CN112898192B - Preparation method of N-acyl indole compound - Google Patents

Abstract

The invention discloses a preparation method of N-acyl indole compound, comprising the following steps: adding palladium catalyst, potassium carbonate, carbon monoxide substitute, 2-alkynyl aniline and aryl iodide into an organic solvent, and heating at 60° C. The reaction was carried out for 24 hours, then silver oxide was added, and the reaction was continued at 60° C. for 24 hours. After the reaction was completed, the N-acyl indole compound was obtained by post-treatment. The preparation method has the advantages of simple operation, cheap and readily available starting materials, high reaction efficiency, good substrate compatibility, and efficient and rapid synthesis of N-acyl indole compounds in one step, which is convenient for operation and broadens the practicability of the method.

Description

A kind of preparation method of N-acyl indole compound

technical field

The invention belongs to the field of organic synthesis, in particular to a preparation method of an N-acyl indole compound.

Background technique

Indole is an important structural backbone and widely exists in natural products and drug molecules. These compounds have antitumor, anti-inflammatory, antiviral, antidiabetic, antidepressant, antihypertensive and other activities (Chem. Rev. 2010, 110, 4489-4497; J. Heterocyclic Chem. 2010, 47, 491-502; , 18, 6620-6662.).

The carbonylation reaction provides an important method for the direct and efficient synthesis of carbonyl compounds (Chem. Rev. 2019, 119, 2090-2127). However, there are few reports on the synthesis of N-acyl indole compounds based on the carbonylation reaction, and they are not widely used at present, but they have great application potential and need to be further studied.

Based on this, we have developed a method for the efficient and rapid synthesis of N-acyl indole compounds via palladium-catalyzed carbonylation cyclization using 2-alkynylanilines and aryl iodides as starting materials.

SUMMARY OF THE INVENTION

The invention provides a preparation method of an N-acyl indole compound. The preparation method has simple steps, can be compatible with various functional groups, and has good reaction applicability.

A preparation method of N-acyl indole compound, comprising the steps of: adding palladium catalyst, potassium carbonate, 1,3,5-tricarboxylic acid phenol ester (TFBen), 2-alkynyl aniline and aryl iodide to organic In the solvent, the reaction is carried out at 50-70° C. for 20-30 hours, then silver oxide is added, and the reaction is continued at 50-70° C. for 20-30 hours. After the reaction is complete, the N-acyl indole compound is obtained by post-processing;

The structure of the 2-alkynyl aniline is shown in formula (II):

The structure of the aryl iodide is shown in formula (III):

The structure of the N-acyl indole compound is shown in formula (I):

R ¹ , R ² and R ³ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, or trifluoromethyl.

The specific reaction formula is as follows:

In the reaction, palladium may be inserted into an aryl iodide to form an aryl palladium intermediate, and carbon monoxide released from 1,3,5-tricarboxylate phenolate is inserted into an aryl palladium intermediate to form an acyl palladium intermediate. Next, 2-alkynylaniline is added to the acylpalladium intermediate, and the amide compound is obtained by reductive elimination. Finally, under the action of silver oxide, the amides are cyclized to form N-acyl indole compounds.

In the present invention, the optional post-processing process includes: filtering, mixing samples with silica gel, and finally purifying by column chromatography to obtain the corresponding N-acyl indole compound, which is a common technical means in the field.

Preferably, R ¹ , R ² , R ³ are independently H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl, and the reaction yield is high; as a further preference, R ¹ is H, F; R ² is H, Me, OMe or F; R ³ is H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl.

Preferably, the reaction time is 48 hours, and it is difficult to ensure the completeness of the reaction if the reaction time is short.

In the present invention, preferably, the organic solvent is acetonitrile, and in this case, various raw materials can be converted into products with a relatively high conversion rate.

The amount of the organic solvent can better dissolve the raw materials, and the amount of the organic solvent used for 1 mmol of 2-alkynylaniline is about 10 mL.

Preferably, the palladium catalyst is tetrakis (triphenylphosphine) palladium, which has higher reaction efficiency among many palladium catalysts.

The molar ratio of described tetrakis (triphenylphosphine) palladium, potassium carbonate, 1,3,5-tricarboxylic acid phenol ester and silver oxide is 0.1:5:5:0.5;

As a further preference, the N-acyl indole compound is one of the compounds represented by formula (I-1)-formula (I-5):

In the above-mentioned preparation method, the described tetrakis (triphenylphosphine) palladium, silver oxide, potassium carbonate and aryl iodide generally adopt commercially available products, which can be easily obtained from the market, and the described 2-alkynylaniline It can be rapidly synthesized from the corresponding 2-iodoaniline and terminal arylyne.

Compared with the prior art, the beneficial effects of the present invention are reflected in the following: the preparation method is easy to operate, and the post-processing is convenient; the starting raw materials for the reaction are cheap and easy to obtain, the substrate functional group tolerance range is wide, the reaction efficiency is high, and the synthesis is efficient and fast in one step. N-acyl indole compounds have strong practicability.

Detailed ways

The present invention will be further described below with reference to specific embodiments.

