阅读说明：本技术 一种n-甲基吲哚的合成方法 (Synthesis method of N-methylindole ) 是由 常宏宏 张娟 延秀银 李学金 刘强 高文超 于 2021-09-07 设计创作，主要内容包括：本发明属于化合物合成技术领域,以苯胺和乙二醇为底物,以负载钯的催化剂Pd/Al-(2)O-(3)作为催化剂,TsOH和ZnO作为助催化剂,合成N-甲基吲哚。过量的乙二醇在高温条件下与催化助剂对甲苯磺酸的质子结合,脱去一分子水,同时N-甲基苯胺脱除质子,与乙醇基团结合生成2-甲基苯基乙醇胺。随后在二氧化锰作用下脱水环化生成吲哚啉,最后在钯催化剂的作用下脱去两原子氢生成N-甲基吲哚。(The invention belongs to the technical field of compound synthesis, and particularly relates to a palladium-loaded catalyst Pd/Al with aniline and ethylene glycol as substrates 2 O 3 As catalyst, TsOH and ZnO as cocatalyst N -methylindole. Excessive glycol is combined with the proton of the catalytic assistant p-toluenesulfonic acid under the high temperature condition to remove one molecule of water, and meanwhile, the excessive glycol is combined with the proton of the catalytic assistant p-toluenesulfonic acid to remove one molecule of water N -methylaniline is deprotonated and combined with ethanol groups to produce 2-methylphenylethanolamine. Then dehydrating and cyclizing under the action of manganese dioxide to generate indoline, and finally removing two-atom hydrogen under the action of palladium catalyst to generate N -methylindole.)

1. A kind ofN-methyl indole synthesis method, characterized in that: takes aniline and ethylene glycol as substrates and uses a catalyst Pd/Al of supported palladium₂O₃As catalyst, TsOH and ZnO as cocatalystN-methylindole.

2. A method as claimed in claim 1N-methyl indole synthesis method, characterized in that: the specific method comprises the following steps: sequentially adding the following components into a pressure-resistant reaction device: 0.15 mmol of palladium-supported catalyst, 0.45mmol of cocatalyst TsOH and 0.45mmol of cocatalyst ZnO, based on the palladium content, were used as catalyst system, and 5mmol of cocatalyst ZnO was added4 mmol of ethylene glycol and 1mmolN-methylaniline, stirring in an oil bath at 190 ℃ and reacting for 24 h; cooling to room temperature after reaction, analyzing by thin layer chromatography, extracting with dichloromethane, rotary evaporating dichloromethane layer organic phase, and separating by column chromatography to obtain pure productN-methylindole.

3. A method as claimed in claim 2N-methyl indole synthesis method, characterized in that: the column chromatography conditions used were: the diameter of the chromatographic column is 17 mm, and the length of the chromatographic column is 200 mm; the silica gel is H-shaped silica gel; eluent is petroleum ether/ethyl acetate =90:10 by volume ratio.

Technical Field

The invention belongs to the technical field of compound synthesis, and particularly relates to a compoundNA method for synthesizing methyl indole.

Background

NThe-methylindole as an important molecular skeleton widely exists in various drug molecules, and as shown in figure 1, the-methylindole exists in both lung cancer targeted drug oxitinib and anti-type A virus B drug abidolN-first of allA basic indole skeleton.

To pairNThe research of the synthesis method of the methyl indole provides a new way for synthesizing the drug molecules. At present, the methodNThe synthesis of methyl indole mainly adopts the following two methods: 1) as shown in figure 2, indole is used as raw material and is p-indole by methyl halideN-direct methylation of H; 2) as shown in FIG. 3, ethylene glycol andNone-step synthesis of (E) -methylanilineN-methylindole. Methylation reaction synthesisNThe yield of the-methylindole is high and can reach 99%, but the raw material indole is expensive, and the methyl halide is expensive and has genotoxicity, so the synthesis method has great limitation.

To be provided withNTwo raw materials of the one-step synthesis method of the methyl aniline are relatively low in price, but most of the currently applied catalysts are noble metal catalysts and the temperature is high. Such as: zhang et al obtained indole in 53% yield at 120 ℃ using an organic homogeneous catalyst of ruthenium metal; takuo et al obtained indole in 47% yield at 325 ℃ using a catalyst in which sodium oxide was supported on alumina; indole (TSUJI Y, HUH K T, WATANABE Y, et al., Ruthenium complex catalyzed N-heterocyclic amides and saccharides [ J ] have also been reported to be synthesized at 200 ℃ in about 50% yield using catalysts such as triphenylphosphine Ruthenium chloride and iridium chloride trihydrate]. Tetrahedron Letters, 1986, 27(3) : 377-380）；（ZHANG M, XIE F, WANG X, et al. Improved indole syntheses from anilines and vicinal diols by cooperative catalysis of ruthenium complex and acid [J]Rsc Advances, 2013, 3 (17): 6022-N-synthesis of methylindole.

