A synthetic method for introducing a trans-prenyl group at the C3 position of indole

Abstract

The application discloses a synthetic method of introducing a trans-isopentenyl group at the C3 position of indole. The method uses indole and 2-methyl-2-butene as starting materials, and a palladate as a catalyst. Through direct oxidative dehydrogenation coupling reaction, the trans-isopentenyl group can be introduced at the C3 position of the indole with high regioselectivity and chemoselectivity. Compared with traditional methods of introducing a trans-isopentenyl group at the C3 position of indole, the method has the advantages of simple operation, low price of reagents, mild reaction conditions, no need for pre-functionalization of the substrate, no need for using ligands, and high atom utilization rate.

Description

TECHNICAL FIELD

[0001] The present application relates to a new method for introducing a trans-prenyl group at the C3 position of indole, belonging to the field of organic synthesis. BACKGROUND

[0002] Prenylindole alkaloids are a class of important organic compounds, widely exist in plants, fungi, bacteria and marine organisms, which generally have excellent biological and medicinal activity. Prenylindole alkaloids as drugs often show different and more diverse drug and pharmacological activity than their non-prenylated indole alkaloid precursors. Studies have shown that the introduction of a prenyl structural unit into a drug molecule can improve its lipophilicity and transmembrane permeation. Currently, the strategy for introducing a prenyl group at the C3 position of indole is mainly achieved by nucleophilic substitution, Friedel-Crafts alkylation reaction, and metal-catalyzed allylation reaction. These strategies all require pre-functionalization of the substrate or the use of C5 olefins containing leaving groups as starting materials, which does not meet the requirements of atomic and step economy, and the reaction cost is high. Therefore, there is a great space for improvement in these traditional methods in terms of step simplicity, atomic economy, and cost reduction.

[0003] The prenylation reaction at the C3 position of indole is a research topic in organic chemistry that has been studied for a long time, and has attracted widespread attention from chemists. Transition metal-catalyzed direct oxidative dehydrogenation cross-coupling reaction can directly construct new C-C bonds by breaking two C-H bonds, which can avoid pre-functionalization of the starting material, thus simplifying the synthesis scheme and meeting the principle of atomic economy. The present application first proposes to use the large amount of chemical 2-methyl-2-butene produced by petroleum hydrocarbon pyrolysis process as a C5 source to directly introduce a trans-prenyl group at the C3 position of indole, which not only realizes the value-added development and utilization of 2-methyl-2-butene in C5 distillate, but also reduces the cost of introducing a trans-prenyl group at the C3 position of indole, reduces resource waste, and meets the requirements of green process synthesis. The reaction has the characteristics of mild reaction conditions, avoidance of ligand addition, high regioselectivity and site selectivity, and is considered to be an ideal chemical reaction. SUMMARY

[0004] The present application aims to provide a simple, low-cost, efficient, high-atom utilization, and high-regioselective synthesis method for introducing a trans-prenyl group at the C3 position of indole.

[0005] The implementation process of the present application is as follows:

[0006] A method for introducing a trans-isopentenyl group at C3 of indole: a trans-isopentenylated indole compound (C) is prepared by direct oxidative dehydrogenative coupling reaction using compound (A) and 2-methyl-2-butene (B) as starting materials, a palladium compound as catalyst, copper sulfate as oxidant, and acetonitrile, acetic acid and hexafluoroisopropanol as mixed solvents,

[0007]

[0008] wherein R 1 is phenyl, naphthyl or hydrogen; R 2 is H, C1-C20 alkyl, alkoxy or aldehyde group, C2-C20 ester group, halogen group or nitro group.

[0009] The above substituent is preferably: R 1 is phenyl, naphthyl or hydrogen; R 2 is H, C1-C5 alkyl, alkoxy or aldehyde group, C2-C6 ester group, halogen group or nitro group.

[0010] The palladium compound catalyst is tris(dibenzylideneacetone)dipalladium or palladium trifluoroacetate.

