Synthesis method of a class of alkenyl indole derivatives

Abstract

The present invention belongs to the field of organic synthesis and relates to a method for synthesizing a class of alkenyl indole derivatives. Alkenyl indole compounds have important research value in synthesis and pharmaceutical activities. However, conventional synthesis steps are cumbersome, the conditions are harsh, and it involves the use of expensive heavy metals and positioning groups. The present invention provides a method for synthesizing a class of alkenyl indole derivatives, using alkenyl-1,3-dithiane derivatives and substituted indoles as raw materials. Under the action of a catalyst, a class of alkenyl indole derivatives is synthesized through the migration of the dithiane ring. The present invention provides a highly efficient and simple synthesis method, which has the advantages of mild reaction, high efficiency, simple operation and economical raw materials, and has strong practicability.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis and relates to a method for synthesizing a class of alkenylindole derivatives. Background Art

[0002] Alkenylindole compounds have important pharmacological activities, such as antitumor effects (J. Med. Chem., 55, 1940 - 1956), anti-inflammatory effects, antifungal effects (Journal of Pharmacy, 5, 459 - 462), antimalarial effects (J. Med. Chem., 56, 6200 - 6215), etc. In addition, alkenylindole derivatives are important intermediates in organic synthesis. Due to the presence of an unsaturated double bond structure in their molecules, alkenylindole derivatives can not only construct different tetrahydrocarbazole structures by reacting with different dienophiles through the Diels - Alder reaction, but also undergo various reactions such as the Pauson - Khand reaction and olefin cross - metathesis. Currently, there are few related studies on alkenylindole structures containing a thiane ring, and there are few reports.

[0003] Currently, the main synthetic methods for synthesizing alkenylindole compounds include: the Wittig reaction occurring at the 3 - position of indole and the indole alkenylation reaction involving neighboring groups.

[0004] Preparing 3 - alkenylated indole derivatives through the Wittig reaction, and the preparation method is as follows:

[0005]

[0006] The disadvantages of this method are that the raw materials are limited to 3 - formylindole, the substrates are relatively limited, and in addition, the reaction conditions are harsh and reflux heating is required.

[0007] Masahiro Miura et al. reported the palladium - catalyzed oxidative vinylation reaction of indole - 3 - carboxylic acid with olefins, realizing indole C - H functionalization and decarboxylation, and synthesizing the corresponding 2 - vinylindole. The preparation method is as follows:

[0008]

[0009] The disadvantages of this method are that the reaction substrates are limited, expensive transition metal catalysts need to be used, there is a potential hazard to the environment, and decarboxylation is required during the reaction process, resulting in low atom economy. Summary of the Invention

[0010] In order to achieve the efficient preparation of alkenylindole compounds, the present invention provides a method for synthesizing alkenylindole derivatives. This method is not only simple to operate, has good selectivity, high functional group tolerance, and high yield, but also the synthesized compounds have rich structures, are easy to separate and purify, and are suitable for large - scale production.

[0011] A method for synthesizing a class of alkenylindole derivatives is characterized by comprising the following steps: adding a substituted indole (I) and an alkenyl-1,3-dithiane derivative (II) into a reactor, reacting under the action of a suitable solvent and a catalyst to synthesize an alkenylindole compound (III), and the chemical reaction equation is as follows:

[0012]

[0013] In the substituted indole (I), R 1 is the substituent at the 1-position of indole, selected from hydrogen, methyl, p-toluenesulfonic acid, tert-butoxycarbonyl, benzyl; R 2 is the substituent at the 2-7 positions of indole, selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, acetyl, amino, carboxyl, hydroxyl, hydroxymethyl, nitro, cyano, halogen, methyl acetate, benzyloxy; the substituted indole (I) can be tryptophol, tryptamine, melatonin, tryptophan derivative, azaindole, 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline;

[0014] R 3 is selected from C1-C10 alkyl, phenyl, substituted phenyl (such as 2-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2,5-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl), naphthyl, heterocycle (indole, pyrrole, thiophene, furan);

[0015] X is Cl, Br, I, OTf.

[0016] A method for preparing a class of alkenylindole derivatives is characterized in that the catalyst used is one or more of indium trichloride, indium tribromide, indium triiodide, ferric trichloride, ferric trichloride hexahydrate, bismuth trichloride, boron trifluoride diethyl ether, iodine, NCS, NBS, DTBP, TEMPO, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, chiral phosphoric acid, acetic acid.

[0017] A method for preparing a class of alkenylindole derivatives is characterized in that the solvent used is one or more of 1,2-dichloroethane, dichloromethane, chloroform, toluene, chlorobenzene.

[0018] A method for preparing a class of alkenylindole derivatives is characterized in that the molar ratio of the catalyst to the reactants is catalyst:β-chloro-vinyl-1,3-dithiane:indole = (0.01-1.0):1:(0.5-3.0).

[0019] A method for preparing a class of alkenylindole derivatives is characterized in that the reaction temperature range is -78 to 100 °C. Specific embodiments

[0020] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way. All raw materials used in the present invention are known compounds, which can be purchased from the market or synthesized by known methods in the art.

[0021] Example 1: Reaction steps for the method of preparing (E)-3-(2-(2-methyl-1,3-dithian-2-yl)vinyl)-1H-indole

[0022] In a 25 mL round-bottom flask, methyl-β-chloro-vinyl-1,3-dithiane (39 mg, 0.2 mmol) and indole (29 mg, 0.25 mmol) were added. After dissolving with 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) and indium tribromide (6.63 mg, 0.03 mmol) were added. The reaction was stirred at room temperature. The reaction was stopped after detection by TLC when the reaction was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 82%).

[0023] The structure and NMR data of the product (E)-3-(2-(2-methyl-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 1 are as follows:

[0024]

[0025] 1 H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.90(d,J=7.0Hz,1H),7.37(d,J=7.5Hz,1H),7.27(d,J=2.6Hz,1H),7.27–7.17(m,2H),7.00(d,J=15.9Hz,1H),6.35(d,J=15.9Hz,1H),3.05–2.94(m,2H),2.84–2.72(m,2H),2.07–1.98(m,1H),1.97–1.86(m,1H),1.75(s,3H). 1313C NMR (101 MHz, CDCl3) δ 136.88, 130.73, 125.60, 124.34, 123.85, 122.75, 120.54, 120.26, 114.38, 111.49, 50.98, 30.11, 27.79, 25.06.