The reaction for synthesizing indole from ethylene glycol and aniline comprises two important processes of dehydrogenation and dehydration, and the selection of the catalyst system needs to be considered from both aspects. The metal palladium is widely applied to the field of catalytic hydrogenation as a catalyst, is often used in the hydrogenation reduction refining process in the industries of petrochemical industry, medicine, electronic industry, spice, dye and the like, and has the advantages of high hydrogenation reduction, good selectivity, stable performance, small material adding ratio during use, repeated use, easy recovery and the like. Dehydrogenation is used as the reverse reaction of hydrogenation reduction, and a plurality of related application reports show that palladium also has good catalysis effect. As shown in fig. 4, under aerobic conditions, divalent palladium can preferentially react with some active C-H bonds through electrophilic palladium to convert it into hydrogen protons, while palladium is reduced to zero valence state, and the hydrogen protons combine with zero-valent palladium to convert it into water under the action of oxygen, thereby completing the dehydrooxidation process.

Disclosure of Invention

The invention aims to solve the problems of the prior glycol andNone-step synthesis of (E) -methylanilineNIn the process of methyl indole, the currently applied catalyst is mostly a noble metal catalyst, and the temperature is high, and the like, and provides the catalystNA method for synthesizing methyl indole.

The invention is realized by the following technical scheme: a kind ofN-methyl indole synthesis method, characterized in that: takes aniline and ethylene glycol as substrates and uses a catalyst Pd/Al of supported palladium₂O₃As catalyst, p-toluenesulfonic acid TsOH and ZnO as cocatalyst, synthesizingN-methylindole.

A method as claimed in claim 1N-methyl indole synthesis method, characterized in that: the specific method comprises the following steps: sequentially adding the following components into a pressure-resistant reaction device: 0.15 mmol of palladium-supported catalyst, 0.45mmol of cocatalyst TsOH and 0.45mmol of cocatalyst ZnO, based on the palladium content, were used as catalyst system, and 54 mmol of ethylene glycol and 1mmol of cocatalyst ZnO were then addedN-methylaniline, stirring in an oil bath at 190 ℃ and reacting for 24 h; cooling to room temperature after reaction, analyzing by thin layer chromatography, extracting with dichloromethane, rotary evaporating dichloromethane layer organic phase, and separating by column chromatography to obtain pure productN-methylindole. The column chromatography conditions used were: the diameter of the chromatographic column is 17 mm, and the length of the chromatographic column is 200 mm; the silica gel is H-shaped silica gel produced by Qingdao ocean chemical industry Co.Ltd; the eluent is petroleum ether/ethyl acetate =90:10 by volume.

The invention discloses an important dehydrogenation and dehydration step in the reaction process of synthesizing indole by taking aniline glycol as a substrate, and the invention firstly applies a palladium supported catalystIn thatNIn the reaction of synthesizing indole by using methyl aniline glycol, the catalytic dehydrogenation process is promoted, and simultaneously organic acid p-toluenesulfonic acid and weak acid salt ZnO which have good dehydration property in the esterification reaction are added as auxiliaries, so that the dehydration process of the reaction is promoted by activating glycol, and the forward progress of the reaction is further promoted.

To pairNOne-step synthesis of (E) -methylaniline and ethylene glycolNThe catalyst of the methyl indole is screened, and under the condition that the catalytic effect of a single catalyst is poor, a plurality of acids which can be helpful to improve the activity of ethylene glycol and metal oxides which are helpful to dehydration are added as auxiliary agents to promote the forward reaction, so that a three-component catalytic system with relatively good catalytic activity is finally obtained: Pd/Al₂O₃TsOH and ZnO. The reaction mechanism is presumed according to the catalytic reaction condition in the reaction process and the captured possible intermediate.

Firstly, excessive glycol is combined with the proton of catalytic auxiliary agent p-toluenesulfonic acid under the condition of high temperature to remove one molecule of water, and simultaneouslyN-methylaniline is deprotonated and combined with ethanol groups to produce 2-methylphenylethanolamine. Then dehydrating and cyclizing under the action of manganese dioxide to generate indoline, and finally removing two-atom hydrogen under the action of palladium catalyst to generateN-methylindole. Selecting Pd/Al₂O₃When the TsOH and ZnO three components are a catalytic system, the optimal yield is 40.0 percent.