[0011] In the above mixed solvent, the volume ratio of acetonitrile, acetic acid and hexafluoroisopropanol is 1.4: (0.2-0.6): (0.2-0.6).

[0012] The present application has the advantages of mild reaction conditions, low cost of raw materials, high efficiency, high atom utilization rate and high product regioselectivity compared with the conventional synthesis method for introducing a trans-isopentenyl group at C3 of indole. Specific implementation method

[0013] The synthesis method of the present application is: a palladium catalyst (10 mol%), an oxidant, an indole are sequentially added in a sealed tube, followed by adding a solvent and 2-methyl-2-butene. Then the reaction tube is sealed and placed in a 60 ℃ oil bath for stirring for 6-18 hours. The reaction is detected by TLC plate until the raw material is completely reacted. After the reaction is completed, the reaction tube is cooled to room temperature, the reaction mixture is filtered with silica gel, followed by adding ethyl acetate, and the mixture is washed with water and brine respectively. Then the organic phase is dried with anhydrous Na2SO4, followed by vacuum concentration. Finally, the trans-isopentenylated indole compound is obtained by column chromatography separation and purification. Example

[0014]

[0015] Compound C-1

[0016] In a 15 mL sealed tube, was charged with: tris(dibenzylideneacetone)dipalladium (18.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), 6-methyl-1-phenyl-1 H indole (41.4 mg, 0.2 mmol, 1 equiv), followed by acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.3 mL), and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in a temperature 60 °C oil bath for 6 hours. The reaction was monitored by TLC plate until the starting material was completely consumed. After the reaction was complete, the reaction tube was cooled to room temperature and the reaction mixture was filtered over silica gel, followed by the addition of ethyl acetate and the mixture was washed with water and brine, respectively. The organic phase was then dried over anhydrous Na2S04, followed by concentration under vacuum. Finally, compound C-1 was isolated and purified by column chromatography. (31 mg, 56%).

[0017] Compound C-1: yellow oil; IR: 2964, 2922, 2360, 2341, 1597, 1501, 1459, 1276, 1261, 765, 751, 699 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz,1H), 7.50 (d, J = 1.7 Hz, 2H), 7.51-7.47 (m, 2H), 7.36 – 7.30 (m, 2H), 7.05 (s,1H), 6.95 (d, J = 8.1 Hz, 1H), 6.16 (dd, J = 17.4, 10.5 Hz, 1H), 5.12 (d, J = 17.4Hz, 1H), 5.05 (d, J = 10.5 Hz, 1H), 2.43 (s, 3H), 1.54 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 147.7, 140.2, 137.5, 132.0, 129.6 (2C), 126.2, 125.4, 124.8, 124.5(2C), 123.8, 121.5, 121.3, 110.9, 110.6, 37.7, 28.2 (2C), 21.9; HRMS (ESI) m / z calculated for C 20 H 21 NNa [M+Na] + : 298.1566; Found: 298.1553. Example

[0018]

[0019] Compound C-2

[0020] In a 15 mL sealed tube, add, in sequence: tris(dibenzylacetone)palladium (18.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), and 5-methoxy-1-phenyl-1-ethylhexylene. H Indole (44.6 mg, 0.2 mmol, 1 equiv) was added, followed by acetonitrile (1.4 mL), acetic acid (0.4 mL), and hexafluoroisopropanol (0.4 mL), and finally 2-methyl-2-butene (84 mL) was added. μ L (1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 °C with stirring for 6 hours. The reaction was monitored by TLC until the starting material was completely reacted. After the reaction was complete, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added. The mixture was washed with water and brine, respectively. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated under vacuum. Finally, compound C-2 (36 mg, 61%) was purified by column chromatography.