[0026] Example 2: Reaction steps for the preparation of (E)-2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-3-methyl-1H-indole:

[0027] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 3-methylindole (52.4 mg, 0.4 mmol) were added. After dissolving in 6 mL of dichloromethane, indium(III) chloride (8.8 mg, 0.03 mmol) was added. The reaction was stirred at 50 °C. The reaction was stopped after detection by TLC when the reaction was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 80%).

[0028] The structure and NMR data of the product (E)-2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-3-methyl-1H-indole obtained in Example 2 are as follows:

[0029]

[0030] 1 1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.28–7.18 (m, 2H), 6.96 (d, J = 16.0 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 3.01 (t, J = 12.2 Hz, 2H), 2.67 (d, J = 14.3 Hz, 2H), 2.01–1.91 (m, 1H), 1.86–1.74 (m, 1H), 1.22 (s, 9H). 1313C NMR (101 MHz, CDCl3) δ 136.92, 128.39, 127.72, 125.60, 123.76, 122.79, 120.61, 120.38, 114.82, 111.53, 66.77, 40.38, 27.52, 26.18, 25.64.

[0031] Example 3: Reaction steps for the method of preparing (E)-3-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indole:

[0032] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and indole (29 mg, 0.25 mmol). After dissolving in 6 mL of chloroform, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at -78 °C. Stop the reaction after detecting complete reaction by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 80%).

[0033] The structure and NMR data of the product (E)-3-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 3 are as follows:

[0034]

[0035] 1 1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.27–7.18 (m, 2H), 6.96 (d, J = 16.0 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 3.01 (t, J = 12.1 Hz, 2H), 2.67 (d, J = 14.3 Hz, 2H), 2.01–1.91 (m, 1H), 1.80 (d, J = 13.4 Hz, 1H), 1.22 (s, 9H). 1313C NMR (101 MHz, CDCl3) δ 136.92, 128.39, 127.72, 125.60, 123.76, 122.79, 120.61, 120.38, 114.82, 111.53, 66.77, 40.38, 27.52, 26.18, 25.64.

[0036] Example 4: Reaction steps for the preparation of (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-1H-indole:

[0037] In a 25 mL round-bottom flask, cyclohexyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 3-methylindole (29 mg, 0.25 mmol) were added. After dissolving with 3 mL of 1,2-dichloroethane and 3 mL of dichloromethane, I2 (7.6 mg, 0.03 mmol) was added. The reaction was stirred at -20 °C. The reaction was stopped after detection by TLC when the reaction was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, column chromatography gave the product (yield 71%).

[0038] The product (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)

[0039] -1H-indole obtained in Example 4 has the following structure and NMR data:

[0040]

[0041] 1 1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23–7.11 (m, 3H), 7.09 (s, 1H), 3.06–2.93 (m, 2H), 2.84–2.73 (m, 2H), 2.76–2.68 (t, 2H), 2.19–2.12 (m, 2H), 2.09–1.92 (m, 2H), 1.87–1.77 (m, 2H), 1.59–1.48 (m, 2H). 13CNMR(101MHz,CDCl3)δ140.57,135.72,127.62,122.58,122.34,119.84,119.53,118.04,113.54,111.16,56.71,41.38,27.84,27.47,26.90,26.14,22.10.

[0042] Example 5: Reaction steps for preparing ((E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-5-methyl-1H-indole):

[0043] In a 25 mL round-bottom flask, add cyclohexyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 5-methylindole (33 mg, 0.25 mmol). After dissolving with 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 75%).

[0044] The structure and NMR data of the product ((E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-5-methyl-1H-indole obtained in Example 5 are as follows:

[0045]

[0046] 1 H NMR(400MHz,Chloroform-d)δ8.07(s,1H),7.40(s,1H),7.24(d,J=8.2Hz,1H),7.10(d,J=1.6Hz,1H),7.06(s,1H),7.03(d,J=7.5Hz,1H),3.03–2.93(m,2H),2.84–2.76(m,2H),2.75–2.70(m,2H),2.46(s,3H),2.18–2.14(m,2H),2.11–1.96(m,2H),1.82(t,J=6.1Hz,2H),1.54(t,J=6.1Hz,2H). 1313C NMR (101 MHz, CDCl3) δ 140.17, 134.06, 129.14, 127.89, 123.97, 122.72, 119.08, 118.15, 113.03, 110.80, 56.74, 41.31, 27.80, 27.47, 26.87, 26.16, 22.14, 21.64.

[0047] Example 6: Reaction steps for the preparation of (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-5-methoxy-1H-indole:

[0048] In a 25 mL round-bottom flask, add cyclohexyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 5-methoxyindole (37 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 73%).

[0049] The structure and NMR data of the product (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-5-methoxy-1H-indole obtained in Example 6 are as follows:

[0050]

[0051] 1 1H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.26 (s, 1H), 7.15 (d, J = 2.6 Hz, 1H), 7.08–7.01 (m, 2H), 6.88 (dd, J = 8.8, 2.5 Hz, 1H), 3.87 (s, 3H), 3.08–2.90 (m, 2H), 2.86–2.76 (m, 2H), 2.73 (t, J = 6.3 Hz, 2H), 2.21–2.14 (m, 2H), 2.12–1.97 (m, 2H), 1.84 (d, J = 6.1 Hz, 2H), 1.61–1.51 (m, 2H). 1313C NMR (101 MHz, CDCl3) δ 154.42, 140.47, 130.98, 128.17, 123.47, 118.09, 113.50, 112.47, 111.85, 101.70, 56.70, 56.09, 41.28, 27.87, 27.48, 27.02, 26.20, 22.20.

[0052] Example 7: Reaction steps for the preparation of (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-5-bromo-1H-indole:

[0053] In a 25 mL round-bottom flask, add cyclohexyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 5-bromoindole (49 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 82%).

[0054] The product obtained in Example 7, (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)

[0055] -5-bromo-1H-indole has the following structure and NMR data:

[0056]

[0057] 1 1H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 7.72 (s, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 6.99 (s, 1H), 3.02–2.90 (m, 2H), 2.87–2.77 (m, 2H), 2.70 (t, J = 6.3 Hz, 2H), 2.20–2.12 (m, 2H), 2.10–1.95 (m, 2H), 1.87–1.78 (m, 2H), 1.54 (t, J = 6.2 Hz, 2H). 1313C NMR (101 MHz, CDCl3) δ 141.60, 134.39, 129.45, 125.27, 123.69, 122.18, 117.26, 113.40, 113.24, 112.60, 56.55, 41.32, 27.85, 27.50, 26.90, 26.12, 22.11.

