A method for synthesizing 2-amino-5-thioindole derivatives

Abstract

The invention discloses a method for synthesizing 2-amino-5-sulfindole derivatives, which uses indole compounds, azole compounds and disulfide compounds as raw materials to synthesize 2-amino-5-sulfindole compounds in the next step under the action of a metal catalyst. Compared with traditional methods, the present invention has obvious advantages in terms of synthesis conditions and practicality. It has the advantages of simple synthesis steps, easy operation, non-toxic and cheap raw materials, good compatibility of functional groups, chemical selectivity and high atom economy. The present invention not only effectively solves the problems of needing to pre-prepare substrates, special catalysts, harsh electrochemical conditions, etc. in existing methods, but also conforms more to the concept of green and sustainable chemistry, and provides more effective technical support for the further modification and chemical transformation of indole drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis of indole derivatives, and in particular relates to a method for synthesizing 2-amino-5-thioindole derivatives. Background Art

[0002] 2-Amino-5-thioindole derivatives are a class of compounds containing an indole ring, a structural unit. The indole skeleton is widely found in natural products and pharmaceuticals. It also serves as an intermediate in pharmaceuticals, pesticides, dyes, and other fine chemicals, making it suitable for applications in dyes, marine antifouling, pharmaceuticals, and pesticides. Indole can be used to produce highly active alkaloids, which can be used to prepare therapeutic drugs, such as those for cardiovascular and hematologic diseases, and some drugs can even treat lung cancer. In recent years, the use of indole compounds in pharmaceuticals has increased significantly. Currently available drugs include the antiviral drug arbidol, indopropanol for treating arrhythmias and hypertension, the anticoagulant indobufen, indomethacin for treating rheumatic diseases and arthritis, and the antihypertensive drugs reserpine, vinblastine, ergonovine, and strychnine. The study of indole compounds has long been a hot topic in organic synthesis, with the functionalization of indoles generating intense interest. While research on indole functionalization has primarily focused on single-site C–H bond functionalization, direct difunctionalization of indoles has been rare. Multifunctionalization of indoles is an important synthetic approach to enhance molecular complexity and chemoselectivity.

[0003] With the continuous development of synthetic chemistry and the increasingly severe environmental and resource issues, the development of atom-economic and step-economical synthesis methods has become one of the important criteria for synthetic chemists to design new reactions. Multicomponent reactions have become a highly efficient synthetic method due to their ability to rapidly construct multiple chemical bonds and are widely sought after. However, the development of new multicomponent reactions is often challenging due to the complexity of the reactions. Most of the existing synthetic methods for 2-amino-5-thioindole derivatives still rely on multi-step reactions, and the reaction conditions are harsh, requiring special metal catalysts, the substrate needs to be pre-prepared, and electrochemical methods are not popular, which greatly limits the practicality of such methods. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a simple, practical, economical, efficient and environmentally friendly method for synthesizing 2-amino-5-thioindole derivatives.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] The method for synthesizing 2-amino-5-thioindole derivatives uses an indoline compound, an azole compound, and a disulfide compound as raw materials to synthesize the 2-amino-5-thioindole compound in a single step under the action of a metal catalyst; the indoline compound, the azole compound, and the disulfide compound are compounds having the following structures:

[0007]

[0008] Among them, Ar is the abbreviation of Aromatic, which represents different aromatic groups; R 1 is an aryl group or an alkyl group; R 2 and R 3 Each of them represents an alkyl group, an alkoxy group, a phenyl group, a nitro group, a nitrile group, a trifluoromethyl group, an ester group, a halogen group or a hydrogen group containing one or more substitutions.

[0009] The above-mentioned synthesis method is carried out according to the following steps: adding an indoline compound, an azole compound, a disulfide compound, a metal catalyst, an additive, an oxidant and a solvent into a reactor, stirring the reaction, cooling to room temperature after the reaction, and removing the solvent by rotary evaporation under reduced pressure to obtain a crude product; the crude product is purified by column chromatography to obtain a 2-amino-5-thioindole derivative.

[0010] This method conforms to the following reaction equation:

[0011]

[0012] The reaction is carried out under oxygen conditions at 25-130° C., the reaction time is 1-24 hours, and the oxygen pressure is 1-30 atmospheres.

[0013] The molar ratio of the indoline compound, the azole compound and the disulfide compound is (1-10):(1-10):1.

[0014] The metal catalyst is one or a mixture of two or more of copper acetate, copper sulfate, cuprous chloride, cupric chloride, copper fluoride, cuprous fluoride, copper iodide, cuprous bromide, cupric bromide, copper trifluoromethanesulfonate and ferric chloride.

[0015] The additive is one or a mixture of two or more of sodium trifluoromethanesulfonate, sodium dodecylbenzenesulfonate, sodium acetate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, molecular sieve, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide; the oxidant is one or a mixture of two or more of metal oxides, peroxides, oxidizing acids, inorganic salts, and oxygen; and the solvent is one or a mixture of two or more of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethanol, 1,2-dichloroethane, isopropyl alcohol, isobutanol, N,N-dimethylformamide, dimethyl sulfoxide, toluene, p-xylene, methanol, and water.