[0021] Compound C-2: Yellow oily substance; IR: 2962, 2923, 2361, 2341, 1597, 1503, 1478, 1157, 796, 751, 700 cm⁻¹ -1 ; 1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 5.8 Hz, 4H),7.46 (d, J = 9.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.83(dd, J = 9.0, 2.3 Hz, 1H), 6.12 (dd, J = 17.4, 10.5 Hz, 1H), 5.12 (d, J =17.4 Hz, 1H), 5.05 (d, J = 10.5 Hz, 1H), 3.76 (s, 3H), 1.50 (s, 6H); 13 C NMR(101 MHz, DMSO-d6) δ 153.7, 147.6, 139.7, 131.6, 130.2 (2C), 128.1, 126.3,125.4, 123.9, 123.8 (2C), 111.8, 111.7, 111.3, 104.1, 55.9, 37.5, 28.1 (2C);HRMS (ESI) m / z calculatedfor C 20 H 22 NO [M+H] + : 292.1696; Found: 292.1684。 Example

[0022]

[0023] Compound C-3

[0024] In a 15 mL sealed tube, sequentially charged: palladium trifluoroacetate (6.6 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), indole-5-carboxaldehyde (29.0 mg, 0.2 mmol, 1 equiv), then acetonitrile (1.4 mL), acetic acid (0.25 mL) and hexafluoroisopropanol (0.25 mL), and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in a temperature 60 °C oil bath for stirring for 18 hours. The reaction was monitored by TLC plates until the complete reaction of the starting material. Once the reaction was complete, the reaction tube was cooled to room temperature and the reaction mixture was filtered through silica gel, followed by the addition of ethyl acetate and washing the mixture with water and brine, respectively. The organic phase was then dried with anhydrous Na2S04, followed by concentration under vacuum. Finally, compound C-3 was obtained by column chromatography purification. (26.9 mg, 63%).

[0025] Compound C-3: yellow solid, melting point 81-82 o C; IR: 1673, 1606, 1573, 1413, 1377, 1261, 749, 689 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 8.48 (s, 1H),8.24 (s, 1H), 7.75 (dd, J = 8.5, 1.4 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.09(d, J = 2.3 Hz, 1H), 6.14 (dd, J = 17.4, 10.5 Hz, 1H), 5.10 (d, J = 13.6 Hz,1H), 5.06 (d, J = 6.7 Hz, 1H), 1.54 (s, 6H); 13 C NMR (101 MHz, CDCl3) δ 192.9, 147.4, 140.8, 129.0, 127.2, 126.1, 126.0, 122.2, 122.0, 112.0, 111.5, 37.7, 28.4 (2C); HRMS (ESI) m / z calculated for C 14 H 14 NO [M-H] - : 212.1081; Found:212.1072. Example

[0026]

[0027] Compound C-4

[0028] Into a 15 mL sealed tube, sequentially charged: palladium trifluoroacetate (6.6 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), methyl indole-6-carboxylate (35.0 mg, 0.2 mmol, 1 equiv), then acetonitrile (1.4 mL), acetic acid (0.4 mL) and hexafluoroisopropanol (0.5 mL), respectively, and finally 2-methyl-2-butene (84 μL (1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in an oil bath at 60 °C with stirring for 18 hours. The reaction was monitored by TLC until the starting material was completely reacted. After the reaction was complete, the reaction tube was cooled to room temperature, the reaction mixture was filtered through silica gel, and then ethyl acetate was added. The mixture was washed with water and brine, respectively. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated under vacuum. Finally, compound C-4 (37.9 mg, 78%) was purified by column chromatography.

