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Method for synthesizing tetrahydroquinoline compounds from arylamine and alpha-ketoester under catalysis of titanocene/Bronsted acid

A special acid-catalyzed arylamine and Bronsted acid technology is applied in the synthesis of tetrahydroquinoline compounds to achieve mild reaction conditions, high atom economy, and avoid the use of toxic reagents.

Active Publication Date: 2019-09-13
SHAANXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the shortcomings of the existing synthetic methods of tetrahydroquinoline compounds, and provide a catalyst that is cheap, easy to obtain, non-toxic, mild in reaction conditions, short in reaction time, single in reaction products, safe and efficient, and high in yield. The synthetic method of high tetrahydroquinoline compounds

Method used

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  • Method for synthesizing tetrahydroquinoline compounds from arylamine and alpha-ketoester under catalysis of titanocene/Bronsted acid
  • Method for synthesizing tetrahydroquinoline compounds from arylamine and alpha-ketoester under catalysis of titanocene/Bronsted acid
  • Method for synthesizing tetrahydroquinoline compounds from arylamine and alpha-ketoester under catalysis of titanocene/Bronsted acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Synthesize 2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinoline diethyl-2,4-dicarboxylate with the following structural formula

[0019]

[0020] Add 12.45mg (0.05mmol) titanocene dichloride and 12.07mg (0.05mmol) 3,5,6-trichlorosalicylic acid, 250μL absolute ethanol, 1750μL ultra Pure water, 132 μL (1.2 mmol) of ethyl pyruvate and 91 μL (1 mmol) of aniline were mixed uniformly and stirred at 40°C for 6 hours. The completion of the reaction was detected by TLC, and then 5 mL of 0.5 mol / L sodium bicarbonate aqueous solution was added to the reaction mixture, the organic phase was extracted with dichloromethane (3×15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product Purified by silica gel (petroleum ether / ethyl acetate) column chromatography to obtain 2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinoline diethyl-2,4-di The yield of carboxylic acid ester is 93%, and the structural characterization data are: 1 H NMR(600MHz, CDCl 3 )δ7...

Embodiment 2

[0022] Synthesize 2,7-dimethyl-4-(p-tolylamino)-1,2,3,4-tetrahydroquinoline-2,4-dicarboxylate with the following structural formula

[0023]

[0024] In this example, the aniline in Example 1 was replaced with equimolar 4-methylaniline, and the other steps were the same as in Example 1, to obtain solid 2,7-dimethyl-4-(p-tolylamino)-1, The yield of 2,3,4-tetrahydroquinoline-2,4-dicarboxylate is 90%, and the structural characterization data are: 1 H NMR(600MHz, CDCl 3 )δ7.04(s,1H), 6.89-6.79(m,3H), 6.52(d,J=7.3Hz,1H), 6.25(d,J=7.0Hz,2H), 4.34(s,1H), 4.20(s,1H),4.08(s,1H),3.78(s,2H),3.31(s,1H),3.17(s,1H), 2.59(d,J=13.5Hz,1H),2.11(d ,J=17.5Hz,6H),1.38(s,3H),1.12(d,J=5.3Hz,3H),0.60(s,3H); 13 C NMR(151MHz, CDCl 3 )δ176.12,173.02,142.71,141.51,130.73,129.62,129.20,127.54,127.19,126.82,119.70,115.76,115.22,114.36,61.68,61.28,60.35,55.17,36.42,27.97,20.59,20.41,14.11,13.11

Embodiment 3

[0026] Synthesize 6-(tert-butyl)-4-((4-(tert-butyl)phenyl)amino)-2-methyl-diethyl-1,2,3,4-tetrahydroquinoline with the following structural formula -2,4-Dicarboxylate

[0027]

[0028] In this example, the aniline in Example 1 was replaced with equimolar p-tert-butylaniline, and the other steps were the same as in Example 1, to obtain a solid 6-(tert-butyl)-4-((4-(tert-butyl) Phenyl)amino)-2-methyl-diethyl-1,2,3,4-tetrahydroquinoline-2,4-dicarboxylate, the yield is 85%, and the structural characterization data are: 1 H NMR(600MHz, CDCl 3 )δ7.17-7.15(m,1H), 7.09(dd,J=8.5,2.3Hz,1H), 7.04(d,J=8.6Hz,2H), 6.56(d,J=8.5Hz,1H), 6.30(d,J=8.6Hz,2H),4.21-4.10(m,2H),3.87-3.74(m,2H),3.34-3.26(m,1H),3.19(d,J=14.0Hz,1H) ,2.57(d,J=14.0Hz,1H),1.39(s,3H),1.19(s,3H),1.17(s,9H),1.12(s,9H),0.55(t,J=7.1Hz, 3H); 13 C NMR(151MHz, CDCl 3 )δ176.30,173.28,142.43,141.20,141.02,140.69,127.12,126.03,125.41,123.69,118.90,115.30,114.95,114.59,61.61,61.35,60.68,55.11,36.54,34.06,33.85,31.58,31.55,31. ,28.15,1...

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Abstract

The invention discloses a method for synthesizing tetrahydroquinoline compounds from arylamine and alpha-ketoester under the catalysis of titanocene / Bronsted acid. According to the method, 3,5,6-trichlorosalicylic acid or 5-nitrosalicylic acid and titanocene dichloride are cooperatively used for catalyzing the synthesis of tetrahydroquinoline compounds from arylamine and alpha-ketoester in a greensystem composed of lower aliphatic alcohol (methanol, ethanol, etc.) and water. The titanocene dichloride used in the invention is cheap and easily available and is stable in air and water; a reaction system is green and environmentally friendly; no precious metal is needed; the pre-synthesis of a catalyst and a substrate is avoided; the mild, green and easy-to-operate synthesis method is established for the synthesis of tetrahydroquinoline derivatives; and the method has the advantages of mild reaction conditions, short reaction time, high atomic economy and high target product yield.

Description

Technical field [0001] The invention belongs to the technical field of synthesis of tetrahydroquinoline compounds, and specifically relates to a method for synthesizing tetrahydroquinoline compounds by reacting an aromatic amine and an α-ketoester catalyzed by titanocene / Bronsted acid. Background technique [0002] Tetrahydroquinoline, as an important subclass of the quinoline family, has been found in natural products, such as Martinic acid, which is a potent bradykinin antagonist. Secondly, it also has excellent effects in medicinal chemistry. Pfizer (CP-529,414, Pfizer), is a potent inhibitor of first cholesterol ester transfer protein, is also an effective non-nucleoside, reverse transcriptase allosteric inhibitor and anti-HIV compound, tetrahydroquinoline structure It can also be used as organic ligands and dyes. [0003] There are many methods for synthesizing tetrahydroquinoline compounds, especially the intramolecular allyl amination method catalyzed by transition metals, ...

Claims

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Application Information

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IPC IPC(8): C07D215/50
CPCC07D215/50
Inventor 高子伟孙晓马富余吴莹苏洁庄梦媛孙华明
Owner SHAANXI NORMAL UNIV
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