Preparation of alpha,alpha-disubstituted-beta-nitro ester compound containing full-carbon quaternary carbon chiral center and nitrogen aromatic heterocyclic ring and derivatives thereof

A chiral center, aromatic heterocycle technology, applied in the preparation of organic compounds, organic chemistry, chemical instruments and methods, etc., can solve problems such as steric hindrance difficult to generate, and achieve high yield, high optical purity, and reaction conditions. mild effect

Active Publication Date: 2016-10-12
CHINA AGRI UNIV
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  • Description
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Problems solved by technology

At present, there are many ways to synthesize β-amino acids with tertiary chiral centers, and the synthesis of β-amino acids with all-carbon quaternary chiral centers 2,2- There are few amino acid methods, mainly because of the relatively large steric hindrance around the all-carbon quaternary carbon chiral center, which makes it difficult to generate

Method used

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  • Preparation of alpha,alpha-disubstituted-beta-nitro ester compound containing full-carbon quaternary carbon chiral center and nitrogen aromatic heterocyclic ring and derivatives thereof
  • Preparation of alpha,alpha-disubstituted-beta-nitro ester compound containing full-carbon quaternary carbon chiral center and nitrogen aromatic heterocyclic ring and derivatives thereof
  • Preparation of alpha,alpha-disubstituted-beta-nitro ester compound containing full-carbon quaternary carbon chiral center and nitrogen aromatic heterocyclic ring and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: Synthesis of (+)-2-nitromethyl-2-aryl-4-(azaaromatic ring-2-yl)-4-butanone ester

[0026] Under the protection of nitrogen atmosphere and room temperature, add bisoxazoline chiral ligand (R is phenyl)-Ni(acac) in isopropanol 2 Or phosphine-oxazoline chiral ligand (R is tert-butyl)-Cu(OAc) 2 .H 2 O, then add 2-acetyl azaaromatic hydrocarbon, after stirring at room temperature for 15 minutes, then add α-substituted-β-nitroacrylate, and continue to stir at room temperature for reaction; after the reaction is completed, the solvent is removed, and purified by silica gel column chromatography to obtain (+)-2-Nitromethyl-2-aryl-4-(azaaromatic ring-2-yl)-4-butanone ester, which contains all-carbon quaternary carbon chiral center and nitrogen aromatic heterocycle α,α-Disubstituted-β-nitroester compounds, the yield and photochemical purity of the reaction are shown in Table 1. It can be seen from Table 1 that the yield of the reaction is high (85%-97%) and the o...

Embodiment 2

[0030] Embodiment 2: Synthesis of (+)-2-nitromethyl-2-phenyl-4-(pyridin-2-yl)-4-oxobutanoic acid tert-butyl ester

[0031]

[0032] To a dry 10 mL round bottom flask was added the bisoxazoline chiral ligand (8.0 mg, 0.024 mmol), Ni(acac) 2 (5.1mg, 0.020mmol), add isopropanol 2mL under nitrogen protection, stir at room temperature for 1.5h, then add 2-acetylpyridine (24.2mg, 0.20mmol), stir for 15min, then add 3-nitro-2-phenyl tert-Butyl acrylate (75.1 mg, 0.30 mmol). After adding the sample, react overnight at room temperature; TLC detects that the reaction is complete, and the reaction mixture is separated and purified by silica gel chromatography (ethyl acetate:petroleum ether=1:10, volume ratio) after desolvation under reduced pressure to obtain a white solid ( +)-tert-butyl 2-nitromethyl-2-phenyl-4-(pyridin-2-yl)-4-oxobutanoate. The yield of reaction is 95%; (c=1.0, CH 2 Cl 2 ), the optical purity is 97% ee.

[0033] The white solid was analyzed and identified by...

Embodiment 3

[0034] Embodiment 3: Synthesis of (+)-2-nitromethyl-2-phenyl-4-(quinolin-2-yl)-4-oxobutanoic acid tert-butyl ester

[0035]

[0036]To a dry 10 mL round bottom flask was added the bisoxazoline chiral ligand (8.1 mg, 0.024 mmol), Ni(acac) 2 (5.1mg, 0.020mmol), add isopropanol 2mL under nitrogen protection, stir at room temperature for 1.5h, then add 2-acetylquinoline (34.2mg, 0.2mmol), stir for 15min and then add 3-nitro-2- Tert-butyl phenylacrylate (75.1mg, 0.3mmol), after adding the sample, react overnight at room temperature; TLC detects that the reaction is complete, and the reaction mixture is separated and purified by silica gel chromatography directly after decompression precipitation (ethyl acetate: petroleum Ether = 1:10, volume ratio), to obtain tert-butyl (+)-2-nitromethyl-2-phenyl-4-(quinolin-2-yl)-4-oxobutanoate as a white solid. The yield of reaction is 97%; (c=0.55, CH 2 Cl 2 ), the photochemical purity is 98% ee.

[0037] The white solid was analyzed an...

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Abstract

The invention discloses preparation of an alpha,alpha-disubstituted-beta-nitro ester compound containing a full-carbon quaternary carbon chiral center and a nitrogen aromatic heterocyclic ring and derivatives thereof. In an organic solvent, under catalysis of a bisoxazoline chiral ligand-nickel catalyst or a phosphine-oxazoline chiral ligand-copper catalyst, 2-acetyl aza aromatic hydrocarbon and alpha-substituted-beta-nitro acrylate are subjected to a reaction to synthesize a compound represented by the formula I; the compound is further converted to gamma-butyrolactone compound represented by the formula II (1), beta 2,2-amino acid ester compound represented by the formula II (2), a succinate compound represented by the formula II (3), or a gamma-lactam compound represented by the formula II (4). The preparation has the advantages of mild reaction conditions, high yield, and high optical purity, and provides a tool for asymmetric synthesis of the alpha,alpha-disubstituted-beta-nitro ester compound containing the full-carbon quaternary carbon chiral center and the nitrogen aromatic heterocyclic ring and the derivatives thereof.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to the preparation of an α,α-disubstituted-β-nitro ester compound containing an all-carbon quaternary carbon chiral center and a nitrogen aromatic heterocycle and derivatives thereof. Background technique [0002] The nitrogen-containing aromatic heterocyclic structure (such as pyridine ring, quinoline ring, oxazole ring, thiazole ring, etc.) is the basic structural skeleton of many natural products and pharmaceutical active molecules; at the same time, due to the particularity of the nitrogen atom, the nitrogen-containing aromatic heterocyclic ring Compounds have extensive and important applications in medicine, pesticides and materials [D.Best and H.-W., Lam, J.Org.Chem.2014, 79, 831.C., Guo; D.-W., Sun ; Sh., Yang; Sh.-J., Mao; X.-H., Xu; Sh.-F., Zhu; and Q.-L., Zhou J.Am.Chem.Soc.2015,137, 90.]. In addition, α,α-disubstituted-β-nitroesters are key intermed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/50C07D241/12C07D239/26C07D215/14C07D277/24C07D263/32C07D233/60C07D277/64C07D409/06C07D405/06C07D405/04C07D207/277C07C201/12C07C205/53
CPCC07C201/12C07D207/277C07D213/50C07D215/14C07D233/60C07D239/26C07D241/12C07D263/32C07D277/24C07D277/64C07D405/04C07D405/06C07D409/06C07C205/53
Inventor 傅滨麻红利谢磊张振华李佳奇
Owner CHINA AGRI UNIV
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