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A kind of synthetic method of 3-acylindole compound without metal participation

The technology of acyl indole and synthesis method is applied in the field of synthesis of 3-acyl indole compounds, which can solve the problems of low atom economy and achieve the effects of cheap catalyst, mild reaction temperature and high atom economy

Active Publication Date: 2022-03-15
LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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Problems solved by technology

The problem with this method is that it requires a stoichiometric amount of Lewis acid, which generates a lot of waste; and because of the competing side reactions of the synthetic method that produce 1-acylindole compounds, this method requires the addition of a stoichiometric amount of an organometallic reagent to form an indole salt to prevent side effects
At present, transition metal-catalyzed amides and organometallic reagents have synthesized various ketones via C-N bond cleavage [(a) Zhou, T.; Li, G.; Nolan, S. P.; Szostak, M. Org. Lett. 2019, 21 , 3304. (b) Liu, C.; Li, G.; Shi, S.; Meng, G.; Lalancette, R.; Szostak, R.; ACS Catal. 2018, 8 , 9131. (c) Boit, T. B.; Weires, N. A.; Kim, J.; Garg, N. K. (d) Liu, X.; Hsiao, C. C.; J. Am. Chem. Soc. 2017, 139 , 15522. (f) Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8 , 75. (g) Meng, G.; Szostak, M. Org. Lett. 2015, 17 , 4364. (h) Li, X.; Zou, G. Chem. Commun. 2015, 51 , 5089], but these reactions have an essential disadvantage: low atom economy

Method used

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  • A kind of synthetic method of 3-acylindole compound without metal participation
  • A kind of synthetic method of 3-acylindole compound without metal participation
  • A kind of synthetic method of 3-acylindole compound without metal participation

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Experimental program
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Effect test

Embodiment 1~16

[0023] Embodiments 1~16 A kind of synthetic method of 3-acylindole compound without metal participation:

[0024] 0.1 mmol of aniline compound , 0.02 mmol nucleophilic organic catalyst (nucleophilic catalyst) and a stirring magnet were added to the reaction bottle, and then the reaction bottle was brought into a glove box filled with nitrogen, and 0.5~2 mL of anhydrous and oxygen-free solvent ( Solvent). Then, it was sealed and removed from the glove box, and reacted at 100 °C for 48 h. After cooling down to room temperature, it was diluted with an appropriate amount of ethyl acetate and n-dodecane was added as an internal standard. The yield of 3-acylindole compound 2a was detected by high pressure liquid chromatography (HP-GC) and determined by the internal standard. Specific examples are as follows in Table 1:

[0025]

[0026] Table 1

[0027]

[0028] a Unless otherwise specified, the amount of 1a used in all reactions is 0.1 mmol, and the reaction is 20 hour...

Embodiment 17

[0030] Example 17 A method for the synthesis of metal-free 3-acylindole compounds:

[0031] 0.1 mmol of aniline compound , 0.02 mmol 4-dimethylaminopyridine and a stirring magnet were added to the reaction bottle, and then the reaction bottle was brought into a glove box filled with nitrogen, and 2 mL of anhydrous and oxygen-free solvent tetrahydrofuran was added. Then, it was sealed and removed from the glove box, and reacted at 100 °C for 48 h. After cooling down to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of ethyl acetate-petroleum ether (1 mL: 30 mL) as an eluent to obtain a colorless oily product with a yield of 63%.

[0032] The product is N -tert-butoxycarbonyl-3-benzoyl-2-methylindole, the structural formula is as follows: .

[0033] The result of NMR analysis was 1 H NMR (400 MHz, CDCl 3 ) 1 H NMR (400 MHz, CDCl 3 ) δ 8.13(d, J = 8.4 Hz, 1H), 7.84 (d...

Embodiment 18

[0034] Example 18 A method for the synthesis of metal-free 3-acylindole compounds:

[0035] 0.1 mmol of aniline compound , 0.02 mmol 4-dimethylaminopyridine and a stirring magnet were added to the reaction bottle, and then the reaction bottle was brought into a glove box filled with nitrogen, and 2 mL of anhydrous and oxygen-free solvent tetrahydrofuran was added. Then, it was sealed and removed from the glove box, and reacted at 100 °C for 48 h. After cooling down to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using a mixed solvent of ethyl acetate-petroleum ether (1 mL: 40 mL) as the eluent to obtain a colorless oily product with a yield of 59%.

[0036] The product is N -tert-butoxycarbonyl-3-benzoyl-2,5-dimethylindole, the structural formula is as follows: .

[0037] The result of NMR analysis was 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7....

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Abstract

The present invention relates to a kind of synthetic method of the 3-acylindole compound that no metal participates in, and this method refers to: N ‑tert-butoxycarbonyl‑ N Add ‑acyl‑2‑alkenyl aniline compound and nucleophilic organic small molecule catalyst into the reaction vessel, add organic solvent under nitrogen atmosphere, react at 50~120°C for 24~48 h, and obtain 3 after separation and purification ‑Acylindole compounds. The present invention uses a nucleophilic organic small molecule catalyst as a catalyst without any additives, and has low cost; the economical efficiency of reaction atoms avoids unnecessary waste; the reaction conditions are relatively mild, the operability is strong, and it has potential industrialization prospects .

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a method for synthesizing 3-acylindole compounds without metal participation. Background technique [0002] As a core unit, the indole skeleton widely exists in natural products, active pharmaceuticals, and organic materials. In particular, 3-acylindole compounds are called "privileged structures" in drugs due to their high affinity with a variety of biological receptors, such as the anti-inflammatory analgesic drug BPR0L075 and the anti-inflammatory analgesic drug Pravadoline. And it can also be used as an important intermediate to synthesize other useful nitrogen-containing heterocyclic compounds. [0003] For the synthesis of 3-acylindole compounds, the traditional and common method is to use indole as a raw material, under the action of Lewis acid, to obtain by Friedel−Crafts acylation of acid chloride or its derivatives [(a) Sundberg, R. ;J. The Chemistry of Indoles; Acad...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/12C07D405/06C07D409/06
CPCC07D209/12C07D405/06C07D409/06
Inventor 夏纪宝张正兵陈洁
Owner LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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