNMR (CDCl3, 400MHz) δ8.93 (d, 2H, J = 4.8Hz), 8.22 (d, 1H, J = 8.4Hz), 7.85 (d, 1H, J = 8.4Hz), 7.50 (t,1H,J=4.8Hz),2.89(t,2H,J=6.0Hz),2.61(t,2H,J=6.4Hz),2.22–2.15(m,2H),1.99(s,3H). 13 C NMR (CDCl3, 100 MHz) δ 194.7, 159.3, 157.4, 156.5, 147.5, 136.3, 129.4, 120.9, 120.5, 119.5, 119.3, 114.6, 38.1, 23.7, 23.1, 16.8. High resolution mass spectrometry calculated value: C 17 H 15 N4O3[M+H] +323.1144, measured value: 323.1136.

[0070] Embodiment 19

[0071] 6-Methoxy-8-methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / dichloromethane / ethyl acetate (v / v / v, 2:1:1). Yield: 48 mg (78%). Pale yellow solid, melting point: 156-158°C. 1 H NMR(CDCl3,400MHz)δ8.93-8.89(m,2H),7.70(s,1H),7.44-7.39(m,1H),6.67(s,1H),3. 88(s,3H),2.86(t,2H,J=6.4Hz),2.58(t,2H,J=6.4Hz),2.25-2.16(m,2H),1.92(s,3H). 13 C NMR (CDCl3, 100 MHz) δ 195.2, 158.9, 157.7, 156.8, 152.8, 130.9, 126.9, 123.2, 120.2, 116.4, 114.9, 101.3, 55.9, 38.3, 23.6, 23.5, 20.3. High resolution mass spectrometry calculated value: C 18 H 18 N3O2[M+H] + 308.1399, measured value: 308.1395.

[0072] Embodiment 20

[0073] 2,6-Dimethyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 43 mg (74%). Pale yellow solid, melting point: 178-180°C. 1 H NMR (CDCl3, 400MHz) δ8.80 (d, 2H, J = 4.8Hz), 8.18-8.13 (m, 2H), 7.22 (t, 1H, J = 4.8Hz), 7.11 (d, 1H, J = 8.8Hz), 3.42 (dd, 1H, J =18.0,3.2Hz),3.03(dd,1H,J=18.4,10.0Hz),2.62(d,1H,J=8.4Hz),2.47(s,3H),2.42–2.39(m,2H),1.19(d,3H,J=7.0Hz). 13C NMR (CDCl3, 100 MHz) δ 195.5, 158.5, 157.7, 152.1, 134.9, 133.7, 126.0, 125.6, 121.4, 118.3, 115.9, 114.0, 46.1, 34.5, 31.7, 21.6, 21.5. High resolution mass spectrometry calculated value: C 18 H 18 N3O[M+H] + 292.1450, measured value: 292.1445.

[0074] Embodiment 21

[0075] 2-Isopropyl-6-methyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 2:1). Yield: 461 mg (76%). Pale yellow solid, melting point: 161-163°C. 1 H NMR (CDCl3, 400MHz) δ8.76 (d, 2H, J = 4.8Hz), 8.15-8.06 (m, 2H), 7.23 (t, 1H, J = 4.8Hz), 7.06 (d, 1H, J = 8.4Hz), 3.37-3.32 (m, 1H), 3 .13-3.06(m,1H),2.65-2.60(m,1H),2.45(s,3H),2.42–2.38(m,1H),2.13-2.03(m,1H),1.77-1.70(m,1H),0.98(d,6H,J=6.4Hz). 13 C NMR (CDCl3, 100 MHz) δ 195.9, 158.5, 157.6, 152.5, 134.9, 133.6, 125.9, 125.6, 121.3, 118.3, 115.9, 113.9, 42.9, 41.9, 32.3, 30.1, 21.5, 20.9, 19.8. High resolution mass spectrometry calculated value: C 20 H 22 N3O[M+H] + 320.1763, measured value: 320.1757.