Add tetrakis(triphenylphosphine)palladium, potassium carbonate, 1,3,5-tricarboxylate phenolate, 2-alkynylaniline (II), aryl iodide to a 35mL Schlenk tube according to the raw material ratio in Table 1 (III) and 2 mL of organic solvent, mixed and stirred uniformly, reacted at 60° C. for 24 hours, then added silver oxide, and continued to react at 60° C. for 24 hours, as shown in Table 1. After the reaction is complete, filter, mix samples with silica gel, and purify by column chromatography to obtain the corresponding N-acyl indole compound (I). The reaction process is shown in the following formula:

The amount of raw materials added in Table 1 Examples 1-15

Table 2

In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is methyl, tBu is tert-butyl, OMe is methoxy, and MeCN is acetonitrile.

The structure confirmation data of the compounds prepared in Examples 1-5:

The nuclear magnetic resonance ( ¹ H NMR, ¹³ C NMR) detection data of the N-acyl indole compound (I-1) prepared in Example 1 are:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71-7.68 (m, 1H), 7.64 (d, J=8.1 Hz, 3H), 7.42-7.37 (m, 2H), 7.34-7.19 (m, 5H) ,7.15(d,J=8.1Hz,2H),6.85(s,1H),2.39(s,3H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.1, 144.0, 141.5, 138.3, 133.1, 132.3, 130.6, 129.3, 129.2, 128.3, 127.6, 124.1, 123.0, 120.8, 114.0, 109.2, 21.8.

The nuclear magnetic resonance ( ¹ H NMR, ¹³ C NMR) detection data of the N-acyl indole compound (I-2) prepared in Example 2 are:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.69–7.61 (m, 3H), 7.58–7.54 (m, 1H), 7.37–7.32 (m, 2H), 7.28–7.20 (m, 4H), 7.19– 7.13(m, 1H), 6.82–6.75(m, 3H), 3.81(s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ 169.4, 163.6, 141.4, 138.3, 133.1, 132.9, 129.3, 128.3, 128.2, 127.6, 127.2, 124.0, 122.8, 120.8, 113.8, 108.8, 55.6.

The nuclear magnetic resonance ( ¹ H NMR, ¹³ C NMR) detection data of the N-acyl indole compound (I-3) prepared from Example 3 are:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.80–7.74 (m, 1H), 7.68–7.63 (m, 1H), 7.57–7.52 (m, 2H), 7.32–7.25 (m, 4H), 7.23– 7.13(m, 5H), 6.79(s, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ169.1, 141.1, 139.2, 138.2, 133.6, 132.9, 131.7, 129.3, 128.6, 128.45, 128.43, 127.9, 124.6, 123.5, 120.9, 114.2, 109.8.

The nuclear magnetic resonance ( ¹ H NMR, ¹³ C NMR) detection data of the N-acyl indole compound (I-4) prepared in Example 4 are:

¹ H NMR (400MHz, CDCl ₃ ): δ 7.67-7.57 (m, 4H), 7.43 (t, J=7.5Hz, 1H), 7.31-7.22 (m, 6H), 6.88 (t, J=8.6Hz) ,2H),6.74(s,1H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.1, 162.2 (d, J=248.0 Hz, 1C), 140.2, 138.2, 135.1, 133.1, 130.3, 130.1 (d, J=8.2 Hz, 1C), 129.3 (d, J=3.4Hz, 1C), 129.25, 128.5, 124.4, 123.3, 120.8, 115.4 (d, J=21.8Hz, 1C), 114.2, 109.7.

The nuclear magnetic resonance ( ¹ H NMR, ¹³ C NMR) detection data of the N-acyl indole compound (I-5) prepared in Example 5 are:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.76-7.71 (m, 1H), 7.67-7.60 (m, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.30-7.23 (m, 4H) ,7.15–7.03(m,3H),6.93(d,J=7.4 Hz,1H),6.78(s,1H),2.24(s,3H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.3, 141.5, 138.3, 137.8, 135.3, 133.0, 132.8, 130.2, 129.4, 129.3, 128.4, 128.3, 128.2, 125.5, 124.3, 123.2, 120.8, 1.4.2.

Claims (5)

1. a preparation method of an N-acyl indole compound is characterized by comprising the following steps: adding a palladium catalyst, alkali, a carbon monoxide substitute, 2-alkynyl aniline and aryl iodide into an organic solvent, reacting for 20-30 hours at 50-70 ℃, then adding an additive, continuing to react for 20-30 hours at 50-70 ℃, and after the reaction is completed, carrying out post-treatment to obtain the N-acylindole compound;

the structure of the 2-alkynyl aniline is shown as the formula (II):

the structure of the aryl iodide is shown as the formula (III):

the structure of the N-acyl indole compound is shown as the formula (I):

R¹、R²、R³independently H, C₁～C₆Alkyl radical, C₁～C₆Alkoxy, halogen or trifluoromethyl;

the palladium catalyst is tetrakis (triphenylphosphine) palladium;

the alkali is potassium carbonate;

the carbon monoxide substitute is phenol ester of 1,3, 5-tricarboxylic acid;

the additive is silver oxide.

2. The method of preparing an N-acylindole compound of claim 1, wherein R is¹H, F;

R²h, Me, OMe or F;

R³is H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl.

3. The process for producing an N-acylindole compound according to claim 1, wherein the molar amount of 2-alkynylaniline: aryl iodide: alkali: palladium catalyst: additive: the carbon monoxide substitute is 1: 1.1-1.2: 4-6: 0.1-0.2: 0.4-0.6: 4-6.

4. The method for preparing an N-acylindole compound according to claim 1, wherein the organic solvent is acetonitrile.

5. The method for preparing an N-acylindole compound according to claim 1, wherein the N-acylindole compound is one of compounds represented by formula (I-1) to formula (I-5):