Method for synthesizing alpha-keto ester by dehydrogenation coupling reaction of 8-methyl quinoline derivatives and alpha-keto acid under palladium catalysis

A technology of methylquinoline and dehydrogenation coupling, applied in the field of synthesis of α-keto ester derivatives, to overcome the effects of high toxicity of reaction reagents, mild reaction conditions and simple steps

Inactive Publication Date: 2019-03-08
XIANGTAN UNIV
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Problems solved by technology

[0004] In view of the deficiencies in the existing method for synthesizing α-keto ester derivatives, such as the need for a large amount of environmentally unfavorable reagents, harsh reaction conditions, potential explosive peroxides as oxidants and other problems, the purpose of the present invention is to provide A palladium-catalyzed method for synthesizing α-ketoesters by the dehydrogenation coupling reaction of 8-methylquinoline derivatives and α-ketoacids, the method has the advantages of mild reaction conditions, one-step reaction, compatibility with air, and scalable Response and other advantages

Method used

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  • Method for synthesizing alpha-keto ester by dehydrogenation coupling reaction of 8-methyl quinoline derivatives and alpha-keto acid under palladium catalysis
  • Method for synthesizing alpha-keto ester by dehydrogenation coupling reaction of 8-methyl quinoline derivatives and alpha-keto acid under palladium catalysis
  • Method for synthesizing alpha-keto ester by dehydrogenation coupling reaction of 8-methyl quinoline derivatives and alpha-keto acid under palladium catalysis

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 8-Methylquinoline (14.3 mg, 0.1 mmol), benzoic acid (30.0 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol), iodobenzene diacetate ( 80.5mg, 0.25mmol), and a stirring bar into the reaction tube, add 1 ml of solvent CHCl 3 , seal the reaction tube. The reaction tube was placed in a 70°C oil bath reaction pot and stirred for 12 hours. After cooling to room temperature, it was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography with ethyl acetate: petroleum ether=1:4 (volume ratio) as the eluent to obtain pure product. White solid, melting point 71-72°C, yield 80%. 1 H NMR (400MHz, CDCl 3 )δ8.97(dd,J=4.2,1.8Hz,1H),8.18(dd,J=8.2,1.8Hz,1H),8.07-8.04(m,2H),7.85(t,J=6.6Hz,2H) ), 7.65-7.62(m, 1H), 7.56(dd, J=8.2, 7.0Hz, 1H),...

Embodiment 2

[0037] 7,8-Dimethylquinoline (15.7 mg, 0.1 mmol), benzoylformic acid (30.0 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol), diacetic acid Iodobenzene (80.5mg, 0.25mmol) and a stirring bar were put into the reaction tube, and 1 ml of solvent CHCl was added 3 , seal the reaction tube. The reaction tube was placed in a 70°C oil bath reaction pot and stirred for 12 hours. After cooling to room temperature, it was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography with ethyl acetate: petroleum ether=1:4 (volume ratio) as the eluent to obtain pure product. White solid, mp 118-119°C, yield 71%. 1 H NMR (400MHz, CDCl 3 )δ8.96(s,1H),8.12(d,J=8.0Hz,1H),8.03(d,J=7.6Hz,2H),7.76(d,J=8.4Hz,1H),7.60(t, J=7.2Hz, 1H), 7.46-7.37(m, 4H), 6...

Embodiment 3

[0039] 6,8-Dimethylquinoline (15.7 mg, 0.1 mmol), benzoylformic acid (30.0 mg, 0.2 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol), diacetic acid Iodobenzene (80.5mg, 0.25mmol) and a stirring bar were put into the reaction tube, and 1 ml of solvent CHCl was added 3 , seal the reaction tube. The reaction tube was placed in a 70°C oil bath reaction pot and stirred for 12 hours. After cooling to room temperature, it was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography with ethyl acetate: petroleum ether=1:4 (volume ratio) as the eluent to obtain pure product. Yellow oil, 75% yield. 1 H NMR (400MHz, CDCl 3 )δ8.90(dd,J=4.0,1.6Hz,1H),8.10-8.05(m,3H),7.68-7.60(m,3H),7.48(t,J=7.8Hz,2H),7.41(dd , J=8.2, 4.2Hz, 1H), 6.11(s, 2H), 2.54(s,...

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Abstract

The invention discloses a method for synthesizing alpha-keto ester by dehydrogenation coupling reaction of 8-methyl quinoline derivatives and alpha-keto acid under palladium catalysis. According to the method, the 8-methyl quinoline derivatives and the alpha-keto acid are reacted under the catalysis action of tri-(benzylidene acetone) dipalladium to generate an alpha-keto ester derivative. The method had the advantages that reaction conditions are mild, peroxide is omitted, the alpha-keto ester and the air are compatible, gram-scale reaction is easily achieved under a palladium catalyst with low load amount and the like, the method overcomes the shortcomings that reaction conditions are rigorous, a lot of reagents unfriendly to the environments are needed, reaction steps are more, by-products are more and the like in the prior art, and the method for synthesizing the alpha-keto ester by dehydrogenation coupling reaction of the 8-methyl quinoline derivatives and the alpha-keto acid is firstly provided.

Description

technical field [0001] The invention relates to a method for synthesizing α-keto ester derivatives, in particular to a method for synthesizing α-keto ester derivatives by palladium-catalyzed dehydrogenation coupling reaction of α-methylquinoline derivatives and α-keto acids The method belongs to the fields of pharmaceutical intermediate synthesis and fine organic synthesis. Background technique [0002] α-ketoester derivatives are one of the important organic compounds, which are widely used in the synthesis of medicines (the following molecular structures) and natural products. However, the methods for synthesizing α-ketoester derivatives are still extremely limited, and the main traditional methods are through Friedel-Crafts acylation reaction, oxidation reaction or hydrolysis reaction. These methods usually require a large number of environmentally unfavorable reagents and harsh reaction conditions, and the substrate scope is limited [(a)R.Deshidi,S.Devari,B.A.Shah,Eur.J...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14C07D215/20C07D215/18
CPCC07D215/14C07D215/18C07D215/20
Inventor 龚行李乐松蔡昌群
Owner XIANGTAN UNIV
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