[0076] Embodiment 22

[0077] 2,2,6-Trimethyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: ethyl acetate / petroleum ether (v / v, 2:1). Yield: 48 mg (78%). Pale yellow solid, melting point: 213-215°C. 1H NMR (CDCl3, 400MHz) δ8.82 (d, 2H, J = 4.8Hz), 8.20-8.14 (m, 2H), 7.24 (t, 1H, J = 4. 8Hz),7.12(d,1H,J=8.0Hz),3.24(s,2H),2.50(s,2H),2.48(s,3H),1.15(s,6H). 13 C NMR (CDCl3, 100 MHz) δ 195.2, 158.5, 157.7, 151.1, 135.0, 133.7, 126.0, 125.6, 121.4, 118.3, 115.1, 113.9, 52.3, 40.2, 35.4, 28.9, 21.6. High resolution mass spectrometry calculated value: C 19 H 20 N3O[M+H] + 306.1606, measured value: 306.1602.

[0078] Embodiment 23

[0079] 6-Methyl-9-(2-pyrimidinyl)-1,9-dihydrospiro[2,1'-cyclopentylcarbazole]-4(3H)-one: Eluent: ethyl acetate / petroleum ether (v / v, 2:1). Yield: 51 mg (77%). Pale yellow solid, melting point: 196-198°C. 1 HNMR (CDCl3, 400MHz) δ8.85 (d, 2H, J = 4.8Hz), 8.21 (d, 1H, J = 8.4Hz), 8.15 (s, 1H), 7.27 (t, 1H, J = 4.8Hz),7.15(dd,1H,J=8.4,1.2Hz),3.35(s,2H),2.63(s,2H),2.50(s,3H),1.72-1.60(m,8H). 13 C NMR (CDCl3, 100 MHz) δ 195.5, 158.5, 157.7, 151.8, 135.0, 133.8, 126.0, 125.6, 121.4, 118.3, 116.0, 113.9, 50.7, 46.3, 39.0, 38.8, 24.6, 21.6 High resolution mass spectrometry calculated value: C 21 H 22 N3O[M+H] + 332.1763, measured value: 332.1758.

[0080] Embodiment 24

[0081] 6-Methyl-2-phenyl-9-(2-pyrimidinyl)-1,2,3,9-tetrahydrocarbazol-4-one: Eluent: petroleum ether / ethyl acetate (v / v, 2:1). Yield: 53 mg (75%). Pale yellow solid, melting point: 183-185°C 1 H NMR (CDCl3, 400MHz) δ8.78 (d, 2H, J = 4.8Hz), 8.21 (d, 1H, J = 8.4Hz), 8.18 (s, 1H), 7.38 -7.14(m,7H),3.68-3.55(m,2H),2.98-2.86(m,2H),2.82-2.72(m,1H),2.49(s,3H). 13 C NMR (CDCl3, 100 MHz) δ 194.6, 158.6, 157.7, 151.5, 143.7, 135.1, 133.9, 129.0, 127.3, 126.0, 126.9, 121.6, 118.4, 116.1, 114.1, 45.2, 42.6, 34.4, 21.6. High resolution mass spectrometry calculated value: C 23 H 20 N3O[M+H] + 354.1606, measured value: 354.1599.

[0082] Embodiment 25

[0083] 2-Methyl-5-(2-pyrimidinyl)-6,7,8,9-tetrahydrocycloheptanone[b]indol-10(5H)-one: Eluent: ethyl acetate / petroleum ether (v / v, 2:1). Yield: 49 mg (84%). Pale yellow solid, melting point: 125-127°C. 1 H NMR (CDCl3, 400MHz) δ8.89 (d, 2H, J = 4.8Hz), 8.22 (s, 1H), 7.79 (d, 1H, J = 4.8Hz), 7.33-7.30 (m, 1 H),7.10-7.07(m,1H),3.32-3.29(m,2H),2.86(t,2H,J=6.0Hz),2.47(s,3H),2.01–1.96(m,4H). 13 C NMR (CDCl3, 100 MHz) δ 199.1, 158.8, 157.5, 149.9, 134.6, 133.4, 127.5, 126.5, 121.7, 119.3, 118.9, 112.2, 42.8, 27.2, 25.5, 22.1, 21.7. High resolution mass spectrometry calculated value: C 18 H 18 N3O[M+H] +292.1450, measured value: 292.1444.