Drawings

FIG. 1 shows two kinds of organic solventsN-a pharmaceutical structural formula of a methyl indole skeleton;

FIG. 2 shows the synthesis of indole as raw materialN-the reaction equation for methylindole;

FIG. 3 is a drawing showingNOne-step synthesis of (E) -methylaniline and ethylene glycolN-the reaction equation for methylindole;

FIG. 4 is a diagram of a palladium catalyst catalytic dehydrogenation reaction process under aerobic conditions;

FIG. 5 is a drawing showingNSynthesis of methyl aniline and ethylene glycolN-the reaction equation for methylindole;

FIG. 6 is a structural formula of an intermediate that may exist in the reaction;

FIG. 7 is a schematic representation of three componentsUnder catalytic systemN-scheme for the synthesis of methylindole;

FIG. 8 is a drawing showingN-nuclear magnetic resonance analysis spectrum of methylindole.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments; all other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

0.15 mmol of palladium-based catalyst (in terms of palladium content), 0.45mmol of the cocatalyst a and 0.45mmol of the cocatalyst b were sequentially charged in a 25 mL pressure-resistant test tube, 54 mmol (3 mL) of ethylene glycol was measured by a microsyringe, and 1mmol (108. mu.L) was measuredN-methylaniline was added to the reaction tube. The reaction tube is placed in an oil bath kettle with the constant temperature of 190 ℃ and reacts for 24 hours under magnetic stirring. After the reaction is finished, the reaction tube is taken out and cooled to room temperature, thin-layer chromatography is firstly used for analysis, then dichloromethane is used for extraction, and a small amount of deionized water can be added to ensure that the effect of extracting and separating liquid is better. The dichloromethane layer organic phase is subjected to rotary evaporation and column chromatography separation to obtain pure dichloromethaneN-methylindole, and the reaction yield is calculated by weighing.

The experimental results are as follows: screening through a series of reaction conditions to obtain a catalytic reaction system shown in Table 1 andN-yield of methylindole synthesis, where the reaction conditions are: catalyst 0.015mmol, 3ml ethylene glycol, 1mmolN-methylaniline, reacting for 24h at 190 ℃, with a catalyst loading of 3 wt%; the yield was then calculated.

Table 1: effect of catalyst composition on yield

It can be seen from the table that when the metallic palladium series catalyst is added in the reaction alone, the yield of the target product indole is low or even no target product, but when some auxiliary agents are added, the reaction yield is obviously improved. When the auxiliary agent ZnO or TsOH is added into the catalytic system, the reaction yield is obviously improved. When Pd/Al is selected₂O₃When the TsOH and ZnO three components are a catalytic system, the optimal yield is 40.0 percent. The reason for this may be: ZnO has oxidability, hydroxyl in an ethylene glycol structure can be oxidized into aldehyde group to generate intermediate glycolaldehyde, an acidic catalyst is favorable for dehydration of alcohol molecules, and the acidity of the catalyst promoter TsOH can further catalyze reaction and dehydration to generate target product indole. Therefore, Pd/Al was determined in the range studied₂O₃TsOH and ZnO are relatively optimal catalytic systems.

The Pd-based catalyst is known to act as a dehydrogenation catalyst in this reaction, and experimental results show that the reaction hardly proceeds with the palladium catalyst alone. When the oxide or p-toluenesulfonic acid is added, the reaction takes place but in lower yields. P-toluenesulfonic acid may play a role in activating glycol and helping glycol dehydration condensation, and ZnO is also often used as a catalyst for hydroxyl oxidation dehydration in organic reactions. Meanwhile, the product shown in the scheme 6 is obtained by separation in the reaction process and is adopted¹H NMR characterized the structure, presumably a key intermediate in the reactionN-methyl-NHydroxyethylaniline, together with a three-component catalyzed reaction mechanism, as speculated in scheme 7.

Firstly, excessive glycol is combined with the proton of catalytic auxiliary agent p-toluenesulfonic acid under the condition of high temperature to remove one molecule of water, and simultaneouslyN-methylaniline is deprotonated and combined with ethanol groups to produce 2-methylphenylethanolamine. Then dehydrating and cyclizing under the action of manganese dioxide to generate indoline, and finally removing two-atom hydrogen under the action of palladium catalyst to generateN-methylindole.

To pairNOne-step synthesis of (E) -methylaniline and ethylene glycolNThe catalyst of-methyl indole is screened and catalyzed by a single catalystUnder the condition of poor chemical effect, several acids which can be helpful to improve the activity of ethylene glycol and metal oxides which are helpful to dehydration are added as auxiliary agents to promote the forward reaction, and finally a three-component catalytic system with relatively good catalytic activity is obtained: Pd/Al₂O₃TsOH and ZnO. The reaction mechanism is presumed according to the catalytic reaction condition in the reaction process and the captured possible intermediate.

The obtained N-methylindole NMR chart is shown in figure 8 and is characterized in that:¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.18 – 7.11 (m, 1H), 7.08 (d, J = 3.1 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 3.81 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 136.5, 128.6, 128.3, 121.3, 120.7, 119.1, 109.0, 100.7, 32.6。

finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.