[0058] Example 8: Reaction steps for the preparation of (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-2-methyl-1H-indole:

[0059] In a 25 mL round-bottom flask, cyclohexyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 2-methylindole (33 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, ferric chloride hexahydrate (8.1 mg, 0.03 mmol) was added. The reaction was stirred at 0 °C. The reaction was stopped after being detected by TLC until complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 77%).

[0060] The structure and NMR data of the product (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-2-methyl-1H-indole obtained in Example 8 are as follows:

[0061]

[0062] 1 1H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.16–7.07 (m, 2H), 6.91 (s, 1H), 3.06–2.97 (m, 2H), 2.83–2.75 (m, 2H), 2.49–2.43 (m, 2H), 2.35 (s, 3H), 2.20–2.15 (m, 2H), 2.12–2.05 (m, 1H), 2.03–1.94 (m, 1H), 1.85–1.75 (m, 2H), 1.50–1.42 (m, 2H). 1313C NMR (101 MHz, CDCl3) δ 142.15, 135.34, 132.07, 128.43, 121.30, 119.60, 119.26, 118.83, 110.63, 110.27, 56.40, 41.57, 28.11, 27.56, 27.52, 26.23, 22.08, 12.89.

[0063] Example 9: Reaction steps for the preparation of (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-2-phenyl-1H-indole

[0064] In a 25 mL round-bottom flask, add cyclohexyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 2-phenylindole (48 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature and stop the reaction after detecting by TLC when the reaction is complete. Quench the mixture with 1N NaHCO3 (10 mL), extract with EtOAc (15 mL), separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 82%).

[0065] The product obtained in Example 9, (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)

[0066] -2-phenyl-1H-indole has the following structure and NMR data:

[0067]

[0068] 1H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.67 (d, J = 7.1 Hz, 2H), 7.49–7.40 (m, 3H), 7.39 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 6.9 Hz, 1H), 7.16 (d, J = 6.7 Hz, 1H), 7.04 (s, 1H), 3.07–2.96 (m, 2H), 2.81–2.71 (m, 2H), 2.49–2.41 (m, 2H), 2.22–2.14 (m, 2H), 2.10–2.03 (m, 1H), 2.01–1.93 (m, 1H), 1.78 (t, J = 6.1 Hz, 2H), 1.37 (t, J = 6.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 141.95, 137.35, 136.38, 132.18, 130.83, 128.96, 128.87, 128.66, 128.54, 128.24, 127.85, 127.72, 126.92, 123.03, 121.00, 120.77, 111.27, 110.61, 60.24, 28.85, 24.71.

[0069] Example 10: Reaction steps for the preparation of (E)-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole:

[0070] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and indole (29 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after detection by TLC when the reaction was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 80%).

[0071] The product (E)-3-((1,5-dithiaspiro[5.5]undecan-7-ylidene)methyl)-1H-indole obtained in Example 10

[0072] has the following structure and NMR data:

[0073]

[0074] 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.94–7.86 (m, 3H), 7.41–7.32 (m, 3H), 7.30 (d, J = 7.3 Hz, 1H), 7.24 (t, J = 3.6 Hz, 2H), 7.23–7.14 (m, 2H), 6.82 (s, 1H), 6.51 (d, J = 15.9 Hz, 1H), 3.07–2.97 (m, 2H), 2.82–2.73 (m, 2H), 2.07–1.93 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 142.04, 136.87, 128.97, 128.87, 128.53, 127.90, 127.25, 125.54, 124.28, 122.81, 120.64, 120.35, 114.34, 111.50, 59.87, 28.91, 24.76.

[0075] Example 11: Reaction steps for the preparation of (E)-5-chloro-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole:

[0076] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and 5-chloroindole (38 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after complete reaction detected by TLC. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 75%).

[0077] The product (E)-5-chloro-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 11

[0078] -1H-indole has the following structure and NMR data:

[0079]

[0080] 11H NMR (400 MHz, DMSO-d6) δ (E-isomer) 11.55 (s, 1H), 7.78 (d, J = 7.1 Hz, 2H), 7.72 (d, J = 2.7 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.45–7.38 (m, 3H), 7.31 (t, J = 7.3 Hz, 1H), 7.15 (dd, J = 8.6, 2.0 Hz, 1H), 6.77 (d, J = 16.0 Hz, 1H), 6.30 (d, J = 16.0 Hz, 1H), 3.00–2.91 (m, 2H), 2.79–2.68 (m, 2H), 2.03–1.93 (m, 2H). 13 13C NMR (101 MHz, DMSO) δ (E-isomer) 142.51, 135.87, 128.98, 128.64, 128.36, 128.34, 127.94, 127.06, 126.57, 124.90, 122.18, 118.70, 114.03, 112.27, 59.57, 28.69, 24.57.

[0081] Example 12: Reaction steps for the preparation of (E)-4-bromo-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole

[0082] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and 4-bromoindole (49 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, phosphoric acid (2.9 mg, 0.03 mmol) was added. The reaction was stirred at 25 °C. The reaction was stopped after completion detected by TLC. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 64%).

[0083] The product (E)-4-bromo-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 12

[0084] -1H-indole has the following structure and NMR data:

[0085]

[0086] 11H NMR (400 MHz, Chloroform-d) δ (E-isomer) 8.25 (s, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 15.7 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.34–7.27 (m, 3H), 7.01 (t, J = 7.9 Hz, 1H), 6.21 (d, J = 15.7 Hz, 1H), 3.12–3.02 (m, 2H), 2.83–2.74 (m, 2H), 2.09–1.96 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ (E-isomer) 141.89, 137.44, 129.75, 128.81, 128.57, 127.92, 127.09, 124.93, 123.25, 122.20, 115.75, 114.44, 110.77, 59.55, 28.81, 24.80.

[0087] Example 13: Reaction steps for the preparation of (E)-5-nitro-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole

[0088] In a 25 mL round-bottom flask, add cyclohexyl-β-chloro-vinyl-1,3-dithiane (64 mg, 0.2 mmol) and 5-nitroindole (41 mg, 0.25 mmol). After dissolving in 6 mL of chlorobenzene, add acetic acid (1.8 mg, 0.03 mmol). Stir the reaction at room temperature and stop the reaction when detected by TLC to be complete. Quench the mixture with 1N NaHCO3 (10 mL), extract with EtOAc (15 mL), separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 78%).