[0029] Compound C-4: Yellow solid, melting point 141-142°C o C; IR (KBr): 3347, 2960, 2925, 1692,1435, 1318, 1276, 1217, 1088, 765, 750 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 8.37 (s,1H), 8.12 (s, 1H), 7.74 (d, J = 2.1 Hz, 2H), 7.14 (d, J = 2.4 Hz, 1H), 6.11(dd, J = 17.4, 10.5 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 5.03 (d, J = 3.4 Hz, 1H), 3.93 (s, 3H), 1.51 (s, 6H); 13 HRMS (ESI) m / z calculated for C 15 H 17 NNaO2[M+Na] + : 266.1151; Found:266.1142. Example

[0030]

[0031] Compound C-5

[0032] In a 15 mL sealed tube, add tris(dibenzylacetone)palladium (18.3 mg, 10 mol%) and copper sulfate (63.8 mg, 0.4 mmol, 2 equiv) in sequence. N-(2-naphthalenyl)-indole (48.6 mg, 0.2 mmol, 1 equiv), followed by acetonitrile (1.4 mL), acetic acid (0.5 mL), and hexafluoroisopropanol (0.4 mL), and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in a temperature 60 °C oil bath for 6 hours. The reaction was monitored by TLC plate until the starting material was completely reacted. After the reaction was complete, the reaction tube was cooled to room temperature and the reaction mixture was filtered over silica gel, followed by the addition of ethyl acetate and washing the mixture with water and brine, respectively. The organic phase was then dried over anhydrous Na2S04, followed by concentration under vacuum. Finally, compound C-5 was isolated and purified by column chromatography. (33 mg, 53%).

[0033] Compound C-5: yellow oil; IR: 3357, 2962, 2922, 2853, 1703, 1439, 1279, 1212, 1140, 903, 747 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.7 Hz, 1H), 7.93 - 7.85 (m, 3H), 7.80 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.7, 2.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.52 (m, 2H), 7.24 - 7.19 (m, 2H), 7.16 - 7.12 (m, 1H), 6.20 (dd, J = 17.4, 10.5 Hz, 1H), 5.16 (dd, J = 17.4, 1.3 Hz, 1H), 5.08 (dd, J = 10.5, 1.3 Hz, 1H), 1.59 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 147.6, 137.5,137.2, 134.0, 131.8, 129.6, 128.0, 127.8, 127.7, 127.0, 126.1, 125.2, 124.5,123.5, 122.3, 122.0, 121.9, 119.7, 111.1, 110.8, 37.7, 28.2 (2C). HRMS (ESI) m / z calculated for C 23 H 22 N [M+H] + : 312.1747, Found: 312.1749. Example

[0034]

[0035] Compound C-6

[0036] In a 15 mL sealed tube, sequentially charged: tris(dibenzylideneacetone)dipalladium (18.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), 6-bromo-1-phenyl-1 H indole (54.2 mg, 0.2 mmol, 1 equiv), then acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.3 mL) were added, respectively, and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). Then the reaction tube was sealed and placed in a temperature 60 °C oil bath for stirring for 18 hours. The reaction was monitored by TLC plate until the complete reaction of the starting material. After the complete reaction, the reaction tube was cooled to room temperature and the reaction mixture was filtered through silica gel, then ethyl acetate was added and the mixture was washed with water and brine, respectively. Then the organic phase was dried over anhydrous Na2S04, then concentrated in vacuo. Finally, compound C-6 was obtained by column chromatography purification. (34 mg, 50%).

[0037] Compound C-6: yellow oil; IR: 2962, 2925, 1595, 1502, 1459, 1439, 1226, 1145, 914, 801, 760, 697 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.61 (d, J= 8.6 Hz, 1H), 7.54 – 7.50 (m, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.38 – 7.34 (m,1H), 7.21 (d, J = 8.6 Hz, 1H), 7.09 (s, 1H), 6.13 (dd, J = 17.4, 10.5 Hz, 1H),5.11 (d, J = 17.6 Hz, 1H), 5.07 (d, J = 11.0 Hz, 1H), 1.53 (s, 6H). 13 C NMR (101MHz, CDCl3) δ 147.3, 139.4, 137.8, 129.9 (2C), 126.8, 126.3, 124.97, 124.95,124.6 (2C), 123.1, 122.8, 116.0, 113.6, 111.3, 37.6, 28.2 (2C). HRMS (ESI) m / z calculated for C 19 H 18 BrNNa [M+Na] + : 362.0515, Found: 362.0521. Example

