CN112898192A - Preparation method of N-acylindole compound - Google Patents
Preparation method of N-acylindole compound Download PDFInfo
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- CN112898192A CN112898192A CN202110186332.3A CN202110186332A CN112898192A CN 112898192 A CN112898192 A CN 112898192A CN 202110186332 A CN202110186332 A CN 202110186332A CN 112898192 A CN112898192 A CN 112898192A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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Abstract
The invention discloses a preparation method of an N-acyl indole compound, which comprises the following steps: adding a palladium catalyst, potassium carbonate, a carbon monoxide substitute, 2-alkynyl aniline and aryl iodide into an organic solvent, reacting for 24 hours at 60 ℃, then adding silver oxide, continuing to react for 24 hours at 60 ℃, and after the reaction is completed, carrying out post-treatment to obtain the N-acylindole compound. The preparation method has the advantages of simple operation, cheap and easily obtained starting raw materials, high reaction efficiency, good substrate compatibility, one-step high-efficiency and rapid synthesis of the N-acyl indole compound, convenient operation and widened practicability of the method.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an N-acyl indole compound.
Background
Indoles are important structural backbones, which are widely found in natural products and drug molecules. These compounds have antitumor, antiinflammatory, antiviral, antidiabetic, antidepressant, antihypertensive activities (chem. Rev.2010,110, 4489-4497; J. heterocyclic chem.2010,47,491 502; macromolecules, 2013,18,6620 and 6662.).
Carbonylation provides an important method for directly and efficiently synthesizing carbonyl compounds (chem. Rev.2019,119, 2090-2127). However, the synthesis of N-acyl indole compounds based on carbonylation reaction has few reports and is not widely applied at present, but has great application potential and needs to be studied deeply.
Based on the above, a method for efficiently and quickly synthesizing an N-acylindole compound by using 2-alkynyl aniline and aryl iodide as starting materials through a carbonylation cyclization reaction catalyzed by palladium is developed.
Disclosure of Invention
The invention provides a preparation method of an N-acyl indole compound, which has simple steps, can be compatible with various functional groups and has good reaction applicability.
A preparation method of an N-acyl indole compound comprises the following steps: adding a palladium catalyst, potassium carbonate, 1,3, 5-tricarboxylic acid phenol ester (TFBen), 2-alkynyl aniline and aryl iodide into an organic solvent, reacting at 50-70 ℃ for 20-30 hours, then adding silver oxide, continuing to react at 50-70 ℃ for 20-30 hours, and after the reaction is completed, performing 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 specific reaction formula is as follows:
the reaction may first undergo palladium insertion into the aryl iodide to form an aryl palladium intermediate, and carbon monoxide evolved from the phenol 1,3, 5-tricarboxylate is inserted into the aryl palladium intermediate to form an acyl palladium intermediate. And secondly, adding the 2-alkynyl aniline and the palladium acyl intermediate, and reducing and eliminating to obtain the amide compound. Finally, under the action of silver oxide, the amide is cyclized to generate the N-acyl indole compound.
In the present invention, the optional post-processing procedure includes: filtering, mixing the sample with silica gel, and finally performing column chromatography purification to obtain the corresponding N-acyl indole compound, wherein the column chromatography purification is a technical means commonly used in the field.
Preferably, R1、R2、R3Independently H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl, and the reaction yield is high; as further preference, R1H, F; r2H, Me, OMe or F; r3Is H, methyl, tert-butyl, methoxy, F, Cl, Br or trifluoromethyl.
Preferably, the reaction time is 48 hours, and the reaction time is short, so that the reaction is difficult to ensure the completeness.
In the present invention, the organic solvent is preferably acetonitrile, in which case various raw materials can be converted into products at a high conversion rate.
The amount of the organic solvent can be used for better dissolving the raw material, and the amount of the organic solvent used for 1mmol of 2-alkynyl aniline is about 10 mL.
Preferably, the palladium catalyst is tetrakis (triphenylphosphine) palladium, and the reaction efficiency is higher in a plurality of palladium catalysts.
The molar ratio of the tetrakis (triphenylphosphine) palladium to the potassium carbonate to the phenol 1,3, 5-tricarboxylate to the silver oxide is 0.1:5:5: 0.5;
as a further preference, the N-acyl indole compound is one of compounds shown in formula (I-1) to formula (I-5):
in the preparation method, the tetrakis (triphenylphosphine) palladium, the silver oxide, the potassium carbonate and the aryl iodide are generally commercially available products and can be conveniently obtained from the market, and the 2-alkynyl aniline can be quickly synthesized from corresponding 2-iodoaniline and terminal aryne.
Compared with the prior art, the invention has the beneficial effects that: the preparation method is easy to operate, and the post-treatment is simple and convenient; the reaction starting material is cheap and easy to obtain, the substrate functional group tolerance range is wide, the reaction efficiency is high, the N-acyl indole compound is efficiently and quickly synthesized in one step, and the practicability is high.
Detailed Description
The invention is further described with reference to specific examples.
Tetrakis (triphenylphosphine) palladium, potassium carbonate, phenol 1,3, 5-tricarboxylate, 2-alkynylaniline (II), aryl iodide (III) and 2mL of an organic solvent were added to a 35mL Schlenk tube according to the raw material ratio of Table 1, mixed and stirred uniformly, reacted at 60 ℃ for 24 hours, then silver oxide was added, and the reaction was continued at 60 ℃ for 24 hours as shown in Table 1. After the reaction is completed, filtering, mixing a silica gel sample, and purifying by column chromatography to obtain the corresponding N-acyl indole compound (I), wherein the reaction process is shown as the following formula:
TABLE 1 raw material addition amounts of examples 1 to 15
TABLE 2
In tables 1 and 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.