[0084] Embodiment 26

[0085] 6-Methyl-9-(2-pyrimidinyl)-1,9-dihydropyrano[3,4-b]indol-4(3H)-one: Eluent: ethyl acetate / petroleum ether (v / v, 1:1). Yield: 36 mg (65%). Pale yellow solid, melting point: 199-201°C. 1 H NMR (CDCl3, 400MHz) δ 8.77-8.75 (m, 2H), 8.53 (d, 2H, J = 8.4Hz), 8.04 (s, 1H), 7.21-7.17 (m, 2H), 5.37 (s, 2H), 4.30 (s, 2H), 2.48 (s, 3H). 13 C NMR (CDCl3, 100 MHz) δ 191.5, 158.4, 157.6, 150.0, 134.4, 134.3, 126.4, 125.7, 121.5, 117.9, 115.7, 114.0, 72.9, 66.1, 21.6. High resolution mass spectrometry calculated value: C 16 H 14 N3O2[M+H] + 280.1086, measured value: 280.1081.

[0086] Embodiment 27

[0087] To a reaction bottle with a rotor, add N-pyrimidinyl-p-methylaniline (37 mg, 0.2 mmol), 1,3-cyclohexanedione (34 mg, 0.3 mmol), iodophenyldiacetic acid (97 mg, 0.3 mmol), sodium hydroxide (12 mg, 0.3 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (6.2 mg, 0.01 mmol, 5 mol%), silver hexafluoroantimonate (13.8 mg, 0.04 mmol, 20 mol%) and water (2.0 mL) in sequence, heat to 80 ° C, time until the reaction is complete, after the reaction is completed, cool to room temperature, extract with ether three times, concentrate the organic phase, and purify by column chromatography to obtain the target compound. N-pyrimidinyl-p-methylaniline (37 mg, 0.2 mmol), 1,3-cyclohexanedione (34 mg, 0.3 mmol), iodophenyl diacetic acid (97 mg, 0.3 mmol), sodium hydroxide (12 mg, 0.3 mmol) were added to the aqueous phase in sequence, and heated to 80°C. The reaction was timed until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, extracted with ether three times, and the organic phase was concentrated and purified by column chromatography to obtain the target compound. The above operation was repeated 5 times, and the yields were: (47 mg, 85%), (47 mg 85%), (48 mg, 87%) (47 mg, 85%), and (45 mg, 83%), respectively. The yields did not change significantly. From the above data, it can be seen that the catalyst can be effectively recycled.

[0088] Through the above examples, it is found that the method can be used to simply and efficiently synthesize carbazole derivatives with high yield, good universality of functional groups, green reaction solvents, and reusable catalysts, thus providing a practical synthesis method for preparing carbazole derivatives.

Claims

1. A method for synthesizing carbazole derivatives by a multi-component "one-pot" method using water as a reaction solvent, characterized in that Proceed as follows: N-pyrimidinylaniline derivative (1), 1,3-diketone derivative (2), iodobenzenediacetic acid and sodium hydroxide react in water phase under the catalysis of rhodium catalyst, and react at 80°C for 18 to 36 hours; after the reaction, organic solvent extraction is performed, and the organic phase is concentrated to obtain tetrahydrocarbazole derivative. The molar ratio of N-pyrimidinylaniline derivative (1): 1,3-diketone derivative (2): iodobenzenediacetic acid: sodium hydroxide is 1:1 to 2:1 to 2:1 to 2; the reaction solvent is water; and the catalytic system is [Cp*RhCl2]2, AgSbF6.

2. A method for synthesizing carbazole derivatives by a multi-component "one-pot" method using water as a reaction solvent according to claim 1, characterized in that The catalytic system can be applied. The specific operation is to add ether to the reaction system after the reaction is completed, extract, and concentrate the organic phase to obtain a tetrahydrocarbazole derivative; add N-pyrimidinylaniline derivative (1), 1,3-diketone derivative (2), iodophenyldiacetic acid and sodium hydroxide to the aqueous phase for heating and reaction, and repeat the above operation after the reaction is completed to obtain a tetrahydrocarbazole derivative.

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