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Preparation method of poly-substituted pyrrolidone derivatives

A pyrrolidone and multi-substitution technology, which is applied in the field of preparation of multi-substituted pyrrolidone derivatives, can solve the problems of difficult coupling reaction and limited application, and achieves the effects of high atom utilization, overcoming steric hindrance, and wide substrate range.

Active Publication Date: 2019-08-20
HUAQIAO UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, due to steric hindrance, internal alkenes have limited application in radical Heck-type reactions, with only examples of 1,2-disubstituted alkenes
As far as the prior art is concerned, trisubstituted alkenes are almost unstudied, with only one example using diphenylpropene and primary alkyl bromide with a yield of 32% (Chem. Eur. J. 2016, 22, 12646-12650)
The use of trisubstituted alkenes and tertiary alkyl halides as coupling agents remains a major challenge in the field
There are two reasons: first, tertiary alkyl halides contain multiple β-hydrogens, which are prone to β-hydrogen elimination side reactions after oxidative addition to metals; There is a lot of steric hindrance, and the coupling reaction is not easy to occur

Method used

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  • Preparation method of poly-substituted pyrrolidone derivatives
  • Preparation method of poly-substituted pyrrolidone derivatives
  • Preparation method of poly-substituted pyrrolidone derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of 1-benzyl-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylic acid dimethyl ester

[0032]

[0033] Add 0.1mmol of primary amine compound, 0.2mmol of ethyl 2-bromodimethylpropionate, 0.1mmol of dimethyl butyndioate, and 0.2mol of potassium acetate, add 0.5mL of methyl tert-butyl ether, and place in a nitrogen atmosphere. In a reactor at 120°C, after reacting for 24 hours, cool to room temperature, then filter the solid impurities with diatomaceous earth, wash with dichloromethane three times to obtain the filtrate, then concentrate the filtrate, and then pass through column chromatography or thin film Purified by layer chromatography to obtain 19.7 mg of the target product with a yield of 62%. The nuclear magnetic characterization of this target product is as follows: 1 H NMR (500MHz, Chloroform-d) δ7.31(m, 3H), 7.18-7.11(d, 2H), 4.75(s, 2H), 3.72(s, 3H), 3.64(s, 3H), 1.43( s, 6H); 13 C NMR (126MHz, Chloroform-d) δ181.6, 162.3, 162.2, 142.9, 1...

Embodiment 2

[0035] Preparation of dimethyl 1-(2,3-dimethylbenzyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylate

[0036]

[0037] Add 0.1mmol of primary amine compound, 0.2mmol of ethyl 2-bromodimethylpropionate, 0.1mmol of dimethyl butyndioate, and 0.2mol of potassium acetate, add 0.5mL of methyl tert-butyl ether, and place in a nitrogen atmosphere. In a reactor at 120°C, after reacting for 24 hours, cool to room temperature, then filter the solid impurities with diatomaceous earth, wash with dichloromethane three times to obtain the filtrate, then concentrate the filtrate, and then pass through column chromatography or thin film Purified by layer chromatography to obtain 21.2 mg of the target product with a yield of 62.5%. The nuclear magnetic characterization of this target product is as follows: 1 H NMR (500MHz, Chloroform-d) δ7.09 (d, J=7.4Hz, 1H), 7.04 (t, J=7.6Hz, 1H), 6.86 (dd, J=7.7, 1.3Hz, 1H), 4.80 (s, 2H), 3.71(s, 3H), 3.51(s, 3H), 2.27(s, 3H), 2.11(s, 3H), ...

Embodiment 3

[0039] Dimethyl 1-(3,4-dimethoxybenzyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylate preparation

[0040]

[0041] Add 0.1mmol of primary amine compound, 0.2mmol of ethyl 2-bromodimethylpropionate, 0.1mmol of dimethyl butyndioate, and 0.2mol of potassium acetate, add 0.5mL of methyl tert-butyl ether, and place in a nitrogen atmosphere. In a reactor at 120°C, after reacting for 24 hours, cool to room temperature, then filter the solid impurities with diatomaceous earth, wash with dichloromethane three times to obtain the filtrate, then concentrate the filtrate, and then pass through column chromatography or thin film Purified by layer chromatography to obtain 26.3 mg of the target product with a yield of 70%. The nuclear magnetic characterization of this target product is as follows: 1 H NMR (500MHz, Chloroform-d) δ6.79(d, J=8.4Hz, 1H), δ6.70(d, J=7.3Hz, 2H), δ4.68(s, 2H), δ3.86( s, 3H), δ3.84(s, 3H), δ3.73(s, 3H), δ3.72(s, 3H), δ1.41(s, 6H); 13C NMR (126M...

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Abstract

The invention discloses a preparation method of poly-substituted pyrrolidone derivatives. The preparation method comprises following steps: (1) sequentially adding an alkali, a copper catalyst, a ligand, alkyl amines, alpha-carbonyl alkyl bromide, alkynes, and an organic solvent into a reaction vessel, which has been blown by nitrogen, and carrying out reactions for 12 to 24 hours at a temperatureof 80 to 120 DEG C in a nitrogen atmosphere; (2) filtering the material prepared in the step (1) by diatomite so as to separate solid impurities, and washing the material by dichloromethane to obtainfiltrate; and (3) concentrating the filtrate obtained in the step (2), and processing the concentrated filtrate by column chromatography or thin-layer chromatography to obtain the poly-substituted pyrrolidone derivatives. Heck reaction between tri-substituted alkenes in-situ prepared from amines and alkynes and tert-alkyl halides is realized, and is used to synthesize poly-substituted pyrrolidone. The reaction can overcome the steric hindrance between substrates. Cheap and easily available raw materials are taken as the synthesis blocks; the yield is high, the reaction conditions are mild, the reaction time is short, the choice of substrates is wide, the atom utilization rate is high, and the post treatment is simple and green.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of polysubstituted pyrrolidone derivatives. Background technique [0002] The Heck reaction is one of the most powerful C–C bond formation methods in synthetic organic chemistry. In 2010, the American chemist Richard Heck and the Japanese Mizuki and Heck found that saturated halogenated hydrocarbons (or trifluoromethanesulfonates) and alkenes can generate substituted alkenes under the catalysis of strong base and palladium. joint reaction. Received the Nobel Prize in Chemistry for this contribution. The traditional Heck reaction mainly focuses on the use of aryl, alkenyl or benzyl halides as synthetic coupling agents. These couplings do not contain β-hydrogen, so after oxidative addition to metals, β- Hydrogen eliminates side reactions. Furthermore, internal alkenes have limited applications in radical Heck-type reactions due to ster...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/38C07D405/06C07D409/06C07D209/54
CPCC07D207/38C07D405/06C07D409/06C07D209/54
Inventor 程国林巴聃
Owner HUAQIAO UNIVERSITY
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