Structure confirmation data of the compounds prepared in examples 1 to 5:
nuclear magnetic resonance of N-acylindole Compound (I-1) prepared in example 1 ((I-1))1H NMR、13C NMR) the data were:
1H NMR(400MHz,CDCl3):δ7.71–7.68(m,1H),7.64(d,J＝8.1Hz,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).
13C NMR(100MHz,CDCl3):δ170.1,144.0,141.5,138.3,133.1,132.3,130.6,129.3,129.2,128.3,127.6,124.1,123.0,120.8,114.0,109.2,21.8.
nuclear magnetic resonance of N-acylindole Compound (I-2) prepared in example 2: (1H NMR、13C NMR) the data were:
1H NMR(400MHz,CDCl3):δ7.69–7.61(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).
13C NMR(100MHz,CDCl3):δ169.4,163.6,141.4,138.3,133.1,132.9,129.3,128.3,128.2,127.6,127.2,124.0,122.8,120.8,113.8,108.8,55.6.
nuclear magnetic resonance of N-acylindole Compound (I-3) prepared in example 3: (1H NMR、13C NMR) the data were:
1H NMR(400MHz,CDCl3):δ7.80–7.74(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).
13C NMR(100MHz,CDCl3):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.
nuclear magnetic resonance of N-acylindole Compound (I-4) prepared in example 4 ((I-4))1H NMR、13C NMR) the data were:
1H NMR(400MHz,CDCl3):δ7.67–7.57(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).
13C NMR(100MHz,CDCl3):δ170.1,162.2(d,J＝248.0Hz,1C),140.2,138.2,135.1,133.1,130.3,130.1(d,J＝8.2Hz,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.
nuclear magnetic resonance of N-acylindole Compound (I-5) prepared in example 5 ((I-5))1H NMR、13C NMR) the data were:
1H NMR(400MHz,CDCl3):δ7.76–7.71(m,1H),7.67–7.60(m,3H),7.39(t,J＝7.4Hz,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).
13C NMR(100MHz,CDCl3):δ170.3,141.5,138.3,137.8,135.3,133.0,132.8,130.2,129.4,129.3,128.4,128.3,128.2,125.5,124.3,123.2,120.8,114.2,109.3,21.4。
Claims (9)
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.
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 of claim 1, wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium.
6. The method of claim 1, wherein the additive is silver oxide.
7. The process for preparing an N-acylindole compound according to claim 1, wherein the base is potassium carbonate.
8. The method of claim 1, wherein the carbon monoxide substitute is phenol 1,3, 5-tricarboxylate.
9. 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):
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539198A (en) * | 2022-02-23 | 2022-05-27 | 浙江理工大学 | Preparation method of amide compound containing (iso) chroman structure |
| CN115246786A (en) * | 2021-11-30 | 2022-10-28 | 浙江理工大学 | Preparation method of indole compound or benzoxazine compound |
| CN115260080A (en) * | 2022-07-01 | 2022-11-01 | 浙江理工大学 | Preparation method of indole-3-carboxamide compound |
| CN115286553A (en) * | 2022-01-05 | 2022-11-04 | 浙江理工大学 | Preparation method of indole compound |
| CN115403505A (en) * | 2022-09-02 | 2022-11-29 | 浙江理工大学 | Preparation method of thioester compound containing indolone structure |
-
2021
- 2021-02-17 CN CN202110186332.3A patent/CN112898192B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| LIN HE等: "A convenient palladium-catalyzed carbonylative synthesis of 4(3H)-quinazolinones from 2-bromoformanilides and organo nitros with Mo(CO)6 as a multiple promoter", 《GREEN CHEM.》 * |
| ZHENGKAI CHEN等: "Palladium-catalyzed three-component carbonylative synthesis of 2-(trifluoromethyl)quinazolin-4(3H)-ones from trifluoroacetimidoyl chlorides and amines", 《ORGANIC CHEMISTRY FRONTIERS》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115246786A (en) * | 2021-11-30 | 2022-10-28 | 浙江理工大学 | Preparation method of indole compound or benzoxazine compound |
| CN115246786B (en) * | 2021-11-30 | 2023-10-03 | 浙江理工大学 | Preparation method of indole compound or benzoxazine compound |
| CN115286553A (en) * | 2022-01-05 | 2022-11-04 | 浙江理工大学 | Preparation method of indole compound |
| CN115286553B (en) * | 2022-01-05 | 2023-10-03 | 浙江理工大学 | Preparation method of indole compound |
| CN114539198A (en) * | 2022-02-23 | 2022-05-27 | 浙江理工大学 | Preparation method of amide compound containing (iso) chroman structure |
| CN114539198B (en) * | 2022-02-23 | 2023-12-19 | 浙江理工大学 | Preparation method of amide compound containing (iso) chroman structure |
| CN115260080A (en) * | 2022-07-01 | 2022-11-01 | 浙江理工大学 | Preparation method of indole-3-carboxamide compound |
| CN115260080B (en) * | 2022-07-01 | 2023-10-20 | 浙江理工大学 | Preparation method of indole-3-formamide compound |
| CN115403505A (en) * | 2022-09-02 | 2022-11-29 | 浙江理工大学 | Preparation method of thioester compound containing indolone structure |
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