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Preparation method of 2-(3-halogen phenyl) pyridine derivative

A technology of pyridine derivatives and phenylpyridine, which is applied in the field of preparation of 2-pyridine derivatives, can solve problems such as unreported methods, and achieve the effects of various types, high yield and simple operation

Active Publication Date: 2015-02-18
TIANJIN UNIV
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AI Technical Summary

Problems solved by technology

[0014] However, the synthesis of 2-(3-halophenyl)pyridine derivatives via transition metal ruthenium-catalyzed meta-selective introduction of aryl halides has not been reported yet.

Method used

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  • Preparation method of 2-(3-halogen phenyl) pyridine derivative
  • Preparation method of 2-(3-halogen phenyl) pyridine derivative
  • Preparation method of 2-(3-halogen phenyl) pyridine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of 2-(3-bromophenyl)pyridine (III-a):

[0033]

[0034] 2-Phenylpyridine (I-a) (47mg, 0.3mmol), N-bromosuccinimide (II) (108mg, 0.6mmol), dissolved in N,N-dimethylacetamide (0.2M, 1.5mL), add (4-methyl-isopropylphenyl) ruthenium dichloride dimer (9mg, 5mol%), react at 70 ℃ for 24 hours, add ethyl acetate (20mL) to extract, water ( 10mLx3) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by spin, and the crude product was separated and purified by column chromatography to obtain 61 mg of 2-(3-bromophenyl)pyridine (III-a) as a colorless oil. Yield: 87%. 1 H NMR (600MHz, CDCl 3 ):δ8.70(t, J=4.8,1H),8.17(t,J=1.6,1H),7.91(d,J=7.8,1H),7.77(td,J=7.8,1.7,1H), 7.71(d, J=7.9,1H),7.54(dd,J=7.9,0.9,1H),7.35(t,J=7.9,1H),7.30–7.25(m,1H). 13 C NMR (151MHz, CDCl 3 )δ154.86, 148.79, 140.40, 135.90, 130.85, 129.23, 129.02, 124.39, 122.04, 121.66, 119.59.

[0035] Replace the N-bromosuccinimide of this embodi...

Embodiment 2

[0037] Preparation of (3-bromo-4-methoxyphenyl)pyridine (III-b):

[0038]

[0039] 2-(4-methoxyphenyl)pyridine (I-b) (56mg, 0.3mmol), N-bromosuccinimide (II) (108mg, 0.6mmol), dissolved in N,N-dimethyl (1,5-Cyclooctadiene) ruthenium dichloride (8mg, 10mol%) was added to methyl formamide (0.2M, 1.5mL), reacted at 150°C for 24 hours, added ethyl acetate (20mL) to extract , washed with water (10mLx3), the organic phase was dried over anhydrous sodium sulfate and filtered, the solvent was removed by spin, and the crude product was separated and purified by column chromatography to obtain (3-bromo-4-methoxyphenyl)pyridine (III-b) 72mg , as a colorless oil, yield: 90%. 1 H NMR (600MHz, CDCl 3 )δ8.66(d, J=4.6Hz, 1H), 8.23(d, J=2.1Hz, 1H), 7.93(dd, J=8.6, 2.0Hz, 1H), 7.73(t, J=7.5Hz, 1H), 7.65(d, J=7.9Hz, 1H), 7.20(t, J=6.0Hz, 1H), 6.99(d, J=8.6Hz, 1H), 3.95(s, 3H). 13 C NMR (151MHz, CDCl 3 )δ156.56, 155.68, 149.65, 136.84, 133.30, 131.85, 127.01, 121.95, 119.87, 112.14, 111.8...

Embodiment 3

[0041] Preparation of 2-(3-bromo-4-methylphenyl)pyridine (III-c):

[0042]

[0043] 2-(4-methylphenyl)pyridine (I-c) (51mg, 0.3mmol), N-bromosuccinimide (II) (108mg, 0.6mmol), dissolved in N-methylpyrrolidone (0.2 M, 1.5mL), add Grubbs catalyst (10mol%), react at 100°C for 48 hours, add ethyl acetate (20mL) for extraction, wash with water (10mLx3), filter the organic phase after drying over anhydrous sodium sulfate, The solvent was spun off, and the crude product was separated and purified by column chromatography to obtain 67 mg of 2-(3-bromo-4-methylphenyl)pyridine (III-c) as a colorless oil, yield: 89%. 1 H NMR (600MHz, CDCl 3 )δ8.61(d, J=4.4Hz, 1H), 8.13(s, 1H), 7.75(dd, J=7.9, 1.4Hz, 1H), 7.67(tt, J=9.1, 4.6Hz, 1H), 7.62(d, J=7.8Hz, 1H), 7.25(d, J=7.9Hz, 1H), 7.16(t, J=6.6Hz, 1H), 2.38(s, 3H). 13 C NMR (151MHz, CDCl 3 )δ155.87, 149.73, 138.77, 138.64, 136.86, 131.05, 130.71, 125.58, 125.48, 122.38, 120.33, 22.77.

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Abstract

The invention discloses a preparation method of a 2-(3-halogen phenyl) pyridine derivative. The preparation method comprises the following steps: dissolving 2-phenylpyridine or substitutive 2-phenylpyridine (I) and N-halogenated butyl diimide (II) into a solvent, adding a ruthenium catalyst for reaction at the temperature of 70-150 DEG C for 24-48 hours to obtain a mixture, extracting with ethyl acetate, separating and purifying the mixture by column chromatography after the mixture is washed and dried to obtain the 2-(3-halogen phenyl) pyridine derivative (III), wherein the reaction formula of the 2-(3-halogen phenyl) pyridine derivative is shown in the specification. The preparation method has the advantages of simplicity in operation, higher yield and the like; furthermore, reaction raw materials and reaction reagents are readily available, and multiple types of product substitutes are produced.

Description

technical field [0001] The invention relates to a preparation method of 2-(3-halogen phenyl)pyridine derivatives. Background technique [0002] Aryl halides are an important class of chemical intermediates, which can introduce different functional groups through transition metal-catalyzed coupling to synthesize more complex compounds, such as some complex natural compounds or drugs. The classic methods for introducing halogens in the past mainly include nucleophilic substitution reactions of aromatic rings and halogenation reactions of intermediates of transition metal compounds. They can only introduce halogen at the electron-donating ortho-para position. For benzene rings substituted by electron-withdrawing groups, due to the passivation of electron-withdrawing groups, there are very few examples of introducing halogen at the meta-position. Therefore, it is of great significance to develop a method that can introduce aromatic ring halogens at the meta position with high ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/26C07D213/30
CPCC07D213/26C07D213/30
Inventor 黄剑辉于庆贞胡乐安王悦赵康
Owner TIANJIN UNIV
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