[0089] The product (E)-5-nitro-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 13

[0090] - has the following structure and NMR data:

[0091]

[0092] 11H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 9.0, 2.2 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 8.9 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 16.0 Hz, 1H), 6.46 (d, J = 16.0 Hz, 1H), 3.06–2.96 (m, 2H), 2.84–2.74 (m, 2H), 2.06–1.98 (m, 1H), 1.91–1.80 (m, 1H). 13 13C NMR (101 MHz, DMSO) δ 142.32, 141.59, 140.43, 129.90, 129.64, 129.05, 128.59, 128.49, 126.10, 124.87, 117.60, 116.37, 114.85, 112.96, 59.33, 28.67, 24.53.

[0093] Example 14: Preparation of (E)-2-methyl-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)

[0094] -1H-indole reaction steps:

[0095] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and 2-methylindole (78.6 mg, 0.6 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, trifluoroacetic acid (6.3 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after completion detected by TLC. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, column chromatography gave the product (yield 90%).

[0096] The product (E)-2-methyl-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)

[0097] -1H-indole obtained in Example 14 has the following structure and NMR data:

[0098]

[0099] 1 1H NMR (400 MHz, Chloroform-d) δ (E-isomer) 7.92 (d, J = 8.6 Hz, 2H), 7.83 (dd, J = 10.1, 5.0 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.32–7.21 (m, 2H), 7.14 (dd, J = 6.0, 2.3 Hz, 2H), 6.82 (d, J = 15.9 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 3.06–2.97 (m, 2H), 2.81–2.73 (m, 2H), 2.38 (s, 3H), 2.09–1.93 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ (E-isomer) 142.18, 135.53, 134.68, 128.85, 128.48, 128.36, 127.86, 126.91, 126.57, 121.83, 120.51, 119.68, 110.60, 110.58, 109.84, 60.23, 28.91, 24.76, 12.34.

[0100] Example 15: Reaction steps for the preparation of (E)-2-phenyl-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole:

[0101] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and 2-phenylindole (48 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, bismuth trichloride (3.15 mg, 0.01 mmol) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the reaction was stopped. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 89%).

[0102] The product (E)-2-phenyl-3-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 16

[0103] - has the following structure and NMR data:

[0104]

[0105] 1 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.00–7.89 (m, 3H), 7.41 (dd, J = 7.8, 1.1 Hz, 2H), 7.39–7.28 (m, 6H), 7.26 (d, J = 7.2 Hz, 1H), 7.25–7.16 (m, 2H), 6.84 (d, J = 15.9 Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H), 2.99–2.91 (m, 2H), 2.78–2.68 (m, 2H), 2.02–1.91 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 141.95, 137.35, 136.38, 132.18, 130.83, 128.96, 128.87, 128.66, 128.54, 128.24, 127.85, 127.72, 126.92, 123.03, 121.00, 120.77, 111.27, 110.61, 60.24, 28.85, 24.71.

[0106] Example 17: Reaction steps for the preparation of (E)-3-(2-(2-(p-tolyl)-1,3-dithian-2-yl)vinyl)-1H-indole:

[0107] In a 25 mL round-bottom flask, 4-methylphenyl-β-chloro-vinyl-1,3-dithiane (54 mg, 0.2 mmol) and indole (29 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after being detected by TLC until complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 80%).

[0108] The structure and NMR data of the product (E)-3-(2-(2-(p-tolyl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 17 are as follows:

[0109]

[0110] 11H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 6.7 Hz, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.26–7.21 (m, 2H), 7.23–7.13 (m, 3H), 6.85 (d, J = 16.0 Hz, 1H), 6.50 (d, J = 16.2 Hz, 1H), 3.07–2.97 (m, 2H), 2.81–2.71 (m, 2H), 2.35 (s, 3H), 2.06–1.92 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 139.08, 137.68, 136.86, 129.24, 129.08, 128.70, 127.12, 125.55, 124.25, 122.77, 120.60, 120.36, 114.35, 111.49, 59.65, 28.94, 24.79, 21.14.

[0111] Example 18: Reaction steps for the preparation of (E)-3-(2-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)vinyl)-1H-indole

[0112] In a 25 mL round-bottom flask, 4-methoxyphenyl-β-chloro-vinyl-1,3-dithiane (29 mg, 0.2 mmol) and 3-methylindole (57 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after complete reaction detected by TLC. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 77%).

[0113] The product (E)-3-(2-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 18

[0114] - has the following structure and NMR data:

[0115]

[0116] 11H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.25–7.16 (m, 2H), 6.93–6.81 (m, 3H), 6.50 (d, J = 15.9 Hz, 1H), 3.82 (s, 3H), 3.08–2.97 (m, 2H), 2.81–2.73 (m, 2H), 2.08–1.94 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 159.11, 136.81, 134.01, 130.05, 129.09, 127.09, 125.50, 124.17, 122.73, 120.56, 120.32, 114.32, 113.71, 111.43, 59.33, 55.33, 28.96, 24.72.

[0117] Example 19: Reaction steps for the preparation of (E)-3-(2-(2-(4-fluorophenyl)-1,3-dithian-2-yl)vinyl)-1H-indole

[0118] In a 25 mL round-bottom flask, 4-fluorophenyl-β-chloro-vinyl-1,3-dithiane (29 mg, 0.2 mmol) and indole (55 mg, 0.25 mmol) were added. After dissolving with 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after being detected by TLC until completion. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 71%).

[0119] The product (E)-3-(2-(2-(4-fluorophenyl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 19

[0120] -1H-indole has the following structure and NMR data:

[0121]

[0122] 11H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.92–7.82 (m, 3H), 7.36 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.24–7.16 (m, 2H), 7.04 (t, J = 8.7 Hz, 2H), 6.82 (d, J = 15.9 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 3.05–2.94 (m, 2H), 2.81–2.70 (m, 2H), 2.05–1.95 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 163.51, 161.05, 137.84, 137.80, 136.86, 130.84, 130.76, 128.67, 127.50, 125.44, 124.45, 122.86, 120.70, 120.30, 115.37, 115.16, 114.15, 111.55, 59.23, 28.93, 24.63. 19 19F NMR (376 MHz, CDCl3) δ -111.65.

[0123] Example 20: Reaction steps for the preparation of (E)-1-(2-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)vinyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline

[0124] In a 25 mL round-bottom flask, 4-methoxyphenyl-β-chloro-vinyl-1,3-dithiane (57 mg, 0.2 mmol) and 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (39 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after being detected by TLC until complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 87%).