[0038]

[0039] Compound C-7

[0040] In a 15 mL sealed tube, sequentially charged: tris(dibenzylideneacetone)dipalladium (18.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), 5-chloro-l-phenyl-l H indole (45.4 mg, 0.2 mmol, 1 equiv), then acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.5 mL) were added respectively, and finally 2-methyl-2-butene (84 μL, 1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in a temperature 60 °C oil bath for stirring for 18 hours. The reaction was monitored by TLC plate until the starting material was completely reacted. After the reaction was complete, the reaction tube was cooled to room temperature and the reaction mixture was filtered through silica gel, followed by the addition of ethyl acetate and the mixture was washed with water and brine, respectively. The organic phase was then dried over anhydrous Na2S04, followed by concentration under vacuum. Finally, compound C-7 was isolated and purified by column chromatography. (29 mg, 50%).

[0041] Compound C-7: yellow solid, m.p. 141-142 o C; IR: 3431, 2965, 2927, 2361, 2342,1463, 1276, 1261, 1070, 915, 764, 751 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.9 Hz, 1H), 7.52 – 7.40 (m, 6H), 7.35 (d, J = 7.1 Hz, 1H), 7.14 (s, 1H),6.13 (dd, J = 17.4, 10.5 Hz, 1H), 5.13 (dd, J = 17.4, 1.3 Hz, 1H), 5.08 (dd, J =10.5, 1.3 Hz, 1H), 1.53 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 147.2, 139.6,135.4, 129. 8 (2C), 128.5, 126.7, 125.6, 125.1, 124.5, 124.4 (2C), 122.4,121.2, 111.7, 111.5, 37.6, 28.2 (2C). HRMS (ESI) m / z calculated forC 19 H 18 ClNNa [M+Na] + : 318.1020, Found: 318.1024. Example

[0042]

[0043] Compound C-8

[0044] In a 15 mL sealed tube, was charged with: tris(dibenzylideneacetone)dipalladium (18.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), 6-nitro-l-phenyl-l H indole (38.6 mg, 0.2 mmol, 1 equiv), followed by acetonitrile (1.4 mL), acetic acid (0.5 mL) and hexafluoroisopropanol (0.3 mL), and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in a temperature 60 °C oil bath for 18 hours. The reaction was monitored by TLC plates until the starting material was completely consumed. After the reaction was complete, the reaction tube was cooled to room temperature and the reaction mixture was filtered over silica gel, followed by the addition of ethyl acetate and washing the mixture with water and brine, respectively. The organic phase was then dried over anhydrous Na2S04, followed by concentration under vacuum. Finally, compound C-8 was isolated and purified by column chromatography. (41 mg, 68%).

[0045] Compound C-8: yellow oil; IR: 2956, 2924, 2360, 1502, 1462, 1336, 1276, 1261, 764, 750 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 2.0 Hz, 1H), 8.00 (dd, J = 8.9, 2.1 Hz, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.52 –7.48 (m, 2H), 7.45 (d, J = 7.3 Hz, 1H), 7.40 (s, 1H), 6.14 (dd, J = 17.4, 10.6Hz, 1H), 5.14 (dd, J = 10.2, 1.2 Hz, 1H), 5.10 (dd, J = 3.5, 1.2 Hz, 1H), 1.57(s, 6H). 13C NMR (101 MHz, CDCl3) δ 146.8, 142.9, 138.6, 135.8, 132.0, 130.2,130.1 (2C), 127.7, 125.6, 124.8 (2C), 121.8, 114.9, 111.8, 107.7, 38.3, 28.2(2C). HRMS (ESI) m / z calculated for C 19 H 19 N2O2[M+H] + : 307.1441, Found:307.1446. Example

[0046]