[0016] The reactor is a Schlenk tube.

[0017] The eluent used for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (1-50):1.

[0018] In response to the problems currently existing in the synthesis of 2-amino-5-thioindole derivatives, the inventors have established a new synthesis method, which uses indoline compounds, azole compounds and disulfide compounds as raw materials to synthesize 2-amino-5-thioindole compounds in the next step under the action of a metal catalyst. Compared with traditional methods, the present invention has obvious advantages in terms of synthesis conditions and practicality. It has the advantages of simple synthesis steps, simple operation, non-toxic and inexpensive raw materials, good compatibility of the synthesis method with functional groups, high chemical selectivity and atom economy. The present invention not only effectively solves the problems of the existing methods such as the need for pre-prepared substrates, special catalysts, and harsh electrochemical conditions, but also better conforms to the concept of green and sustainable chemistry, and also provides more effective technical support for the further modification and chemical transformation of indole drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is the hydrogen spectrum of the target product obtained in Example 1.

[0020] Figure 2 This is the carbon spectrum of the target product obtained in Example 1.

[0021] Figure 3 This is the hydrogen spectrum of the target product obtained in Example 2.

[0022] Figure 4 This is the carbon spectrum of the target product obtained in Example 2.

[0023] Figure 5 This is the hydrogen spectrum of the target product obtained in Example 3.

[0024] Figure 6 This is the carbon spectrum of the target product obtained in Example 3.

[0025] Figure 7 This is the hydrogen spectrum of the target product obtained in Example 4.

[0026] Figure 8 This is the carbon spectrum of the target product obtained in Example 4.

[0027] Figure 9 This is the hydrogen spectrum of the target product obtained in Example 5.

[0028] Figure 10 This is the carbon spectrum of the target product obtained in Example 5. DETAILED DESCRIPTION

[0029] Example 1

[0030] 0.6 mmol N-methylindoline, 0.8 mmol pyrazole, 0.2 mmol diphenyl disulfide, 0.04 mmol copper iodide, 0.2 mmol elemental iodine, and 2 mL 1,2-dichloroethane were added to a Schlenk tube. The mixture was stirred at 80°C under O2 conditions (the oxygen pressure used was one atmosphere) for 12 hours. The heating and stirring were then stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The target product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 19:1.

[0031] The hydrogen and carbon spectra of the obtained products are shown as follows: Figure 1 and Figure 2 The structural characterization data are as follows:

[0032] 1 H NMR(600MHz,Chloroform-d)δ7.86(s,2H),7.78(d,J=2.3Hz,1H),7.46(d,J=8.5Hz,1H),7.39(d,J=8.5Hz,1H),7 .25(t,J=7.7Hz,2H),7.23–7.19(m,2H),7.15(t,J=7.2Hz,1H),6.53(s,1H),6.52(t,J=2.1Hz,1H),3.74(s,3H).

[0033] 13 C NMR(151MHz,Chloroform-d)δ142.10,139.46,136.53,135.59,132.33,128.88, 128.69,127.89,127.34,126.98,125.50,124.00,110.83,107.09,95.82,30.28.

[0034] According to the above data, the structure of the target product is as follows:

[0035]

[0036] Example 2

[0037] 0.6 mmol N-methylindoline, 0.8 mmol 4-methylpyrazole, 0.2 mmol diphenyl disulfide, 0.04 mmol copper iodide, 0.2 mmol elemental iodine, and 2 mL 1,2-dichloroethane were added to a Schlenk tube. The mixture was stirred at 80°C under O2 conditions (the oxygen pressure used was one atmosphere) for 12 hours. The heating and stirring were then stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The target product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 19:1.

[0038] The hydrogen and carbon spectra of the obtained products are shown as follows: Figure 3 and Figure 4 The structural characterization data are as follows:

[0039] 1 H NMR(600MHz,Chloroform-d)δ7.84(s,1H),7.66(s,1H),7.54(s,1H),7.44(d,J=8.5Hz,1H),7.37(d,J=8.5Hz ,1H),7.25(t,J=7.5Hz,2H),7.22–7.18(m,2H),7.15(t,J=7.2Hz,1H),6.47(s,1H),3.75(s,3H),2.21(s,3H).

[0040] 13 C NMR(151MHz,Chloroform-d)δ142.95,139.53,136.85,135.55,130.69,128.86,128 .52,127.84,127.27,127.06,125.45,123.83,117.61,110.77,95.29,30.31,8.81.

[0041] According to the above data, the structure of the target product is as follows:

[0042]

[0043] Example 3

[0044] 0.6 mmol N-methylindoline, 0.8 mmol pyrazole, 0.2 mmol 4,4-dimethyldiphenyl disulfide, 0.04 mmol copper iodide, 0.2 mmol elemental iodine, and 2 mL 1,2-dichloroethane were added to a Schlenk tube. The mixture was stirred at 80°C under O2 conditions (the oxygen pressure used was one atmosphere) for 12 hours. The heating and stirring were then stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The target product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 19:1.