[0125] The product obtained in Example 20, (E)-1-(2-(2-(4-methoxyphenyl)-1,3-dithian-2-yl)vinyl)

[0126] The structure and NMR data of -5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline are as follows:

[0127]

[0128] 1 H NMR(400MHz,Chloroform-d)δ7.80(d,J=8.9Hz,2H),7.71(d,J=9.0Hz,1H),7.12(s,1H),7.12–7.04(m,1H),6.95(d,J=6.6Hz,1H),6.90–6.79(m,3H),6.46(d,J=15.9Hz,1H),4.14–4.06(m,2H),3.80(s,3H),3.07–2.93(m,4H),2.78–2.69(m,2H),2.25–2.16(m,2H),2.05–1.91(m,2H). 13 C NMR(101MHz,CDCl3)δ159.11,135.16,134.29,130.06,127.99,127.87,126.56,123.52,122.11,120.67,119.50,118.22,113.68,112.93,59.47,55.35,44.24,29.04,24.81,24.71,22.82.

[0129] Example 21: Reaction steps for the preparation of (E)-3-methyl-2-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indole

[0130] In a 25 mL round-bottom flask, phenyl-β-chloro-vinyl-1,3-dithiane (33 mg, 0.2 mmol) and 3-methylindole (51 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at 100 °C. The reaction was stopped after detection by TLC when the reaction was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 72%).

[0131] The product obtained in Example 22, (E)-3-methyl-2-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)

[0132] -1H-indole has the following structure and NMR data:

[0133]

[0134] 1 H NMR(400MHz,Chloroform-d)δ7.96(s,1H),7.86(d,J=7.1Hz,2H),7.51(d,J=8.8Hz,1H),7.39(t,J=7.5Hz,2H),7.30(t,J=7.3Hz,1H),7.24(d,J=3.1Hz,1H),7.18(t,J=7.2Hz,1H),7.08(t,J=6.9Hz,1H),6.84(d,J=16.0Hz,1H),6.16(d,J=16.0Hz,1H),3.03–2.93(m,2H),2.82–2.73(m,2H),2.31(s,3H),2.08–1.94(m,2H). 13 C NMR(101MHz,CDCl3)δ141.40,136.45,130.89,129.46,128.64,128.62,128.13,123.36,122.88,119.58,119.10,112.82,110.53,59.23,28.78,24.54,8.81.

[0135] Example 23: The reaction steps for preparing (E)-2-(2-(2-(4-chlorophenyl)-1,3-dithian-2-yl)vinyl)

[0136] -3-methyl-1H-indole method:

[0137] In a 25 mL round-bottom flask, 4-chlorophenyl-β-chloro-vinyl-1,3-dithiane (58 mg, 0.2 mmol) and 3-methylindole (33 mg, 0.25 mmol) were added. After dissolving with 6 mL of 1,2-dichloroethane, boron trifluoride diethyl etherate (3.45 mg, 0.03 mmol) was added. The reaction was stirred at 30 °C. The reaction was stopped after detection by TLC when the reaction was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, column chromatography gave the product (yield 72%).

[0138] The product obtained in Example 23, (E)-2-(2-(2-(4-chlorophenyl)-1,3-dithian-2-yl)vinyl)

[0139] -3-methyl-1H-indole has the following structure and NMR data:

[0140]

[0141] 1 H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 3.8 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.09 (t, J = 6.9 Hz, 1H), 6.79 (d, J = 16.0 Hz, 1H), 6.13 (d, J = 16.0 Hz, 1H), 2.99–2.91 (m, 2H), 2.80–2.73 (m, 2H), 2.31 (s, 3H), 2.08–1.92 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 140.01, 136.47, 133.98, 130.63, 130.23, 129.41, 128.90, 128.71, 123.49, 123.12, 119.63, 119.14, 113.14, 110.50, 58.66, 28.73, 24.35, 8.81.

[0142] Example 24: Preparation of (E)-2-(2-(2-(4-bromophenyl)-1,3-dithian-2-yl)vinyl)

[0143] Reaction steps of the -3-methyl-1H-indole method:

[0144] In a 25 mL round-bottom flask, 4-bromophenyl-β-chloro-vinyl-1,3-dithiane (67 mg, 0.2 mmol) and 3-methylindole (33 mg, 0.25 mmol) were added. After dissolving in 6 mL of toluene, NCS (4.0 mg, 0.03 mmol) was added. The reaction was stirred at room temperature. The reaction was stopped after being detected by TLC when it was complete. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporating the solvent, the product was obtained by column chromatography (yield 71%).

[0145] The product obtained in Example 24, (E)-2-(2-(2-(4-bromophenyl)-1,3-dithian-2-yl)vinyl)

[0146] -3-methyl-1H-indole has the following structure and NMR data:

[0147]

[0148] 1 H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.75(d,J=8.7Hz,2H),7.56–7.48(m,3H),7.28(d,J=8.1Hz,1H),7.24–7.16(m,1H),7.13–7.04(m,1H),6.80(d,J=16.0Hz,1H),6.12(d,J=16.0Hz,1H),2.99–2.91(m,2H),2.83–2.72(m,2H),2.31(s,3H),2.09–1.94(m,2H). 13 C NMR(101MHz,CDCl3)δ140.65,136.54,131.76,130.69,130.66,129.48,128.89,123.58,123.21,122.32,119.71,119.23,113.24,110.58,58.80,28.80,24.42,8.90.

[0149] Example 25: Reaction steps for the preparation of (E)-3-methyl-2-(2-(2-(naphthalen-2-yl)-1,3-dithian-2-yl)vinyl)-1H-indole:

[0150] In a 25 mL round-bottom flask, add naphthyl-β-chloro-vinyl-1,3-dithiane (61 mg, 0.2 mmol) and 3-methylindole (33 mg, 0.25 mmol). After dissolving in 6 mL of chlorobenzene, add indium(III) iodide (14.9 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL) and extract with EtOAc (15 mL). Separate the organic layer and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and purify by column chromatography to obtain the product (yield 70%).

[0151] The structure and NMR data of the product (E)-3-methyl-2-(2-(2-(naphthalen-2-yl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 25 are as follows:

[0152]

[0153] 1 H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.04–7.97 (m, 2H), 7.90–7.81 (m, 3H), 7.55–7.46 (m, 3H), 7.27 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H), 3.06–2.95 (m, 2H), 2.86–2.78 (m, 2H), 2.30 (s, 3H), 2.05 (dd, J = 16.5, 8.0 Hz, 2H). 1313C NMR (101 MHz, CDCl3) δ 138.68, 136.52, 133.23, 132.99, 130.94, 129.52, 129.41, 128.55, 128.44, 128.04, 127.58, 126.64, 126.52, 126.34, 123.47, 123.07, 119.65, 119.18, 113.02, 110.57, 59.42, 28.83, 24.56, 8.91.