[0047] Compound C-9

[0048] In a 15 mL sealed tube, was charged with palladium acetate (3.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), 1-phenyl-1 H indole (35.0 mg, 0.2 mmol, 1 equiv), followed by acetonitrile (1.4 mL), acetic acid (0.3 mL) and hexafluoroisopropanol (0.3 mL), and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). The reaction tube was then sealed and placed in a temperature 60 °C oil bath for 18 hours. The reaction was monitored by TLC plate until the starting material was completely consumed. After the reaction was complete, the reaction tube was cooled to room temperature and the reaction mixture was filtered over silica gel, followed by the addition of ethyl acetate and washing the mixture with water and brine, respectively. The organic phase was then dried over anhydrous Na2S04, followed by concentration under vacuum. Finally, compound C-9 was obtained by column chromatography purification. (32 mg, 42%).

[0049] Compound C-9: yellow oil; IR: 2923, 2868, 1597, 1502, 1458, 1376, 1229, 911, 742, 697 cm -1 ; 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.51 – 7.45 (m, 4H), 7.33 – 7.28 (m, 1H), 7.19 (d,J = 6.9 Hz,1H), 7.15 – 7.09 (m, 2H), 6.17 (dd, J = 17.4, 10.5 Hz, 1H), 5.14 (dd, J = 17.4,1.4 Hz, 1H), 5.06 (dd, J = 10.5, 1.0 Hz, 1H), 1.56 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 147.6, 140.0, 136.9, 129.7 (2C), 127.6, 126.3, 124.9, 124.4 (2C), 124.3, 122.1, 121.9, 119.6, 111.0, 110.7, 37.7, 28.2 (2C). HRMS (ESI) m / z calcd for C 19 H 19 NNa [M+Na] + : 284.1410, Found: 284.1404. Example

[0050] The synthesis of compound C-9 was taken as an example, and different solvents were selected for synthesis experiments.

[0051] In a 15 mL sealed tube, sequentially loaded: tris(dibenzylideneacetone)dipalladium (18.3 mg, 10 mol%), copper sulfate (63.8 mg, 0.4 mmol, 2 equiv), 1-phenyl-1 H indole (35.0 mg, 0.2 mmol, 1 equiv), then 2 mL of the following table solvents (each solvent ratio is in the brackets), and finally 2-methyl-2-butene (84 μ L, 1.0 mmol, 5 equiv). Then the reaction tube was sealed and placed in a 60 ℃ oil bath for stirring for 18 hours. TLC plate was used to detect the reaction until the raw material was completely reacted. After the reaction was completed, the reaction tube was cooled to room temperature, and the reaction mixture was filtered with silica gel, followed by the addition of ethyl acetate, and the mixture was washed with water and brine. Then the organic phase was dried with anhydrous Na2SO4, followed by vacuum concentration. Finally, compound C-9 was obtained by column chromatography purification, and the yield was shown in Table 1.

[0052] Table 1 Synthesis experiment results using different solvents

[0053] No. Solvent (volume ratio) Yield (%) 1 CH3CN:HOAc:HFIP (7:1.5:1.5) 62 2 HOAc:DMSO (9:1) trace 3 CH3CN:HFIP (10:1) 48 4 CH3CN:HOAc (10:1) 46 5 CH3CN no product 6 HOAc no product 7 CH3CN:HCOOH (10:1) trace

Claims

1. A method for introducing a trans-prenyl group at the C3 position of an indole, characterized by: Trans-iso-prenylated indole compound (C) is prepared by direct oxidative dehydrogenation coupling reaction using compound (A) and 2-methyl-2-butene (B) as starting materials, tris(dibenzylideneacetone)dipalladium or palladium trifluoroacetate as catalyst, copper sulfate as oxidant, and a mixed solvent of acetonitrile, acetic acid and hexafluoroisopropanol in a volume ratio of 1.4: (0.2-0.6): (0.2-0.6), ； In the formula, R1 is phenyl, naphthyl or hydrogen; R2 is H, C1-C5 alkyl, alkoxy or aldehyde group, C2-C6 ester group, halogen group or nitro group.

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