[0045] The hydrogen and carbon spectra of the obtained products are shown as follows: Figure 5 and Figure 6 The structural characterization data are as follows:

[0046] 1 H NMR(600MHz,Chloroform-d)δ7.87(d,J=4.7Hz,1H),7.82(d,J=6.7Hz,1H),7.77(d,J=2.4Hz,1H),7.45–7.41(m,1H),7. 36(d,J=8.5Hz,1H),7.20(t,J=9.1Hz,2H),7.10(t,J=6.9Hz,2H),6.52(dd,J=4.3,2.4Hz,2H),3.73(s,3H),2.34(s,3H).

[0047] 13 C NMR(151MHz,Chloroform-d)δ142.07,136.48,135.78,135.38,135.29,132.34,129 .75,128.97,128.00,126.92,126.37,125.27,110.73,107.08,95.74,30.27,21.03.

[0048] According to the above data, the structure of the target product is as follows:

[0049]

[0050] Example 4

[0051] 0.6 mmol N-methylindoline, 0.8 mmol pyrazole, 0.2 mmol 4,4-dichlorodiphenyl disulfide, 0.04 mmol copper iodide, 0.2 mmol elemental iodine, and 2 mL 1,2-dichloroethane were added to a Schlenk tube. The mixture was stirred at 80°C under O2 conditions (the oxygen pressure was one atmosphere) for 12 hours. The heating and stirring were then stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The target product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 19:1.

[0052] The hydrogen and carbon spectra of the obtained products are shown as follows: Figure 7 and Figure 8 The structural characterization data are as follows:

[0053] 1 H NMR(600MHz,Chloroform-d)δ7.86(s,1H),7.84(s,1H),7.78(d,J=2.4Hz,1H),7.42(d,J=8.5Hz,1H),7.39( d,J=8.5Hz,1H),7.20(d,J=8.7Hz,2H),7.11(d,J=8.7Hz,2H),6.53(s,1H),6.53–6.52(m,1H),3.74(s,3H).

[0054] 13 C NMR(151MHz,Chloroform-d)δ142.14,138.21,136.66,135.69,132.32,131.29, 129.00,128.94,128.62,127.47,127.03,123.48,110.99,107.13,95.82,30.31.

[0055] According to the above data, the structure of the target product is as follows:

[0056]

[0057] Example 5

[0058] 0.6 mmol N-methylindoline, 0.8 mmol pyrazole, 0.2 mmol 4,4-dinitrodiphenyl disulfide, 0.04 mmol copper iodide, 0.2 mmol elemental iodine, and 2 mL 1,2-dichloroethane were added to a Schlenk tube. The mixture was stirred at 80°C under O2 conditions (the oxygen pressure used was one atmosphere) for 12 hours. Then, heating and stirring were stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation under reduced pressure. The target product was then separated and purified by column chromatography. The column chromatography eluent used was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 19:1.

[0059] The hydrogen and carbon spectra of the obtained products are shown as follows: Figure 9 and Figure 10 The structural characterization data are as follows:

[0060] 1 H NMR(600MHz,Chloroform-d)δ8.04(d,J=9.0Hz,2H),7.91(dd,J=1.6,0.8Hz,1H),7.87(d,J=1.9Hz,1H),7.80 (d,J=2.4Hz,1H),7.49–7.45(m,2H),7.12(d,J=9.0Hz,2H),6.58(s,1H),6.54(t,J=2.1Hz,1H),3.79(s,3H).

[0061] 13 C NMR(151MHz,Chloroform-d)δ150.83,144.89,142.28,137.03,136.27,132.32, 129.41,129.01,127.36,125.51,123.91,120.04,111.52,107.28,95.96,30.44.

[0062] According to the above data, the structure of the target product is as follows:

[0063] .

Claims

1. A method for synthesizing 2-amino-5-thioindole derivatives, characterized in that 2-Amino-5-thioindole compounds were synthesized in one step using indoline compounds, azole compounds and disulfide compounds as raw materials under the action of metal catalysts; The indoline compound, azole compound and disulfide compound are compounds having the following structures: Wherein, Ar is an aromatic group; R 1 is an alkyl group; R 2 and R 3 is alkyl, nitro, halogen or hydrogen; the synthetic reaction is carried out under oxygen conditions, and the metal catalyst is a mixture of copper iodide and iodine; the structure of the 2-amino-5-thioindole derivative is 2. The synthesis method according to claim 1, wherein: The reaction is carried out under oxygen conditions at 25-130° C., the reaction time is 1-24 hours, and the oxygen pressure is 1-30 atmospheres.

3. The synthesis method according to claim 1, wherein: The molar ratio of the indoline compound, the azole compound and the disulfide compound is (1-10):(1-10):1.

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