[0154] Example 26: Reaction steps for the preparation of (E)-3-methyl-2-(2-(2-methyl-1,3-dithian-2-yl)vinyl)-1H-indole:

[0155] In a 25 mL round-bottom flask, add methyl-β-chloro-vinyl-1,3-dithiane (39 mg, 0.2 mmol) and 3-methylindole (33 mg, 0.25 mmol). After dissolving in 6 mL of toluene, add NBS (5.3 mg, 0.03 mmol). Stir the reaction at room temperature and stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), extract with EtOAc (15 mL), separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 75%).

[0156] The product (E)-3-methyl-2-(2-(2-methyl-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 26

[0157] - has the following structure and NMR data:

[0158]

[0159] 11H NMR (400 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.21–7.13 (m, 1H), 7.12–7.04 (m, 1H), 6.94 (d, J = 15.9 Hz, 1H), 6.02 (d, J = 15.9 Hz, 1H), 2.99–2.88 (m, 2H), 2.80–2.70 (m, 2H), 2.35 (s, 3H), 2.05–1.96 (m, 1H), 1.93–1.87 (m, 1H), 1.72 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 136.42, 131.30, 131.03, 129.52, 123.17, 120.49, 119.52, 119.02, 112.25, 110.50, 50.51, 29.93, 27.69, 24.80, 8.83.

[0160] Example 27: Reaction steps for the preparation of (E)-2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)acetate:

[0161] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 3-acetoxymethyl indole (47 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 78%).

[0162] The product (E)-2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)

[0163] -1H-indol-3-yl)acetate obtained in Example 27 has the following structure and NMR data:

[0164]

[0165] 11H NMR (400 MHz, Chloroform-d) δ (E-isomer) 8.26 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24–7.15 (m, 1H), 7.11 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 16.1 Hz, 1H), 6.16 (d, J = 16.0 Hz, 1H), 3.85 (s, 2H), 3.66 (s, 3H), 2.98–2.86 (m, 2H), 2.73–2.63 (m, 2H), 2.01–1.93 (m, 1H), 1.86–1.74 (m, 1H), 1.20 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ (E-isomer) 172.00, 136.15, 132.68, 130.20, 128.69, 123.87, 123.41, 120.21, 119.06, 110.67, 108.27, 65.87, 52.14, 40.48, 30.33, 27.35, 26.13, 25.33.

[0166] Example 28: Preparation of (E)-2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol

[0167] -3-yl)acetic acid reaction steps of the method:

[0168] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and 3-acetylindole (35 mg, 0.25 mmol). After dissolving with 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction after detecting by TLC when the reaction is complete. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 76%).

[0169] The product (E)-2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)

[0170] -1H-indol-3-yl)acetic acid obtained in Example 28 has the following structure and NMR data:

[0171]

[0172] 1 1H NMR (400 MHz, DMSO-d6) δ 12.27–12.14 (m, 1H), 11.28 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 16.0 Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H), 3.67 (s, 2H), 2.82 (t, J = 12.6 Hz, 2H), 2.74–2.63 (m, 2H), 1.96–1.89 (m, 1H), 1.63–1.54 (m, 1H), 1.12 (s, 9H). 13 13C NMR (101 MHz, DMSO) δ 173.26, 136.75, 133.34, 130.18, 128.74, 124.10, 122.71, 119.30, 119.05, 111.20, 108.18, 66.12, 30.38, 27.03, 26.29, 25.29.

[0173] Example 29: Reaction steps for the preparation of (E)-2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)ethan-1-ol:

[0174] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (32.2 mg, 0.2 mmol) and tryptophol (47.2 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature and stop the reaction when detected by TLC to be complete. Quench the mixture with 1N NaHCO3 (10 mL) and extract with EtOAc (15 mL). Separate the organic layer and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 76%).

[0175] The structure and NMR data of the product (E)-2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)ethan-1-ol obtained in Example 29 are as follows:

[0176]

[0177] 1 1H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.0 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 16.1 Hz, 1H), 6.13 (d, J = 16.1 Hz, 1H), 3.87 (t, J = 6.5 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H), 2.93–2.83 (m, 2H), 2.70–2.60 (m, 2H), 1.98–1.89 (m, 1H), 1.84–1.71 (m, 2H), 1.18 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 136.47, 132.57, 129.39, 128.91, 123.98, 123.34, 119.90, 118.92, 112.16, 110.68, 65.92, 63.19, 40.51, 27.74, 27.36, 26.11, 25.27.

[0178] Example 30: Reaction steps for the preparation of (8R,9S,13S,14S,E)-16-((1H-indol-3-yl)methylene)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-17,2'-

[0179] [1,3]dithian]-3-ol method:

[0180] In a 25 mL round-bottom flask, 17-chloro-16-(1,3-dithiophen-2-yl)-13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-3-ol (81 mg, 0.2 mmol) and indole (48 mg, 0.25 mmol) were added. After dissolving in 6 mL of 1,2-dichloroethane, indium tribromide (29 mg, 0.03 mmol) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the reaction was stopped. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 75%).

[0181] The structure and NMR data of the product (8R,9S,13S,14S,E)-16-((1H-indol-3-yl)methylene)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dithian]-3-ol obtained in Example 30 are as follows:

[0182]

[0183] 1 H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.40–7.29 (m, 2H), 7.26–7.12 (m, 4H), 6.64 (dd, J = 8.4, 2.8 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 4.85 (s, 1H), 3.19–2.92 (m, 3H), 2.87–2.78 (m, 3H), 2.68 (dd, J = 16.0, 7.6 Hz, 1H), 2.44–2.21 (m, 4H), 2.14–1.92 (m, 5H), 1.62–1.42 (m, 3H), 1.01 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 153.42, 142.41, 138.16, 135.42, 132.60, 127.24, 126.45, 122.58, 122.43, 119.90, 119.08, 117.38, 115.33, 114.55, 112.78, 111.01, 67.64, 52.48, 47.18, 43.36, 39.38, 34.71, 32.37, 29.64, 28.48, 28.36, 27.94, 26.76, 24.65, 17.43.

[0184] Example 31: Reaction steps for the preparation of (E)-N-(2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)ethyl)acetamide:

[0185] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and N-(2-(1H-indol-3-yl)ethyl)acetamide (47 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add DTBP (4.4 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction after detecting complete reaction by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), dry over anhydrous Na2SO4, evaporate the solvent, and obtain the product by column chromatography (yield 79%).

