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Method for Synthesizing Tetrahydroquinolines from Arylamine and α-Ketoester Catalyzed by Titanocene/Bronsted Acid

A technique for catalyzing aromatic amines and Bronsted acids with special acids, which is applied in the field of synthesis of tetrahydroquinoline compounds to achieve the effects of air and water stability, mild reaction conditions and high yields

Active Publication Date: 2022-06-07
SHAANXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 Tetrahydroquinolines from Arylamine and α-Ketoester Catalyzed by Titanocene/Bronsted Acid
  • Method for Synthesizing Tetrahydroquinolines from Arylamine and α-Ketoester Catalyzed by Titanocene/Bronsted Acid
  • Method for Synthesizing Tetrahydroquinolines from Arylamine and α-Ketoester Catalyzed by Titanocene/Bronsted Acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0019]

[0020] 12.45mg (0.05mmol) dichlorotitanocene, 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 then stirred at 40° C. for 6 hours. The completion of the reaction was detected by TLC, 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 obtain the crude product Purification by silica gel (petroleum ether / ethyl acetate) column chromatography to give 2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinoline diethyl ester-2,4-diethyl ester Carboxylate, the yield is 93%, and the structural characterization data are: 1 H NMR...

Embodiment 2

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

[0023]

[0024] In this embodiment, the aniline in embodiment 1 is replaced with equimolar 4-methylaniline, and other steps are the same as those in embodiment 1 to obtain solid 2,7-dimethyl-4-(p-tolylamino)-1, Diethyl 2,3,4-tetrahydroquinoline-2,4-dicarboxylate, the yield 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 )δ176.12,173.02,142.71,141.51,130.73,129.62,129.20,127.54,127.19,126.82,119.70,115.76,115.22,114.36,61.68,61.28,60.35,55.17,36.42,27.97,20.59,20.41,14.11,13.26.

Embodiment 3

[0026] Synthesis of 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 other steps were the same as those in Example 1 to obtain 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....

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Abstract

The invention discloses a method for synthesizing tetrahydroquinoline compounds from arylamines and α-keto esters catalyzed by titanocene / Bronsted acid, the method is through 3,5,6-trichlorosalicylic acid or 5-nitrate A method for synthesizing tetrahydroquinolines from aromatic amines and α-ketoesters in the green system of lower aliphatic alcohols (methanol, ethanol, etc.) and water in conjunction with dichlorotitanium based salicylic acid. The titanocene dichloride used in the present invention is cheap and easy to obtain, stable to air and water, and the reaction system is green and environmentally friendly, without the use of precious metals, avoiding the pre-synthesis of catalysts and substrates, and establishing a method for the synthesis of tetrahydroquinoline derivatives Mild, green, and easy-to-operate synthesis method with mild reaction conditions, short reaction time, high atom economy, and high yield of the target product.

Description

technical field [0001] The invention belongs to the technical field of synthesis of tetrahydroquinoline compounds, in particular to a method for synthesizing tetrahydroquinoline compounds through the reaction of titanocene / Brönsted acid catalyzed arylamine and α-ketoester. Background technique [0002] As an important subclass of the quinoline family, tetrahydroquinoline has been found in natural products such as martinic acid, a potent bradykinin antagonist, and secondly, it also has excellent effects in medicinal chemistry, such as Chip (CP-529,414, Pfizer), a potent inhibitor of the first cholesteryl ester transfer protein, is also a potent non-nucleoside, allosteric inhibitor of reverse transcriptase 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 intramolecular allyl amination catalyzed by transition metals, N-aryl imines and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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