[0186] The structure and NMR data of the product (E)-N-(2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)ethyl)acetamide obtained in Example 31 are as follows:

[0187]

[0188] 11H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 9.4 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.13–7.04 (m, 1H), 6.93 (d, J = 16.0 Hz, 1H), 6.19 (d, J = 16.0 Hz, 1H), 5.59 (s, 1H), 3.61–3.50 (m, 2H), 3.06 (t, J = 6.6 Hz, 2H), 2.88 (t, J = 12.0 Hz, 2H), 2.68 (d, J = 14.4 Hz, 2H), 1.96 (dd, J = 10.1, 3.7 Hz, 1H), 1.89 (s, 3H), 1.85–1.74 (m, 1H), 1.19 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 170.16, 136.56, 132.24, 129.69, 128.82, 123.53, 123.34, 119.93, 118.80, 112.84, 110.81, 65.88, 40.55, 40.51, 27.40, 26.13, 25.26, 24.25, 23.43.

[0189] Example 32: Reaction steps for the preparation of (E)-N-(2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-5-methoxy-1H-indol-3-yl)ethyl)acetamide:

[0190] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide (58 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 81%).

[0191] The structure and NMR data of the product (E)-N-(2-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-5-methoxy-1H-indol-3-yl)ethyl)acetamide obtained in Example 32 are as follows:

[0192]

[0193] 1 H NMR(400MHz,Chloroform-d)δ8.91(d,J=7.7Hz,1H),7.23(d,J=8.7Hz,1H),7.01(d,J=2.4Hz,1H),6.90(d,J=16.0Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),6.20(d,J=16.0Hz,1H),5.72(s,1H),3.84(s,3H),3.55(d,J=6.3Hz,2H),3.03(t,J=6.6Hz,2H),2.87(t,J=12.1Hz,2H),2.65(d,J=14.3Hz,2H),2.00–1.92(m,1H),1.92(s,3H),1.81–1.72(m,1H),1.18(s,9H). 13 C NMR(101MHz,CDCl3)δ170.21,154.21,132.98,131.72,129.41,129.13,123.61,113.38,112.44,111.61,100.39,65.88,55.90,40.44,27.33,26.07,25.22,24.23,23.43.

[0194] Example 33: Reaction steps of the method for preparing (S,E)-2-acetamido-3-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)

[0195] vinyl)-1H-indol-3-yl)propanoic acid

[0196] In a 25 mL round-bottom flask, add tert-butyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and acetyl-L-tryptophan (62 mg, 0.25 mmol). After dissolving with 6 mL of 1,2-dichloroethane, add TEMPO (4.7 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. After evaporating the solvent, column chromatography gives the product (yield 80%).

[0197] The structure and NMR data of the product (S,E)-2-acetamido-3-(2-(2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)propanoic acid obtained in Example 33 are as follows:

[0198]

[0199] 1 H NMR (400 MHz, Chloroform-d) δ 8.52 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 16.0 Hz, 1H), 6.26–6.08 (m, 2H), 4.97–4.84 (m, 1H), 3.38 (dd, J = 13.7, 5.8 Hz, 2H), 2.90–2.78 (m, 2H), 2.74–2.58 (m, 2H), 1.99–1.89 (m, 1H), 1.90 (s, 3H), 1.80–1.68 (m, 1H), 1.18 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 174.54, 171.16, 136.43, 133.10, 130.34, 129.10, 123.50, 123.24, 120.20, 118.87, 110.86, 109.71, 65.82, 53.23, 40.59, 27.40, 26.60, 26.19, 25.23, 23.12.

[0200] Example 34: Reaction steps for the preparation of (S,E)-2-acetamido-3-(2-(2-(2-phenyl-1,3-dithian-2-yl)

[0201] vinyl)-1H-indol-3-yl)propanoic acid:

[0202] In a 25 mL round-bottom flask, add phenyl-β-chloro-vinyl-1,3-dithiane (51 mg, 0.2 mmol) and acetyl-L-tryptophan (62 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature and stop the reaction when detected by TLC to be complete. Quench the mixture with 1N NaHCO3 (10 mL), extract with EtOAc (15 mL), separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 62%).

[0203] The structure and NMR data of the product (S,E)-2-acetamido-3-(2-(2-(2-phenyl-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)propanoic acid obtained in Example 34 are as follows:

[0204]

[0205] 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (s, 1H), 7.83 (d, J = 7.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 15.9 Hz, 1H), 6.24 (d, J = 15.9 Hz, 1H), 6.16 (d, J = 7.3 Hz, 1H), 4.91–4.76 (m, 1H), 3.27 (s, 2H), 2.92–2.83 (m, 2H), 2.77–2.68 (m, 2H), 2.02–1.87 (m, 2H), 1.77 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 174.25, 171.19, 141.35, 136.57, 132.78, 131.16, 128.96, 128.72, 128.23, 123.60, 122.01, 120.11, 119.01, 110.93, 110.57, 59.06, 52.95, 28.78, 28.71, 26.46, 24.46, 23.16.

[0206] Example 35: Reaction steps for the preparation of (S,E)-2-acetamido-3-(2-(2-(2-(3-chlorophenyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)propanoic acid

[0207] In a 25 mL round-bottom flask, 3-chlorophenyl-β-chloro-vinyl-1,3-dithiane (58 mg, 0.2 mmol) and acetyl-L-tryptophan (48 mg, 0.25 mmol) were added. After dissolving with 6 mL of 1,2-dichloroethane, indium tribromide (10.6 mg, 0.03 mmol) was added. The reaction was stirred at room temperature and monitored by TLC. After the reaction was complete, the reaction was stopped. The mixture was quenched with 1N NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was separated, and the aqueous phase was re-extracted with EtOAc (15 x 3 mL). The combined organic extracts were washed with brine (15 x 3 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the product was obtained by column chromatography (yield 71%).

[0208] The structure and NMR data of the product (S,E)-2-acetamido-3-(2-(2-(2-(3-chlorophenyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)propanoic acid obtained in Example 35 are as follows

[0209]

[0210] 11H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 7.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.24 (s, 2H), 7.13 (t, J = 7.0 Hz, 1H), 7.04–6.95 (m, 1H), 6.75 (d, J = 15.9 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 6.18 (d, J = 15.9 Hz, 1H), 4.92–4.83 (m, 1H), 3.29 (d, J = 5.4 Hz, 2H), 2.92–2.83 (m, 2H), 2.74–2.65 (m, 2H), 1.99–1.87 (m, 2H), 1.78 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 174.34, 171.36, 143.74, 136.67, 134.52, 132.64, 130.23, 130.00, 128.81, 128.39, 127.09, 123.73, 122.41, 120.10, 119.05, 110.96, 110.78, 58.53, 52.83, 28.75, 28.72, 26.53, 24.29, 23.14.

[0211] Example 36: Preparation of (E)-3-(2-(2-(3,4,5-trimethoxyphenyl)-1,3-dithian-2-yl)

[0212] vinyl)-1H-indole reaction steps:

[0213] In a 25 mL round-bottom flask, add trimethoxyphenyl-β-chloro-vinyl-1,3-dithiane (69 mg, 0.2 mmol) and indole (29 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction when the reaction is complete as detected by TLC. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 45%).

[0214] The structure and NMR data of the product (E)-3-(2-(2-(3,4,5-trimethoxyphenyl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 36 are as follows:

[0215]

[0216] 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.91(d,J=7.8Hz,1H),7.39(d,J=7.7Hz,1H),7.29(d,J=2.6Hz,1H),7.22(d,J=14.4Hz,4H),6.85(d,J=15.9Hz,1H),6.48(d,J=16.0Hz,1H),3.87(s,3H),3.86(s,6H),3.09–2.96(m,2H),2.87–2.75(m,2H),2.07–1.99(m,2H). 13 C NMR(101MHz,CDCl3)δ152.98,137.66,137.45,136.90,128.71,127.38,125.53,124.49,122.80,120.65,120.28,114.22,111.57,106.19,60.91,60.19,56.27,29.06,24.65.

[0217] Example 37: Reaction steps for the preparation of (E)-5-bromo-3-(2-(2-(3,4,5-trimethoxyphenyl)-1,3-dithian-2-yl)vinyl)-1H-indole:

[0218] In a 25 mL round-bottom flask, add trimethoxyphenyl-β-chloro-vinyl-1,3-dithiane (69 mg, 0.2 mmol) and 5-bromoindole (49 mg, 0.25 mmol). After dissolving with 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature. Stop the reaction after detecting by TLC that the reaction is complete. Quench the mixture with 1N NaHCO3 (10 mL), and extract with EtOAc (15 mL). Separate the organic layer, and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL), and dry over anhydrous Na2SO4. After evaporating the solvent, perform column chromatography to obtain the product (yield 58%).

[0219] The structure and NMR data of the product (E)-5-bromo-3-(2-(2-(3,4,5-trimethoxyphenyl)-1,3-dithian-2-yl)vinyl)-1H-indole obtained in Example 37 are as follows:

[0220]

[0221] 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.99(d,J=1.8Hz,1H),7.31(dd,J=8.7,1.8Hz,1H),7.28(d,J=2.7Hz,1H),7.26(s,1H),7.20(s,2H),6.77(d,J=15.9Hz,1H),6.40(d,J=16.0Hz,1H),3.88(s,3H),3.87(s,6H),3.01–2.96(m,2H),2.84–2.78(m,2H),2.07–2.00(m,2H). 13 C NMR(101MHz,CDCl3)δ153.03,137.45,135.48,129.35,127.26,126.52,125.65,125.35,122.71,113.94,113.87,112.99,106.24,60.91,60.02,56.31,29.04,24.59.

[0222] Example 38: Reaction steps for the preparation of Methyl(S)-2-((S)-2-acetamidopropanamido)-3-(2-((E)-2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)propanoate

[0223] In a 25 mL round-bottom flask, add trimethylphenyl-β-chloro-vinyl-1,3-dithiane (47 mg, 0.2 mmol) and acetyl-L-alanyl-L-tryptophan methyl ester (83 mg, 0.25 mmol). After dissolving in 6 mL of 1,2-dichloroethane, add indium tribromide (10.6 mg, 0.03 mmol). Stir the reaction at room temperature and stop the reaction when monitored by TLC until the reaction is complete. Quench the mixture with 1N NaHCO3 (10 mL) and extract with EtOAc (15 mL). Separate the organic layer and re-extract the aqueous phase with EtOAc (15 x 3 mL). Wash the combined organic extracts with brine (15 x 3 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and perform column chromatography to obtain the product (yield 68%).

[0224] The structure and NMR data of the product Methyl (S)-2-((S)-2-acetamidopropanamido)-3-(2-((E)-2-(2-(tert-butyl)-1,3-dithian-2-yl)vinyl)-1H-indol-3-yl)propanoate obtained in Example 38 are as follows:

[0225]

[0226] 1 H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.33–7.28 (m, 1H), 7.22–7.13 (m, 1H), 7.13–7.05 (m, 1H), 6.87 (d, J = 16.0 Hz, 1H), 6.50 (d, J = 7.9 Hz, 1H), 6.18 (d, J = 16.0 Hz, 1H), 6.09 (d, J = 7.5 Hz, 1H), 4.94–4.83 (m, 1H), 4.49–4.34 (m, 1H), 3.67 (s, 3H), 3.45–3.27 (m, 2H), 2.98–2.78 (m, 2H), 2.73–2.63 (m, 2H), 2.04–1.95 (m, 1H), 1.89 (s, 3H), 1.84–1.73 (m, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.19 (s, 10H). 1313C NMR (101 MHz, CDCl3) δ 172.1, 172.0, 169.8, 136.4, 133.0, 130.6, 129.1, 123.5, 123.2, 120.2, 118.9, 110.9, 109.7, 65.8, 53.3, 52.7, 48.8, 40.6, 27.4, 27.4, 27.0, 26.2, 25.2, 23.2, 18.7.

Claims

1. A method for synthesizing a class of alkenyl indole derivatives, characterized in that It includes the following steps: Add substituted indole Ⅰ and alkenyl-1,3-dithiane derivative Ⅱ into a reactor and react under the action of a suitable solvent and a catalyst to achieve the synthesis of alkenylindole compound Ⅲ. The chemical reaction equation is as follows: Substituted indole I wherein R 1 is a substituent at the 1-position of indole and is selected from hydrogen, methyl, tert-butoxycarbonyl, benzyl; R 2 is a substituent at the 2-7 positions of indole and is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, acetyl, amino, carboxyl, hydroxyl, hydroxymethyl, nitro, cyano, halogen, benzyloxy; R 3 is selected from C1-C10 alkyl, phenyl, 2-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 2,5-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl, naphthyl, indolyl, pyrrolyl, thienyl, furyl; The catalyst is one or more of indium trichloride, indium tribromide, indium triiodide, ferric trichloride, boron trifluoride diethyl etherate, iodine, NCS, NBS, DTBP, TEMPO, phosphoric acid, acetic acid; The solvent is one or more of 1,2-dichloroethane, dichloromethane, chloroform, toluene, chlorobenzene.

2. The synthesis method of a class of alkenylindole derivatives according to claim 1, characterized in that: The reaction temperature range is -78 - 100 °C.

Images